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Published: 20 June 2018

Cardiovascular disease (CVD) and associated risk factors among older adults in six low-and middle-income countries: results from SAGE Wave 1

Ye Ruan 1 na1 ,
Yanfei Guo 1 na1 ,
Yang Zheng 1 ,
Zhezhou Huang 1 ,
Shuangyuan Sun 1 ,
Paul Kowal 2 , 3 ,
Yan Shi 1 &

BMC Public Health volume 18 , Article number: 778 ( 2018 ) Cite this article

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Cardiovascular disease (CVD) is one of the leading causes of death worldwide. Our study aimed to investigate the prevalence of two conditions, angina and stroke, and relevant risk factors among older adults in six low- and middle- income countries(LMICs).

The data was from World Health Organization (WHO) Study on global AGEing and adult Health (SAGE) Wave 1 in China, Ghana, India, Mexico, Russian Federation and South Africa. Presence of CVD was based on self-report of angina and stroke. Multivariate logistic regression was performed to examine the relationship between CVD and selected variables, including age, sex, urban/rural setting, household wealth, and risk factors such as smoking, alcohol drinking, fruit/vegetable intake, physical activity and BMI.

The age standardized prevalence of angina ranged from 9.5 % (South Africa) to 47.5 % (Russian Federation), and for stoke from 2.0% (India) to 6.1 % (Russia). Hypertension was associated with angina in China, India and Russian Federation after adjustment for age, sex, urban/rural setting, education and marital status (OR ranging from 1.3 [1.1-1.6] in India to 3.8 [2.9-5.0] in Russian Federation), furthermore it was a risk factor of stroke in five countries except Mexico. Low or moderate physical activity were also associated with angina in China, and were also strongly associated with stroke in all countries except Ghana and India. Obesity had a stronger association with angina in Russian Federation and China(ORs were 1.5[1.1-2.0] and 1.2 [1.0-1.5] respectively), and increased the risk of stroke in China. Smoking was associated with angina in India and South Africa(ORs were 1.6[1.0-2.4] and 2.1 [1.2-3.6] respectively ), and was also a risk factor of stroke in South Africa. We observed a stronger association between frequent heavy drinking and stroke in India. Household income was associated with reduced odds of angina in China, India and Russian Federation, however higher household income was a risk factor of angina in South Africa.

While the specific mix of risk factors contribute to disease prevalence in different ways in these six countries – they should all be targeted in multi-sectoral efforts to reduce the high burden of CVD in today’s society.

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Cardiovascular diseases (CVDs) are by far the leading cause of death in the world. An estimated 17.9 million people died from CVDs in 2015. Ischemic heart disease (IHD) and stroke were the top two leading causes of CVD health lost in each world region [ 1 , 2 ]. By 2030 more than 22.2 million people will die annually from CVDs. Populations in low and middle income countries (LMICs) now contribute 75% of the CVD deaths, which leads to 7% reduction of gross domestic product(GDP) in these countries [ 3 ].

A larger proportion of the global burden of CVDs is now borne by LMICs than in high income countries, this is despite a comparatively lower burden from risk factors in low compared to high income countries [ 4 , 5 , 6 ]. Given the high prevalence of CVD among older adults in LMIC, the projected increases in this population will be a major challenge for the health care system. Twenty-three percent of the total global burden of disease(GBD) was attributed to disorders in people aged 60 years and older. The main contributors to disease burden were CVDs, accounting for 30.3% of the total burden in older people in 2010 [ 7 ]. Reliable and comparable analysis of risks to CVD is especially important for projecting future disease burden and for shaping disease prevention efforts.

A number of population-based studies from lower income countries have suggested that socio-demographic characteristics are associated with CVD, with increasing age, female sex and lower education consistently associated with higher prevalence of CVD. Some epidemiological evidence also suggests that CVD is associated with behavioral risk factors such as smoking, alcohol use, low physical activity levels, and insufficient vegetable and fruit intake, hypertension is also regarded as a very important risk factor for CVD. Independently or in combination, these risk factors present an opportunity for interventions to reduce future CVD burdens in ageing populations in LMIC.A number of large recent studies have compared CVD risks in higher and lower income countries, providing valuable and needed information about CVD and CVD risks [ 4 , 5 , 6 ]. However, the results of these studies may not be representative of the older adult population. For example, the Prospective Urban Rural Epidemiology (PURE) study sampling strategy and distributions provide less reliable estimates at older ages [ 8 ]. The World Health Organization Study on global AGEing and adult health (SAGE) is focused on older adults and use similar methodology across countries to improve comparability of important covariates and disease prevalence. Three of the countries overlap in PURE and SAGE (China, India and South Africa) where SAGE includes three additional middle income countries (Ghana, Mexico and the Russian Federation).

The aim of the present study was to investigate the prevalence of two main CVDs (angina, stroke) and behavioural risk factors and associated social-economic status (SES) factors among older adults using a unique data set with nationally representative samples in six low and middle income countries.

Sample and procedure

The data was from World Health Organization (WHO) Study on Global AGEing and adult health (SAGE) Wave 1, a longitudinal cohort study of ageing and older adults from 2007 to 2010 in six low- and middle-income countries (China, Ghana, India, Mexico, Russian Federation and South Africa) [ 9 ]. SAGE Wave 1 used face-to-face individual interviews to capture data. All six countries implemented multistage cluster sampling strategies which resulted in nationally representative cohorts of older adults ( http://www.who.int/healthinfo/sage/SAGEWorkingPaper5_Wave1Sampling.pdf?ua=1 ). Response rates for SAGE countries were Mexico 51%, India 68%, Ghana 80%, Russian Federation 83%, South Africa 77% and China 93%. Examination of non-respondent data suggested non-significant differences on some covariates (data not shown). Data were obtained following application for access through http://apps.who.int/healthinfo/systems/surveydata/index.php/catalog .

SAGE has been approved by the World Health Organization's Ethical Review Board. Additionally, each partner organization obtained ethical clearance through their respective review bodies. All study participants signed informed consent.

CVDs conditions

Two methods of assessing presence or absence of CVD were used. One was based on self-report of angina or stroke; and the second used an algorithm based on validated symptom-reporting methods to estimate and compare prevalence rates.

Sociodemographic variables

Socio-demographic variables contain age, sex, education, rural/urban residence, and income quintiles. Age was categorized into four groups: 50 to 59 years; 60 to 69 years; 70 to 79 years; and 80 years or older. Education level was classified into seven categories for analysis using an international classification scheme [ 10 ]. The income quintiles were generated using an asset-based approach- possession of assets and dwelling characteristics [ 11 ], with quintile 1(Q1) the quintile of the poorest households and quintile 5(Q5) the quintile of the richest.

Risk factors

Tobacco use.

Tobacco use was assessed by self-report and included different forms (manufactured or hand-rolled cigarettes, cigars, cheroots or whether tobacco is smoked, chewed, sucked or inhaled), and frequency of smoking, snuffing or chewing in each day over the week before interview[ 12 ], classified into four groups: never smoker, not current smokers, smokers(not daily) and current daily smokers.

Alcohol consumption

Alcohol consumption was categorized into four groups: life time abstainer, non-heavy drinkers, infrequent heavy drinkers and frequent heavy drinkers according to the consumption number of standard drinks of beer, wine and or spirit, fermented cider, and other alcoholic drinks during the week before interview.

Physical activity

Physical activity was measured by the Global Physical Activity Questionnaire (GPAQ) and assessed intensity, duration, and frequency of physical activity in three domains: occupational, transport-related, and discretionary or leisure time. Based on a standard classification scheme, three categories were generated: low, moderate and high levels [ 13 ].

Fruit and vegetable consumption

Fruit and vegetable consumption was assessed according to the number of daily servings eaten – with each serving approximating 80 grams. Five or more servings were defined as sufficient daily intake (at least 400 grams per day), fewer than five servings were categorized as insufficient [ 14 ].

Hypertension

The definition of hypertension used was systolic blood pressure ≥140mmHg and/or diastolic blood pressure ≥ 90mmHg and/or self-reported treatment with antihypertensive medication during the two weeks before interview. Blood pressure measurements were conducted three times on the right arm of the seated respondent with an automated recording device (OMRON R6 Wrist Blood Pressure Monitor, HEM-6000-E, Omron Healthcare Europe), and calculated as an average of the latter two measurements.

According to the classification criteria proposed by the WHO [ 15 ], body mass index (BMI) of <18.5 kg/m 2 , 25–29.9 kg/m 2 and ≥30 kg/m 2 are used to define underweight, overweight and obesity, respectively. Modified BMI cutoffs for China and India were used to perform an additional set of analyses that describes overweight (BMI 23.0-27.5) and obesity (BMI >27.5) in Asian populations [ 16 ].

Statistical methods

Statistic analyse were conducted using STATA SE version 11 (Stata Corp, College Station, TX). The prevalence of angina and stroke were calculated by using normalized weights in each country. Weights were based on selection probability, non-response, and post-stratification adjustments. To improve comparability across countries, the prevalence rates were age-standardized using the WHO World Standard Population Distribution based on world average population 2000-2025 [ 17 ]. Multivariate logistic regression was performed to examine the relationship between CVD and selected variables, including the socio-demographics such as age, sex, urban/rural setting, education, household wealth, and health risk factors such as smoking, alcohol drinking, fruit/vegetable intake, physical activity, hypertension and obesity. P < 0.05 from two-sided statistical tests was considered statistically significant.

A total of 34,114 individuals were included in the final analyses. Table 1 shows the sample distribution and demographic, socioeconomic and lifestyle characteristics by countries. The proportions of women are higher than men in four countries, except Ghana and India. The majority of older Indian lived in rural locations, while compared to urban areas in the other countries. The 50-59 age groups had the largest proportions in all countries, but the SAGE sample population distributions match those of the United Nations and US Census Bureau’s International Data Base estimates [ 18 ]. The percentage of respondents with no formal education were higher in Ghana (54.0%) and India (51.2%). In contrast, Russian Federation had the highest educational level with only 0.5% with no formal education and over 20% with a college degree or higher.

The rate of daily smoking ranged from 7.6% (Ghana) to 46.9% (India), frequent heavy drinker was the highest in China (6.4%) and lowest in Mexico (0.1%), and the highest rate of low physical activity was in South Africa (59.5%). Insufficient fruit and vegetable intake was more common in India, the Russian Federation and Mexico (90.6, 81.0 and 81.4%, respectively) compared with China, South Africa and Ghana (35.7, 68.5 and 68.9%, respectively).

The age standardized prevalence of angina ranged from 9.5 % (South Africa) to 47.5 % (Russian Federation). It was higher in women than in men in all six countries. The rates were higher in rural than in urban locations other than in China. Angina rose with age in each country except Mexico, and a slight drop was seen in the highest age group in Ghana, India, Russian Federation and South Africa. The lowest prevalence of angina was found in individuals with the highest household income in China, Ghana, India and Russian Federation, respectively (see Table 2 ).

The prevalence of stroke was 6.1% in Russian Federation, which was higher than the other SAGE countries, while India had the lowest prevalence of 2.0%. In Russian Federation, the prevalence of stroke in men was almost twice that of women. Stroke was higher in urban than in rural locations in all six countries. Stroke prevalence tended to increase with age in all SAGE countries, but a slight drop in 80+ age group in Mexico and Russian Federation. In China, the wealthiest older adults had the lowest stroke prevalence (see Table 3 ).

Table 4 shows the Odds ratios for likelihood of angina by risk factors. Hypertension was associated with angina in China, India and Russian Federation after adjustment for age, sex, urban/rural setting and education (OR ranging from 1.32 [1.13-1.55] in India to 3.80 [2.91-4.96] in Russian Federation). Low and moderate physical activity was also associated with angina in China (ORs were 1.46 [1.22-1.76] and 1.66[1.39-1.99], respectively). Obesity had a stronger association with angina in Russian Federation and China (ORs were 1.48[1.08-2.02] and 1.24[1.01-1.53], respectively). Smoking was associated with angina in India and South Africa (ORs were 1.56[1.02-2.36] and 2.11 [1.23-3.61], respectively). Non-heavy drinking was a protective factor for angina in China (OR was 0.67[0.51-0.87]). The OR (1.56[1.19-2.05]) for insufficient fruits and vegetables intake was highest in Ghana. Household income was associated with reduced odds ratios of angina in China, India and Russian Federation, however higher household income was a risk factor of angina in South Africa (see Table 4 ).

In all six LIMCs except Mexico, hypertension was associated with stroke (OR ranging from 1.98[1.04-3.80] in Ghana to 3.16[1.72-5.83] in Russian Federation). Low, moderate physical activity were also strongly associated with stroke in four LMICs apart from Ghana and India. In China, Obesity increased the risk of stroke (OR was 1.66[1.20-2.28]). Smoking was also a risk factor of stroke in South Africa. We observed a stronger association between frequent heavy drinking and stroke in India (OR 6.64[1.39 – 31.82]). Insufficient fruit and vegetable intake and household income were not significantly associated with stroke in any of the countries (see Table 5 ).

This study reports the prevalence of two common cardiovascular diseases, angina and stroke, and the relevant risk factors among older adults in six LIMCs. Globally, the age-adjusted CVDs mortality continues to be unevenly distributed: where it has decreased in high income countries(HICs) by 43% in recent decades [ 19 ], while LIMCs are drowning in a rising tide of CVD. Although age-standardized rates of death attributable to CVD declined 13% in LMICs from 381 per 100000 in 1990 to 332 per 100000 in 2013, the number of deaths increased 66% from 7.21 million to 12 million in 2013 with ageing and population growth ascribed as the main drivers [ 19 ]. Ischaemic heart disease and cerebrovascular disease (stroke) combined accounted for more than 85.1% of all cardiovascular disease deaths in 2016[ 20 ]. Our study indicated that CVDs(angina, stroke) were prevalent and variable among older adults in six countries. Angina and stroke were both highest in Russian Federation(47.5%, 6.1% respectively). Women were more likely to have angina than men in all six countries. Stroke was more prevalent in urban than in rural. Angina and stroke both tended to increase with age in China.

Prevalence of CVDs generally appeared to be most closely linked to a country’s stage of epidemiological transition [ 21 ], especially when high disease rates in middle age carry through into older ages. Underlying social, environmental, and economic shifts in many countries have led to increasing levels of predominant causes such as tobacco and alcohol use, sedentary lifestyle, unhealthy diets, and suboptimum levels of weight, blood pressure, cholesterol, and plasma glucose. The high and growing prevalence of CVD in LIMCs largely reflects the burden of these key risk factors. Our study revealed that hypertension, high BMI, decreased physical activity, frequent heavy drinking and lower household health were key risk factors of angina and stroke. However, the distribution of risk factors in six counties was unequal, for example, the factor with highest OR of angina in China and Russian Federation was hypertension, whereas it was smoking in India and South Africa.

Hypertension has been shown to be an independent risk factor for acute myocardial infarction and stroke in older people [ 22 , 23 ]. We found that hypertension was associated with angina in China, India and Russian Federation, in addition it was a risk factor of stroke in five of the six countries in this study (not Mexico). Between 1980 and 2008, blood pressure decreased by 2.0mmHg or more (for men) and 3.5 mmHg or more (for women) per decade in western Europe and Australia but increased by up to 2.7 mmHg over this same period in Oceania, East and West Africa and South and Southeast Asia [ 24 ]. Systematic review revealed that blood pressure lowering greatly reduced the major cardiovascular disease events and all-cause mortality, irrespective of starting blood pressure [ 25 ].However among these six LIMCs 66% hypertensives were undiagnosed before the survey, 73% untreated and 90% uncontrolled. Although the proportions of undiagnosed and untreated were lowest in Russia (30% and 35%), the uncontrolled rate was higher (83%) [ 26 ], low level of health care (primary and secondary prevention) and irregular treatment continued to be a major problem [ 27 ]. Hence, further research on early screening strategies, available health care and effective treatment of hypertension may be critical for improving outcomes.

Our study also showed that low physical activity and obesity besides hypertension were both associated with angina and stroke in China, and insufficient fruit and vegetable intake was risk factor of angina in Ghana. Compared with data from 1997, total physical activity in 2009 has decreased by 29% in males and by 38% in females in China [ 28 ], and physical inactivity was estimated the third leading risk factor for coronary heart disease [ 29 ]. As the relation between physical and obesity well recognized, obesity was an important risk factor of CVD. People are becoming more and more obese. Global age-standardised mean BMI increased from 21.7 kg/m 2 in 1975 to 24.2 kg/m 2 in 2014 in men, and from 22.1 kg/m 2 in 1975 to 24.4 kg/m 2 in 2014 in women. Over this period, age-standardised prevalence of obesity increased from 3.2% in 1975 to 10.8% in 2014 in men, and from 6·4 to 14.9% in women [ 30 ]. More than 50% of the obese individuals in the world lived in just 10 countries (listed in order of number of obese individuals): USA, China, India, Russia, Brazil, Mexico, Egypt, Pakistan, Indonesia, and Germany, and China and India jointly accounting for 15% in 2013[ 31 ]. China has moved from 60th place for men and 41st place for women in 1975 to second for both men and women in 2014 in the worldwide ranking of the number of severely obese individuals [ 30 ]. Unfortunately, the prevalence of obesity among children and adolescents are both on the rise. In comparison with obesity rate in 1985, it increased by 8.7 times for children and 38.1 times for adolescents [ 32 ]. In the World Health Survey 2002-2003, prevalence of low fruits and vegetable consumption among individuals aged 18-99 years in Ghana was the lowest among 52 countries [ 33 ]. However, the prevalence was higher (68.9%) among persons aged 50 years and older [ 34 ]. We also found that insufficient fruits and vegetables intake was associated with angina in Ghana. All of these contribute to the increasing burden of CVD.

We observed a relationship between smoking and angina, frequent heavy drinking and stroke in India. The prevalence of angina was 19.6% (95%CI:16.5-23.0) in India, the second highest for these six countries. CVD-related conditions contributed nearly two-thirds of the burden of NCD mortality in India [ 35 ], with ischemic heart disease(IHD) and stroke contributing substantially to CVD mortality in India (83%) [ 36 ].Up to 35% of adults in India consume tobacco [ 37 ], with the rate of daily tobacco use was highest(46.9%) among the six LIMCs in this study, highest in younger individuals (20–35 years) [ 38 ].The relation between alcohol consumption and CVD has been widely studied. Several analyses showed that low-moderate levels of alcohol consumption had cardio protective effects, while heavy drinking is harmful, usually described as “U-shaped” or “J-shaped” relationship [ 39 , 40 ]. Aside from alcohol consumption, drinking pattern (binge-pattern drinking) played an important role in elevating the risk of CVD [ 41 , 42 ]. Another cohort study showed that heterogeneous associations exist between level of alcohol consumption and CVD: compared with moderate drinking, heavy drinking raised risk of coronary death, heart failure, cardiac arrest, ischaemic stroke but a lower risk of myocardial infarction or stable angina [ 43 ]. We found that in China non-heavy drinking was a protective factor for angina and stroke, and frequent heavy drinking showed a dangerous effect for stroke in India.

There were a few limitations in our study. Firstly, although SAGE assembled nationally representative cohorts from six countries, the response rates were different across the countries, ranging from 51% in Mexico to 93% in China. The low response rate in Mexico was for specific reasons related to timing of the survey and inability to engage in repeat visits to households to maintain the sample and we note this introduces the potential for selection bias into the results for Mexico. Secondly, the data for stroke and some risk factors were based on self-reports, which may lead to recall bias. However, validated symptom-reporting methods were also used in these analyses to estimate and compare prevalence rates for angina to improve prevalence estimates. Thirdly, the question on stroke in SAGE did not distinguish between ischemic stroke and hemorrhagic stroke. Last, these results are based on cross-sectional data and as such, cannot be sure of the direction of the associations we identified.

Conclusions

In conclusion, our study provided representative prevalence of angina and stroke and relevant risk factors in elders in six LIMCs. Due to the variation pattern of prevalence and risk factors distribution, policies and health interventions will need to be targeted and tailored for a broad range of local conditions to achieve the health goals set by the United Nations for 2025.

Abbreviations

Body mass index

Cardiovascular disease

Global burden of disease

Gross national income

Global Physical Activity Questionnaire

High income countries

Ischemic heart disease

Low- and middle- income countries

Study on global AGEing and adult Health

Social-economic status

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Acknowledgements

The authors would like to thank the respondents and interviewers from all six SAGE countries for their contributions and hard work.

This work was supported by WHO, the US National Institutes on Aging through Interagency Agreements [OGHA 04034785; YA1323-08-CN-0020; Y1-AG-1005-01] and through a research grant (R01-AG034479), and Three-year Action Plan on Public Health, Phase IV, Shanghai, China[15GWZK0801;GWIV-22].

Availability of data and materials

The datasets supporting the conclusions of this article are available upon request in the website of WHO ( http://apps.who.int/healthinfo/systems/surveydata/index.php/catalog/sage ).

Author information

Ye Ruan and Yanfei Guo contributed equally to this work.

Authors and Affiliations

Shanghai Municipal Center for Disease Control and Prevention (Shanghai CDC), Shanghai, China

Ye Ruan, Yanfei Guo, Yang Zheng, Zhezhou Huang, Shuangyuan Sun, Yan Shi & Fan Wu

World Health Organization, Geneva, Switzerland

Research Institute for Health Sciences, Chiang Mai University, Chiang Mai, Thailand

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Contributions

FW, PK, YFG and YZ designed, implemented the conduct of this study. YR and YFG conceived of the analysis, and drafted the manuscript. YR, YFG, YS, ZZH, YZ and SYS contributed to the statistical analyses. ZZH and SYS contributed to the editing of initial draft. All authors read and approved the final manuscript.

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Correspondence to Yan Shi or Fan Wu .

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Ruan, Y., Guo, Y., Zheng, Y. et al. Cardiovascular disease (CVD) and associated risk factors among older adults in six low-and middle-income countries: results from SAGE Wave 1. BMC Public Health 18 , 778 (2018). https://doi.org/10.1186/s12889-018-5653-9

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Hot topics and trends in cardiovascular research

Affiliations.

1 Department of Cardiovascular Sciences, KU Leuven, Campus Gasthuisberg O/N1 704, Herestraat 49, Leuven, Belgium.
2 ECOOM, Department of Managerial Economics, Strategy and Innovation, KU Leuven, Naamsestraat 61, Leuven, Belgium.
3 Department Science Policy & Scientometrics, Library of the Hungarian Academy of Sciences, Arany János u. 1, Budapest, Hungary.
PMID: 31162536
PMCID: PMC6642725
DOI: 10.1093/eurheartj/ehz282

Aims: Comprehensive data on research undertaken in cardiovascular medicine can inform the scientific community and can support policy building. We used the publication output from 2004 to 2013 and the 2014 references to these documents, to identify research topics and trends in the field of cardiovascular disease.

Methods and results: Text fragments were extracted from the titles and abstracts of 478 000 publications using natural language processing. Through machine-learning algorithms, these text fragments combined to identify specific topics across all publications. A second method, which included cross-references, assigned each publication document to a specific cluster. Experts named the topics and document clusters based on various outputs from these semi-automatic methods. We identified and labelled 175 cardiovascular topics and 20 large document clusters, with concordance between the approaches. Overarching, strongly growing topics in clinical and population sciences are evidence-based guidance for treatment, research on outcomes, prognosis, and risk factors. 'Hot' topics include novel treatments in valve disease and in coronary artery disease, and imaging. Basic research decreases its share over time but sees substantial growth of research on stem cells and tissue engineering, as well as in translational research. Inflammation, biomarkers, metabolic syndrome, obesity, and lipids are hot topics across population, clinical and basic research, supporting integration across the cardiovascular field.

Conclusion: Growth in clinical and population research emphasizes improving patient outcomes through novel treatments, risk stratification, and prevention. Translation and innovation redefine basic research in cardiovascular disease. Medical need, funding and publishing policies, and scientific opportunities are potential drivers for these evolutions.

Keywords: Cardiovascular research; Clinical care; Innovation; Outcomes; Prevention.

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Effects of Exercise to Improve Cardiovascular Health

Obesity is a complex disease that affects whole body metabolism and is associated with an increased risk of cardiovascular disease (CVD) and Type 2 diabetes (T2D). Physical exercise results in numerous health benefits and is an important tool to combat obesity and its co-morbidities, including cardiovascular disease. Exercise prevents both the onset and development of cardiovascular disease and is an important therapeutic tool to improve outcomes for patients with cardiovascular disease. Some benefits of exercise include enhanced mitochondrial function, restoration and improvement of vasculature, and the release of myokines from skeletal muscle that preserve or augment cardiovascular function. In this review we will discuss the mechanisms through which exercise promotes cardiovascular health.

Introduction

Obesity and its associated co-morbidities are increasing at rapid rates across the United States and worldwide ( 1 ). Obesity is associated with many adverse health effects, including increased risks of cardiovascular disease (CVD), type 2 diabetes (T2D), certain cancers, and death ( 2 – 6 ). As obesity rates continue to rise, the prevalence of associated comorbidities including T2D and CVD increase concomitantly ( 7 ); overweight people are twice as likely, and severely obese people are ten times more likely to develop cardiovascular diseases than individuals of a healthy weight ( 8 ).

Regular physical exercise has several beneficial effects on overall health. While decreasing body mass and adiposity are not the primary outcomes of exercise, exercise can mediate several diseases that accompany obesity including T2D and CVD ( 9 – 14 ). Several recent studies have shown that sustained physical activity is associated with decreased markers of inflammation, improved metabolic health, decreased risk of heart failure, and improved overall survival ( 15 – 17 ). Exercise improves overall metabolic health and reduces the development of T2D ( 18 ) by improving glucose tolerance ( 19 ), insulin sensitivity ( 20 ), and decreasing circulating lipid concentrations ( 21 ). This occurs primarily through adaptations to the skeletal muscle, liver, and adipose tissue ( 16 , 22 , 23 ). Physical exercise can also improve cardiovascular function through adaptations to the heart and vascular system ( 17 , 24 – 27 ). Regular physical exercise decreases resting heart rate, blood pressure, and atherogenic markers, and increases physiological cardiac hypertrophy ( 13 – 15 , 28 ). Exercise improves myocardial perfusion and increases high-density lipoprotein (HDL) cholesterol levels, all of which reduce stress on the heart and improve cardiovascular function in healthy and diseased individuals ( 11 , 15 , 29 , 30 ). Given the increasing interest in exercise-based therapies, we will discuss the benefits of exercise on cardiovascular health and the potential mechanisms through which they occur.

Cardiovascular Disease

Cardiovascular disease (CVD) is the leading cause of morbidity and mortality worldwide ( 31 , 32 ). Almost half of all adults in the United States have at least one key risk factor for development of CVD (i.e., high blood pressure, high cholesterol, or smoking) ( 33 ). CVD encompasses a wide range of conditions that affect the heart and vasculature including arrhythmias, dilated, hypertrophic, or idiopathic cardiomyopathies, heart failure and atherosclerosis ( 34 , 35 ). These conditions can lead to potentially fatal cardiac events such as stroke, myocardial infarction (heart attack), or cardiac arrest ( 31 , 36 ). Thus, determining various therapeutic tools to prevent or reduce the incidence of CVD is vital.

Although cardiovascular disease can arise in response to multiple factors, the prevalence of obesity-related CVD is rapidly increasing ( 8 ). This can occur for several reasons, one being that a high fat diet or obesity can lead to hypertension. In obesity, angiotensin II and aldosterone secretion from abdominal subcutaneous adipose tissue drives activation of the renin-angiotensin system ( 37 – 41 ). Angiotensin II induces vasoconstriction in arterioles, causing arteriolar resistance and increased systemic blood pressure, in addition to stimulating the release of anti-diuretic hormone, which increases water reabsorption in the kidneys. Aldosterone increases the reabsorption of water and sodium into the blood, resulting in increased extracellular fluid volume, thus increasing blood pressure. The renin-angiotensin system also affects the sympathetic nervous system through inhibition of norepinephrine reuptake in the pre-synaptic sympathetic nerve terminals, increasing resting norepinephrine concentration ( 42 ), which can cause an increased resting heart rate and eventually development of hypertension ( 43 , 44 ). Therefore, the renin-angiotensin system and sympathetic nervous system create a positive feedback loop to increase hypertension in obese individuals ( 40 ).

Sustained hypertension increases left ventricular afterload, forcing the left ventricle to work harder ( 45 ). This leads to pathologic hypertrophy of the ventricular walls and ventricular chamber dilation, eventually culminating in decreased myocardial function and the onset of heart failure ( 46 , 47 ). As myocardial function declines, the cardiovascular system becomes impaired, resulting in insufficient blood flow. Oxygen and nutrients are then unable to meet the physiological demands of the body, resulting in tachycardia and extreme fatigue, as well as compounding health issues such as pulmonary congestion, fluid retention, and arrhythmias ( 48 , 49 ).

Another potential cause of obesity-related CVD is metabolic overload of the heart, which can occur independent of hypertension. The heart is a “metabolic omnivore” ( 50 ), but in the obesogenic state, and particularly with insulin resistance, fatty acid uptake and utilization is significantly increased ( 51 ). This can lead to inefficient β-oxidation and intramyocardial lipid accumulation ( 52 ). Because the heart has limited storage capacity, abundant accumulation of excess lipids and toxic lipid metabolites results in “lipotoxicity” which contributes to cardiac dysfunction ( 53 – 55 ). Indeed, several studies have demonstrated that metabolic changes precede structural changes in the heart ( 56 , 57 ). Cardiac metabolism is also altered in T2D patients who are not obese. As in obesity, T2D is associated with elevated circulating free fatty acids, increased myocardial fatty acid uptake and utilization, and myocardial insulin resistance leading to decreased glucose uptake and utilization in the heart ( 58 – 61 ).

Atherosclerosis is the most common form of CVD, and the development of atherosclerosis progresses slowly in response to persistent exposure to an unhealthy, sedentary lifestyle, including obesity ( 34 , 62 ). In an obese state, circulating levels of triglycerides and LDL cholesterol are increased ( 63 ), causing small plaques to form under endothelial cells of the innermost surface of artery walls ( 34 , 62 , 64 ). While normal endothelial cells can prevent adhesion of these plaques by leukocytes, under obese conditions LDL molecules are oxidized causing endothelial cells to instead express adhesion molecules and chemoattractants ( 65 – 67 ). In response, macrophages take up oxidized LDL and are transformed into foam cells ( 64 , 65 ) which localize to the fatty plaques within arteries and secrete factors that further promote plaque formation ( 67 , 68 ). Resulting plaques cause vessel walls to thicken and stiffen, inhibiting blood flow ( 69 ). If the plaques become large enough or thrombosis occurs, the inhibition of blood flow can lead to ischemic conditions and cardiac events including stroke, myocardial infarction (MI), or cardiac arrest ( 70 ), all of which can be fatal.

Exercise Training Improves Cardiovascular Health

There are several risk factors leading to the development and progression of CVD, but one of the most prominent is a sedentary lifestyle ( 34 , 35 , 71 ). A sedentary lifestyle can be characterized by both obesity and consistently low levels of physical activity. Thus, lifestyle interventions that aim to increase physical activity and decrease obesity are attractive therapeutic methods to combat most non-congenital types of CVD.

Physical Activity Decreases Cardiovascular Risk Factors

Regular physical exercise is associated with numerous health benefits to reduce the progression and development of obesity, T2D, and CVD ( 9 – 14 ). Several randomized clinical trials have demonstrated that lifestyle interventions including moderate exercise and a healthy diet improve cardiovascular health in at-risk populations ( 72 , 73 ). Individuals with metabolic syndrome who participated in a 4 month program of either a diet (caloric restriction) or exercise intervention had reduced adiposity, decreased systolic, diastolic and mean arterial blood pressure, and lower total and low-density lipoprotein (LDL) cholesterol lipid profiles compared to the control group ( 12 ). Both the diet and exercise intervention improve these cardiovascular outcomes to a similar extent ( 74 ).

Several previous studies have investigated the effects of diet and exercise, independently or in combination, on metabolic and cardiovascular health and have determined that diet, exercise, or a combination of diet and exercise induces weight loss, decreases visceral adiposity, lowers plasma triglycerides, plasma glucose, HDL levels, and blood pressure, and improves VO 2max ( 75 – 78 ). Importantly, several of these beneficial effects of exercise are evident independent of weight loss ( 79 ). Studies have shown that exercise can improve metabolic and cardiovascular health independent of changes in body weight, including improved glucose homeostasis ( 80 , 81 ), endothelial function ( 82 ), blood pressure ( 83 ), and HDL levels ( 84 , 85 ). These data indicate exercise, independent of changes in body mass, results in significant improvements in cardiovascular and metabolic health. Although a detailed analysis of the vast impact of diet on cardiometabolic health is outside the scope of this review, the importance of diet and exercise in tandem should not be ignored, as many studies have shown that cardiometabolic health is improved to a higher extent in response to a combined diet and exercise programs compared to either intervention alone ( 86 – 89 ).

Exercise has a similar effect on cardiovascular improvements in lean and overweight normoglycemic subjects. In a 1 year study of non-obese individuals, a 16–20% increase in energy expenditure (of any form of exercise) with no diet intervention resulted in a 22.3% decrease in body fat mass and reduced LDL cholesterol, total cholesterol/HDL ratio, and C-reactive protein concentrations, all risk factors associated with CVD ( 74 ). In overweight individuals, 7–9 months of low-intensity exercise (walking ~19 km per week at 40–55% VO 2 peak) significantly increased cardiorespiratory fitness compared to sedentary individuals ( 90 ). Together these data indicate that exercise interventions decrease the risk or severity of CVD in subjects who are lean, obese, or have type 2 diabetes ( 12 , 74 , 90 ).

Physical Activity Improves Cardiovascular Function in Patients With CVD

Exercise is also an important therapeutic treatment for patients who have cardiovascular diseases ( 14 ). A systematic review of 63 studies found that exercise-based cardiac rehabilitation improved cardiovascular function ( 91 ). These studies consisted of various forms of aerobic exercise at a range of intensities (from 50 to 95% VO 2 ), over a multitude of time periods (1–47 months). Overall, exercise significantly reduced CVD-related mortality, decreased risk of MI, and improved quality of life ( 91 ). Another study looked specifically in patients with atherosclerosis post-revascularization surgery. Patients who underwent 60 min of exercise per day on a cycle ergometer for 4 weeks had an increase blood flow reserve (29%) and improved endothelium-dependent vasodilatation ( 10 ). A recent study provided personalized aerobic exercise rehabilitation programs for patients who had an acute myocardial infarction for 1 year after a coronary intervention surgery ( 92 ). The patients who underwent the exercise rehabilitation program had increased ejection fraction (60.81 vs. 53% control group), increased exercise tolerance, and reduced cardiovascular risk factors 6 months after starting the exercise rehabilitation program ( 92 ). This improvement in cardiovascular health in patients with atherosclerosis or post-MI is likely the result of increased myocardial perfusion in response to exercise, however more research is required to fully understand these mechanisms ( 10 ).

One defining characteristic of heart failure is exercise intolerance ( 93 ), which resulted in a prescription of bed rest for these patients until the 1950s ( 94 ). However, it has now been shown that a monitored rehabilitation program using moderate intensity exercise is safe for heart failure patients, and this has now become an important therapeutic for patients with heart failure ( 95 – 97 ). Meta-analyses and systemic reviews have shown that exercise training in heart failure patients is associated with improved quality of life, reduced risk of hospitalization and decreased rates of long-term mortality ( 93 , 98 – 102 ). One study of heart failure patients found that aerobic exercise (walking or cycling) at 60–70% of heart rate reserve 3–5 times per week for over 3 years led to improved health and overall quality of life (determined by a self-reported Kansas City Cardiomyopathy Questionnaire, a 23-question disease-specific questionnaire) ( 103 ). Other studies have shown that exercise-based rehabilitation at a moderate intensity in heart failure patients improves cardiorespiratory fitness and increases both exercise endurance capacity and VO 2 max (12–31% increase) ( 101 , 104 ).

More recent studies have examined the effects of high-intensity exercise on patients with heart failure. A recent study found that 12 weeks of high intensity interval training (HIIT) in heart failure patients (with reduced ejection fraction) was well-tolerated and had similar benefits compared to patients who underwent moderate continuous exercise (MCE) training, including improved left ventricular remodeling and aerobic capacity ( 105 ). A separate study found that 4 weeks of HIIT in heart failure patients with preserved ejection fraction improved VO 2peak and reduced diastolic dysfunction compared to both pre-training values and compared to the MCE group ( 78 ). These studies indicate that both moderate and high intensity exercise training improve cardiovascular function in heart failure patients, likely related to increased endothelium-dependent vasodilation ( 106 ) and improved aerobic capacity ( 78 , 101 , 105 ).

Mechanisms Regulating Exercise-Induced Benefits on Cardiovascular Health

Multiple mechanisms mediate the benefits of regular physical exercise on cardiovascular health ( 13 , 14 ) ( Figure 1 ). Exercise represents a major challenge to whole-body homeostasis, and provokes widespread changes in numerous cells, tissues, and organs in response to the increased metabolic demand ( 121 ), including adaptations to the cardiovascular system ( 13 , 14 ).

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Exercise improves cardiovascular health by inducing changes in oxygen delivery, vasculature, peripheral tissues, and inflammation. (A) Exercise improves oxygen delivery throughout the body through promotion of vasodilation and angiogenesis ( 107 – 110 ). (B) Exercise increases mitochondrial biogenesis in adipocytes ( 104 , 111 , 112 ), skeletal muscle myotubes ( 113 ), and cardiomyocytes ( 14 , 114 , 115 ). (C) Exercise causes a long-term anti-inflammatory effect (which is inversely related to the increased inflammation typically seen in CVD and obesity) ( 116 ). Myokines released from skeletal muscle during physical exercise partially mediate these anti-inflammatory effects, and promote inter-tissue cross talk to mediate further cardiovascular benefits ( 117 – 120 ).

Exercise induces adaptations in several cell types and tissues throughout the body. Exercise increases mitochondrial biogenesis in adipocytes ( 104 , 111 , 112 ), skeletal muscle myocytes ( 113 ), and cardiomyocytes ( 14 , 114 , 115 ), increasing aerobic respiration within these tissues. Additionally, exercise improves oxygen delivery throughout the body through vasodilation and angiogenesis ( 107 – 110 ), protecting against ischemia-reperfusion injury in the heart ( 122 , 123 ). Further, exercise causes a long-term anti-inflammatory effect which is inversely related to the increased inflammation typically seen in CVD and obesity ( 116 ). Myokines released from skeletal muscle during physical exercise partially mediate these anti-inflammatory effects, and promote inter-tissue cross talk to mediate further cardiovascular benefits ( 117 – 120 ).

Exercise Improves Mitochondrial Biogenesis and Function

Many of the benefits sustained by exercise are due to mitochondrial adaptations throughout the body. For example, exercise improves long-term cardiorespiratory fitness (VO 2 ) by increasing the mitochondrial content and desaturation of myoglobin in skeletal muscle tissue, improving the oxidative capacity of skeletal muscle ( 113 , 124 , 125 ). The increase of oxygen uptake and utilization by skeletal muscle (as indicated by arteriovenous oxygen difference; a-vO 2 ) in response to regular exercise ( 126 ) is protective against a decrease in obesity-related a-vO2, resulting in individuals to require more blood to receive the same amount of oxygen ( 127 ).

Mitochondrial biogenesis is augmented in cardiomyocytes in response to exercise ( 14 , 114 , 115 , 128 ). This is likely due to enhanced activation of AMP-activated protein kinase (AMPK) and subsequent increase mitochondrial PGC-1α expression ( 109 , 114 ) Exercise also increases the ability of mitochondria to oxidize fatty acids (the predominant substrate utilized in healthy myocardium), thus increasing the capacity for ATP synthesis ( 14 , 129 – 133 ). These exercise-induced enhancements of mitochondrial function are important in preventing cardiovascular dysfunctions often caused by obesity.

Obesity is associated with defective mitochondrial biogenesis in the myocardium ( 134 ) and reduced mitochondrial capacity for oxidative phosphorylation and ATP synthesis ( 135 , 136 ). In heart failure, fatty acid uptake, and utilization is decreased ( 137 ), likely causing the heart failure associated shift toward glucose metabolism in order to preserve cardiovascular function ( 130 , 137 , 138 ). However, in advanced heart failure, diabetes, or obesity, myocardial insulin resistance may develop, impairing glucose uptake and accelerating cardiovascular dysfunction ( 139 – 141 ). Importantly, insulin sensitivity is improved in response to regular exercise ( 142 ) which is vital in reducing the risk of obesity-related insulin resistance. Insulin has also been indicated to directly regulate mitochondrial metabolism by promoting induction of OPA1, a GTPase that controls mitochondrial cristae integrity, energetics and mitochondrial DNA maintenance ( 143 , 144 ), thus indicating another potential mechanism of exercise-induced improvements in cardiovascular health through mitochondrial function enhancement.

Reactive oxygen species (ROS) are physiological byproducts of aerobic mitochondrial metabolism and while necessary for initiating cellular repair or apoptosis, increased levels of ROS are associated with inflammation and several forms of CVD ( 145 ). While exercise increases the direct production of ROS by mitochondria, the net cellular ROS load is reduced by exercise due to increased action of antioxidant systems ( 146 ). Essentially, exercise creates a system in which cells exhibit a “favorable” response within low exposures of ROS, allowing antioxidant systems to work effectively ( 147 ).

By increasing the ability of mitochondria to prevent oxidative damage, exercise-induced modifications to mitochondria protect against ischemia-reperfusion damage to the heart. During ischemia, the absence of oxygen from the heart creates an environment in which the return of oxygenated blood flow leads to the induction of inflammation and oxidative stress rather than restoration of normal function ( 148 ). In contrast, exercise-induced adaptations to cardiomyocyte mitochondria dampen oxidative damage caused by ischemia-reperfusion, resulting in reduced cardiac injury and decreasing the risk of ischemia-related cardiac dysfunction or death ( 149 – 151 ).

Exercise Improves Vasculature and Myocardial Perfusion

Exercise training induces vascular adaptations to several tissues ( 107 , 108 ). In the heart, the increase in vascularization protects against vascular stress and reduces the likelihood of a cardiac event ( 24 – 26 ). These adaptations are mediated through increased expression of vascular endothelial nitric oxide synthase (eNOS). Exercise increases the intensity of physiological shear stress, inducing the shear stress-dependent activity of c-Src in endothelial cells and increasing expression of eNOS ( 27 , 152 ). In the vascular endothelium, eNOS catalyzes the production of nitric oxide (NO) which causes vasodilation, inhibits platelet aggregation and prevents leukocyte adhesion to vessel walls, thus reducing the onset of atherosclerosis, thrombosis, ischemia, or other cardiac events ( 152 , 153 ).

Exercise also induces angiogenesis, however the mechanisms regulating this process are unclear. It has been hypothesized that the increase in nitric oxide (NO) production after exercise upregulates pro-angiogenic factors, particularly vascular endothelial growth factor (VEGF) ( 154 ). One recent study determined that male rats who underwent exercise training for 10 weeks after MI had increased Akt phosphorylation of eNOS, and reactivation of cardiac VEGF pathway activity, resulting in increased angiogenesis ( 155 ). While the mechanisms are not completely defined, it is clear that exercise induces arteriogenesis, increases angiogenesis and protects against vascular stress, thus decreasing the possibility of a cardiac event ( 107 – 110 , 122 , 123 ).

Exercise Reduces Chronic Inflammation

Inflammation is a complex yet normal biological reaction to damaging stimuli ( 156 ). Chronic inflammation is associated with multiple diseases including obesity, T2D, and CVD ( 116 , 157 ). Excess consumption of nutrients causes cells including adipocytes ( 158 ), hepatocytes ( 159 ), islet cells ( 160 ), and skeletal muscle cells ( 161 ) to activate the transcription factors nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) and activator protein 1 (AP-1), increase expression of toll-like receptor 4 (TLR4) ( 162 , 163 ), and stimulate the release of cytokines such as TNF-α, IL-6, IL-1β, and CCL2 ( 158 , 164 ). The subsequent inflammation is modest in comparison to inflammatory responses during infection or injury ( 165 ) but remains as a chronic response to obesity termed “meta-inflammation” ( 163 ). Exercise, however, results in a long-term anti-inflammatory effect ( 116 , 156 ). The exercise-induced reduction of meta-inflammation during disease is hypothesized by some to be related to downregulation of NF-κB ( 166 – 168 ), but exercise also decreases monocyte accumulation and suppresses the release of TNF-α and other pro-inflammatory adipokines, creating an anti-inflammatory effect ( 169 – 172 ).

Excess immune activation caused by obesity is of particular concern for vascular health, as activation of TLR4 causes monocyte recruitment and conversion to foam cells, driving the progression of atherosclerosis ( 67 , 173 ). Exercise prevents the development of atherosclerosis by reducing expression of TLRs on monocytes and macrophages, which subsequently decreases the availability of TLR4 ligands and inhibiting pro-inflammatory cytokine production ( 170 , 171 , 174 ). Exercise also decreases pro-inflammatory N-terminal pro b-type natriuretic (NT-proBNP) and high-sensitivity C-reactive protein (hsCRP) within the heart, both of which are predictors of heart failure in atherosclerosis ( 175 , 176 ).

Exercise Enhances Inter-tissue Communication Through Release of Myokines

Skeletal muscle can act as a secretory organ by stimulating the production, secretion, and expression of specific myokines after contraction ( 177 – 179 ). Myokines are chemical messengers that function in an autocrine, paracrine, or endocrine manner to influence crosstalk between different organs including skeletal muscle, liver, and adipose tissue ( 180 – 185 ). They are of great interest with regards to cardiovascular health because the well-known protective actions of exercise on cardiovascular function are at least partially mediated by increased secretion of myokines ( Figure 2 ) ( 195 ). Some myokines that impact cardiovascular health include IL-6, myonectin, Fstl1, and NDNF ( 196 ).

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Exercise-induced myokines mediate organ cross-talk and improve cardiometabolic health. (A) The myokine IL-6 inhibits TNF-α ( 186 ), reducing inflammation and protecting against the formation of atherosclerosis ( 187 ); stimulates GLP-1 secretion causing improved insulin secretion ( 188 ); increases lipolysis and fatty acid oxidation in adipose tissue ( 189 ) and increases glucose uptake through the AMPK signaling pathway ( 190 , 191 ). (B) Fstl1 decreases ischemic injury size through activation of the Akt/AMPK pathway (activating eNOS and enhancing revascularization) ( 118 , 119 ) and early fibroblast stimulation (which aids in repair after ischemia-reperfusion) ( 192 ). (C) Myonectin (MyoN) increases fatty acid uptake in adipocytes and hepatocytes ( 117 ), and promotes protects against ischemic injury in the heart, possibly through Akt activation ( 193 ). (D) NDNF improves survival after myocardial infarction (MI) by reducing apoptosis ( 120 ) through stimulation of the Akt/AMPK/eNOS pathway (enhancing revascularization) ( 194 ).

Interleukin-6 (IL-6)

IL-6 was introduced as the first myokine over a decade ago ( 197 ). Circulating levels of IL-6 are increased in response an acute bout of aerobic exercise ( 198 , 199 ) and can act in an endocrine fashion to improve metabolic and cardiovascular health. Exercise-induced elevated concentrations of IL-6 can stimulate glucagon-like peptide-1 (GLP-1) secretion from intestinal L cells and pancreatic α cells, leading to improvements in insulin secretion and glycemia ( 188 ). IL-6 also increases lipolysis and fatty acid oxidation in adipose tissue ( 189 ) and can increase glucose uptake through stimulation of the AMP-activated protein kinase (AMPK) signaling pathway ( 190 , 191 ). With regard to cardiovascular function, IL-6 can reduce inflammation by inhibiting tumor necrosis factor-α (TNF- α) ( 186 ). This results in a protective effect on cardiovascular health because TNF- α is involved in the formation of atherosclerosis, development of heart failure, and subsequent complications, including myocardial infarction (MI) ( 187 ). More investigation is required to determine the direct effects of IL-6 action on cardiovascular health.

Myonectin (or CTRP15) is abundantly expressed in skeletal muscle and is increased in response to chronic aerobic exercise ( 117 ). Importantly, injection of myonectin into wild-type mice decreases circulating free fatty acids levels by increasing fatty acid uptake in adipocytes and hepatocytes ( 117 ). Myonectin has also been identified to have protective effects on cardiovascular health; mice deficient in Myonectin had enhanced ischemic injury in response to MI while systemic delivery of myonectin attenuated ischemic injury ( 200 ). Further work is needed to determine whether these benefits are observed in response to an increase in myonectin after exercise.

Follistatin-Like 1 (Fstl1)

Fstl1, also referred to as TSC-36, is a secreted glycoprotein that belongs to the follistatin family of proteins and is upregulated in skeletal muscle in response to exercise ( 194 , 201 , 202 ). Expression of Fstl1 is also increased in ischemic and hypertrophic hearts of mice and functions in a protective manner ( 118 ). Systemic administration of Fstl1 in both mouse and swine models led to reduced apoptosis, inflammation and injury size following ischemia-reperfusion ( 118 , 119 ). In vitro , treatment of cultured cardiomyocytes with Fstl1 reduces apoptosis in response to hypoxia-reoxygenation by activating Akt and AMPK ( 118 , 119 ). One recent study demonstrated that Fstl1 stimulates early fibroblast activation, which is required for acute repair and protects the heart from rupture after ischemia-reperfusion ( 192 ). While the exact role of an exercise-induced increase in Flst1 on cardiovascular function has not been defined, these data indicate that Fstl1 is increased in response to exercise, and an increase in circulating Fstl1 functions to repair cardiovascular damage and improve cardiovascular function ( 202 ).

Neuron-Derived Neurotrophic Factor (NDNF)

NDNF is a glycosylated protein secreted from the endothelial cells of skeletal muscle ( 203 ). Although initially identified as a neurotrophic factor expressed in mouse brain and spinal cord ( 204 ), NDNF is also released from skeletal muscle in response to exercise ( 203 ) and acts as a hypoxia-induced pro-angiogenic factor that stimulates endothelial cell network formation through activation of the Akt/eNOS signaling pathway ( 194 ). This pro-angiogenic affect is an important component in the recovery from MI; intramuscular administration of NDNF using an adenoviral vector improved systolic function in a mouse model after MI ( 120 ). Increased NDNF levels are also associated with reduced myocardial hypertrophy and apoptosis in post-MI hearts ( 120 ). Another study showed that down-regulation of NDNF by siRNA impairs recovery from ischemia-reperfusion injury ( 205 ). Treatment of NDNF in cardiomyocytes also reduces hypoxia-induced apoptosis via activation of the focal adhesion kinase/Akt-dependent pathway ( 120 ). Additionally, increased levels of NDNF released from skeletal muscle in response to exercise enhance fatty acid oxidation through activation of AMPK ( 203 ). These data demonstrate the importance of NDNF as an endogenous ischemia- and exercise inducible factor that can enhance revascularization and therefore have a cardiovascular protective effect.

Conclusions

The rate of obesity-related cardiovascular disease is rapidly increasing, and often associated with additional co-morbidities including type 2 diabetes ( 3 , 6 , 8 ). It is clear that exercise reduces cardiovascular risk factors, and this reduction in risk factors is independent of changes to body weight or incidence of type 2 diabetes ( 75 – 77 , 79 , 206 , 207 ). Exercise is also an important therapeutic treatment for patients who have cardiovascular diseases ( 14 ), further demonstrating the protective and restorative properties of exercise. In patients with CVD, exercise improved endothelium-dependent vasodilatation, increased ejection fraction and exercise tolerance, improved quality of life, and reduced CVD-related mortality ( 10 , 91 , 92 , 101 , 103 , 208 – 211 ). Exercise improves cardiovascular health by several mechanisms including increased mitochondrial biogenesis and fatty acid oxidation ( 14 , 114 , 115 , 128 – 130 ) dilation of blood vessels causing improved myocardial perfusion ( 9 – 11 ), and reduction of inflammation providing protection against the development of atherosclerosis ( 67 , 116 , 156 ). Myokines released from skeletal muscle during exercise also mediate systemic and cardiovascular health benefits through an anti-inflammatory action, increased fatty acid oxidation, increased glucose uptake, and improved insulin secretion and sensitivity ( 117 , 186 , 193 , 196 , 212 – 214 ). Importantly, several myokines (IL-6, Myonectin, Fstl1, and NDNF) have also been shown to have cardiovascular protective effects in response to ischemia-reperfusion injury ( 117 – 120 , 186 , 187 ).

While it is clear that exercise is important, the mechanistic pathways behind exercise-induced benefits on cardiovascular health are still being identified. Further understanding of the molecular mechanisms through which exercise improves cardiovascular function will lead to the development of therapeutics which can act in conjunction with exercise programs, and for individuals whom are unable or unwilling to exercise to amplify the beneficial effects of exercise.

Future research will investigate the effects of cardiac specific proteins on cardiovascular health, expanding research into the areas of system cross-talk will help delineate how other tissues, skeletal muscle in particular, can mediate cardiovascular improvements via myokine release. How these myokines affect cardiovascular function, including adaptations to mitochondrial activity, angiogenesis and inflammatory responses will provide insight into new mechanisms for the beneficial effects of exercise on cardiovascular function. Accordingly, myokines may act as potential targets for heart disease prevention and therapies. Recent studies have investigated the use of gene therapies, including the use of adeno-associated virus, on cardiovascular function. While these therapies have not been fully optimized with remaining issues in immunogenicity, efficacy and genotoxicity ( 215 ), their development provides excitement for the potential therapies focused on exercise-induced myokines that improve cardiovascular function as a treatment for patients who are unable, or perhaps unwilling, to exercise. Together these data highlight the importance of exercise and exercise-related therapies to both prevents the development of cardiovascular disease and promotes recovery and improved health in patients with CVD.

Author Contributions

KP, KKB, and KIS outlined, drafted, and contributed to the writing of the manuscript. All authors approved the final version of the manuscript.

Conflict of Interest Statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Funding. This work was supported by National Institutes of Health Grants R01-HL138738 and 17CSA33610078 to KIS and K01-DK116916 to KKB.

The use of nanotechnology in cardiovascular disease

Review Article
Open access
Published: 16 August 2018
Volume 8 , pages 1607–1619, ( 2018 )

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Meera Chandarana 1 ,
Anthony Curtis 1 &
Clare Hoskins ORCID: orcid.org/0000-0002-7200-0566 1

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Cardiovascular diseases claim a number of lives globally; many of which are preventable. With the increase in diets that consist of high saturated fat, salt, and sugar, people often living sedentary lifestyles, and a rise in cases of obesity, the incidence of cardiovascular disease is increasing. These contributing factors, coupled with more advanced methods of diagnosis, have delivered statistics that clearly show that there is a rising trend in the prevalence of cardiovascular disease. Treatment for cardiovascular diseases is limited currently to oral medicines or invasive surgery. There is a huge gap in this area of medicine for novel therapeutics for improved patient outcomes. Nanotechnology may provide a solution to more effective treatment of disease, with better prognoses and a reduced side effect profile. This review will explore for potential solutions to the limited pharmacological therapies currently on the market and the future that lies ahead for the place of nanotechnology within cardiovascular medicine.

Cardiovascular Nanotechnology

Atherosclerosis and Nanotechnology: Diagnostic and Therapeutic Applications

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Introduction

Cardiovascular diseases (CVDs) are the leading cause of death worldwide, claiming 17.7 million lives in 2015, and this figure is projected to increase to 23.6 million in 2030 (WHO 2017 ). The term ‘cardiovascular diseases’ encompasses, but is not limited to coronary heart disease, deep vein thrombosis, pulmonary embolism, and myocardial infarction (MI), all of which result in ischaemia and tissue death. Of these, MI and heart failure are the major conditions which lead to mortality.

A MI, known commonly as a heart attack, is the result of total occlusion of the major arteries supplying the heart leading to a decrease in blood flow, oxygen, and nutrient supply. Ultimately, this results in myocardial tissue death by apoptosis or necrosis due to coronary occlusion. An MI can manifest as two different forms, ST-elevation MI (STEMI) or non-ST-elevation MI (NSTEMI), dependant on the visible changes on an ECG trace (NICE 2013 ). The current treatment for MI is reperfusion in the shortest period of time following arterial obstruction, which can be achieved through invasive methods such as percutaneous coronary intervention (PCI) or coronary artery bypass graft (CABG), or through pharmacological therapy (Ruiz-Esparza et al. 2013 ).

Heart failure is a clinical disease state that presents with symptoms of breathlessness, peripheral oedema, and fatigue, all of which are a result of reduced cardiac functionality (Ponikowski et al. 2016 ). This form of cardiomyopathy is a state in which the heart muscle is unable to pump efficiently to satisfy the body’s metabolic requirements (Ruiz-Esparza et al. 2013 ). Disease of the coronary artery is the largest contributory factor in the development of heart failure (Fox et al. 2001 ). Heart failure is an umbrella term that refers to a range of various cardiac syndromes, including: left-ventricular dysfunction, valvular, pericardial, or endocardial abnormalities, and irregularity of rhythm (Ponikowski et al. 2016 ). It is estimated that up to 2 million people are living with heart failure in the UK, a figure that is continuously increasing due primarily to the significantly aging population (Mitchell et al. 2015 ). Currently, guidance recommends ACE inhibitors and β-receptor blockers as the first-line treatment for heart failure (NICE 2010 ).

The current statistics regarding the incidence of CVDs highlight the need for new therapies and technological advancements to combat these diseases.

Atherosclerosis is the precursor to several vascular diseases. Atherosclerotic plaques are formed of macrophage cells, fat, cholesterol, and calcium, which become deposited in the vasculature and the growing plaques harden over time. This results in narrowing of the blood vessels, a reduction in blood flow, rupture, and ultimately ischaemia ((Weaver 2013 ) (Fig. 1 ). Histologically, the rupture of plaques, which leads to a cardiovascular event, is a result of poor fibrous plaque caps containing increased concentrations of matrix metalloproteinases (MMPs) that cause weakness in the plaque (Qin et al. 2016 ). Lifestyle factors are eminent contributors to the development of atheromatous plaques. It is widely accepted that consuming foods rich in salt, sugar, and saturated fat greatly increases the risk of suffering from a CVD in later life. Having a high low-density lipoprotein (LDL)-to-high-density lipoprotein (HDL) ratio is also a risk factor as LDLs are deposited on the walls of blood vessels and contribute to the development of plaques. Hypertension, smoking, lack of physical activity, family history, obesity, age, and stress all play a role in the development of CVDs, estimated to cost the economy £19 billion per annum, with the National Health Service (NHS) bearing a burden of £9 billion (British Heart Foundation 2017 ).

Progression of atherosclerotic plaque showing narrowing of the blood vessel

Current treatments for CVDs are focussed on restoring normal blood flow through or around the damaged vasculature and the prevention of recurrent cardiovascular insults. Reduction in further build up and thickening of atherosclerotic plaques, as well as effects on external elastic membranes and fibrous and dense calcium volumes is achieved by statin therapy (Banach et al. 2015 ). Dual antiplatelet therapies using cyclooxygenase inhibitors such as aspirin and P2Y12 inhibitor such as clopidogrel are first-line treatments for prevention of CVDs, which aim to reduce clot formation and platelet aggregation (Kapil et al. 2017 ). There is a requirement for improvement in these treatments, primarily due to the risks associated with taking antiplatelet therapy which significantly adverse side effect profiles, and poor patient compliance (Harrington et al. 2003 ). In addition to this, some patients do not respond well to antiplatelet therapy, which has a negative effect on their long-term prognosis. Studies have demonstrated that patients who have suffered an acute myocardial infarction but have a low response to clopidogrel are at increased risk of recurrent cardiovascular events at follow-up (Geisler et al. 2006 ). This supports the necessity for advancements in technology and an opportunity for nanomedicine (Fig. 2 ).

Use of nanotechnology for cardiovascular disease

Nanotechnologies for treatment

The field of nanomedicine comprises the diagnosis, treatment, and prevention of disease or injury to improve and maintain a good quality of life and health, with use of nanotechnology (Patil et al. 2008 ). For example, a domain of nanomedicine aims to control and manipulate biomacromolecular and supramolecular entities which are vital to human health, encompassing DNA, RNA, cell membranes, and lipid bilayers (Tomalia et al. 2007 ). Nanoparticles, in particular, are widely accepted as having physicochemical properties that improve biological function, such as a high surface energy due to their large surface area to volume ratio, wettability, reactivity, and roughness (Jiang et al. 2017 ). The British Standards Institute defines nanoparticles as microscopic particles with all three dimensions in the nanoscale, ranging from 1 to 100 nm (British Standards Institute 2011 ). Advancements in nanomedicine research have led to better ways to reduce toxicity, prolong the half-life of drugs, and reduce side effects through alteration of nanoparticle properties, whilst maintaining the particle biocompatibility (Gupta and Gupta 2005 ). Targeted drug delivery in treatment of disease using nanoparticles is possible through active or passive means: active targeting requires conjugation of the therapeutic agent to a tissue- or cell-specific ligand, whereas passive targeting involves coupling of the therapeutic agent to a high-molecular-weight polymer that has enhanced permeation and retention to vascular tissue (Patel and Bailey 2007 ).

A diverse range of nanotechnologies have been developed for biomedicine within the past 2 decades, each with their own unique properties and advantages. These include micelles, liposomes, dendrimers, nanoparticles, and the use of nano-coatings (De Jong and Borm 2008 ) (Fig. 3 ). Currently, therapeutic applications of nanotechnology within medicine are focused around cancer treatment and diagnosis (Sanna et al. 2014 ); however, the focus is shifting to other areas of therapeutics, such as cardiovascular medicine (Binsalamah et al. 2012 ) and antimicrobial resistance (Kumar et al. 2018 ). Table 1 summarises the main classes of technologies under exploration in this area.

Nanocarriers for the delivery of therapeutic agents: a micelle, b liposome, and c dendrimer

Liposomes form phospholipid bilayer structures, around 50–200 nm in size, with aqueous cores encapsulated within natural phospholipids, such as cholesterol (Akbarzadeh et al. 2013 ). As they possess qualities of both hydrophilicity and hydrophobicity, liposomes can be used as effective drug delivery systems. There are three classifications of liposomes, based on their size and number of bilayers. Variable size, method of preparation, surface charge, and lipid composition are all contributing factors to the properties displayed by a liposome (Sahoo and Labhasetwar 2003 ). Small unilamellar vesicles (SUV) have a single lipid bilayer; large unilamellar vesicles (LUV) are similar to SUVs, whereas multilamellar vesicles (MLV) have numerous bilayers (Sahoo and Labhasetwar 2003 ). Manipulation of the surface of liposomes can be undertaken via the addition of poly(ethylene glycol) (PEG), giving the carrier ‘stealth’-like properties (Immordino et al. 2006 ). The ‘stealth liposomes’ have a prolonged circulation time, reduced uptake, and reduced clearance by phagocytes or the liver (Sahoo and Labhasetwar 2003 ). Furthermore, antibodies or other targeting moieties can be attached to the liposomal surface to target specific areas (Levchenko et al. 2012 ). Due to the processes of platelet aggregation in myocardial infarction, atherosclerosis, and thrombosis, platelet-targeted liposomal drug delivery may prove to have potential therapeutic applications (Ruiz-Esparza et al. 2013 ). In regard to applications in cardiovascular medicine, liposomes have the potential to be utilised to treat peripheral artery disease and intermitted claudication. Currently, research into the liposomal drug delivery of prostaglandin E-1 (PGE-1), under the trade name Liprostin, is undergoing phase III clinical trials (Bulbake et al. 2017 ). PGE-1 possesses a wide range of pharmacological properties, including vasodilation, inhibition of platelet aggregation and leukocyte adhesion, and anti-inflammatory qualities (Gao et al. 2010 ). Encapsulation of PGE-1 within lipid nanoparticles reduced the degradation of PGE-1 and improved both the prolongation of the drug outcome and the anti-inflammatory effect (Gao et al. 2010 ), exhibiting real potential for PGE-1-loaded lipid nanoparticles in clinical application.

Liposomes have been designed for targeted treatment of thrombosis. Thrombosis, a blockage of the blood vessels, is associated with myocardial infarction (and stroke). Recently, liposomes carrying thrombolytic drug urokinase were reported; these were surface functionalised with a cyclic arginyl-glycyl-aspartic acid (cRGD) peptide (Zhang et al. 2018 ). cRGD peptides selectively bind onto the GPIIb/IIIa receptors on the active platelets conferring targeted delivery. In the cRGD, liposomes demonstrated similar effect to the free drug at 75% less drug dosage in a mouse mesenteric thrombosis model (Zhang et al. 2018 ).

Multiple studies have reported the encapsulation and delivery of berberine (Allijn et al. 2017 ; Lou et al. 2013 ; Sailor 2015 ). Berberine is a small fluorescent isoquinoline quaternary alkaloid which has proven to be useful at high doses as a cardio-protectant (Zhang et al. 2014 ) and for improvement of cardiac function (Huang et al. 2015 ). Berberine-loaded liposomes have been developed and tested for IL-6 secretion inhibition and cardiac function protection against adverse remodelling after MI in C57BL/6J mice (Allijn et al. 2017 ). In vivo, the liposomal berberine formulation significantly preserved cardiac ejection fraction 28 days post-MI by 64% compared with the unloaded liposomes and free drug. This study highlights the potential which liposomal berberine formulation possess as a potential treatment of adverse remodelling after MI.

The use of liposomes is relatively old compared to the polymer-based systems and it is likely that these systems will be clinically applicable at an earlier stage. However, as observed in other liposomal drug delivery applications, there are some disadvantages. These include the lack of long-term stability of these systems resulting in premature drug release, as well. In addition, increased excipient-to-drug ratios are often required making them more expensive and less effective than some of the polymer-based systems.

Polymeric nanoparticles

Polymeric nanoparticles have attracted particular interest in the nanomedicine field, due to the manipulative qualities of the materials and the potential of reabsorption in the body (Jiang et al. 2017 ). The route of delivery of polymeric nanoparticles is dependent on their site of action and the most minimally invasive method of getting them into systemic circulation. Intravenous injection is the most common method of administration; however, oral, mucosal, dermal, or transdermal administration is also viable (Elsabahy and Wooley 2012 ). Polymeric nanoparticles make up a large class of systems. These include solid nanoparticles, amphiphilic nanoparticles (forming micelles, vesicles, and rods), dendrimers, and star-shaped systems. All of these systems possess their own unique architecture and properties (Hoskins et al. 2012 ). In general, polymer-based systems are more cost-effective and easier to manufacture and scale up compared to liposomes with longer stability profiles.

There are a number of non-biodegradable polymers such as poly(methyl methacrylate) (PMMA), poly(acrylamide), poly(styrene), and poly(acrylates), (Banik et al. 2016 ); however, chronic toxicity has been observed in studies using these materials. This has led a focus on biodegradable polymers (Burman et al. 2015 ), examples of which include synthetic polymers such as poly(lactide) (PLA), poly(lactide-co-glycolide) copolymers (PLGA), poly(ε-caprolactone) (PCL), and 17 and poly(amino acids) (Elsabahy and Wooley 2012 ).

Expanded polytetrafluoroethylene (ePTFE) grafts are most commonly used to substitute blood vessels that have been damaged as a result of ischaemia or atherosclerotic plaques, re-establishing regular blood flow. A study was conducted using poly(lactic- co -glycolic acid) (PLGA) nanoparticles covalently bonded to ePTFE surfaces to test their therapeutic effects. Following oxidation of the ePTFE surface using H 2 O 2 /H 2 SO 4 , aminolyzation using 3-aminopropyl triethoxysilane was undertaken. The nanoparticles showed good stability on the ePTFE surface and the biocompatibility of the graft with mouse fibroblasts which demonstrated no substantial cytotoxicity (Al Meslmani et al. 2017 ), suggesting promise for the use of ePTFE for the treatment of CVD by incorporating antithrombotic drugs to the polymer grafts. Korin et al. ( 2012 ) studied the effects of biodegradable poly(lactic- co -glycolic) acid (PLGA) nanoparticles laden with the enzyme tissue plasminogen activator (tPA) which aids in the dispersion of clots. The nanoparticles were designed specifically to disintegrate and release the drug upon encountering high shear stress resulting from the narrowing of the surrounding vasculature (Korin et al. 2012 ). In in vivo studies, the complexes released tPA rapidly, thus dissolving the clot swiftly, which increased the survival rate following an induced pulmonary embolism (Korin et al. 2012 ). Furthermore, the results indicated that lower doses of tPA were required if it was incorporated in the polymeric grafts, suggesting a reduced side effect profile. This research clearly indicates that there are applications for this technology in the treatment of CVDs with the potential to transform cardiovascular medicine.

Quercetin (Qu) encapsulated within polymeric nanoparticles (Giannouli et al. 2018 ) or as solid drug nanoparticles (Kakran et al. 2012 ; Tefas et al. 2015 ) has been the subject of a number of investigations. Qu is an antioxidant drug which has shown to protect against CVDs. One recent study reported a novel poly(lactic- co -glycolic acid) (PLGA) loaded with Qu for atherosclerosis prevention (Giannouli et al. 2018 ). The particles showed promising encapsulation efficiencies and drug release profiles indicating these systems as possible formulations to protect against CVDs (Giannouli et al. 2018 ). Work is ongoing to further explore the in vitro and in vivo potential of these particles.

Micelles are amphiphilic structures with characteristic hydrophobic cores and hydrophilic shells, fashioned from either polymer- or lipid-based amphiphilic molecules (Gupta 2011 ). They form spontaneously due to a reduction in free energy arising from aggregation of the hydrophobic portions from the aqueous surrounding, and the creation of a micelle core stabilised with hydrophilic fragments exposed to the water (Mourya et al. 2011 ). As the concentration of an amphiphile increases in solution, an increase in the free energy of the system occurs due to the unfavourable conditions of the environment, as a result of interactions between water and the hydrophobic section of the amphiphile, which results in a decrease in the system entropy and structuring of the water in solution (Letchford and Burt 2007 ). Micelles are formed as the critical micelle concentration (CMC) is reached (Trinh et al. 2017 ). The formation of micelles at the CMC lessens the number of undesirable interactions with water as the hydrophobic moieties are effectively removed from the aqueous environment. The hydrophobic nature of the core allows for encapsulation of drugs, and the hydrophilic shell increases circulation time and systemic exposure to the micelle. Their small size and physicochemical properties allow for entry into tissues by crossing membranes (Eniola-Adefeso et al. 2012 ). Polymeric nanoparticles possess increased stability compared to low-molecular-weight surfactants and liposomes; this is due to their extremely low excipient:drug ratios. Hence, there is reduced chance of systemic toxicity resulting from the carrier vehicle but also makes them more cost-effective. The synthesis is highly controllable, and they can easily be tailor made to application, i.e., addition of targeting ligands or tracking molecules. Most commonly, the polymers used for micellar drug delivery are comprised of polyester or poly(amino acid) derivatives to form the hydrophobic region (Gaucher et al. 2005 ). Forms of polyester that are approved for use in human applications include poly(lactic acid) (PLA), poly(ɛ-caprolactone) (PCL), and poly(glycolic acid) due to their biocompatibility, biodegradability, and structural properties (Gaucher et al. 2005 ). Reports on the use of polymeric micelles for cardiovascular disease are rapidly emerging in the literature (Ma et al. 2017 ; Chmielowski et al. 2017 ; Singla et al. 2018 ; Wu et al. 2018 ).

An in vitro study demonstrated successfully the use of a block co-polymer micelle formed from poly(ethylene glycol)(PEG)- block -polycation carrying a (PEG- b -P[Asp(DET)]) side chain as a gene delivery vector for treatment of vascular disease, with efficient gene expression and low cytotoxicity in vascular smooth muscle cells (Akagi et al. 2007 ). To fully understand the in vivo outcome of gene transfer, the PEG- b -P[Asp(DET)] micellar formulation was implanted to a rabbit carotid artery and the degree of gene expression of plasmid DNA (pDNA) to the vascular region was determined. The carotid was wounded using a balloon catheter, inducing neointimal hyperplasia, and the encapsulated pDNA was administered. The presence of pDNA was detected using the FLAG sequence (p-MP-FLAG). The artery was stained with an anti-FLAG antibody to confirm the expression of the gene, the results of which confirmed that the micellar formulation was superior in comparison to the controls, homopolymer P[Asp(DET)], and branched polyethyleneimine (BPEI). The control vectors displayed a significant vessel occlusion by thrombus, which the micellar vectors studied did not exhibit (Akagi et al. 2007 ). The results of this study show that limitations with the current technology which uses viral vectors, such as antigenicity and oncogenicity, directs research towards use of non-viral vectors, since the safety and efficacy profiles of nanomicelles are superior (Kagaya et al. 2011 ).

Recently, an intelligent delivery system which responds to the oxidative atherosclerotic plaque microenvironment was reported (Wu et al. 2018 ). Block copolymer micelles were constructed using poly(ethylene glycol) and poly(propylene sulphide) (PEG-PPS). The micelles were used to solubilise andrographolide to decrease inflammatory response and the level of reactive oxygen species (ROS) for atherosclerosis treatment. Andrographolide is a plant-derived compound which exhibits cardiovascular protection effects via downregulation of inducible nitric oxide synthase expression and upregulation of endothelial nitric oxide synthase expression (Kajal et al. 2016 ). The stimuli responsive micelles formed resulted in rapid drug release triggered by the ROS, but also consumed the ROS by itself at the pathologic sites, resulting in the suppression of the pro-inflammatory cytokines (Wu et al. 2018 ). The authors concluded that the novel formulation demonstrated excellent therapeutic effects both in vitro and in vivo, and hence, it may have promising potential against atherosclerosis (Wu et al. 2018 ).

Cationic-mixed polymeric micelles have been developed for targeted delivery of lumbrokinase (LK) for the treatment of thrombosis (Pan et al. 2018 ). LK is a fibrinolytic enzyme originated from earthworm which has shown to possess antithrombotic action (Wang et al. 2013 ). The micelles consisted of a block copolymer of polycaprolactone- b -poly(2-(dimethylamino) ethyl methacrylate) (PCL-PDMAEMA), as well as a block copolymer of methoxy polyethylene glycol- b -polycaprolactone (mPEG-PCL) missed with a block copolymer of polycaprolactone- b -polyethylene glycol with an RGD peptide conjugated (PCL-PEG-RGDfk) forming a treatment known as LKTM (Pan et al. 2018 ). The formulations were tested in vivo in a thrombosis model in mice. The study showed that those mice treated with LKTM exhibited a significantly shorter tail bleeding time compared to those treated with LK alone or the LK micelles without targeting, hence, suggesting that the novel LKTM had effectively reduced the bleeding risk (Pan et al. 2018 ).

Other mixed micelle systems reported include the blending of different Pluronic ® mixtures (F127 &P123) for the solubilisation of olmesartan medoxomil (OLM) (El-Gendy et al. 2017 ). OLM is an antihypertensive drug with poor aqueous solubility which results in low bioavailability (Norwood et al. 2002 ) OLM was loaded into mixed micelles carriers to overcome this physicochemical barrier. Three drugs: Pluronic ® mixture ratios (1:40, 1:50, and 1:60) and various F127:P123 ratios were prepared. The study showed that the mixed micelles were capable of up to 43% release efficiency compared to 35% in the drug suspension (El-Gendy et al. 2017 ).

The term dendrimer stems from the Greek ‘dendron’, meaning tree, accurately reflecting the structure of these repeatedly branched molecules (Crampton and Simanek 2007 ). The uniqueness of dendrimers stems from their multibranched, three-dimensional architecture, coupled with low polydispersity and great functionality (Sherje et al. 2018 ). There are many apparent advantages to the utilisation of dendrimers as non-viral vectors for therapeutic indications, as opposed to other nanotechnologies. Their high solubility, greater stability, minimal immunogenicity, and ability to facilitate effective delivery of drug molecules, DNA, and RNAs make them superior to other viral and non-viral counterparts (Mendes et al. 2017 ). One drawback to dendrimers is that they often possess highly charged exteriors due to their high number of branches at their surface all with their own surface charges; this can often result in either highly cationic or highly anionic nature and, if not fully addressed, can lead to toxicity issues (Jain et al. 2010 ).

The topology of dendrimers is classified as the focal core, multiple peripheral functional groups, and building blocks with a number of repeating units within the inner core (Jang and Aida 2003 ). The focal core within a dendrimer has been exploited to host chemical species within, due to the nanoscale environment generated through extensive branching. Second, dendrimers can display various, multiple functional groups on the periphery, allowing for a variety of interactions between other dendrimers and the surrounding molecular environment. Coupled with this, the repeated units permit flexibility within the dendrimer, allowing for the manipulation and encapsulation of drug molecules within (Jang and Aida 2003 ). The exclusivity of these properties to dendritic molecules gives rise to the possibility for their use as drug delivery systems. The improved efficacy and lower leakage percentages in dendrimers make them more suitable in various formulations, including oral, ocular, and transdermal, since the pharmacokinetic parameters for dendrimers are also promising (Yu et al. 2015 ).

Nitric oxide (NO) is a potent vasodilator, regulator of vascular cell proliferation, and maintains vascular homeostasis. Due to these effects, it can, therefore, play a key role in preventing atherosclerosis (Napoli et al. 2006 ). Studies have shown that there is potential for NO encapsulation within dendrimers as a targeted therapy for damaged tissue. Lu et al. ( 2011 ) reported that NO release was successful from poly(propylene imine) dendrimers, which shows promise in their potential uses as drug delivery systems (Lu et al. 2011 ). Dendrimers with potential as gene delivery agents for the treatment of CVDs have also been investigated, in an effort to control the upregulation of inflammation in targeted sites within insulted vasculature. Studies have shown that dendrimers carrying DNA plasmids enhanced survivability, stability, and viability of the gene within the nucleus (Gothwal et al. 2015 ), demonstrating viability as prospective therapeutic agents.

Recently, a dendrimer composed of poly(glutamic acid) and poly(ethylene glycol) (PEG) (Gn-PEG-Gn) was reported for the delivery of nattokinase (NK) (Zhang et al. 2017 ). NK is a thrombolytic drug, which possessed high safety levels and low side effects, however, extremely sensitive to degradation from the external environment. Hence, careful formulation is required for the drug to be clinically useful. The NK-loaded G3-PEG-G3 dendrimer formed exhibited excellent thrombolytic activity in vitro, and further work is ongoing to elucidate the in vivo potential of this system (Zhang et al. 2017 ).

Another study reported the development of a poly(amidoamine) (PAMAM) dendrimer-based system as drug carriers for combined delivery of ramipril (RAPL) and hydrochlorothiazide (HCTZ) (Singh et al. 2017 ). RAPL is an antihypertensive drug and HCTZ is a diuretics drug, both of which are used in the treatment of high blood pressure (de Leeuw and Birkenhäger 1987 ; Roush and Sica 2016 ). At 0.8% (w/v), dendrimer concentration the RAPL solubility was increased 4.91-fold with amine-terminated dendrimer, whilst the optimal dendrimer for HCTZ solubilisation (3.72-fold) was with carboxy-terminated functional groups. The novel formulations resulted in more rapid dissolution compared to the free drugs. Hybrid formulations showed similar dissolution patterns compared to the single drug-loaded dendrimer. The authors concluded that the formulation strategy held promise for application and more work is ongoing to push this technology forward (Singh et al. 2017 ).

Gel nanoparticles

The least common on the polymer-based particles are the gelated nanoparticles. These nanoparticles form at with increased polymer concentration into hydrogel matrices into which drugs can be incorporated. These systems allow for a greater retardation of drug release and greater long-term stability (Hamidi et al. 2008 ).

Regeneration of the ischaemic heart through utilisation of vascular endothelial growth factor (VEGF)-loaded core/shell nanoparticles and their gelation behaviour was monitored to assess vascular cell regeneration (Oh et al. 2010 ). The core of the gel nanoparticle was constituted from lecithin containing VEGF, with a shell comprising of Pluronic F-127 (poly(ethylene oxide)-poly(propylene oxide)-poly(ethylene oxide) triblock copolymer) (Oh et al. 2010 ). The temperature-induced gel was formed when the nanoparticles were added to a solution containing propylene glycol monocaprylate at body temperature. Gelated and non-gelated nanoparticles were added to the in vivo sample and functional analysis tests were conducted on the myocardial tissue. The results demonstrated that there was a greater improvement to heart function (cardiac output and ejection fraction) with gelated VEGF-loaded core/shell nanoparticles as compared to non-gelated nanoparticulates (Oh et al. 2010 ).

Nano-coated stents

Coronary artery bypass graft (CABG) and percutaneous transluminal coronary angioplasty (PTCA)/percutaneous coronary intervention (PCI) are invasive therapies used commonly within clinical practice to relive blockages in myocardial vasculature. CABG involves major cardiac surgery, whereas PTCA is a non-surgical procedure, whereby an artery is widened using a balloon and, in some instances, is held open using a stent (NICE 2008 ). The stents used are composed of thin wire mesh, which is used to retain sufficient blood flow through the previously occluded artery, thus preserving its patency (Fig. 4 ).

Use of a stent to widen an occluded blood vessel

The overbearing issue with the use of stents in reperfusion of cardiac tissue leads to a significant risk of restenosis within the vasculature. Restenosis occurs due to overdistention of the diseased vessel, resulting in endothelial disruption, internal elastic laminal fracture, and medical dissection (Bennett 2003 ). A number of processes contribute to in-stent stenosis including elastic recoil, relocation of axially positioned plaques, and negative remodelling. Neointima formation is the major cause of in-stent stenosis, whereby platelets, mitogens, and cytokines aggregate. Cell proliferation results and synthesis of the extracellular matrix and collagen lead to the creation of the neointima (Bennett 2003 ).

A method that can be employed to reduce the incidence of in-stent stenosis is the use of drug-eluting stents (DES), which release the incorporated drug to the locality of its placement. The stents can be coated in various polymers, such as poly(lactic- co -glycolic acid) (PLGA), polyethylene glycol (PEG), and polycaprolactone (PCL) (Acharya et al. 2012 ). The use of polyhedral oligomeric silsesquioxane poly(carbonate-urea) urethane (POSS-PCU) polymer with attached anti-CD34 antibodies was studied as a possible nanocomposite polymer to coat bare metal stents, in an attempt to improve endothelial revascularisation (Tan et al. 2013 ). The results of this study indicated that POSS-PCU had advanced biocompatibility and haemo-compatibility in vitro. This is further supported by research into the use of POSS-PCU in the field of heart valve replacements. Synthetic valves made of POSS-PCU nanocomposites have been successfully tested, demonstrating their biocompatibility and biostability against oxidation, hydrolysis, and enzymatic attack in vitro and in vivo (Kidane et al. 2009 ). However, it has also been demonstrated that the use of drug-eluting stents in animal models led to delayed arterial healing and promoted inflammation at the site of the overlap in the implanted stents. Overlapping paclitaxel-eluting stents (PES) showed a greater degree of fibrin deposition and neointima formation, raising concerns over safety in human subjects, drug toxicity, and further systemic complications arising from sites of overlap (Finn et al. 2005 ). Use of POSS-PCU as a nanocomposite coating on stents has been taken forward into human trials. The first-in-man trial (FIM) studied the efficacy and long-term implications of non-polymeric drug-coated stents (DCS) in patients with de novo coronary artery disease, with follow-up times of 4 months, 12 months, and 5 years. Notably, at 4 months, there was a significantly lower rate of lumen loss with the DCS than PES. The results demonstrated no inferiority to PES in the rate of lumen loss, a subclass of neointimal hyperplasia (Costa et al. 2016 ). The use of nano-coatings on stents is being trialled currently in the United States: The COBRA PzF Stenting to Reduce the Duration of Triple Therapy in Patients Treated With Oral Anticoagulation Undergoing Percutaneous Coronary Intervention trial is ongoing and aims to investigate if the COBRA PzF stent with a polyzene-F nano-coating can successfully reduce bleeding compared to DES, through reducing the duration of oral anticoagulation therapy to 14 days, rather than the current 6 months, in patients undergoing PCI (US National Library of Medicine 2018 ). Polyzene-F is a new generation nano-coating based on cobalt–chromium, designed to be highly biocompatible and easily deliverable (CeloNova Biosciences 2018 ).

Stents and drug-eluting stents are one of the most established technologies for cardiovascular disease treatment. However, as discussed, there are problems in their usage, and although nanotechnology has been employed in their coating to reduce occurrence of rejection in vivo and restenosis, there is a move away from these technology towards flexible polymer scaffolds.

Nanoparticles for diagnostic imaging

Nanoparticles also have a place in medicine to fulfil an unmet need in the field of imaging. Nanoparticles offer real potential in medical imaging due to their good bioavailability profiles, versatility of use, and ease of manipulation. Nanoparticles offer adaptable qualities to generate multimodal and multifunctional imaging vehicles with modifiable features, allowing for the integration of contrast materials, ligands, and functional groups (Stendahl and Sinusas 2015 ). Cardiovascular magnetic resonance (CMR) is a non-invasive method for the detection of inflammation: Due to the pathophysiology of coronary heart disease, inflammation is a major complication of the illness, and early detection through the utilisation of these methods can improve prognosis. CMR relies on the observation of changes in myocardial tissue configuration (Bietenbeck et al. 2015 ). Gadolinium shows the composition of plaques, including the details of the fibrous cap, necrotic core (Cai et al. 2005 ), macrophage content, and extent of plaque revascularisation (Kampschulte et al. 2004 ). Furthermore, contrast-enhanced CMR (ceCMR) can be employed for the recognition of myocardial oedema, necrosis, and fibrosis, using gadolinium or fluorine-19 ( 19 F) contrast agents (Friedrich et al. 2009 ). Healthy myocardium clears the contrast agent rapidly, while damaged tissues retain the dye (Bietenbeck et al. 2015 ). T1-weighted imaging established CMR imaging as a technique, whereby gadolinium-contrast agent was detected in > 90% of the myocardium following insult as a result of induced MI in in vivo models, successfully demonstrating the accuracy of CMR as a diagnostic tool (Kim et al. 1996 ). Such advances in diagnostic imaging will also allow a better patient-centred therapy, by clearer identification of atherosclerotic plaques and the extent of atherosclerosis to guide the dosage of statins required to have a better prophylactic effect, for example.

Gold nanoparticles have also shown great promise in both cardiovascular medicine and oncology imaging. Gold is a noble metal and essentially an inert material which is stable and biocompatible (Thakor et al. 2011 ). Gold particulates occur in a variety of shapes and sizes, including rods, spheres, cages, stars, crescents, and prisms, with sizes varying from 1 to 500 nm. Gold particles are excreted renally. The elimination rate through glomerular filtration can be modified by attaching PEG chains to the nanoparticle surface to increase hydrophilicity and circulation time of the nanoparticle (Varna et al. 2018 ). Gold nanoparticles can be used in cardiovascular optical imaging: photoacoustic imaging is based on detection of both ultrasound and optical imaging, whereby light is used a source of excitation and ultrasound detects sound waves generated by the target, generating images of optical absorption (Chen et al. 2014 ).

Future perspectives

Medical technology and treatments for CVDs, in particular, have significantly advanced in an aim to increase the quality of and prolong life. It is imperative to find better solutions for the treatment of CVD as it is estimated that only 15% of current guidelines for practice are supported by high-quality evidence (Califf 2016 ). Better lifestyle, diet, medial intervention, earlier detection, prevention strategies, and improved standard of living have all contributed to better prognoses. A large proportion of all premature deaths under the age of 75, within persons whom are residents of the European Union are due to CVDs. Therefore, it is imperative that solutions are sought quickly to effectively treat this pandemic, with the goal to prevent around 80% of all cardiovascular diseases through the use of nanotechnologies (Letourneur et al. 2014 ). As of 2014, a study showed that there were 122 nanomedicines going through clinical development, of which 17 had made it to phase II or III trials (Letourneur et al. 2014 ). Of those in progress, 70 products were oncology based, 19 for infectious diseases, and only 7 for cardiovascular medicine (Letourneur et al. 2014 ). This highlights the desperate need for greater research and development in this field. There are a number of current, ongoing trials into the therapeutic use of nanotechnology in cardiovascular medicine, notably, the NanoAthero project, funded by the European Commission. The objectives of this phase I trial include successfully undertaking thrombus imaging and treating vulnerable plaques using novel carriers (European Commission 2017 ). Further to this, Habib et al. are currently studying the possibility of diagnosing heart failure using breath samples and sensors based on nanomaterials (US National Library of Medicine 2018 ). Further clinical trials are being conducted in the uses of nanotechnology in drug-eluting stents in comparison to bare metal stents: The research has a participant size of 8000 and thus far has demonstrated the promising results (US National Library of Medicine 2018 ).

The evidence presented within this review demonstrates that nanotechnology does hold potential for application in the treatment of CVD, demonstrated by translational clinical trials. With increasing investment into the field of nanotechnology and suitable infrastructure worldwide, it is only a matter of time before nanomedicines, nanomaterial devices, and other related technologies successfully complete the rigorous clinical trial process and come onto the market. A certainty is that nanotechnology holds promise to improve patient health and well-being, and that any progression on the current therapies will positively impact the lives of patients globally. To have the greatest possible impact in medicine, more in vivo studies will need to be conducted and clinical trials commissioned to fully understand the behaviours of nanoparticulates systemically. As the future in therapeutics is becoming more geared towards personalised medicine, nanotechnology may be best placed to achieve this intended goal to tailor treatment to individual disease states. Furthermore, increasing healthcare costs mean that it is imperative to seek alternatives to the existing pharmacological and surgical management, to curb these exponential increases. However, there is substantial evidence to support the concept that nanotechnology is yet to make its full impact to revolutionise medicine.

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Chandarana, M., Curtis, A. & Hoskins, C. The use of nanotechnology in cardiovascular disease. Appl Nanosci 8 , 1607–1619 (2018). https://doi.org/10.1007/s13204-018-0856-z

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Received : 03 May 2018

Accepted : 10 August 2018

Published : 16 August 2018

Issue Date : October 2018

DOI : https://doi.org/10.1007/s13204-018-0856-z

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Patients’ knowledge on cardiovascular risk factors and associated lifestyle behaviour in Ethiopia in 2018: A cross-sectional study

Roles Conceptualization, Formal analysis, Methodology, Project administration, Writing – original draft, Writing – review & editing

* E-mail: [email protected]

Affiliations Adelaide Nursing School, The University of Adelaide, Adelaide, Australia, College of Health and Medical Sciences, Haramaya University, Harar, Ethiopia

Roles Conceptualization, Methodology, Supervision, Writing – review & editing

Affiliation Adelaide Nursing School, The University of Adelaide, Adelaide, Australia

Roles Conceptualization, Investigation, Methodology, Supervision, Writing – review & editing

Affiliations Royal Adelaide Hospital, College of Nursing and Health Sciences, Flinders University and Centre for Heart Rhythm Disorders, Adelaide, Australia, Department of Medical and Health Sciences, Linköping University, Linköping, Sweden

Lemma B. Negesa,
Judy Magarey,
Philippa Rasmussen,
Jeroen M. L. Hendriks

Published: June 4, 2020
https://doi.org/10.1371/journal.pone.0234198
Reader Comments

Cardiovascular disease (CVD) is posing a major public health challenge globally. Evidence reports significant gaps in knowledge of cardiovascular risk factors among patients with CVD. Despite the growing burden of cardiovascular disease in developing countries, there is limited data available to improve the awareness of this area, which is crucial for the implementation of prevention programs.

A cross-sectional survey was conducted in two referral hospitals in Eastern Ethiopia from June-September 2018. Outpatients with a confirmed diagnosis cardiovascular conditions were eligible for participation in the study. A convenience sampling technique was used. The primary outcome of the study was knowledge of cardiovascular risk factors among patients with cardiovascular disease. The knowledge of cardiovascular disease risk factors was measured using a validated instrument (heart disease fact questionnaire). A score less than 70% was defined as suboptimal knowledge. Multivariable linear regression was used to examine the relationship between knowledge of cardiovascular risk factors and explanatory variables.

A total of 287 patients were enrolled in the study. Mean age was 47±11yrs and 56.4% of patients were females. More than half of patients (54%) had good knowledge on cardiovascular risk factors (scored>70%), whilst 46% demonstrated suboptimal knowledge levels in this area. Urban residency was associated with higher cardiovascular risk factors knowledge scores, whereas, never married and no formal education or lower education were identified as predictors of lower knowledge scores. There was no statistically significant association between knowledge of cardiovascular risk factors and actual cumulative risk behaviour.

Almost half of CVD patients in Ethiopia have suboptimal knowledge regarding cardiovascular risk factors. Residence, education level and marital status were associated with knowledge of cardiovascular risk factors. Implementation of innovative interventions and structured, nurse-led lifestyle counselling would be required to effectively guide patients in developing lifestyle modification and achieve sustainable behaviour change.

Citation: Negesa LB, Magarey J, Rasmussen P, Hendriks JML (2020) Patients’ knowledge on cardiovascular risk factors and associated lifestyle behaviour in Ethiopia in 2018: A cross-sectional study. PLoS ONE 15(6): e0234198. https://doi.org/10.1371/journal.pone.0234198

Editor: Baltica Cabieses, Universidad del Desarrollo, CHILE

Received: February 4, 2020; Accepted: May 20, 2020; Published: June 4, 2020

Copyright: © 2020 Negesa et al. This is an open access article distributed under the terms of the Creative Commons Attribution License , which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Data Availability: Data cannot be shared publicly because of ethical issues. Data are available from the University of Adelaide, Adelaide Nursing School (contact via [email protected] ) for researchers who meet the criteria for access to confidential data.

Funding: The study was supported by University of Adelaide.

Competing interests: The authors have declared that no competing interests exist.

Introduction

Cardiovascular disease (CVD) remains a global major cause of death [ 1 ] and represents a significant disease burden in populations around the world. The global burden of disease studies reported an estimated 422.7 million cases of CVD, causing 17.92 million deaths worldwide in 2015 [ 1 ]. Developing countries are facing a high burden of CVD whilst awareness of disease and associated risk factors is limited [ 2 , 3 ]. Those living in poverty and especially those in low-income countries are significantly more impacted by CVD [ 4 ]. Moreover, findings show that the prevalence of CVD is increasing and posing a public health challenge in developing countries [ 1 , 5 ]. High blood pressure is of major influence in the increasing CVD burden in these countries [ 1 ]. For most patients with hypertension it is uncontrolled which causes further cardiovascular (CV) complications [ 6 ]. Hypertension affects more than 1.3 billion people worldwide and one third of adults have the condition [ 7 , 8 ]. The number of adults with hypertension in 2025 is predicted to increase by about 60% [ 9 ]. Moreover, the total number of individuals with hypertension is increasing rapidly to epidemic levels with a projected 125.5 million individuals affected by 2025 in Sub-Saharan Africa [ 10 ].

From an epidemiologic view on disease prevalence, Ethiopia is in epidemiologic transition from predominantly infectious diseases to chronic diseases. CVD is a major public health challenge in Ethiopia. The overall prevalence of hypertension among the Ethiopian population is 19.6%, and is higher among the urban population (23.7%) [ 11 ]. In 2015, ischemic heart disease was the first leading causes of age standardised death rates and fourth leading causes of age standardized disability adjusted life years with rates of 141.9 and 2535.7 per 100,000 population respectively [ 12 ]. The increasing prevalence of CVD in developing countries is related to unhealthy lifestyle behaviours. Except few region based studies, evidence on CV risk behaviours is scarce in Ethiopia. Findings from the Southern part of the country show that 10.8% of CV patients smoke cigarettes, 12.1% drink alcohol and 73.9% don’t do any physical activity [ 13 ]. A study performed in the capital of Ethiopia reported 68.6% of hypertensive patients don’t exercise, 14.1% smoke cigarette, 25.2% drink alcohol and 30.9% don’t adhere to healthy diet [ 14 ].

According to the health belief model, knowledge regarding health behaviour is a strong modifying factor for healthy lifestyle, however it should be combined with other factors such as good perceptions, positive health attitudes and many other conditions such as socioeconomic factors [ 15 ]. Studies also have revealed knowledge of specific risk factors is associated with healthy behaviour, however, knowledge alone does not motivate behavioural change [ 16 – 19 ]. The Heart disease fact questionnaire which was designed and validated by Wagner et al. (2005) and has been commonly used for the assessment of knowledge of CV risk factors knowledge [ 20 ].

There is limited research regarding the knowledge of CV risk factors in developing countries [ 3 , 21 – 23 ]. The majority of adults in Sub-Saharan Africa fail to name even one CV risk factor, [ 22 ] and in Nigeria almost 50% have poor knowledge about CV risk factors [ 3 ]. In Cameroon, this knowledge level is also suboptimal, such that 36% of adults are unaware of CV risk factors [ 21 ]. Nevertheless, in South Africa, most adults are aware that cigarette smoking and excessive alcohol consumption are risk factors for CVD [ 24 ]. The level of education and place of residence have a significant influence on health literacy. It has been reported that higher education levels correlate with a better knowledge of CVD, less number of risk factors and changes in health related behaviour [ 22 , 25 ].

Gaps in evidence on CVD and risk factors form a barrier to effective prevention of cardiovascular conditions. Thus, evidence on patients’ knowledge of CV risk factors is paramount in primary and secondary prevention of CVD [ 26 ]. However, research to reduce the existing evidence gap and the increasing burden of CV risk behaviours in developing countries is scarce. Few studies conducted so far in Ethiopia focussed at describing the high burden of CVD, none of the studies explored CV patients’ knowledge of CV risk factors. Evidence on patients’ knowledge of CV risk factors has vital importance for evidence based health policy and help to design customised interventions. Therefore, the purpose of this study was to assess knowledge of cardiovascular risk factors and associated factors among patients with CVD.

Design, settings and sampling

A cross-sectional survey was conducted in two main referral hospitals in East- Ethiopia, Hiwot Fana Specialised University Hospital and Dilchora Referral Hospital. This study was conducted in chronic follow up units of the two hospitals. The chronic follow up unit provides regular outpatient care for patients with chronic conditions such as hypertension, heart failure, myocardial infarction and diabetes mellitus. The clinic specifically focusses on providing follow up services which include treatment of CVD and counselling of patients to achieve healthy lifestyle behaviours. During the study period (June to September 2018), a total of 820 patients with CVD attended the follow up care in the two participating hospitals.

Patients with a confirmed diagnosis of hypertension, heart failure, or myocardial infarction, in the age range between 18-64yrs were eligible for participation in the study. Patients with congenital heart disorders, rheumatic heart disease, infectious heart disease and inflammatory heart disease were excluded. Mentally ill patients and those with a disability (hearing and talking impairment) which would hinder their ability to participate in the study were also excluded.

The sample size was determined using single population proportion formula with the following assumptions: 95% confidence level, 1.96 (Zα/2), 50% proportion, 5% degree of precision (d), and N (820) total CVD patients attending chronic follow up units of the two hospitals. Based on this assumption and using finite correction, the sample size was 261, and predicting a 10% nonresponse rate, the final sample size was 287. The total 287 calculated sample was allocated for the two hospitals proportional to their total number of patients attending each chronic follow up unit. A convenience sampling was used to select study participants.

Participants were given overview of the study by nurse or physician who were working in follow up unit, then, they were referred to poster information which was posted outside the follow up unit. The poster information contained title of the study, researchers name, eligibility criteria and contact address (mobile phone and email) of data collector. Voluntary participants contacted data collector through phone address or the data collector approached the patients and provided additional information using participant information sheet upon their exit from follow up unit. Recruitment of the patients took place from June to September 2018.

Ethical considerations

Ethical approval was obtained from the Human Research Ethics Review Committee, University of Adelaide, Australia, and the Institutional Health Research Ethics Review Committee, Haramaya University, Ethiopia before commencing the study. Informed and written consent was obtained from each participant prior to participation in the study.

Data collection and tools

Data were collected using three validated tools, the World Health Organisation (WHO) STEPs instrument, International physical activity questionnaire and the Heart Disease Fact Questions. The WHO STEPs instrument follows a stepwise approach to chronic disease risk factor surveillance in individuals aged 18–64 years [ 27 ]. Ethiopian Public Health Institute adapted the WHO STEPs instrument to Ethiopian context by including khat chewing and the use of local alcohol and cigarette products in the risk behaviour assessment. Locally adapted version of WHO STEPs instrument was translated and used to assess sociodemographic variables and CV risk behaviours including cigarette smoking, alcohol consumption, khat chewing and fruit and vegetable consumption. The international physical activity questionnaire was used to assess physical activity [ 28 ].

The primary outcome of the study was knowledge of cardiovascular risk factors among patients with cardiovascular disease. The ‘Heart Disease Fact Questionnaire’ (HDFQ) was used to assess the patient’s knowledge of CV risk factors. The HDFQ showed good content and face validity, and demonstrated adequate internal consistency, with Kuder–Richardson-20 formula of 0.77 [ 20 ]. The English version of both the international physical activity questionnaire and the HDFQ were translated into local languages and were back translated into English by language experts to check reliability of the translations. Two nurses who have bachelor qualifications conducted data collection through face to face interviews with patients.

Current smoking, khat chewing and alcohol drinking were defined as use within the last 30 days. Inadequate consumption of fruit and vegetables was defined as consumption of less than five servings (equivalent to 400g) of fruit and vegetables per day [ 27 ]. Physical activity (PA) level was measured by computing Metabolic Equivalent (MET)-minutes per week for vigorous intensity PA, moderate intensity PA and walking. Vigorous intensity PA was defined as requiring a large amount of effort (>6 METs) and causes rapid breathing and a substantial increase in heart rate. Moderate intensity PA was defined as requiring a moderate amount of effort (3–6 METs) and noticeably acceleration in heart rate. Low level PA was defined as attaining less than 600 MET-minutes per week [ 29 ].

Actual cumulative risk behaviour was obtained from the five lifestyle risk behaviours assessed among the patients, (smoking, alcohol drinking, khat chewing, inadequate consumtion of fruit and vegetables and physical inacativity), with a maximum score of 5 (all risk behaviours present) and a minimum score of zero (none of the risk behaviours present).

The patient’s knowledge of CV disease risk was measured using the HDFQ [ 20 ] on a two point scale with “0” = wrong answer and “1” = correct answer. Then, it was scored by adding the correct scores of all the items for each participant. A higher score was used to indicate a better knowledge of CV risk factors. The score out of 100 was categorised as good/optimal knowledge (score ≥70%), fair knowledge (score between 50% and 69%) and poor level of knowledge (score <50%). A score < 70% was categorised as suboptimal knowledge [ 3 ].

Statistical analysis

The data was entered on Epidata version 3.0 and were checked for completeness and consistency. Statistical analysis was performed by using IBM SPSS statistics version 25. The univariate analysis was reported as proportion, percentage, and frequency, and continuous data were reported as mean and standard deviation. A normality test was done for continuous variables age and knowledge of CV risk factors. A linear regression model was used to assess association between knowledge of CV risk factors and independent variables. First, associations between knowledge and predictors were analysed by means of bivariate linear regression to identify factors associated with the dependent variable. Then, those variables with a P -value < 0.2 on bivariate linear regression were included in a multivariable linear regression model to test for significant associations. The magnitude of the association between different independent variables in relation to the dependent variable was measured using estimates and 95% confidence intervals, and P -values < 0.05 were considered to be statistically significant.

Characteristics of the participants

A total of 287 patients diagnosed with CVD who attended the chronic follow up care were enrolled in the study; 115 patients from Hiwot Fana Specialised University Hospital and 172 patients from Dilchora Referral Hospital. Mean age was 47 years (±11 SD) and 56.4% of patients were of the female gender. The majority (70.7%) of the patients were diagnosed with hypertension. More than half of the patients had a low level of education. The sociodemographic characteristics of the participants are depicted in Table 1 .

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https://doi.org/10.1371/journal.pone.0234198.t001

Knowledge of cardiovascular risk factors

The mean percentage HDFQ score was 70.5% (±15.3). Overall, 155 patients (54%) had optimal knowledge of risk factors (scored ≥70%), whereas, the remaining 132 patients (46%) had sub-optimal knowledge ( Fig 1 ). The majority of patients demonstrated significant knowledge about facts that age, 228 (79.4%), smoking 280 (97.6%), being overweight 262 (91.3%) and high blood pressure 235 (81.9%) are risk factors for cardiovascular disease. At the same time patients had deficient knowledge about the fact that family history of heart disease 249 (86.8%) and diabetes 184 (64.1%) are also risk factors. Almost one fifth 55 (19.2%) did not understand that keeping blood pressure under control reduces the risk of developing cardiovascular disease, 52 (18.1%) were unable to identify eating fatty food affects blood cholesterol level, and 115 (40.1%) assume only exercising at a gym or in an exercise class lower a chance of developing cardiovascular disease. Table 2 shows the percentage of patients who answered the heart disease fact questions correctly.

https://doi.org/10.1371/journal.pone.0234198.g001

https://doi.org/10.1371/journal.pone.0234198.t002

Actual cumulative risk behaviour and knowledge of cardiovascular disease risk factors association

Through our previous study [ 30 ], we have assessed five CV risk behaviours, i.e. smoking, alcohol drinking, khat chewing, fruit and vegetable intake and physical activity. None of the patients met the WHO recommendation for fruit and vegetable consumption (more than five serving daily), 148 (51.6%) were physically inactive (attained less than 600 MET-min per week), 57 (19.9%) were current khat chewers, 54 (18.8%) were current alcohol drinkers and 3 (1%) were current smokers. Almost one-third 86 (30%) them had one risk behaviour, more than half 149 (51.9%) had two risk behaviours, and 43 (18.1%) had three or more risk behaviours. Out of the total recruited patients, 201 (70%) had multiple risk behaviours (two or more behaviours).

Regarding bivariate linear regression analysis age, sex, residence, ethnicity, marital status, education level and number of actual risk behaviours got p<0.2 ( Table 3 ). These variables were taken in to multivariable linear regression model to identify independent predictors of CV risk factors knowledge.

https://doi.org/10.1371/journal.pone.0234198.t003

In the multivariable linear regression analysis, knowledge of CV risk factors was significantly associated with place of residence, level of education and marital status. There was a statistically significant association between knowledge of CV risk factors and residence (P < 0.001). Urban residents had 12.84 units higher mean knowledge score than rural residents (β = 12.84, 95% CI 6.91 to 18.77; P < 0.001). In addition, level of education is associated with knowledge of CV risk factors (P < 0.001), those who had no formal education had -18.80 units lower mean knowledge score compared to those who completed college or university (β = -18.80, 95% CI -24.76 to -12.85; P < 0.001). Those who attained less than primary school education had -12.02 units less knowledge score compared to those who completed college or university (β = -12.02, 95% CI -17.63 to -6.40; P < 0.001). There was also a statistically significant association between knowledge and marital status (P < 0.001). Those who were never married had -14.01 units lower mean knowledge score than those who were currently married (β = -14.01, 95% CI -20.71 to -7.29; P < 0.001). There was no statistically significant association between knowledge of CV risk factors and actual cumulative risk behaviour (P = 0.076) or age (P = 0.718) or sex (P = 0.259) or ethnicity (P = 0.196) ( Table 4 ).

https://doi.org/10.1371/journal.pone.0234198.t004

This study examined the level of knowledge of cardiovascular risk factors and associated factors among known CV patients who were attending chronic follow up care at two public referral hospitals in eastern Ethiopia. The study demonstrates that almost half of CVD patients have suboptimal knowledge regarding CV risk factors which may impede secondary CV prevention if effective interventions are not implemented. Thus, the findings of this study warrant the need of improved preventive interventions to achieve optimal knowledge in the general population.

Knowledge of CV risk factors among CVD patients was unsatisfactory, and about half of the patients have suboptimal knowledge, which is in line with existing findings reported from India and United Arab Emirates [ 16 , 31 ]. However, the mean CV risk factors knowledge score in the current study (70.5%) is higher compared to finding from Nigeria (48.6%), and this could be due to difference in population characteristics [ 3 ]. Consistent with the finding of this study, a systematic review showed low level knowledge and awareness of CVD and associated risk factors among populations in Sub-Saharan Africa [ 22 ]. The possible reasons for the suboptimal knowledge may be attributed to a lower level of educational attainment of the patients, poor patient counselling during follow up care appointment and absence of intensive lifestyle counselling programs. Moreover, low health literacy may be due to lack of effective patient counselling methodologies that fits the cultural and sociodemographic context and poor health information seeking behaviour of patients. Implementation of innovative health education strategies may help to improve health literacy for CV patients and for the general population as well.

Residence, education level and marital status were associated with knowledge of cardiovascular risk factors, which mirrors that social, cultural and economic factors are major determinants of awareness and health behaviour change [ 32 ]. In line with the finding of the current study, numerous studies [ 25 , 33 , 34 ] have revealed higher education is associated with better health literacy. A review conducted in Sub-Saharan Africa reported that place of residence is an important determinant of knowledge of cardiovascular risk factors, i.e. urban residence is associated with improved knowledge of CV risk factors [ 22 ]. In Ethiopia, rural residents attain lower educational level and have poor access to health information as compared to urban residents who relatively have better health literacy. Thus, low knowledge of CV risk factors in rural residents could be due to their lower education attainment. Moreover, the current study shows that those who were never married have lower levels of knowledge regarding CV risk factors compared to those who were married. Consistent with this, Manfredini et al. reported that being married is associated with, lower risk factors, better knowledge and better CV health status [ 35 ].

Studies from Nigeria, Germany and Luxembourg reported that a higher level of education is associated with healthy lifestyle and appropriate self-care behaviours [ 25 , 36 , 37 ]. In addition, evidence from a review revealed that a lower educational level is associated with lower knowledge of CV risk factors, and this also concurs with the finding of the current study [ 22 ]. Findings from Pakistan also support those of this study where lack of formal education is associated with lower knowledge of cardiovascular disease risk factors [ 38 ]. However, about one-third of the patients in the current study had no formal education, thus, improving literacy in developing countries is vital in tackling the emerging burden of chronic diseases, in particular, CVD and its associated lifestyle behaviours, as demonstrated previously [ 22 ].

The prevalence of alcohol drinking, inadequate fruit and vegetable consumption and physical inactivity in the current study is comparable to findings from Addis Ababa [ 14 ], Kenya [ 39 ] and Nigeria [ 40 ]. However, the rate of smoking in this study is lower compared to findings from Addis Ababa [ 14 ], Ghana [ 41 ], Kenya [ 42 ] and Uganda [ 43 ], and this could be due to differences in sociocultural characteristics of participants.

According to the Health Belief Model, knowledge of health behaviour is an important determinant of adherence to healthy lifestyle behaviours. Though, knowledge alone is not sufficient, and patients’ perceptions and attitudes of health behaviours are also important predictors of health lifestyle behaviours. The current study demonstrated that occurrence of actual cumulative risk behaviours is not associated with knowledge of CV risk factors. Thus, as patients’ perceptions and attitudes of CV risk factors are important determinants of behaviour change, these need to be explored in further research. Consolidating this, Tran et al (2017) states a high level of knowledge of CV risk factors is not sufficient to reduce cardiovascular risk, however, improving the perception of adults regarding CV risk factors plays an important role in reducing long term cardiovascular risk [ 23 ]. Nevertheless, the finding of Alzaman et al. which states awareness of modifiable CV risk factors is positively associated with health behaviour for adult patients [ 44 ] is inconsistent with the finding of the current study. A potential reason may be due to differences in education profile.

Even though the overall actual risk behaviour is not associated with occurrence of actual cumulative risk behaviour, the vast majority of patients had good knowledge and practice healthy behaviour regarding smoking. Available evidence reports that most adults are aware of the fact that cigarette smoking is a risk factor for CV disease [ 22 , 24 , 45 ]. Inadequate consumption of fruit and vegetables was highly and equally (100%) prevalent among those who have good or fair or poor level knowledge of CV risk factors. In addition, the majority of patients knew physical activity lowers the chance of developing heart disease, however, more than half of them failed to achieve this. This shows the existence of other factors that determine patients’ health behaviours, including individual perceptions and beliefs regarding the disease and the risk factors. This issue needs to be explored more through further research.

Findings show intensive lifestyle counselling improves awareness and adherence to healthy lifestyle behaviours [ 25 , 26 , 46 ]. In the current study, about half of CVD patients who had received follow up care with a focus on the management of CV risk factors had sub-optimal knowledge of these and they were indulged in multiple unhealthy behaviours. This is consistent with findings from America which reported African Americans have cluster of CV risk behaviours [ 47 ]. In addition, about one fifth do not know high blood pressure is a risk factor for heart disease, and this indicates a need for implementing targeted education strategies. Overall, the finding of this study show existing follow-up service is not optimal, and the probable reasons for this may be poor patient counselling service and limitation of resources. This signifies there is a need to improve the follow up service to promote healthy lifestyle behaviours for the patients. Implementing intensive lifestyle support programs based on developed guidelines and delivered by trained health professionals may also help to improve patients’ knowledge and health behaviours [ 48 , 49 ]. Absence of CVD prevention policies and strategies at population level could also have contributed to this problem in Ethiopia. Various CVD prevention guidelines have been developed and are in use to promote effective prevention of CVD in developed countries. The European Society of Cardiology guidelines focus on the importance of patient involvement and patient education which may potentially improve knowledge levels and motivation in patients [ 50 ]. The American College of Cardiology (ACC) and the American Heart Association (AHA) guidelines recommend promotion of lifetime risk estimation and which may represent an additional step forward in supporting lifestyle behaviour change counselling programs [ 51 ]. Other than a recently developed National Strategic Action Plan (NSAP) for prevention & control of non-communicable diseases [ 52 ], there are no specific guidelines for prevention of CVD in use in Ethiopia. Therefore, there is a need for the development and implementation of context specific guidelines and innovations to improve knowledge levels and patient motivation towards healthy lifestyle behaviour, particularly for poorly educated and rural residents.

Adoption of healthy lifestyle behaviours promote better health related quality of life [ 53 ], however, the patients in the current study had unhealthy behaviours that may predispose them for further complications and affect their health related quality of life, and this may contribute to the increased CVD related mortality in Ethiopia. Despite the rise in the burden of CV risk factors and lack of awareness among adult population, there is no prevention strategy implemented to reduce the burden of CVD in Ethiopia. The findings of this study have practical implications for health care workers and should inform policy makers that change is required to improve patients’ understanding of cardiovascular disease risk factors and reduce the burden of CV risk behaviours.

Given that the actual risk behaviour is not associated with the required knowledge of risk factors in this population, warrants the design and implementation of innovative interventions, in which patients are educated and empowered to self-manage their risk factors. As an example, structured and systematic nurse-led lifestyle counselling effectively reduce cardiovascular risk behaviour, improve patients’ knowledge of CV risk factors and promote healthy lifestyle behaviours [ 46 ]. Moreover, health care providers should identify patients with limited understanding of risk factors and actual risk behaviours and provide tailored interventions. Indeed, it is essential to explore how patients perceive their own risk of CV disease and the risk factors, since these are key determinants of health behaviour change according to the Health Belief Model. Therefore, the findings of this study warrant attention and are a call for action from policy makers. As such the presented data can be used as baseline data for the development of intervention programs, specifically focussed at Ethiopia that aim to improve patients’ awareness of CV disease risk factors and reduce the burden of CV risk behaviours. Indeed, it is important to design and implement monitoring and evaluation systems to improve the follow up service.

Limitations

This study may be subject to bias. Firstly, the study is subject to the limitations of patient recall and social desirability bias, and the self-reported measurement of risk behaviours may have underestimated the CV risk behaviours. However, this underlines that the real-world problem may be even worse in developing countries, and that a call for action is required. Secondly, the use of cross-sectional study design does not establish causal relationships.

The burden of CV risk behaviours is increasing whilst the patients’ understanding of associated risk factors is limited. Almost half of CVD patients have suboptimal knowledge regarding CV disease risk factors, and they have multiple unhealthy behaviours though they attend chronic follow up care clinics. Lower education, rural residence and single marital status were associated with lower knowledge of cardiovascular risk factors. Therefore, this study is important to demonstrate the need for implementing an effective prevention program. In line with intensive patient counselling and education to improve awareness regarding CV risk factors, implementation of multidisciplinary, innovative interventions and systematic nurse-led lifestyle counselling is indeed important to effectively assist CV patients in adopting positive lifestyle behaviours. Moreover, implementation of CVD prevention programs should be considered for the disease prevention policy agenda in Ethiopia.

Supporting information

S1 checklist. strobe statement—checklist of items that should be included in reports of cross-sectional studies ..

https://doi.org/10.1371/journal.pone.0234198.s001

Acknowledgments

The authors would like to thank the University of Adelaide for supporting this study. We are also grateful to the study participants, data collectors and health care workers who were directly or indirectly involved in this study. We are thankful to Suzzane Edwards for her statistical advice.

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2 Division of Cardiovascular Disease, Department of Medicine, University of Alabama at Birmingham, Lyons Harrison Research Building 306, 1900 University BLVD, Birmingham, AL, 35294, USA. [email protected]. 3 Section of Cardiology, Birmingham Veterans Affairs Medical Center, Birmingham, AL, USA. [email protected].
PDF An active learning machine technique based prediction of cardiovascular
Heart and blood vessel diseases, or CVDs, include coronary artery disease, myocarditis, vascular disease, and other conditions. Stroke and heart disease kill 80% of all people
Hot topics and trends in cardiovascular research
Inflammation, biomarkers, metabolic syndrome, obesity, and lipids are hot topics across population, clinical and basic research, supporting integration across the cardiovascular field. Conclusion: Growth in clinical and population research emphasizes improving patient outcomes through novel treatments, risk stratification, and prevention.
Effects of Exercise to Improve Cardiovascular Health
Physical Activity Decreases Cardiovascular Risk Factors. Regular physical exercise is associated with numerous health benefits to reduce the progression and development of obesity, T2D, and CVD (9-14).Several randomized clinical trials have demonstrated that lifestyle interventions including moderate exercise and a healthy diet improve cardiovascular health in at-risk populations (72, 73).
The use of nanotechnology in cardiovascular disease
Cardiovascular diseases claim a number of lives globally; many of which are preventable. With the increase in diets that consist of high saturated fat, salt, and sugar, people often living sedentary lifestyles, and a rise in cases of obesity, the incidence of cardiovascular disease is increasing. These contributing factors, coupled with more advanced methods of diagnosis, have delivered ...
(PDF) Physiology of the Cardiovascular system
In addition, the fetal cardiovascular system is designed in such a way that the most highly oxygenated blood is delivered to the myocardium and brain. These circulatory adaptations are achieved in ...
Most Important Outcomes Research Papers on Hypertension
Summary: Guidelines recommend treatment of hypertension when BP exceeds 140/90 mm Hg or 130/80 mm Hg for patients at high risk of cardiovascular (CV) events. 3 However, whether this lower threshold for treatment in patients at high risk necessarily leads to fewer CV events is uncertain with a few studies suggesting no benefit or even harm from the excessive lowering of BP. 10,11 The Ongoing ...
Patients' knowledge on cardiovascular risk factors and ...
Background Cardiovascular disease (CVD) is posing a major public health challenge globally. Evidence reports significant gaps in knowledge of cardiovascular risk factors among patients with CVD. Despite the growing burden of cardiovascular disease in developing countries, there is limited data available to improve the awareness of this area, which is crucial for the implementation of ...
Heart Failure: Causes and Nursing Management
This thesis work will seek to highlight causes and management of heart failure. Heart failure has negative connotations because education on the subject, to the authors' opinion, is limited. It is used to describe the heart bruise as a result of continuous heart depreciation of cardiac functions, fluid congestion, and tissue perfusion.
Cardiovascular Research Topics
Breakthrough Discoveries Core Lab. The Johns Hopkins Core Lab provides access to Small Animal Cardiovascular Phenotyping and Model Core. Learn more about the lab.
A Study of Heart Disease Diagnosis Using Machine Learning and Data Mining
3) Machine Learning algorithms allowed us to analyze clinical data, draw. relationships between diagnostic variables, design the predictive model, and. tests it against the new case. The predictive model achieved an accuracy of 89.4. percent using RandomForest Classifier's default setting to predict heart diseases.

Cardiovascular disease (CVD) and associated risk factors among older adults in six low-and middle-income countries: results from SAGE Wave 1

Sample and procedure

CVDs conditions

Sociodemographic variables

Risk factors

Alcohol consumption

Physical activity

Fruit and vegetable consumption

Hypertension

Statistical methods

Conclusions

Abbreviations

Acknowledgements

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Hot topics and trends in cardiovascular research

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Effects of Exercise to Improve Cardiovascular Health

Introduction

Cardiovascular Disease

Exercise Training Improves Cardiovascular Health

Physical Activity Decreases Cardiovascular Risk Factors

Physical Activity Improves Cardiovascular Function in Patients With CVD

Mechanisms Regulating Exercise-Induced Benefits on Cardiovascular Health

Exercise Improves Mitochondrial Biogenesis and Function

Exercise Improves Vasculature and Myocardial Perfusion

Exercise Reduces Chronic Inflammation

Exercise Enhances Inter-tissue Communication Through Release of Myokines

Interleukin-6 (IL-6)

Follistatin-Like 1 (Fstl1)

Neuron-Derived Neurotrophic Factor (NDNF)

Conclusions

Author Contributions

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Cardiovascular Nanotechnology

Atherosclerosis and Nanotechnology: Diagnostic and Therapeutic Applications

Introduction

Nanotechnologies for treatment

Polymeric nanoparticles

Gel nanoparticles

Nano-coated stents

Nanoparticles for diagnostic imaging

Future perspectives

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Physiology of the Cardiovascular system

Patients’ knowledge on cardiovascular risk factors and associated lifestyle behaviour in Ethiopia in 2018: A cross-sectional study

Introduction

Design, settings and sampling

Ethical considerations

Data collection and tools

Statistical analysis

Characteristics of the participants

Knowledge of cardiovascular risk factors

Actual cumulative risk behaviour and knowledge of cardiovascular disease risk factors association

Limitations

Supporting information

Acknowledgments

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