1.1. Cardiovascular Risk Stratification to Prevent and Treat Atherosclerosis

The first manifestation of atherosclerotic disease in approximately half of the people who have this complication is an acute coronary event. Therefore, identifying asymptomatic individuals with higher predisposition is crucial for effective prevention associated with the correct definition of therapeutic targets. The so-called risk scores and algorithms based on regression analysis of population studies were created to estimate the severity of CVD, substantially enhancing the identification of overall risk. The Framingham gloal risk score (GRS)⁶ included the estimate of 10 years of coronary and cerebrovascular events, peripheral arterial disease, or heart failure (HF) and was the score adopted by the Department of Atherosclerosis of SBC (Departamento de Aterosclerose da Sociedade Brasileira de Cardiologia - SBC-DA).⁷

In addition, individuals who have multiple risk factors for CV, subclinical atherosclerosis, or already had manifestations of CVD have a high risk for events and can be classified differently.

Thus, the new CV risk stratification proposed by the SBC-DA defines four levels of CV risk:

Strategies for primary or secondary prevention of the disease are proposed based on the characterization of CV risk.

1.2. Very High Risk

Individuals who have a significant atherosclerotic disease (coronary, cerebrovascular, or peripheral vascular) with or without clinical events belong to this category (Chart 1.1).

1.3. High Risk

Patients in primary prevention who present ORS > 20% (men) or > 10% (women) or aggravating risk conditions based on clinical data or subclinical atherosclerosis (Chart 1.2).

1.4. Moderate Risk

The estimated risk for atherosclerotic disease results from the sum of the risk associated with each risk factor and the powering caused by synergisms between some of these factors. Given the complexity of these interactions, intuitive risk allocation often leads to under- or overestimation of higher or lower risk cases, respectively. Among the algorithms created to stratify CV risk, the last Updated Brazilian Guideline for Dyslipidemia and Atherosclerosis Prevention recommends the use of ORS, which estimates the risk for myocardial infarction, cerebrovascular accident (CVA), HF - fatal or non-fatal -, or peripheral vascular insufficiency in 10 years.

Based on this score, individuals with GRS ranging from 5 to 20% (males) and 5 to 10% (females) are classified as moderate risk. Patients with diabetes mellitus (DM) without SAD criteria or RS are also considered at moderate risk. Many middle-aged individuals belong to this risk category (Chart 1.3). Part of the latest recommendations leans towards inflammatory conditions and the use of coronary calcium to restratify patients at moderate risk.⁸

1.5. Low Risk

Any estimated CV risk based on findings of observational studies inevitably has limitations related to calibration and discriminatory power: the attempt to allocate a certain risk percentage to each patient collides with individual aspects, not covered by risk prediction equations. The idea of restoring the concept of aggravating risk - understood as individual phenotypic expressions causally related to greater chances of a CV outcome - to improve somewhat the individualization of the algorithms created from large population samples has been gaining strength.⁸ However, in the low-risk population stratum, an aggravating risk in those with less than 5% chance of having a CV outcome in 10 years^6,8 would hardly have a decisive influence in this relatively short time interval. On the other hand, as age is one of the most important determinants of risk for CV events, a man aged 62 years, without SAD, normotensive, non-smoker, non-diabetic, and with optimal levels of serum lipids would already be classified by ORS as moderate risk, even without any aggravating factor.⁶

Therefore, adults considered at low CV risk are those aged 30 to 74 years, of both genders, whose risk for CV events calculated by GRS is lower than 5% in 10 years^6,7 (Chart 1.4).

Although the calcium score is not recommended for low-risk patients, non-diabetic individuals at moderate risk, without a family history of premature coronary disease, who have a zero calcium score can be considered at low risk and postpone the start of the cholesterol-lowering therapy with statins.⁸

Aggravating risk factors are not used in patients considered at low CV risk. The North American guideline of 2018 considers restratifying moderate risk to low in patients with zero calcium score (non-diabetics and without a family history of premature coronary disease).⁸

Charts 1.5, 1.6, 1.7, and 1.8 present the GRS for men and women in 10 years.

Table 1.1 summarizes the recommendations for cardiovascular risk stratification.

Figure 1 Cardiovascular risk stratification. CKD: chronic kidney disease (glomerular filtration rate < 60 ml/min/m2, non-dialysis); GRS: global risk score; RS: risk stratifiers; SAD: subclinical atherosclerotic disease. 

2.1. Introduction

Dyslipidemias represent an important CV risk factor, with low-density lipoprotein cholesterol (LDL-c) as the most relevant modifiable risk factor for CAD.¹¹ Genetic¹² and clinical studies with statins and other lipid-lowering drugs provide ample evidence that lower LDL-c levels are associated with the proportional decrease in CV outcomes, including myocardial infarction, CVA, and CV death.^13,14

The 2017 Updated Brazilian Guideline for Dyslipidemia incorporated some changes in the approach of dyslipidemias compared to the previous version.⁷ One of the changes was that fasting was no longer mandatory for total cholesterol (TC) and high-density lipoprotein cholesterol (HDL-c) tests, provided that the laboratory specifies the situation in the report, without fasting or with 12-hour fasting. As for triglycerides (TG), it might increase in the absence of fasting. In hypertriglyceridemia, particularly with a value > 440 mg/dL, a new collection after 12-hour fasting is crucial.¹⁵ Apolipoprotein (ApoA1 and ApoB) levels can be determined in a sample without prior fasting, and moderately high TG levels do not influence immunochemical methods. The analytical performance of this methodology is good, and the levels can be measured in automated platforms with an immunoturbidimetry or nephelometry profile.

There is evidence of an independent association between elevated lipoprotein (a) [Lp(a)] and CVD risk in the general population,¹⁶ not only for the lipid content of Lp(a) but also for its prothrombotic and proinflammatory properties. The gold standard for quantification of plasma concentrations is the measurement of Apo(a) mass by turbidimetry, nephelometry, or chemiluminescence, using isoform-insensitive assays, which are little affected by the heterogeneity in Apo(a) isoforms. It does not require fasting and provides accurate data. Its analysis is not recommended for routine assessment of CVD risk in the general population, but it should be determined in the risk stratification of individuals with a family history of premature atherosclerotic disease and familial hypercholesterolemia (FH).⁷ Lp(a) values above 50 mg/dL, equivalent to 80%, are considered high; if the result is in nmol/L, it should be multiplied by 2.5, with Lp(a) values above 125 nmol/L classified as high.⁷

Table 2.1 reports the reference values of the lipid profile with and without fasting, according to the evaluation of CV risk in adults.

The primary (LDL-c) and secondary (non-high-density lipoprotein cholesterol - non-HDL-c) therapeutic targets for lipid control are established following the risk stratification of patients (discussed in Chapter 1). This stratification considers the presence or absence of clinical or subclinical atherosclerotic disease, the presence of diabetes, and the GRS, with subsequent risk classification into four possible categories: low (< 5%), moderate (5-10% in women and 5-20% in men), high (> 10% in women and > 20% in men), and very high (clinical atherosclerotic cardiovascular disease, > 30%) risk. Chapter 1 presents the complete risk stratification. Specific targets for each category were defined in accordance with Table 2.1.⁷

The Updated Brazilian Guideline for Dyslipidemia and Atherosclerosis Prevention⁷ also included a change in CV risk stratification for individuals already using statins. Considering the imprecision of risk calculation in these patients, the guideline proposes using a correction factor for TC to estimate the risk score in this context, derived from studies that compared the efficacy of different statins in the doses used and that allowed an average LDL-c reduction of ~ 30% with the treatment.¹⁷ This situation applies to most patients who take moderate doses of statins. Given the average TC reduction of 30% with statins, patients who use these medicines should have their TC multiplied by 1.43.¹⁷ Moreover, in the initial approach, the target for individuals who are not on lipid-lowering treatment should be decreasing the percentage of LDL-c and non-HDL-c. For those already on lipid-lowering therapy, the recent guideline also established a reduction in absolute LDL-c and non-HDL-c values with the treatment, as shown in Table 2.2.

2.2. Dyslipidemia Treatment

3.1. Myocardial Risk

Patients with DM2 have a 2 to 5 times greater risk for HF compared to non-diabetic individuals.³⁴ As CAD patients are excluded, the incidence of HF in the diabetic population decreases but remains significantly higher than in non-diabetic individuals. In type 1 diabetes, above 7%, each 1% increment in glycated hemoglobin (HbA1c) was associated with a 30% increase in HF risk,³⁵ while type 2 diabetes was associated with a 16% increase in the risk, regardless of other risk factors, including obesity, smoking, hypertension, dyslipidemia, and coronary disease.^36,37

Diabetic cardiomyopathy is characterized by myocardial fibrosis and left ventricular hypertrophy with diastolic dysfunction, initially asymptomatic, and that progresses slowly to diastolic or systolic dysfunction, followed by HF with clinical repercussion.³⁸

Occasionally, diabetic cardiomyopathy can manifest as arrhythmias and sudden death. Mechanisms involved in the pathophysiological process include mitochondrial dysfunction, oxidative stress, inflammation, dysfunction in the mitochondrial Ca²⁺ management, activation of the renin-angiotensin-aldosterone system (RAAS) and the sympathetic nervous system (SNS), cardiac autonomic neuropathy, endoplasmic reticulum stress, microvascular dysfunction, and disorders of cardiac energy metabolism.^39-41

3.1.1. Myocardial Risk Estimate

Despite the lack of an universally accepted method to estimate HF risk specifically in diabetic individuals, methods such as plasma brain natriuretic peptide (BNP), echocardiographic evaluation of diastolic dysfunction, and risk calculators such as the Health ABC Heart Failure Score and the Framingham Heart Failure Risk Score are often used to estimate the future risk for symptomatic HF.

Elaborating a standardized strategy to screen and intervene in patients at HF risk might be difficult due to its different definitions, the heterogeneity of its prevalence in various populations, its inconstant duration until the development of clinic HF or left ventricular dysfunction, and the varying interventions to modify or treat risk factors. As we shall see below, the Health ABC Heart Failure Score is the mechanism with the highest sensitivity and specificity and should be recommended as the primary strategy in risk stratification of symptomatic HF. Nonetheless, BNP can be used concomitantly to reclassify individuals at high risk for HF.

The evidence that supports the use of BNP in diabetic patients to predict the HF risk is based on two randomized controlled trials. As shown in Table 3.1, these programs recruited 1,674 patients without HF for randomization and identified a total of 29 subsequent events of hospitalization for HF. The combined statistical power of these studies is limited but provides the perspective for the potential benefit of screening based on biomarkers such as BNP.

Table 3.1 BNP screening to guide the primary prevention strategy for diabetes mellitus 

	Study design and intervention	Study population	N without prior HF	Hospitalizations for HF/follow-up duration	Effect on hospitalization for HF	Effect on major CV events*
STOP-HF42	Randomized controlled trial with BNP screening versus usual primary treatment	Age > 40 years without HF but with CV disease or CV risk factors	1,374	21 / 4.2 years	OR 0.48 (95% confidence interval 0.20-1.20)	OR 0.60 (95% confidence interval 0.45-0.81)
PONTIAC43	Randomized controlled study, with treatment in a cardiology outpatient clinic for titration of RAAS inhibitors and beta-blockers associated with care in a DM treatment unit versus care in an isolated DM unit	DM2 without known CV disease and NT-proBNP > 125 pg/mL	300	8 / 2 years	HR 0.14 (95% confidence interval 0.02-1.14)	HR 0.35 (95% confidence interval 0.13-0.97)

BNP: brain natriuretic peptide; CV: cardiovascular; DM: diabetes mellitus; HF: heart failure; RAAS: renin-angiotensin-aldosterone system.

^*Major CV events, defined as unplanned hospitalizations for CV causes and deaths.

Diastolic dysfunction on the echocardiogram - Historically, experts disagree on recommendations for echocardiographic diagnosis of diastolic dysfunction, as shown in the 2009 guidelines of the American Society of Echocardiography and the European Association of Cardiovascular Imaging (ASE/EACVI) and the Canberra Study Criteria (CSC).^44,45 Based on these recommendations, epidemiological studies and a meta-analysis^46,47 suggest that preclinical diastolic dysfunction (Stage B HF), defined as diastolic dysfunction with normal systolic function and without HF symptoms, is common in DM, and that its presence increases by 61 to 70% the risk for developing symptomatic HF (stages C and D). Despite being simple and non-invasive,^46,47 the echocardiographic diagnosis for patients at higher risk for HF does not seem to be as cost-effective as the measurement of BNP,^48,49 although these data are not specifically available for the Brazilian population.

The diagnostic criteria became more specific and less sensitive in the 2016 ASE/EACVI guideline,^50,51 despite the simplification. With these criteria, the prevalence of diastolic dysfunction in the general population ranges from 1 to 7%. However, no studies have been designed to focus on primary prevention based on this diagnostic criterion.

Risk scores for future HF - The HF risk in patients with DM and metabolic syndrome (MS) can be predicted with clinical scores. Although no scores have been developed specifically for patients with DM or MS, several studies have demonstrated good performance in these populations. Among the most used scores are the

1. Health ABC Heart Failure Score;⁵² the

2. The Framingham Heart Failure Risk Score;⁵³ and the

3. And the Atherosclerosis Risk in Communities (ARIC) Heart Failure Risk Score.⁵⁴

The variables included in the Framingham Heart Failure Risk Score are age, gender, CAD, diabetes, left ventricular hypertrophy based on electrocardiogram (ECG), valvular disease, heart rate, and systolic blood pressure (SBP). The Health ABC Heart Failure Score includes the Framingham variables with the following differences: addition of serum albumin, serum creatinine, and smoking; replacement of glucose for diabetes; and exclusion of valvular disease. The ARIC Heart Failure Risk Score includes age, ethnicity, gender, CAD, diabetes, SBP, use of medicines for blood pressure (BP), heart rate, smoking, and body mass index (BMI).

Designed for a community population of older adults, the Health ABC Heart Failure Score reached a positive and negative predictive power of 10 and 15% in comparison with the Framingham Heart Failure Risk Score⁵² and 2 to 4% above the ARIC Heart Failure Risk.⁵⁴ The Health ABC Heart Failure Score is an instrument validated in observational and intervention studies and, thus, considered a reference for estimating the future HF risk in patients with DM and MS (detailed description in Figure 3.1).

Figure 3.1 Health ABC Heart Failure Score. 

Although all scores are designed with only the variables listed above, the addition of BNP or NT-proBNP as linear variables would significantly increase the predictive power of all scores.^52,54 Based on the thresholds used in the studies PONTIAC⁴³ and STOP-HF,⁴² we suggest reclassifying individuals with BNP ≥ 50 pg/mL or NT-proBNP ≥ 125 pg/mL into a higher risk category.

3.2. Atherosclerotic Risk

3.2.1. Metabolic Syndrome, Diabetes Mellitus, and the Continuous Corollary of Coronary Artery Disease

MS and the DM comprise a spectrum of multisystemic diseases, particularly in the vascular endothelium, that contribute dramatically to the progression of pathophysiological substrates of CAD. Robust evidence suggests that CV risk increases even in stages that precede the clinical diagnosis of DM in 10 to 20 years, based on current criteria. As MS is one of the main risk factors for DM, considering it within a continuum of metabolic changes related to coronary atherothrombosis is reasonable.^70,71

In fact, estimates indicate that glucose metabolic changes precede the diagnosis of diabetes in 4 to 12 years⁷² (Figure 3.2). While in early stages the overproduction of insulin can compensate its resistance, after a certain point, the pancreatic functional reserve is exhausted, and the production of insulin no longer compensates its resistance. After this moment, the diagnosis will be established by hyperglycemia, but CV changes adaptive to insulin resistance and cellular oxidative stress become irreversible.

Figure 3.2 Progression of micro- and macrovascular disease in type 2 diabetes and its relationship with the functional reserve of pancreatic beta-cells and hyperglycemia. 

Another mechanism that seems to occur even in early stages (pre-hyperglycemia) is the accumulation of fatty acids in various tissues, such as pancreas, heart, and liver, accelerating the dysfunction in insulin production, hepatic glucose production, and left ventricular diastole.⁷³ Therefore, even remotely before the period of hyperglycemia, several cellular mechanisms cooperate to determine the endothelial dysfunction, the phenotypic changes in lipids with hypertriglyceridemia, and small, dense LDL, creating the ideal scenario for accelerated atherogenesis.⁷⁴ Together, these data suggest that CAD becomes accelerated many years before the onset of hyperglycemia.

4.1. Introduction

In the past decades, Brazil underwent a process called nutritional transition¹¹² - a concept related to secular changes in dietary patterns and nutritional status - and important modifications regarding food intake and PA patterns, as a consequence of economic, social, demographic, and health transformations.¹¹³ Obesity and overweight are complex and chronic conditions, whose prevalence has grown inexorably in the last 4 to 5 decades.¹¹⁴ Between 1980 and 2013, the global percentage of individuals with a BMI ≥ 25 kg/m² rose from 28.8 to 36.9% in men and 29.8 to 38.0% in women.¹¹⁵ In Brazil, 52.4% of the population was overweight in 2014, with 17.9% of them classified as obese.¹¹⁶ According to data from the 2018 Risk Factors Surveillance and Chronic Disease Protection by Telephone Survey (VIGITEL), the incidence of overweight reached 55.8% and of obesity, 18.7% among men over 20 years of age; while for women, these values were 53.9% and 20.7%, respectively.¹¹⁷ In 34 years, the prevalence of obesity increased over four times for men (from 2.8 to 12.4%) and more than twice for women (from 8 to 16.9%).^118,119 Brazil currently holds the fourth place among the countries with the highest prevalence of obesity and the number of overweight adults will exceed those with low weight.¹¹⁸ There is a significant rise in overweight and obesity among children and adolescents, regardless of gender and social status, and a considerable proportion of these individuals will become obese adults.

Obesity has a multifactorial nature and is one of the leading factors to explain the growth in the chronic NCD burden, given its frequent association with CVD, such as arterial hypertension (AH), CVA, HF,¹²⁰ dyslipidemias, type 2 diabetes, atrial fibrillation,^121,122 osteoarthritis, and certain types of cancer. Also, obesity is an important condition that predisposes the individual to mortality.^118,119

In addition, weight gain over time is associated with MS, increased risk for CVA, and death in late stages of life.^123-125 Many patients who present some of these changes have hypertriglyceridemia and increased levels of plasma fatty acids, stored as lipid droplets in the heart. Intramyocardial lipids that exceed the storage and oxidation capacity can become toxic and lead to non-ischemic and non-hypertensive cardiomyopathy, known as diabetic or lipotoxic cardiomyopathy.¹²⁶ Significant weight loss (≥ 5% of initial weight) improves BP, LDL-c, TG, and glucose levels, delaying the onset of type 2 diabetes.¹²⁷

4.2. Primary Prevention

According to the World Health Organization (WHO), an inadequate diet is the main risk factor for early mortality worldwide.¹²⁸ Therefore, a healthy diet is recommended for everyone, and the ability to prepare healthy meals has beneficial correlations with the consumption of equally healthy foods.¹²⁹ However, studies have shown a reduction in the habit of cooking in some countries, which has encouraged health specialists to elaborate nutritional education strategies focused on nutrients and tools, such as the proper purchase and storage of food, and planning and preparing meals at home.¹³⁰

Also, we emphasize that the biological moment that could prevent weight gain is of the utmost importance. In females, the moment of greatest risk seems to be the reproductive age, specifically during pregnancy and the first two years postpartum, and the period post-menopause.^131,132 Among children and adolescents, prevention of excessive weight gain was expected precisely because the growth phase requires extra energy, and the possibility of energy expenditure is higher compared to other life stages. These potential facilitators, however, do not seem to overcome the factors associated with obesity and those responsible for the epidemic growth also in these age groups and life stages.¹³³ In this regard, we underline the so-called “obesogenic environment,” that is, the role of the food industry, fast food chains, advertisements, TV shows, movies, and videogames, leading to situations that keep the children more sedentary and subjected to excessive energy intake. The most appropriate interventions should combine environmental and behavioral changes.^134-136

A study conducted with 422 adolescents, with a mean age of 12.5 years, compared students who practiced competitive physical activity daily for 2 hours with those from a standard school who have only one hour of physical activity per week. The percentage of overweight/obesity in the first group was 49.8% and in the second, 37.3%, which reveals the high prevalence of this change in the two groups.¹³⁷ A similar sample submitted to a multidisciplinary program of moderate intensity, that could be easily incorporated in the daily routine, showed positive advances in risk factors when compared to the control group.¹³⁸

Among adults, studies show a decline in the consumption of rice and beans, increase in the intake of processed products (particularly cookies and soft drinks), excessive consumption of sugar, more saturated fats, and insufficient intake of fruits and vegetables, creating an environment with habits that do not favor a healthy dietary pattern, directly associated with the increase in chronic NCD, especially obesity.^139-142

A recommendation from the 2014 Dietary Guidelines for the Brazilian Population proposes 10 steps for a healthy diet:

Some other useful pieces of advice are:^143,144

Table 4.1 lists the recommendations on how to approach overweight and obese adults.

5.1. Introduction

AH is the most prevalent chronic disease in the world, affecting approximately one-third of the adult population. BP is maintained by several factors, particularly the intravascular volume, cardiac output, peripheral vascular resistance, and the elasticity of arterial vessels. Among the various regulatory mechanisms, RAAS - involving the renal system - has significant participation; an imbalance in this complex regulatory system, however, can result in chronic elevation of BP levels, known as AH. AH is one of the most important CV risk factors, as hypertensive individuals present much more atherosclerosis, leading to CVA, HF, coronary disease, peripheral vascular insufficiency, and kidney disease.¹⁴⁵

Although we have efficient drugs with few adverse effects, the worldwide control of this condition still leaves much to be desired, since we are dealing with completely asymptomatic disease, a fact that makes care adherence very difficult.

According to the 7^th Brazilian Guideline of Arterial Hypertension, an individual is hypertensive when his or her SBP and diastolic blood pressure (DBP) are equal to or higher than 140/90 mmHg (Table 5.1).¹⁴⁶ Figure 5.1 shows the flowchart for the diagnosis of hypertension.

Figure 5.1 Flowchart for the diagnosis of arterial hypertension. BP: blood pressure; ABPM: ambulatory BP monitoring; HBPM: home BP monitoring. Modified from references.^9,10,189  

The genesis of primary AH is multifactorial, with genetic and environmental influences. Although the genetic mechanisms involved are still obscure, there is evidence that children of hypertensive individuals have a greater chance of becoming hypertensive. However, the environmental aspect has an essential role in the development of AH. As the individual ages, the prevalence of AH increases significantly; therefore, detecting predisposing factors is important to prevent this critical CV risk factor properly. Besides family history, age, ethnicity, and insulin resistance, there are also environmental factors related to the development of AH that can be modified, such as obesity, psychosocial aspects, diet, sodium intake, sedentary lifestyle, and alcohol consumption.

5.2. Physical Activity and Hypertension

Epidemiological studies suggest that regular aerobic physical activity can be beneficial in preventing and treating hypertension, as well as reducing CV risk and mortality. A meta-analysis with 93 articles and 5,223 individuals showed that aerobic training, dynamic resistance, and isometric resistance reduce SBP and DBP at rest by 3.5/2.5, 1.8/3.2, and 10.9/6.2 mmHg, respectively, in the general population.¹⁴⁷

Resistance training, but not other types of training, further reduces BP in hypertensive individuals (8.3/5.2 mmHg). Regular physical activity of lower intensity and duration reduces BP less than moderate or vigorous training but is associated with a decrease in mortality by at least 15% in cohort studies.^148,149

This evidence suggests that hypertensive patients should be advised to practice dynamic aerobic exercise of moderate intensity (walking, running, cycling, or swimming) for at least 30 minutes 5 to 7 days per week. The practice of resistive exercises 2 to 3 days per week could also be recommended. Also, healthy adults could benefit from gradually increasing moderate aerobic physical activity to 300 minutes per week, vigorous aerobic physical activity to 150 minutes per week, or an equivalent combination of the two, ideally with supervised daily exercise.^6,9 The impact of isometric exercises on BP and CV risk is less well established.

Table 5.2 demonstrates the classification of physical activity intensity and the levels of absolute and relative intensity. Table 5.3 shows the v goals to prevent and treat AH.

5.3. Psychosocial Factors

Some psychosocial factors, such as work and family stress, depression, anxiety, hostility, and type D personality, as well as low socioeconomic and cultural status, increase the risk for AH - and consequently CVD - and reduce the adherence to a healthy lifestyle and drug treatment. On the other hand, CVD also increase the risk of manifesting these psychosocial factors, indicating a bidirectional and robust relationship.¹⁵⁴

Moreover, the prevalence of CVD and AH is higher in developing countries, where the control rate of these diseases tends to be poor, decreasing life expectancy and increasing the pathologies and frailties related to aging.¹⁵⁵ Several prospective studies and systematic reviews have addressed socioeconomic status, showing that low schooling and income, low-status jobs, as well as living in poor residential areas are associated with the increase in BP levels and consequently CV risk.^156,157

Individuals with mood and personality disorders present an increase in the incidence and worsening of the prognosis of CVD, especially among those with depression or anxiety.¹⁵⁷ Similarly, personality traits associated with hostility or distress also worsen the prognosis.¹⁵⁸

The management of psychosocial stress with several existing techniques, among them meditation, music therapy, yoga, and slow breathing, can be crucial in preventing and controlling BP. In general, such techniques can mildly reduce BP levels in hypertensive individuals.^159,160

5.4. Diets that Promote the Prevention and Control of Arterial Hypertension

In 2017, the Global Burden of Disease Group considered unhealthy diet as one of the main as risk factors for premature death and disability.¹⁶¹ Adjustments in the diet of individuals with normotension (NT) or pre-hypertension (PH) have the potential of reducing BP and preventing AH.¹⁶² National and international guidelines recommend that all patients with PH or AH reduce their sodium intake and consume adequate amounts of fresh fruit, vegetables, and low-fat dairy products.¹⁶³ Furthermore, these documents emphasize the importance of maintaining body weight and waist circumference within the normal range.¹⁶⁴

Many dietary patterns have been proposed to prevent and control AH, as well as maintain global and CV health. Among the dietary models proposed, with different levels of evidence and effectiveness to prevent and control AH, we highlight the Dietary Approaches to Stop Hypertension (DASH), low-fat, high-protein, low-carbohydrate, moderate carbohydrate, low-glycemic index/low-glycemic load, low-sodium, vegetarian/vegan, Mediterranean, paleolithic, Nordic, and Tibetan¹⁶⁵ (Chart 5.1).

A meta-analysis of 67 studies published between 1981 and 2016 compared the effects of these dietary patterns on patients with PH and AH. DASH, Mediterranean, low-carbohydrate, paleolithic, high-protein, low-glycemic index, low-sodium, and low-fat were significantly more effective in reducing SBP (-8,73 to -2,32 mmHg) and DBP (-4,85 to -1,27 mmHg) compared to the control diet.¹⁶⁵

Regarding food supplements, several meta-analyses have evaluated the potential effects of additives on BP reduction with supplementation of certain substances in populations of individuals with NT, PH, and AH.¹⁶⁶ The effects of these supplements on BP reduction are usually mild, heterogeneous, and their statistical significance is difficult to assess. The substances whose supplementation has evidence of significant BP reduction are: potassium, vitamin C, food-derived bioactive peptides, garlic, dietary fiber, linseed, dark chocolate (cocoa), soy, organic nitrates, and omega-3.¹⁶⁷ Chart 5.2 shows the recommended mean daily portions, their potential impact on BP, the level of evidence, and the recommendation grade of each of these supplements, as well as other food interventions. Supplementation with calcium, magnesium, combined vitamins, tea, and coenzyme Q10 did not present a significant BP reduction.¹⁶⁸

5.5. Alcohol and Hypertension

The relationship between alcohol consumption and hypertension is known since 1915, when a pioneer publication reported this association.¹⁶⁹ Several epidemiological studies corroborate the almost linear and dose-dependent relationship between alcohol and AH.¹⁷⁰

The difficulty in determining the effect of alcohol on the development of AH is the difference in the quantification of the consumption pattern, and the varying alcohol concentration of these beverages. Heterogeneous results originate from the influence of the type of beverage ingested, volume consumed, lifestyle, intake pattern, and socioeconomic status of the population studied.^171-172

The INTERSALT study evaluated the consumption of 300 ml of ethanol weekly (34 g, 3 or 4 drinks/day) and found a BP increase in drinkers compared to non-drinkers.¹⁷³ Estimates indicate that excessive alcohol consumption is responsible for approximately 10-30% of AH cases.¹⁷⁴ The ARIC study followed 8,834 individuals for eight years and, at the end of the investigation, the patients with high alcohol consumption had a greater incidence of AH, regardless of the type of beverage, gender, or ethnicity. Moderate alcohol consumption was associated with risk of developing AH, not only in African Americans but also in the Brazilian population.¹⁷⁵ Approximately 6% of all-cause mortality worldwide is attributed to alcohol.¹⁷⁶ When ingested in a single dose, alcohol has a dose-dependent biphasic effect characterized by BP reduction, vasodilation, and increase in HR with a subsequent BP elevation.¹⁷⁷

In a study using the Ambulatory Blood Pressure Monitoring (ABPM) in pre-menopausal women, the group who consumed 20-300 ml of red wine/day (146-218 g of alcohol/week) showed a significant increase in BP.¹⁷⁸ The same situation occurred in normotensive men who ingested an average of 40 g/day of ethanol, compared to the group who did not consume alcohol for four weeks.¹⁷⁹

A meta-analysis with 15 RCTs, involving 2,234 participants, assessed the effects of reducing the consumption of ethanol on BP and estimated that a 2-mmHg reduction in DBP could decrease the prevalence of AH by 17%, the CAD risk by 6%, and the ischemic CVA and transient ischemic attack by 15%.¹⁸⁰

5.6. Weight Loss and Prevention of Arterial Hypertension

Overweight is recognized as a factor related to BP elevation, and the greater the BMI, the higher risk for AH.¹⁸¹ Central obesity and weight gain over time stand out as important factors for the development of AH. The Nurses’ Health Study revealed that women who gained 5.0 to 9.9 kg and those who gained more than 25 kg in 18 years of follow-up had a higher risk for AH - 1.7 and 5.2, respectively. However, estimates suggest that only 26 to 40% of AH cases are attributable to overweight, emphasizing the multifactorial nature of AH.¹⁸²

Weight loss as a non-pharmacological approach reduces BP in normotensive individuals and can prevent the development of AH. Changes in lifestyle are crucial for weight loss, focusing on the adoption of a hypocaloric diet and regular PA, with the reduction in caloric intake being more important than following specific diets.¹⁸³

Regular isolated PA, without a concomitant dietary approach rich in fruits, vegetables, grains, seeds, nuts, fish, and dairy products, and poor in meats, sugars, and alcohol in general, is not enough for a significant weight loss.¹⁸⁴

A meta-analysis of controlled studies with 4,184 individuals showed a reduction in SBP and DBP of 1.05 and 0.92 mmHg, respectively, for each 1 kg of weight lost. In healthy obese individuals, the combination of a low-calorie diet and BMI reduction was associated with an average decrease of 4.73/2.75 mmHg in SBP and DBP.¹⁸⁵

A systematic review of studies with hypertensive subjects showed that the magnitude of BP reduction with weight loss was on average 4.5/3.2 mmHg for SBP and DBP, respectively, underlining that the greater the weight loss, the higher the BP reduction.¹⁸⁶

The Framingham Study revealed a reduction in the risk of developing AH of 22 to 26% in individuals aged 30-49 and 50-65 years, respectively, who maintained a weight loss of 6.8 kg, in 8 years. In this context, regular PA stands as a measure of great importance in the maintenance of weight loss.¹⁸⁷

5.7. Low-Sodium Diet in the Prevention of Arterial Hypertension

Prospective cohort studies have demonstrated that high sodium intake increases the risk of death and CV events. These studies also reported that decreasing sodium intake to below a certain value (approximately 3 g of sodium per day) further reduced BP. Paradoxically, low sodium intake was associated with an increased CV risk and risk of all-cause mortality in the general population and hypertensive individuals, suggesting a J-curve phenomenon. The mechanism of this apparent increased risk with low sodium intake is probably related to higher activity in the renin-angiotensin system under a very high restriction of salt in the diet. No epidemiological study has evidenced that very low sodium intake can be harmful.¹⁰

On the other hand, there is evidence of a causal relationship between sodium intake and an increase in BP. Excessive sodium intake (> 5 g of sodium per day) increases BP and is associated with a higher prevalence of systolic AH with aging.¹⁸⁸

Many studies have shown that sodium restriction decreases BP. A meta-analysis revealed that a reduction of 1.75 g of sodium per day (4.4 g of salt/day) was associated with an average decrease of 4.2 and 2.1 mmHg in SBP and DBP, respectively, with a more pronounced effect in hypertensive individuals - 5.4 and 2.8 mmHg. The reducing effect of sodium restriction on BP is more significant in black people, older adults, and individuals with DM, MS, and chronic kidney disease (CKD).¹⁶⁴

In Western populations, such as the Brazilian, the usual sodium intake is estimated between 3.5 to 5.5 g/day (which corresponds to 9 to 12 g of salt per day), with marked differences among countries or even regions.¹⁸⁹

Sodium intake should be limited to approximately 2.0 g/day (equivalent to about 5.0 g of salt per day) in the population in general, but especially in hypertensive individuals.

The effective reduction of salt is not easy, and information about which foods have high levels of salt is often scarce. It is crucial that the population pay very careful attention to the amount of salt added to meals and with foods high in salt (processed products). Reducing salt intake remains a public health priority, but it requires a combined effort between the food industry, governments, and the general population since 80% of the salt consumed originates from processed foods. The adequate consumption of fruits and vegetables enhances the beneficial effect of a low-sodium diet on BP, mainly due to the increased intake of potassium, known for reducing BP.

It is possible to prevent or postpone AH with a change in lifestyle, which can effectively promote the primary prevention of systemic arterial hypertension (SAH), especially in individuals with borderline BP.¹⁰ Healthy lifestyle habits should be adopted since childhood and adolescence, respecting the regional, cultural, social, and economic characteristics of individuals (Chart 5.3).

5.8. Antihypertensive Control in Primary Prevention of Diabetes Mellitus and Metabolic Syndrome

BP control is one of the more robust tools for reducing CV risk. Reducing 20 mmHg in SBP can decrease CAD mortality by 40%, CVA mortality by 50%, and HF mortality by 47%. However, AH is still the most common and potent risk factor for loss of life expectancy, due to the suboptimal population control of this condition.^190-192

Based on the non-automated measurement taken in the doctor’s office, the recommended BP target is < 130/80 mmHg for individuals with stages 1 and 2 hypertension at low and moderate CV risk, and those with stage 3 hypertension at low, moderate, and high CV risk.¹⁴⁶ This recommendation is based on meta-analyses of randomized studies,^193,194 which demonstrated the superiority of this BP target compared to values above 150/90 mmHg. Decreasing this target to 130/80 mmHg seems to be safe in this lower-risk population, as observational¹⁹⁵ and some randomized studies corroborate,^194,196 although the additional benefit is relatively small and counterbalanced by the risk for symptomatic hypotension and adverse effects of drugs.

On the other hand, individuals with stages 1 and 2 hypertension at high or very high CV risk or with three or more risk factors, and/or MS, and/or target-organ damage should have BP levels < 130/80 mmHg.¹⁴⁶ In the SPRINT study,¹⁹⁷ among the 9,361 non-diabetic individuals at high CV risk (median of 24.8% in 10 years), 39% met the criteria for MS. The study population was randomized for a more (< 120 mmHg) and less intense (< 140 mmHg) reduction in SBP - automated BP measurement (on average, 10 mmHg lower than the SBP measured at the doctor’s office with a non-automated method). Among patients with MS, the reduction in the primary outcome - comprising acute coronary syndromes, CVA, HF, or CV death - was similar to that of patients without MS after 3.26 years of follow-up. The most intense SBP treatment arm presented a decrease of 25% in the risk of primary outcome compared to that with less intense reduction (HR 0.75; 95% confidence interval: 0.57-0.96; p < 0.001).^198,199

Among patients with coronary disease, the recommended BP target should be between 130 x 80 and 120 x 70 mmHg, particularly avoiding a DBP below 60 mmHg due to the risk for coronary hypoperfusion, myocardial damage, and CV events.¹⁴⁶ A J curve has been consistently identified in this population, with SBP < 120 mmHg and DBP < 70 mmHg being associated with higher mortality.²⁰⁰

6.1. Introduction

Several observational studies have found a strong association between the consumption of grains, fruits, and vegetables - foods rich in vitamins and minerals - and low CV mortality²⁰¹ and lower risk for myocardial infarction.²⁰² Given this strong evidence, numerous intervention studies have tested the impact of supplementation with micronutrients (vitamins) and certain fatty acids (omega-3 series) on primary and secondary prevention of CV events. From a practical point of view, most of these studies showed no clinical benefit related to supplementation in the doses studied and in the face of the drug therapies used to prevent CV. Tables 6.1. to 6.3 summarize the recommendations for and against the use of these supplements.

6.2. Carotenoids

Carotenoids are a class with over 600 compounds, responsible for the yellow, red, and orange pigments in plants, with a-carotene, b-carotene, b-cryptoxanthin, lycopene, lutein, and zeaxanthin being the most commonly found in food. Known primarily as precursors of vitamin A, carotenoids are also essential suppressors of free radicals and act as potent antioxidants.²⁰³ The evidence for the role of carotenoids in CVD originated from studies showing that increased consumption of fruits and vegetables was associated with a lower risk for CVD.²⁰⁴ A series of retrospective and prospective longitudinal studies identified an inverse association between carotenoid intake and risk for CVD.²⁰⁴ However, the effect of carotenoids is complex and probably does not result from a single isolated compound. In contrast, prospective randomized studies showed no benefit of carotenoid supplementation for CVD.^204,205 Corroborating this information, a cross-sectional analysis, consisting of 894 members of the cohort study Kardiovize, revealed that the consumption of foods containing vitamins (carotene, zinc, selenium, and vitamins A and C) was associated with a reduction in the intimal thickening of the carotids in women.²⁰⁶ In this research, the authors developed a “dietary antioxidant index” to categorize the foods, excluding individuals who used antioxidant supplements. Therefore, the use of supplements only with carotenoids, b-carotene, or similar compounds is not recommended. Instead, efforts should be directed toward increasing the consumption of fruits and vegetables rich in these nutrients.

6.3. Vitamin E

Vitamin E is the main fat-soluble antioxidant in the human body and is present in a complex of four isomers (a-, b-, g-, and d-tocopherol). The interest in the potential benefit of vitamin E for risk of CVD was related to its antioxidant capacity and the possibility of modifying oxidized low-density lipoprotein (Ox-LDL), particularly involved in atherogenesis.²⁰⁷ However, prospective randomized studies, such as the ATBC, CHAOS, GISSI, and HOPE, showed no benefit of vitamin E supplementation for CVD.^205,208 The effect of supplementation with vitamin E and vitamin C on alternate days for eight years on 14,641 individuals did not reduce the incidence of myocardial infarction, CVA, and CV mortality, in addition to being associated with an increased incidence of hemorrhagic CVA.²⁰⁹ Despite the solid molecular basis theory of oxidative stress and its role in atherosclerosis, these clinical trials do not corroborate the use of vitamin E supplementation to prevent CVD. On the other hand, consuming foods containing vitamins E, A, and C was associated with a lower risk for adverse CV outcomes, as demonstrated in the Hong Kong Cardiovascular Risk Factor Prevalence Study (CRISPS), a longitudinal study comprising 875 participants.²¹⁰ Thus, the consumption of foods with vitamin E has proven to be more effective and safe, and vitamin E supplementation is not recommended to prevent CVD.

6.4. Vitamin D

Vitamin D is an important precursor of the steroid hormone calcitriol, which is crucial for mineral and bone metabolism. In addition, it has other functions and supplementation with this vitamin to prevent and treat a wide range of diseases has increased considerably in the past decade.²¹¹ Its two main forms are vitamin D2 (ergocalciferol) and D3 (cholecalciferol). Vitamin D3 can be synthesized by human skin cells after exposure to UV-B radiation from sunlight. In the absence of sunlight, the intake of vitamin D is crucial. Vitamin D and dietary supplements are absorbed by the intestine and then converted into 25-hydroxyvitamin D3 [25(OH)D] in the liver, and 1.25 dihydroxyvitamin D3 [1.25(OH)2D3], the active form of vitamin D, in the kidney. Zittermann et al.²¹² summarized the underlying mechanisms for the potential role of vitamin D in preventing coronary disease. They include inhibiting the proliferation of vascular smooth muscle, suppressing vascular calcification, down-regulating pro-inflammatory cytokines, up-regulating anti-inflammatory cytokines, and acting as a negative endocrine regulator of the renin-angiotensin system. Low concentrations of circulating vitamin D were associated with AH, obesity, DM, and MS; furthermore, observational studies associated the deficiency of this vitamin with the risk for CVD.^212,213 Some ecological studies suggest that vitamin D has a role in CVD, showing an increase in cardiac disease events according to the geographical latitude, that is, associated with lower exposure to solar radiation, with the concentration of vitamin D decreasing with latitude. Several prospective studies have investigated the association between plasma concentration of 25-hydroxyvitamin D and CVD, indicating an inverse relationship between the concentrations of this vitamin in the blood and the risk for CVD.^213,214 Despite this evidence, data from a systematic review conducted by Beveridge et al.²¹⁵ showed a lack of consistent benefit of vitamin D supplementation for the main markers of endothelial and vascular function.²¹⁵ A randomized, controlled, double-blind study that lasted 5.3 years tested the efficiency of daily supplementation with 2,000 IU of vitamin D3 (cholecalciferol) in 25,871 participants.²¹⁶ The primary outcomes assessed were myocardial infarction, CVA, and mortality from all CV causes, in addition to secondary outcomes of CV events. Vitamin D supplementation did not result in a lower incidence of CV events compared to placebo. The ViDA (Vitamin D Assessment) trial involved 5,108 participants in New Zealand aged 50-84 years. In the treatment group, participants received an initial dose of 200,000 IU followed a month later by 100,000 IU or placebo for an average of 3.3 years. The study found no significant reduction in CVD and mortality in the group that received vitamin D in comparison with the placebo group.²¹⁷

Although observational studies demonstrate a positive association between low concentrations of 25hydroxyvitamin D and the risk for CV events, its supplementation is not indicated to prevent CV at the moment. However, studies with an adequate design still need to prospectively investigate populations with prominent deficiencies, especially patients with CKD, and other doses of this vitamin.²¹⁸

6.5. Vitamin K

The review prepared by the Cochrane Library could not assess the effectiveness of vitamin K supplementation in decreasing all-cause mortality, including CV and non-fatal outcomes (myocardial infarction, CVA, and angina), in depth because only one study met the pre-established inclusion criteria.²¹⁹ This study comprised 60 individuals aged 40-65 years investigated for three months and revealed that vitamin K2 did not change their BP and concentration of plasma lipids. The very limited results of this review highlight the lack of robust data about the efficiency of vitamin K in the primary prevention of CVD. However, the authors declared that the evidence for this assertion was minimal.

A recent systematic review and meta-analysis, registered as the PROSPERO study, analyzed the results of 13 clinical trials that evaluated the effects of vitamin K supplementation on cardiometabolic risk factors in healthy individuals or a population at high risk for CVD. The study found no benefit for plasma lipids, inflammatory cytokines - such as CRP and interleukin-6 - SBP, and DBP, both in healthy individuals and among those at CV risk.²²⁰ Therefore, the literature has no evidence to recommend vitamin K for CV prevention.

6.6. Vitamin C

Vitamin C or ascorbic acid is soluble in water and a very effective antioxidant since it loses electrons easily. The free radical theory of the aging process clarifies its role in the progression of chronic diseases.²⁰⁷ The Japan Collaborative Cohort Study (JACC)²²¹ assessed food intake in 23,119 men and 35,611 women aged 40 to 79 years without a history of CVD, and showed that the consumption of foods rich in vitamin C was inversely associated with mortality from CVD in Japanese women. Despite the beneficial effects of consuming foods rich in vitamin C shown in observational studies, RCTs do not confirm the efficiency of its supplementation in primary or secondary prevention of CVD.²²² Consequently, vitamin C supplementation is not recommended to prevent CVD.

6.7. B Vitamins and Folate

Evidence of a connection between vitamin B and CVD was demonstrated by the effect of these vitamins on the reduction of homocysteine.^223,224 Homocysteine, an amino acid containing sulfur, is a metabolite produced indirectly in the demethylation of methionine. Prospective studies have shown an independent but modest association between plasma concentrations of homocysteine and the risk for CVD.²²³ Some factors identified as associated with high concentrations of homocysteine are: inadequate intake of folic acid and vitamins B6 and/or B12; for this reason, the growth in plasma concentrations of homocysteine can only be one follow-up marker of an inadequate diet. Other factors that might be associated with increased homocysteine include: preexisting atherosclerotic disease, consumption of coffee and alcohol, smoking, DM, use of antiepileptic drugs or methotrexate, renal failure, rheumatoid arthritis (RA), hypothyroidism, and cystathionine beta-synthase and methylenetetrahydrofolate reductase mutations. Prospective randomized studies with a large number of CV events failed to show any benefit of folate and B complex supplementation in reducing homocysteine and preventing CVD.²⁰⁸ The disagreement between the results of epidemiological studies and clinical trials might be partially due to the inclusion of different populations and the use of folic acid-fortified foods in some countries. Folic acid or B complex supplementation is not recommended to prevent CVD.²²⁴

A recent observational study conducted in 195 countries reiterated the efficiency of consuming foods containing vitamins to prevent CV risk and mortality, associating the mortality rate of CVD attributed to diet with low intake of fruits, grains, and vegetables.¹⁶⁴ In conclusion, based on current evidence, a diet rich in vitamins must be encouraged; however, there is no indication that supplementation with these compounds can prevent CV events.

6.8. Omega-3 Polyunsaturated Fatty Acids of Marine Origin (Docosahexaenoic Acid and Eicosapentaenoic Acid)

Omega-3 fatty acids of marine origin - docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA) - produce numerous effects on different physiological and metabolic aspects that can influence the chance of developing CVD.^225,226 Despite the general agreement that regular consumption of fish rich in omega-3 fatty acids is part of a healthy diet, recommending dietary supplementation with fish oil capsules is controversial, fostered by conflicting results of clinical studies.^32,227-229

6.9. Effects of Omega-3 on the Lipid Profile

Clinical studies show that 2 to 4 grams of EPA/DHA supplementation per day can reduce TG levels by up to 25 to 30%, slightly increase HDL-c (1 to 3%), and raise LDL-c by 5-10%.³² The ability to decrease TG levels depends on the dose, with a reduction of approximately 5 to 10% for each 1 g of EPA/DHA consumed per day, which can be higher in individuals with greater baseline TG concentrations. These data show that high doses of omega-3 supplementation can be used to treat hypertriglyceridemia.

6.10. Omega-3 and Cardiovascular Outcomes

In a meta-analysis of 36 RCT, supplementation with fish oil (median dose of 3.7 g/day) reduced SBP by 3.5 mmHg and DBP by 2.4 mmHg.²³⁰ The decrease in adrenergic tonus and systemic vascular resistance is a proposed mechanism. Although several old pieces of evidence suggest a protective effect of fish and omega-3 fatty acids of marine origin on CV events,²³⁰ particularly in individuals with established CVD, more recent studies, showed no benefit of omega-3 supplementation for subjects who had or had not presented manifestations of atherosclerotic disease.^227,228 In fact, a meta-analysis of 10 studies involving 77,917 individuals both in secondary (64% with prior coronary disease, 28% with prior CVA) and primary prevention (37% of diabetic individuals) failed to show any benefit of omega-3 supplementation (EPA doses ranging from 226 to 1,800 mg/day and DHA from 0 to 1,700 mg/d) after a mean follow-up of 4.4 years, presenting 6,273 coronary events (2,695 coronary deaths).²³¹ These results were confirmed in an extensive systematic review and meta-analysis by the Cochrane group, with more than 119,000 individuals from 79 randomized studies.²³² Also, the same meta-analysis did not find the benefit of supplementation with alpha-linolenic acid (ALA), the plant omega-3. Possible reasons for the divergent results between old and contemporary studies concern the profile of the population studied, mainly regarding the more frequent use of medicines known as protectors (e.g., statins, beta-blockers, ACEI), the more aggressive control of traditional risk factors, and the higher number of myocardial revascularization procedures in more recent studies. Another difficulty in analyzing studies with omega-3 supplementation is the diversity in its composition and the lack of control regarding the intake of omega-3 in the diet.

More recently, two published clinical trials used low doses (up to 1 g/day of EPA + DHA) of omega-3 in primary prevention of CVD. One of them has assessed the role of omega-3 in the primary prevention of CVD and cancer among men over 50 years of age and women over 55 years of age (VITAL study).²³³ Using a formulation containing 460 mg of EPA and 380 mg of DHA, the study included 25,871 patients with a median follow-up of 5.3 years and found no benefit of omega-3 in reducing major CV event or invasive cancer.²³³ Another study on primary prevention, but in diabetic patients, also examined the combination of EPA/DHA in the same composition of the VITAL study. It included 15,480 diabetic patients followed for an average of 7.4 years and found no benefit of omega-3 in reducing major vascular event.²³⁴ Thus, the role of omega-3 fatty acids in the doses used with respect to the primary prevention of CV events is questionable.

The Reduction of Cardiovascular Events with Icosapent Ethyl-Intervention Trial (REDUCE-IT)³³ tested omega-3 in the reduction of CV outcomes among patients with hypertriglyceridemia and established CVD or diabetic patients with an additional risk factor. The patients received highly purified EPA (icosapent ethyl) at a dose of 4 g/day. The study included 8,179 patients who used statins and had TG ranging from 135 to 499 mg/dL (median of 216 mg/dL) and a median LDL-c of 74 mg/dL. The median reduction was 18% for TG and 6.6% for LDL-c in the EPA group. REDUCE-IT showed a relative decrease of 25% in composite CV outcomes among patients who received EPA and an absolute risk reduction of 4.8%, NNT of 22 patients to prevent an event. The hierarchical analysis demonstrated a significant decrease of 20% in CV mortality. On the other hand, the risk of hospitalization for atrial flutter or fibrillation presented a relative increase of 67% (1% absolute) with the treatment. The reduction of events in the REDUCE-IT study is similar to the results of the Japan EPA Lipid Intervention Study (JELIS), in which 1.8 g/day of EPA also led to a significant decrease in CV events among individuals who already used low doses of statins.²²⁷ However, the results of this last study are limited by their open design and lack of a placebo group.

Data from these studies suggest that high doses of EPA (4 g) can be used in patients with prior CVD and who remain with elevated TG levels, despite taking statins to prevent CVD. However, there is no evidence for the use of lower doses and other formulations of omega-3 for CV prevention, both primary and secondary. We emphasize, however, that several studies are still testing moderate to high doses of EPA and EPA + DHA in individuals at high risk for CVD who present persistent moderately high TG.

6.11. Omega-3 in Heart Failure

The GISSI-Heart Failure (GISSI-HF) trial evaluated the role of omega-3 in HF.²³⁵ This study randomized patients with chronic HF functional class II-IV of different etiologies to receive 1 g of omega-3 (EPA + DHA) (n = 3,494) or placebo (n = 3,481) per day.²³⁵ The primary outcome was time to death and time to death or hospitalization for CV causes. During a median follow-up of 3.9 years, the omega-3 group presented lower mortality rate (27 versus 29%, HR 0.91, 95% confidence interval 0.83-0.99, p = 0.041, with NNT = 56) and lower incidence of primary outcome (57 versus 59%, HR 0.92, 95% confidence interval 0.84-0.99, p = 0.009, with NNT = 44).²³⁵ Data from this study, however, need to be confirmed.

6.12. Omega-3 Polyunsaturated Fatty Acids of Plant Origin

ALA has shown inconsistent effects on lipid levels.^236,237 A systematic review and meta-analysis of 14 randomized controlled trials with ALA supplementation found no significant influence on TC, LDL-c, or TG and only a minimal effect on HDL-c (a 0.4 mg/dL reduction).²³⁸

Specifically, the effects of linseed on experimental animals range from zero to a slight lipid decrease, and a review suggested a reducing impact on TG due to humans consuming large amounts of linseed oil.²³⁸ Observational studies indicate a modest reduction in the risk for CVD with the consumption of ALA.²³⁸ Data from the Alpha-omega study showed no benefits of ALA supplementation in preventing CVD among individuals who had a prior CVD. More recent data from the Cochrane group meta-analysis suggest that increasing the intake of ALA probably makes little or no difference in all-cause mortality, CV mortality, and coronary events.²³² Its effects on CVA are unclear. However, the authors recognize the low quality of most studies; therefore, further studies on ALA supplementation are necessary to prove or refute its effectiveness in preventing CVD. We can conclude that, at the moment, there is no evidence to recommend ALA supplementation to prevent CVD. Table 3.3 presents the recommendations for ALA consumption and supplementation.

7.1. Introduction

Smoking control in Brazil has been considered as a model, not only for its programming, but for the results, with tobacco use being reduced by at least half when compared to the last decades of the 1900s. Increased cost-effective taxes, a ban on advertising, a ban on indoor use (smoke-free laws), the sale of tobacco products to minors, discussion of the subject in the school curriculum, and warnings and information about Harmful effects of smoking on schools, universities, the media, and on cigarette packs themselves were effective measures to reduce smoking. There are currently over one billion smokers in the world. Brazil is considered one of the countries in the world that has most reduced the prevalence of smokers in the last thirty years. In 1989, about 32% of the population over the age of 15 were smokers, according to the National Health and Nutrition Survey of the Brazilian Institute of Geography and Statistics (IBGE). In 2018, the VIGITEL Survey of the Ministry of Health, through a telephone survey in 27 Brazilian cities, found a frequency of adult smokers over 18 years of age of 10.1%, being higher in males (13.2%) and lower in females (7.5%). The highest frequencies were found in men between the cities of Curitiba and Porto Alegre (17.3%) and São Paulo (15.6%).²³⁹ For the CV system, continued long-term use of tobacco and its derivatives leads to the onset of chronic diseases, which will manifest around 30 years after the start of regular smoking. As most smokers become addicted to nicotine before age 18, the health consequences are disastrous given the long exposure of the body to the harmful components contained in cigarettes. Therefore, prevention is the key to this health catastrophe.

Smoking Prevention: Despite worldwide tobacco control efforts, the number of nicotine addicts is still substantial. Effective public policies against the sale, advertising and use of cigarettes in public areas are important tools in primary prevention, as they prevent non-smokers, especially children and adolescents, from being exposed to nicotine. Therefore, the experimentation rate should be reduced in young people under 15 years of age. This initiative will surely reduce the number of potential tobacco users.

Primordial prevention of smoking: “Primordial prevention of smoking” is understood to be established before the initiation of smoking. It first identifies the risk factors for smoking, with a wide range from the individual’s own vulnerability, such as the surrounding social determinants. Providing a personalized and continuing education and enabling information exchange requires the formation of a multidisciplinary team.²⁴⁰ The aim of this team is to work with individuals and their families on the risks of smoking, to outline strategies to prevent them from smoking and to promote health.^241,242

Factors that contribute to starting smoking:

7.2. Strategies in Combating Smoking Initiation ^257,258

One way to approach primordial prevention is by age groups, observing for each group five main items (5 As):

Group 0 to 4 years: Ask parents and other family members about their smoking habits; advise to keep the environment free of cigarette smoke; the message should include information about the risks to parents and children, as well as the importance of the parental model; assess willingness to cooperate between parents and other family members; assist parents with trying to quit by informing them about self-help material and/or referring them to their own doctors; make an appointment with clinic within 3 months if a relative is a smoker; check parental progress at each subsequent pediatric visit.

5 to 12 years old group: Ask children about how they feel when someone is smoking nearby and what they do about it if they think it is dangerous to try smoking and if they think they will smoke when they are older, if they have tried smoking or if they have friends who smoke; advise children not to try smoking, praise them for remaining a non-smoker and/or staying away from cigarette smoke; remind children about the short-term negative effects of tobacco, such as reduced ability to smell and athletic capacity, as well as personal health risks (e,g., asthma exacerbation); advise parents to quit smoking and to give clear anti-smoking information to their children; assess the risk factors of smoking initiation or regular smoking progression, including level of experimentation, smoking among friends, depressive symptoms, school performance and adverse experiences; help parents in trying to quit smoking; assist children with developing skills to refuse smoking and exposure to it; assist parents in efforts to prevent tobacco use by their children through parenting and firm anti-smoking messages; make an appointment with clinic within 1-2 months for any child who is smoking or has worrisome risk factors for smoking, refer as necessary cases of social or learning difficulties and mental disorders as well.

Group of adolescents and young adults: ask adolescents about smoking behavior, confidentially about friends who smoke and about light cigarettes; advise adolescents to stop smoking, reinforcing personal health risks and danger of addiction; commend adolescents who are not smoking and remind them about the health risks; assess the motivation and symptoms of tobacco dependence among adolescents who are smoking; assess risk factors for smoking initiation among non-smokers; assist adolescents who are smoking with trying to quit, including nicotine replacement and referring if necessary; help parents with their efforts to prevent smoking initiation among their children through parenting and firm anti-smoking information; make an appointment with clinic within one month for each teenager who is smoking, supporting attempts to quit or assessing motivation and barriers to quitting; refer as necessary if risk factors are identified, such as social or learning difficulties, or findings of mental disorders.

Primordial Prevention of CVD, in its broadest context, it involves avoiding the establishment of modifiable CVD risk factors, including smoking, and effective strategies for promoting CV health of the individual and the population. Therefore, the joint action of interdiscipline teams (doctors, nurses, psychologists, physical educators, educators, nutritionists, social workers, communicators, managers) and intersectoral (family, school, government, society specialists, university) teams is necessary in a continuous and simultaneous way.

7.3. How to Treat Smoker’s Psychological Dependence

Nicotine addiction is a highly complex process that should be addressed by all health professionals. Every healthcare professional, especially the doctor during consultations, as well as the multidisciplinary team, should ask if the patient is a smoker. This question is essential. If the patient is a smoker, two types of approach can be used.

Basic approach where the goal is to ask if you smoke, to evaluate the smoker’s profile, to advise to quit smoking, to prepare for cessation and to accompany the smoker to the cessation of smoking. This approach should always be performed by the physician during the routine consultation, with an average duration of 3 (minimum) to 5 (maximum) minutes with each contact the patient makes. The patient should be questioned and asked systematically at each consultation and feedback on the evolution of the cessation process. Suitable for all smokers. Meta-analysis involving 29 studies showed that cessation rates were 19.9% for those who underwent medical intervention.²⁵⁹

Specific Intensive Approach: performed by health professionals available and trained to make a more in-depth follow-up with the patient, including the doctor. In this case, the professional should have a structured program available to the patient with scheduled sessions (8 group/individual sessions), and will use national reference medication for treatment of smoking, as well as the cognitive behavioral approach. If possible, the patient should be followed up to 1 year of treatment. The cognitive behavioral approach is a psychological approach that is based on working out the automatic thoughts that the smoker has and that lead him/her to get a cigarette. These thoughts are often accompanied by emotion and behaviors associated with smoking. It is important for the patient to feel welcomed by the doctor, to show empathy, not to judge or condemn because of difficulties in smoking cessation. Another aspect is that the better the smoker knows his/her addiction profile, the easier it is to work on ways to control smoking addiction.^259,260

In the cognitive-behavioral approach it is necessary to: distinguish the patient’s automatic (dysfunctional) thoughts - example: “if I do not smoke I cannot think” - helping him to seek coping strategies for situations other than getting a cigarette. Behavioral techniques most commonly used: self-observation, control of stimuli or triggers that lead to smoking (telephone, computer, alcohol, bathroom, car), identification and learning of functional thinking patterns, relaxation techniques, deep breathing, postponement and breaking of conditioning, assertiveness training (so that one can face situations where there is the temptation to smoke), self-instruction (situations in which patients are taught to argue with themselves about the situation that tries to induce them to smoke) and problem-solving so that patients are taught about appropriate ways to solve a problem situation.^260-262

Instruments that help in assessing and understanding the patient profile:

7.4. Pharmacological Treatment of Smoking

7.5. Anti-Smoking Drug Combinations

The effectiveness of first-line anti-smoking drugs is between 20 and 25% for nicotine replacement and bupoprione, and does not exceed 35% with varenicline.²⁶⁸ Thus, we can imagine that out of 10 patients treated, about 3 will quit and 7 will not.

The combination of anti-smoking drugs seems to be a reasonable application option to improve success rates. Despite the increase in cost, it should be considered that quitting smoking has an substantial cost-benefit ratio, so the proposal is perfectly viable, leaving the perspective of dealing with the possible increase in side effects as the main factor to be managed.

Some studies with the combination of patches and oral nicotine have shown improved results. Meta-analysis of 9 studies²⁷⁷ that combined a nicotine patch with a nicotine rapid-release drug (gum, spray, lozenge) proved to be more effective than a single type of NRT (RR 1.34, 95% confidence interval 1.18 to 1.51).

The combination of NRT and bupropion was more effective than bupropion alone in the meta-analysis of 4 studies.²⁷⁷ (RR 1,24; 95% confidence interval 1.06 to1.45).

The combination of varenicline and bupropion appears to be the most effective of all (Evidence B);²⁸⁵ however, randomized studies²⁸⁶ of greater consistency need to be performed.

7.6. Future Proposals

The use of serotonin reuptake inhibitors has not proven to be an option for treatment of withdrawal symptoms,²⁸¹ but considering how often depressive symptoms manifest during smoking cessation,²⁸⁵ with or without drugs,²⁸⁶ randomized trials to test concomitant use of this drug should be conducted to assess whether results are improving, as nicotine has an action on monoaminoxidase A, which is responsible for serotonin degradation, among many other neurotransmitters, which would explain the high frequency of this condition. smoking cessation, with or without anti-smoking medication. Bupropion and varenicline have no action on serotonin, explaining the higher frequency of mood disorders in drug users compared to those on nicotine replacement.

We believe that this event is more likely to occur in varenicline users due to the high antagonist potency in the a4 b2 receptor, thus preventing nicotinic action, even if the patient smokes. From this perspective, the longitudinal, observational study that evaluated the effectiveness of the combination of varenicline, bupropion and sertraline²⁸⁷ had a better success rate among those that used all three drugs. These findings warrant corroboration through a randomized, placebo-controlled study, so that there is indeed robust evidence of the benefit of these combinations, as well as testing whether the use of serotonin reuptake inhibitors is confirmed as an ancillary strategy in anti-smoking treatment in patients who manifest depressive symptoms during smoking treatment.^288,289

Nicotine vaccines,²⁹⁰ long awaited to comprise the therapeutic arsenal, are still under study. They act by stimulating the immune system to produce specific antibodies that bind with great affinity to nicotine in plasma and extracellular fluids.Nicotine bound to antibodies cannot cross the blood-brain barrier because of its size, the vicious circle of gratification for brain receptor activation is broken. The main brands under study are: Nic-VAX®, TA-Nic® and Nic-Qb®.

7.7. Nicotine Electronic Devices (Electronic Cigarette, Heated Cigarette, Pen Drives)

These devices were launched in 2006 and have since been refined by their manufacturers to replace the conventional cigarette. The industry of these products insists on seeing them as “smoking cessation treatment,” arguing that smokers, by replacing the use of ordinary cigarettes with these devices, would reduce the risk of disease by consuming a product with less toxic substances. With this argument, they are investing heavily in marketing, and Phillips Morris, one of the largest conventional cigarette manufacturers in the world, is widely publicizing its strategy to stop producing ordinary cigarettes and replace it with heated cigarettes, also an electronic nicotine-release device, without combustion.²⁹¹

The marketing, importation and advertising of any electronic smoking device, including electronic cigarette and heated cigarette, have been banned by Anvisa (National Health Surveillance Agency) since 2009 in Brazil (RDC 46). The agency considers that there is no scientific evidence to aid smoking cessation - meaning cessation as a treatment process for nicotine addiction - or scientific arguments that actually prove reduced morbidity and mortality by tobacco-related diseases in populations that have replaced tobacco use. Although they contain less toxic substances than conventional non-combustion cigarettes, those present are not harmless, and nicotine is a substance known to have CV effects, and perpetuates the addiction condition.²⁹²

The impact of the use of these products on people’s health is not yet known, and although manufacturers are betting on their use as a harm reduction policy, the concern is that there is an epidemic of consumption and a setback in encouraging smoking cessation worldwide. Therefore, WHO does not recognize these devices as a treatment for smoking and warns that they cause nicotine addiction just as much as regular cigarettes, and looks forward to studies evaluating the impact of these products on morbidity and mortality.²⁹³

7.8. Hookah

Contrary to popular belief that hookah is less harmful and less addictive than cigarettes, research shows that both carry significant health risks, and may induce nicotine addiction.^294,295

The world panorama shows that the trends of hookah use are alarming and have shifted from being a social phenomenon among young people in some regions to becoming the beginning of a global epidemic.²⁹⁶

In Brazil, the frequency of hookah use in the Brazilian adult population aged 18 to 59 years was determined in a population-based cross-sectional study using the 2013 National Health Survey (PNS). Of the 60,225 adults interviewed, 15% reported using any tobacco use, with the frequency of hookah use being 1.2% (95% confidence interval 0.8 - 1.6), higher in the male, white and younger age groups, with medium to high schooling, and urban and southern and midwestern residents; Among those who tried hookah, 50% used it sporadically, 12.8% monthly, 27.3% weekly and 6.8% daily. These results point to the need for supervision and educational campaigns on the risks of hookah use.²⁹⁷

7.9. Conclusion

Pharmacological treatment of smoking should be considered as a secondary prevention strategy, mainly aimed at reducing CV injury. Smoking is a chronic degenerative disease, and should be viewed by the cardiologist like the other common illnesses in their care routine, such as hypertension and DM.

Defining criteria for choosing which anti-smoking drug will initially be used for patient treatment is still a challenge for treatment guides and guidelines because of the lack of systematization of models to be tested. In clinical practice, the choice of drugs is made on the basis of contraindications, drug availability and price, among other criteria. Therefore, systematically discussing criterion models for this choice becomes relevant and necessary for increasing the efficacy of anti-smoking treatment.

The high degree of nicotine dependence²⁹⁸ could be a factor in decision making, as well as factors that identify subpopulations that benefit from any particular drug, considering gender, age, pharmacogenetics²⁹⁹ (genetic polymorphism of nicotinic, dopamine and hepatic receptors) among others. These factors are not yet known at this time.

Recommendations for addressing adult smokers can be found in Table 7.1 and Charts 7.1, 7.2, ^7.3 and ^7.4.

8.1. Introduction

Physical inactivity is one of the major public health problems, and physical inactivity, which is strongly related to all-cause and CVD mortality, is highly prevalent in Brazil and worldwide.^301,302 Increased physical activity is related to health gain, better quality of life and greater life expectancy.^303-307 Therefore, both in an individual and population-based CVD prevention strategy, it is of utmost importance to prioritize a strong fight against sedentarism, and requiring the questioning of PA habits and encouragement of adopting a more active lifestyle should be routinely done at medical office visits.³⁰⁸

8.2. Relevant Concepts and Expressions in Physical Activity

PA is used as a broad term that includes both structured and unstructured forms of leisure, sports, transportation, and domestic and work-related activities. physical activity involves body movement, with increased energy expenditure in relation to rest, and can be classified in terms of intensity as mild, moderate or high. Physical exercise is defined as a subset of structured activities aimed at improving cardiorespiratory fitness, balance, flexibility, strength and/or power and even cognitive function, particularly important in the elderly.³⁰⁹

Thus, physical activity, physical exercise and sports are related but distinct terms, and Table 8.1 defines some concepts and expressions.

There is a strong association of different levels of physical fitness components with all-cause mortality and the occurrence of unfavorable CV events, with inverse association, i.e., the lower the physical fitness, the higher the mortality,^310-317 requiring preventive action, focusing on combating physical inactivity as of childhood. WHO recently presented specific recommendations for children 0 to 5 years of age related to daily physical activity/exercise and sleep times, which considerably limits or restricts sitting time in front of screens.³¹⁸ Table 8.2 presents a classification of the profile of children and adolescents according to physical exercise.³¹⁹

8.3. Main Acute and Chronic Effects of Exercise

The effects of exercise can be divided into acute and chronic.³²⁰ The acute effect is that which dissipates rapidly and may be immediate after a single session or last for up to 24 hours (subacute or late acute effect). Improvement in flow-mediated response with respect to endothelial function is an example of the acute effect of a single exercise session. The chronic effect is achieved by repeated acute/subacute effects and can be evaluated at rest, even if long after the last exercise session. Resting bradycardia observed in athletes of predominantly aerobic modalities is an example of chronic effect. Repetition of responses can produce a chronic effect, as in the case of decreased blood pressure. Some of the main effects of exercise are listed in Chart 8.1.

8.4. Epidemiological Rationale of the Benefits of Physical Exercise

In addition to aerobic fitness,^{312-315,321,322} other components of physical fitness are associated with prognosis, with higher mortality associated with poor fitness. proven as a predictor of mortality in middle-aged and elderly men and women.^311,323 Other studies on muscle strength and power have also shown associations with mortality.^316,317

Scientific findings support the previous recommendations of national^324,328 and international guidelines³²⁹ that recommend the regular and combined practice of aerobic and resistance exercises. Flexibility and balance exercises should be part of an exercise program, especially aimed at the elderly.

Regarding PE, the greatest benefit is when comparing sedentary individuals and those who engage in very little or no exercise, since the positive impact of abandoning a sedentary lifestyle is very significant. However, comparing the varying degrees of aerobic fitness on an increasing scale, we realize that there is a continuous decrease in the risk of cardiac death and all-cause death. The higher aerobic fitness, the lower the risk is of total morbidity and mortality and CVD both in healthy individuals and in CVD patients.^{312-315,321,322}

Greater physical fitness and amount of physical activity are associated with lower risk of developing hypertension.³³⁰ In already hypertensive individuals, PE reduces BP, and better results have been found with aerobic exercise (mean SBP reduction of 8.3 mmHg and DBP 5.2 mmHg). Smaller but significant reductions also occur with dynamic resistance training.¹⁵⁰ Another useful and clinically safe strategy for BP reduction is based on manual isometric training.^150,331 In patients with resistant hypertension - those with over-target BP despite the use of three or more antihypertensive medications, exercise in warm water (30 to 32°C) resulted in a more marked reduction in BP, and should be considered when available.^332-334

The effects of reducing blood pressure levels during exercise occur immediately after the end of exercise and last up to 24 to 48 hours. Thus, as with drugs, this action in the CV system needs to be repeated periodically for the benefit to be chronically maintained. Regular PE exerts a hypotensive action, which adds to the effects of pharmacotherapy³³⁵ and may, in some cases, require reduction of medication doses.

It has also been suggested that dyslipidemic individuals with higher cardiorespiratory fitness, even without statin use, have a lower CVD risk than those with poor fitness using medication. Those with higher aerobic fitness and statin use have lower all-cause mortality, which reinforces the importance of physical exercise and greater physical fitness, even in patients with optimized drug treatment.^336,337

8.5. Risks of Physical Activity, Physical Exercise and Sport

Healthy individuals have an extremely low risk of events due to regular exercise. A study of more than 20,000 physicians with an average follow-up of 12 years found that the risk was approximately one out of every 1.5 million hours of exercise exposure (during and within the first 30 minutes post-exercise).³³⁸ Thus, the recommendation to be physically active is quite safe and the fear of exercise-related problems should not be a barrier or justification for maintaining a sedentary lifestyle. This message needs to be widely disseminated to the population because the percentage of physically active individuals is very low in our country.³³⁹

For further information regarding sport and pre-participation assessment, it is recommended to read the recent update of the Brazilian Society of Cardiology Guidelines for Cardiology of Sport and Exercise.³²⁸

8.6. Recommendations for Exercise and Physical Activity

Although a meta-analysis has shown that simply stimulating the adoption of a more active lifestyle can increase physical activity levels,^340,341 the physician’s guidance should be for physical exercise to be in an organized and structured manner. A good weekly goal for CVD health promotion and prevention is physical activity/exercise/sport for at least 150 minutes of moderate intensity or 75 minutes of high intensity.^10,342,347 Getting more than 300 minutes per week of moderate to high intensity exercise may provide additional benefit. However, there is no scientific evidence for a clear delineation of an upper limit from which there would be a greater possibility of harm to a healthy individual.³⁰³

More recent studies have associated sedentary time, such as watching television, with higher all-cause mortality, CV mortality, and the risk of developing DM.³⁴⁸

8.7. Prescription for Exercises

Exercises may be prescribed for their characteristics, such as type (aerobic, muscle endurance, flexibility), modality (walking, running, cycling, dancing), duration (running time), weekly frequency and its intensity (Tables 8.4 and 8.5).

Previously sedentary patients may begin exercise at the lower end of the prescription and progress to higher intensities gradually over the following weeks. The progression should initially be made in the duration of the session and later in the intensity of the exercises. Already physically active patients, according to individual assessment, can perform exercises at more intense levels, aiming at a minimum of 75 minutes, ideally divided into two or more weekly sessions.

Localized muscular endurance and strengthening or power exercises have been shown to be very beneficial for general health and for CV and musculoskeletal systems, being of fundamental importance in patients with sarcopenia and/or osteopenia. They should be performed at least twice a week, favoring large muscle groups of the upper and lower limbs and trunk. They can be made using one’s own body or using attachments such as free weights, shin guards, elastic bands and weight machines. The load or weight for each exercise or movement must be individually adjusted. Due attention should be given to the execution of the movements so that technique and posture are correct.

There are different protocols for resistance exercise, from the number of exercises used per session from 6 to 15 (when done daily, there is a tendency to work a muscle group on alternate days), ranging from one to three sets for each exercise and also in the number of repetitions from 6 to 15. When training muscle power, the speed of execution should be as fast as possible in the concentric phase of the movement. In this case, only 6 to 8 repetitions per exercise are used, requiring only 20 to 30 second interval between each series to allow replenishment of the adenosine triphosphate (ATP) and phosphocreatine stocks needed to perform the next series. This strategy also has the advantage of greatly reducing the time dedicated to resistance exercises, which in many situations may represent the difference between adhering to the prescribed exercise program and not.

Flexibility exercises can offer osteomyoarticular benefits, health-related quality of life and prevention of falling in the elderly. By contributing to easier and more efficient joint movement, they ultimately reduce the demand for oxygen in moving situations and thus benefit the CV system. In these exercises, we seek to reach the maximum range of motion, reaching the point of slight discomfort and statically held position for 10 to 30 seconds. Flexibility exercises should ideally be individualized from specific assessments, such as the.³⁴⁹ In general, women tend to be more flexible than men, and there is a tendency for a progressive loss of flexibility with aging. tends to be proportionally larger in shoulder and trunk movements.

Depending on the age range, clinical conditions and objectives of the exercise program for a given patient, other forms of exercise may be included in the prescription, such as motor coordination and balance exercises, not to mention the numerous opportunities generated by more playful forms and exercise socializers such as ballroom dancing and Tai-Chi-Chuan.^351,352

Performing assessments of aerobic and non-aerobic fitness allows a more individualized prescription of physical exercise, aiming to obtain the best results and, through risk stratification and search for hidden abnormalities, minimize the risks of exercise of any kind or intensity.

The initial evaluation consists of anamnesis, physical examination and ECG. More detailed assessments should be individualized, with exercise testing or maximal exercise cardiopulmonary testing, anthropometric assessment, muscle strength/power and flexibility. In the initial evaluation, we can quantify the functional deficit against the desirable, as well as set goals to be achieved. It is important to emphasize that even those with low initial levels of physical fitness can benefit from and become adherent to a supervised exercise program.³⁵³ It is also possible to obtain clinical and functional support for appropriate counseling on sexual activity based on the KiTOMI model proposed by Brazilian authors in 2016.³⁵⁴ It is essential for commitment to be encouraged in the patient on reevaluation, while measuring his/her evolution and benefits obtained.

8.8. Formal and Informal Physical Activity: Encouraging Referral, Implementation and Adherence

Although health benefits occur with relatively low intensity activities resulting from informal daily actions such as walking, climbing stairs, cycling and dancing, it is ideal that regular exercise (formal activities) also occur, which provides greater gains.

Patients with heart disease also benefit from regular physical exercise, ideally in the context of a formal CV rehabilitation program (or supervised physical exercise). CV rehabilitation acts on major disease outcomes, with proven effects by meta-analyses of randomized trials, reducing CV mortality, reducing hospitalizations^355,356 and improving quality of life. In addition, CV rehabilitation is a cost-effective treatment.^357,358

A possible way to improve exercise counseling by health professionals would be to combat their physical inactivity, as it has been shown that physically active people have greater knowledge about recommendations on prescribed exercises and can motivate more.³⁵⁹

In addition to direct medical practice, there is a need for changes in public and private policies, with the need for comprehensive strategies established through simultaneous actions, such as increasing physical activity in school programs; transport policies and systems that favor commuting through walking, cycling and public transportation; public education, including public awareness campaigns; sports organization at various levels (school, work, community etc.), with proposals that encourage and enable lifelong sports, from childhood to old age.

8.9. Final Messages

Physical inactivity should be combated by increasing physical activity in its various forms, both structured, physical and unstructured, favoring urban mobility with bicycle paths and facilitating travel through walking.

There is a consensus that a good and plausible weekly goal for health promotion and CVD prevention is to engage in physical activity/exercise/sport for at least 150 minutes of moderate intensity or 75 minutes of high intensity.

Given the current stage of knowledge, it can be said that:

9.1. Concepts, Definitions and Rationale

9.2. Spiritual History and Scales for Measuring Religiosity and Spirituality

The degree of spirituality and religiosity of patients can be assessed in spiritual history or anamnesis, understood as “the set of questions asked to the patient to share their spiritual and religious values, to identify possible spiritual issues that may contribute to or undermine the therapy, as well as feelings that are used in daily life, in the life of relationship, whether positive (edifying) or negative (not edifying).” It should always be patient-centered and guided by what it expresses about its spirituality.³⁷⁸ At first, spiritual anamnesis as an integral part of clinical history should be obtained from all patients seeking medical attention, but especially those hospitalized with serious, chronic, progressive or debilitating illness.

9.3. Primary Prevention

Available scientific evidence describes that high levels of spirituality and religiosity are associated with lower prevalence of smoking, alcohol consumption, sedentarism/PA, better nutritional and pharmacological adherence in dyslipidemia, hypertension, obesity and DM.^365,399-401

Alcohol: In many studies that examined the relationship between spirituality and religiosity with alcohol use, an inverse relationship was found; that is, there were higher rates of spirituality or frequency of religious activity, with lower alcohol consumption. According to the same authors, several studies have shown that more religious individuals are more physically active. There is also a positive relationship between spirituality and religiosity and PA.³⁶⁵ Among Brazilian university students, a higher prevalence of alcohol consumption, smoking and use of at least one illicit drug in the last 30 days among those who had less frequent religious involvement.³⁹⁹

Smoking: In the CARDIA cohort study, it was observed that religiosity was related to lower risk of subclinical carotid atherosclerosis and had a positive association with higher consumption of fiber, vegetables and fruits, and lower consumption of processed foods.^401,402

Obesity: In both the MESA and CARDIA studies, a higher association was observed between extent of religious involvement and higher propensity for obesity.^401,402 Compared to those who did not participate in any religious activity, individuals with different frequencies of religious involvement were significantly more prone to obesity even after adjusting for demographic and smoking characteristics.

Diabetes mellitus: Regarding diabetes, although they are more prone to obesity, patients with greater religiosity had no higher risk of being diabetic. This may be explained by better diet or better treatment adherence.³⁶⁶ In contrast, in the Third National Health and Nutrition Examination Survey (NHANES III) study, there was no association between diabetes and attendance at religious services.³⁷⁰

Hypertension: Regarding hypertension, the results are contradictory. In the Chicago Community Adult Health Study, it was found that higher religiosity indicators were not associated with hypertension.⁴⁰³ In the prospective Black Women’s Health Study, after an 8-year follow-up, the greater involvement with spirituality and religiosity employed in coping with stressful events was associated with a lower risk of developing hypertension, especially in women with higher stress.⁴⁰⁴ A national study involving a highly religious community found that the prevalence of hypertension among these individuals was lower than the national prevalence.⁴⁰⁵

Meditation is one of the most studied interventions among practices related to spirituality and religiosity and the repercussions on BP levels. In these studies, the magnitude of BP reduction varies significantly. Studies have methodological limitations with data bias, high dropout rates, and different populations studied.

In a systematic literature review, transcendental meditation reduced SBP by ~4 mmHg and DBP by ~2 mmHg, effects comparable to other lifestyle interventions such as weight loss and exercise.⁴⁰⁷ The mechanisms by which meditation reduces PA have not yet been fully elucidated. Possibly, the long-term neurophysiological changes that occur with meditation may lead to changes mediated by the autonomic nervous system in BP. The impact of stress reduction on BP remains to be better defined.⁴⁰⁶

9.4. Secondary Prevention

As with primary prevention, secondary prevention should be viewed as comprehensive and taking into account psychosocial factors such as socioeconomic status, depression, anxiety, hostility/anger, and type D personality that may aggravate CVD.² In this context, some of these factors should be highlighted, as well as the results obtained with new proposals for intervention in the field of spirituality, religiosity and related areas.

Forgiveness: Evaluated by various scales as tendency and attitude, forgiveness determines multiple effects, generating states more favorable to homeostasis in the emotional, cognitive, physiological, psychological, and spiritual aspects. Forgiveness broadens the possibilities for behavior by building better adaptive strategies and counteracting the feelings of anxiety, anger, and hostility that are potent CV risk factors. It also reduces stress, drug addiction and rumination; improves social support, interpersonal relationships, and health self-care.^409-413

One study analyzed the effect of forgiveness on myocardial ischemia, ischemia generated by stress and measured by scintigraphy techniques. Patients were randomized to receive or not a series of psychotherapy sessions to develop interpersonal forgiveness. After 10 weeks of follow-up, the forgiveness intervention was able to reduce the burden of anger-induced myocardial ischemia in patients with CAD.⁴¹⁴

Gratitude: In clinical practice, gratitude can be assessed by specific questionnaires such as the Gratitude Questionnaire - 6 (GQ-6),⁴¹⁵ allowing the analysis of behavioral interactions and physiological, pathophysiological and clinical outcomes. Individuals with greater gratitude have a better CV health profile, similarly to those with higher spirituality and religiosity indices.

In asymptomatic HF patients assessed by the gratitude, depression, sleep, gratitude, and spiritual well-being questionnaires, the latter two correlated with better inflammatory profile and better mood and sleep quality, less fatigue, and greater self-efficacy.⁴¹⁶ Psychological strategies that may increase feelings of gratitude such as regular journaling, thoughts, meditation, and fact-checking, or grateful people have been studied, demonstrating increased feelings of gratitude and reduced inflammatory markers.⁴¹⁷

Depression and Resilience: Depression is significantly more common in patients with CVD than in the general community. This higher prevalence is often secondary to the disease as an adaptation disorder, with symptoms disappearing spontaneously in most patients. However, approximately 15% of them develop a major depressive disorder, which is an independent risk marker of increased morbidity and mortality.^418,419

In a cross-sectional study including 133 patients diagnosed with ischemic heart disease assessed by the Wagnild & Young Resilience Scale, 81% were classified as resilient, suggesting that disease may act as a facilitator for the presence of this feeling.⁴²⁰

Resilience is a behavior that greatly improves treatment adherence as well as quality of life and can be acquired at any stage of life, regardless of age and disease state. Spirituality and religiosity are associated with higher levels of resilience.^420,421

In another series, elderly patients (≥ 65 years) were significantly more resilient than younger patients. Resilience correlated negatively with depression and inversely with affective, cognitive, and somatic symptoms of depression and was responsible for greater variation in the affective characteristics of depression than in the somatic characteristics.⁴¹⁹

In a long-term cohort, patients were analyzed for functional social support, BMI, recent history of major depression, coronary artery disease, hypertension, and diabetes. After 13 years, it was observed that social support was responsible for reducing the relationship between depression and the occurrence of coronary artery disease. Specifically, depression was prospectively associated with coronary artery disease among individuals with low social support but not those with high support, suggesting that it may function as a resilience factor against CV risk associated with depression.⁴²²

The Palliative Care in Heart Failure study was the first randomized controlled trial involving palliative care to demonstrate the significant clinical benefit of incorporating interdisciplinary interventions in the management of patients with advanced HF. The addition of palliative care improved physical and psychosocial condition (anxiety/depression), and spiritual quality of life.⁴²³

Relaxation and Meditation: Relaxation and meditation are well-established mind/body approaches to improving stress, and their benefit has been demonstrated in many populations, including heart disease.^344.424-426 Easy to learn and practical, they are inexpensive and widely accessible techniques.

In an observational study in patients with coronary artery disease, the cardiac rehabilitation strategy associated with a 13-week program was analyzed using self-relaxation, spiritual well-being and psychological stress control techniques. There were significant increases in relaxation practice time and spiritual well-being scores, as well as improvement in depression, anxiety, hostility, and overall severity scores. A greater increase in relaxation practice time was associated with spiritual well-being, which in turn was associated with improved psychological outcomes.⁴²⁴

Patients with coronary artery disease were enrolled in a transcendental meditation or health education program with an average follow-up of 5.4 years. Transcendental meditation significantly reduced the risk of mortality, myocardial infarction, and stroke, these changes being associated with lower BP levels and psychosocial stressors.

Additionally, a national study randomized patients with chronic HF to do meditation or not, demonstrating a reduction in serum norepinephrine and VE/VCO₂ slope in the cardiopulmonary test and improved quality of life assessed by the Minnesota Living with Heart Failure questionnaire.⁴²⁶

A recent paper by the American Heart Association reviews various forms of meditation and highlights the prolonged effects observed on brain physiology and anatomy, possibly responsible for better systemic physiological status and reduced cardiovascular risk. Meditation shows a better physiological response to stress, smoking cessation, reduced BP, insulin resistance and metabolic syndrome, endothelial function, inducible myocardial ischemia, and primary and secondary prevention of CVD. Although some data on CVD risk reduction are limited, meditation can be considered as a complement to risk reduction and lifestyle modification.³⁴⁴

In a robust study involving 1,120 meditators, other complex domains have been identified that may be crucial to people’s psychological and spiritual development by acting as mediators and/or mechanisms responsible for the effects of meditation. Of difficult measurement, relational and transpersonal aspects, mystics, and anomalous or extraordinary phenomena linked to meditation deserve further study.

The extent of the possible effects to be obtained with each form of meditation remains open. Transcendental meditation has been shown to reduce anxiety, improve mood, and to double the acute pain tolerance time when compared to secular forms of meditation.⁴²⁸

Medication adherence: In a cohort of 130 HF patients, adequate adherence score was observed in only 38.5% of patients. Spirituality, religiosity, and personal beliefs were the only variables consistently associated with adherence. It is noteworthy that depression or religiosity were not correlated with adherence when evaluated separately. When spirituality was assessed by both, it was positively correlated with adherence, adjusted for demographic and clinical characteristics and psychosocial instruments.⁴²⁹

Cardiac Rehabilitation: Several studies report improvement in psychological stress in patients with coronary artery disease undergoing CV rehabilitation. In addition, a meta-analysis of 23 randomized controlled trials involving 3,180 coronary artery disease patients seeking to assess the impact of adding psychosocial interventions to standard rehabilitation exercise reported greater reduction in psychological distress and improvements in SBP and serum cholesterol.⁴³⁰ The scope of cardiac rehabilitation can be amplified by positive psychology techniques. In patients undergoing coronary angioplasty, these explanatory techniques, with telephone contacts and inductive correspondence, resulted in better physical performance (caloric expenditure), with a reduction in medical events, as opposed to the effects observed by stress.⁴³¹

In another meta-analysis, the influence of rehabilitation associated with psychosocial and/or educational interventions in 14,486 individuals with pre-established coronary artery disease with a median follow-up of 12 months was evaluated. In general, rehabilitation led to a reduction in CVD mortality and the risk of hospitalizations and a better quality of life.³⁵⁴

9.5. Recommendations for Clinical Practice

Most patients and their families, guardians or caregivers have varying degrees of religiosity and spiritual needs and, importantly, expect health professionals to know their beliefs and to be part of the decision-making process, reinforcing the concept of integrality.

Health professionals involved should keep in mind that spirituality and religiosity favorably influence ability to cope with the disease, but the isolation imposed by hospitalization may be negative as it removes patients from their religious meetings or practices, from religious leaders and of dedicated communities.

These beliefs and practices can impact and often antagonize proposed medical strategies. It is worth noting that health professionals also present their own profiles of spirituality and religiosity, influencing their practice, especially in severe, critical or limiting situations.

Every professional should be aware of the relevance of screening involving spirituality, and those focused on direct care such as doctors, nurses, and chaplains should have an anamnesis of spirituality and religiosity, viewed not only as part of identifying where professed religion is concerned, but how a broader construction obtained by structured or unstructured questionnaires, allowing to penetrate and understand the true identity of spirituality and religiosity in patients and relatives.^387,432,433 Most professionals are sensitive to the demand of patients only when informed, but the contemporary view is to actively search for this information and demands, because the patient often does not feel comfortable discussing it.⁴³²

In a holistic view of a human being, the anamnesis of spirituality and religiosity should be remembered in each care interaction and by all health professionals.^366,433 Naturally, this approach may be unimportant or difficult to use in many situations, such as in major emergencies, but it is of enormous relevance in critical, terminal, chronic degenerative diseases or palliative care.

Critically ill patients have high rates of not only pain, dyspnea, anorexia, and fatigue, but also of anxiety, nervousness, sadness and depression. For this patient profile, Cicely Saunders’ concept of “total pain,” understood as a sum of physical, psychological, social, emotional and spiritual elements, must be valued and addressed in a systematic and structured manner, even in the first days of hospitalization.^434,435

Patient-centered approaches with a greater focus on spirituality make it easy to understand and value the motivations for consultation, understand the patient’s universe (including emotional and existential issues), and strengthen the relationship between practitioners and patients, shared decision making, and prevention and promotion of health.^433,436

It is essential for professionals to be technically prepared and the patient to agree on addressing issues related to spirituality and religiosity so that the interaction is constructive and without conflict. In the absence of technical training or resistance to the subject by the patient, the spiritual history should be postponed to a more opportune time or even canceled. When these alignments do not occur, serious conflicts can develop and sometimes very deleterious to medical management.

To avoid conflicts in the doctor-patient relationship, it should always be borne in mind that this area is deeply personal as well as intensely emotional, and therefore, the physician should not address emotional issues without proper approximation of spiritual and/or religious aspects. The physician should be sure of the patient’s agreement to address the issue.

Health professionals, especially those involved in critical or terminal patient care or palliative care, are subject to a significant burden of professional stress. This work involves a lot of compassion, understood as an attitude of addressing the needs of others and helping those in distress, which can be viewed as a spiritual practice. Training and practice strategies on spirituality and religiosity in this setting can contribute to a better sense of meaning and purpose at work, spiritual well-being, less fatigue and reduced burnout.³⁶⁶

The reasons for professionals not addressing spirituality and religiosity are diverse, such as feeling uncertain about initiating spiritual discussions, being misunderstood as imposing religion, invasion of privacy, causing discomfort, difficulties with the language of spirituality.⁴³⁶ These justifications have also been identified in Brazilian medical students⁴³⁷ and represent weaknesses in medical education and practice, with specific ignorance or inadequate dimensioning, lack of mastery of specific tools and training.

The solution to these limitations lies in the development of hospital spirituality support and training programs. These programs contribute to well-being and health improvement, assist with misunderstanding in conducts, and meet patients’ expectations, and they are part of accreditation processes and prospects for reducing hospitalization costs.⁴³⁸ For the development of these programs, there should be deep institutional involvement, formal training of the teams most directly connected to care, availability of infrastructure and resources, adjustments to care routines, and alignment with the various religious communities.

Health teams, especially when acting in scenarios where there is a higher demand for spirituality and religiosity, should be structured with systematic training and clear definition of responsibilities, such as obtaining and recording anamnesis in medical records, clarifying the observed demands and the implemented clinical course, as well as the observed outcomes. At initial contact, spiritual history can be obtained through open and brief questions by the doctor, nurse or chaplain, thus tracking needs and anticipating conflicts. For the spiritual approach, no professional is expected to be able to do so, but a certified chaplain or a spiritual care professional with equivalent technical training and structured standards and concepts to develop a spiritual care plan.³⁸⁷

Religion should never be prescribed, forced or even encouraged, at the risk of adding guilt to the burden of disease. Identifying the right time for spirituality and religiosity approaches is important to avoid any kind of misunderstanding, always under the rule of common sense. We emphasize that the evaluation of spirituality is always desirable, enabling the search for information in all patients regardless of religion or religiosity, but the approach in extreme situations can lead to stress and even worsen patient evolution.

Respect for spirituality, religiosity and individual beliefs is essential and should match the therapeutic plan if it is not harmful. If necessary and at the patient’s wishes and in the face of risk or harm or in conflict situations, the presence of religious representatives or leaders can bring comfort, balance and better management and can contribute to a desired consensus.

The approach of spirituality and religiosity topics in medical consultation in an area such as cardiology, where the patient is generally in a situation of fragility, and more sensitive and stressful, increases the complexity of the multiple variables already mentioned and may generate some conflicts. The misunderstanding or intolerance of the parties involved are major factors and can generate conflicts of various kinds and at all interfaces involving the patients, their families and their relationships, within the multidisciplinary team itself and between the team and the patient. All these problems can be prevented by good management of the doctor-patient relationship which, once consolidated, will make all other situations less influential.

Conflicts can be avoided even for untrained professionals, as long as some important steps are followed: conduct spiritual anamnesis without prejudice, showing deep interest and respect for the patient, seeking to understand their religion, beliefs, and practices,³⁶³ encourage questions to help patients clarify their feelings and thoughts about the spiritual perspective of what is going on or even their possible spiritual problems.³⁹³ In questions related to spirituality and religiosity, it should be kept in mind that it is always better to understand than to advise.

Concepts involving evidence-based medicine have also been applied in the realm of spirituality, but the available evidence is not always ideal and definitive. In these scenarios, available evidence should be used to improve this practice, also contributing to the revision of old concepts, the development of new research and the advancement of science in the field of spirituality. In Chart 9.4, GEMCA gathers recommendations that may be useful for improving cardiology practice in our country.

10.1. Introduction

In the last century, humanity has undergone an epidemiological transition in relation to the causes of death; infectious diseases are no longer the leading cause of death while chronic degenerative diseases, especially CVD now take the lead. Although they are still the leading causes of mortality worldwide, from the late 1950s, a decline in CVD mortality began in industrialized countries. In Brazil, this decrease in CVD mortality began to be observed in the late 1970s, with a significant reduction in these rates, despite significant regional differences.^2,440,441

It is not possible to only associate the reduction in mortality due to CVD to the better control of classic CV risk factors such as diabetes, hypertension, obesity, dyslipidemia and smoking, since all of these, except smoking, have increased in prevalence in recent decades. This led to new concepts about occupational, behavioral and environmental risk factors, which are directly influenced by the socioeconomic conditions of the populations and have an important relationship with the causes of mortality.

In this chapter, we describe important conditions associated with increased CV risk that require concomitant assessment with classic CV risk factors when addressing CVD as a complex relationship between patients and the context in which they live.

10.2. Socioeconomic Factors and Cardiovascular Risk

The health conditions of populations are influenced in a complex way by social determinants such as income distribution, wealth and education. These indicators act as interdependent risk factors for disease occurrence. Relationships between mortality rates and socioeconomic level have already been evidenced in Brazil and other countries, showing an inverse relationship, i.e., low socioeconomic levels are related to high mortality rates. These relationships between reductions in mortality rates, in particular deaths from diseases of the circulatory system (DCS), and improvement in socioeconomic indicators are highly correlated. Several prospective studies have shown that low socioeconomic status, defined as low educational level, low income, low status employment, or living in poorer residential areas, have contributed to the increase in all causes of death, as well as the risk of death from CVD.^9,442-446

Low socioeconomic status, when defined as an independent CV risk factor, has been shown to confer an increased risk for CVD; with RR mortality between 1.3 and 2.0.^445,447 The time periods in which there was a reduction in mortality rates due to diseases of the circulatory system were preceded by periods with improvement in socioeconomic indicators. In Brazil, between the 1930s and 1980s, there was great economic growth that, despite the concentration of income, enabled educational, sanitary, economic and infrastructure improvements, reducing infectious diseases and inflammatory processes. In developed countries, the decline in CVD mortality began a little over a decade after the end of World War II, which followed the great depression of the early 1930s and the 1918 influenza pandemic. The same decline began just over 40 years after the beginning of the period of economic growth. Exposure to infectious agents and other unhealthy conditions in the early years of life may make individuals more susceptible to the development of atherothrombogenesis. It is also possible that the reduction in exposure to infectious diseases in the early stages of life is related to the observed decline in adult CV mortality.^{442,446,448-452}

Strong correlations have been shown between the Human Development Index, falling child mortality, rising per capita gross domestic product (GDP) and the increasing education levels; with the reduction in mortality from diseases of the circulatory system in adults, from 1980, in some Brazilian states and municipalities, showing that the improvement in socioeconomic indicators preceded the reduction of CV deaths. The great increase in education over the last decades, which practically doubled in the states of Rio de Janeiro, São Paulo and Rio Grande do Sul, had a great impact on mortality, and is related to the reduction of more than 100 deaths from CVD with a one-year increase in average years of study in adults. Comprehensive measures to improve socioeconomic indicators should be part of the paradigm for CV disease control. These relationships show the importance of improving the living conditions of the population in order to reduce CV mortality.^{442,446,448,449,453,454} The assessment of social factors in patients and people with CV risk factors is essential as a means to stratify future preventive efforts with individual’s risk profile.

Recommendations for socioeconomic indicators and CV risk are listed in Table 10.1.

10.3. Environmental Factors and Cardiovascular Risk

Atherosclerosis has a complex and multifactorial pathophysiology, depending on the integration of several factors inherent to the individual, acquired or not, with the environment in which he is inserted. The impact of environmental factors on the epidemiology of CV disease has been increasingly studied and recognized, especially in relation to the possibility of adopting preventive strategies. In this context, in addition to the influence of socioeconomic factors such as income and education, the characteristics of the individual’s own habitat and lifestyle are also considered. Thus, the natural and social environments are two different types that potentially influence CV disease.⁴⁵⁵

The natural environment is determined by specificites of the place where the individual resides such as altitude and latitude, density of wooded areas, seasons, exposure to sunlight and atmospheric temperature. A study by Massa et al.,⁴⁵⁶ in the city of São Paulo in 2010, suggested an inverse relationship between green area density and CV risk, regardless of income.⁴⁵⁶ In addition, CVD lethality appears to be higher in winter months, while in some places there is an increase of up to 53% in the incidence of AMI.⁴⁵⁷ This increase occurs similarly in young adults (< 55 years) and in elderly (> 75 years) individuals, and may be a consequence of both hemodynamic variations. (e.g., elevated BP), as well as the higher incidence of respiratory infections at this time (e.g., influenza), which are known to increase the risk of heart attack.⁴⁵⁵ However, elevated temperatures are also associated with a higher CVD risk, especially when there is an abrupt variation in temperature.⁴⁵⁸

The social environment is related to the artificial forms of housing and the characteristic of daily life in modern society, especially in the urban environment. Population, noise level, violence, access to clean water, sanitation and air pollution may limit health promotion and promote the development of infectious and chronic diseases. In this context, air pollution was established as the most important modifiable environmental determinant of CVD risk, consisting of a complex mixture of gaseous particles and components.⁴⁵⁹

Among such pollutants, particulate matter (PM) is the element that is most relevant to health, which is formed by substances whose size and types of particles vary over time in the same region. The main sources of PM are motor vehicle emissions, tire fragmentation and reuse in asphalt production, energy industry-related combustion, ore processing, agriculture, construction and demolition activities, forest burning and volcanic eruptions, among others.⁴⁶⁰ Thus, because of the complexity related to their composition, the particles are identified according to their diameter: coarse PM or PM10 (< 10 and ≥ 2.5 µm); Fine PM or PM2.5 (< 2.5 and ≥ 0.1 µm); Ultrathin PM or PM0.1 (< 0.1 µm).⁴⁵⁹

Current evidence suggests that PM2.5 is the major pollutant associated with increased CVD risk for both fatal and nonfatal events. The central justification for this relationship is the increased oxidative stress and systemic inflammation promoted by the particles. These effects result in the amplification of other traditional risk factors already present and in the potential instability of coronary plaques.⁴⁶¹ According to the WHO, the mean daily PM2.5 concentration should be < 20 µm/m³, and the annual < 10 µm/m³. With each 10µm/m³ increase in short-term exposure, there is a 2.5, 1 and 2.1% increase in the risks of admission or death from AMI, stroke and HF, respectively. However, as exposure tends to occur over several years, atherosclerosis becomes progressive and cumulative, and also affects regional CV mortality. Thus, recurrent events may occur even with average annual PM2.5 concentrations below the WHO targets. Other consequences possibly associated with short- and long-term pollution are venous thromboembolism, acute atrial fibrillation, hypertension, and insulin resistance.⁴⁵⁹

The recommendations for environmental indicators and CVD risk can be seen in Table 10.2.

10.4. Vaccination for People with Heart Disease

In most clinical situations, vaccination is identified as a primary prevention action. When it is transposed to heart disease, it is usually secondary prevention for decompensations that aggravate pre-existing CV disease. Several vaccines are indicated for adults, with priority to patients with NCD, such as heart disease. We will list those prescribed for adults with heart disease. There is a specific guideline published by the Brazilian Society of Cardiology regarding indications and doses of vaccines indicated for children and adolescents with heart disease.

10.5. Lower Extremity Peripheral Artery Disease

10.6. Autoimmune Diseases and Cardiovascular Risk

Several autoimmune diseases can affect the heart through various manifestations including arrhythmias, pericardial, myocardial and coronary artery diseases. In relation to this last complication, advances and research in the field of atherosclerosis have increasingly reinforced the participation of the immune system in its pathophysiology. The presence of lymphocytes and macrophages within atheromatous plaques suggests that inflammation is a major factor in the disease evolution cascade. This hypothesis even motivated a recent clinical trial that evaluated the effect of low dose methotrexate on the reduction of CV events in patients without autoimmune diseases but with previous infarction. Although the reduction in the primary outcome was not achieved in this study, further work in this area is still ongoing.

However, in patients with rheumatic diseases, the systemic inflammatory process is amplified and which may result in the occurrence of accelerated atherosclerosis.⁵⁰⁹ This condition may be the main explanation for the high percentages of morbidity and mortality in these patients.⁵¹⁰ In addition, the use of certain immunosuppressive medications, such as corticosteroids, may also contribute to the worsening of the CV risk profile. It is worth mentioning RA and systemic lupus erythematosus (SLE) among the diseases that may have this pathophysiological feature, although other conditions such as scleroderma, inflammatory bowel diseases, psoriasis and certain primary vasculitis such as polyangeitis granulomatosis, are also relevant.^509-511

RA is associated with a 3-fold reduction in survival, with ischemic heart disease accounting for about 40% of deaths.⁵¹² In addition, the risk of AMI is about 2 times higher than in the general population, and the prognosis after the event tends to be worse. This scenario begins to develop at the onset of the disease and independently of other factors classically associated with atherosclerosis. Vascular inflammation caused by autoimmunity seems to play a more important role in this context. Some population studies even suggest a recent reduction in CV lethality in these patients, perhaps due to the greater availability of disease-specific treatments.⁵¹³ Nevertheless, functional limitation and consequent physical inactivity imposed by RA may also increase the likelihood of developing other risk factors, such as obesity, hypertension and diabetes. On the other hand, it is noteworthy that systemic inflammation in individuals with RA can reduce serum levels of total cholesterol and LDL, promoting what is known as the “lipid paradox”, since the risk of events remains high even with this metabolic profile.^513,514 Nevertheless, control of traditional risk factors remains the main strategy for preventing CV events in these patients. Like RA, SLE also behaves as an independent risk factor for CV disease, with a coronary disease prevalence of up to 10% and a risk of events up to 8 times higher than the general population. Some studies suggest that AMI may be the cause of death in up to 25% of cases, especially in patients who have the disease for longer.⁵⁰⁹ At the same time, the prevalence of major CV risk factors such as hypertension, diabetes, obesity, physical inactivity and dyslipidemia is also higher in individuals with SLE. Frequent use of corticosteroids for disease management is another condition that worsens the metabolic profile, although daily doses of prednisone below 10 mg appear to be safe in this respect, as do antimalarial drugs.⁵¹⁵ Nevertheless, risk calculators using traditional factors often underestimate the incidence of events in these patients. Other markers associated with atherosclerosis that are more relevant in individuals with SLE, such as osteoprotegerin and osteopontin, are promising predictors that could refine this estimate. The fact that disease-associated coronary artery disease is more often associated with atherosclerosis than vasculitis corroborates this expectation.⁵¹⁶

As most autoimmune diseases are more common among women, a thorough stratification of CV risk in females is essential in the presence of these conditions, despite the limitations already mentioned. Even so, the fundamental issue is the absence of clinical studies demonstrating a benefit in treating this group of patients more aggressively. To date, there is no evidence that therapeutic targets for blood pressure, blood glucose, LDL cholesterol, or any other risk factor should be modified due to the presence of an autoimmune disease. The relatively low prevalence of these diseases in the population is the main factor limiting good quality studies to answer these questions. Therefore, each case needs to be individualized, with constant reassessments throughout the disease evolution of the potential risks and benefits of treatment.

Recommendations for autoimmune diseases and CV risk are shown in Table 10.4.

10.7. Chronic Kidney Disease

The overall prevalence of CKD is estimated at 11-13%,⁵¹⁷ and in Brazil, despite inconsistent data, it is estimated that between three and six million people have the disease.⁵¹⁸ The relationship between CKD and CVD is complex, dynamic and multifactorial. In addition to both sharing risk factors such as systemic arterial hypertension, diabetes and advanced age, there is a higher prevalence of traditional CVD risk factors in patients with CKD.^519,520 In a study by Foley et al.,⁵¹⁹ with more than 15,000 patients, 83.6% of those with estimated glomerular filtration rate (eGFR) < 60 ml/min/1.73 m² and 100% of those with GFR-e < 30 ml/min/1.73 m² had at least two risk factors for CVD.⁵¹⁹ Furthermore, the loss of renal function itself causes changes that can accelerate CVD, such as arterial stiffness and anemia contributing to left ventricular hypertrophy, endothelial dysfunction disease, chronic inflammation, vitamin D deficiency, oxidative stress, and activation of the renin-angiotensin system.^520-523

The result of this interaction is that CVD is the leading cause of death in patients with CKD.⁵²¹ In a meta-analysis by van der Velde et al.,⁵²⁴ evaluating cohorts of patients with hypertension, diabetes or CV disease, they observed an increase in all causes of mortality with eGFR reduction, and rates of 60, 45 and 15 ml/min/1.73m² presented a hazard ratio of 1.03, 1.38 and 3.11, respectively, when compared to patients with eGFR 95 ml/min/1.73 m². In addition, the presence of albuminuria, even when borderline, was also associated with higher mortality in this same study, and urinary albumin-creatinine ratios of 10 mg/g, 30 mg/g and 300 mg/g presented a hazard ratio of 1.08, 1.38 and 2.16 when compared to the ratio of 5 mg/g.⁵²⁴

Currently, CKD⁵²⁵ and albuminuria are considered independent predictors of CV^522-526 events and thus, CV prevention plays a key role in the management of CKD patients. Overall, the risk assessment should be individualized and CKD should be interpreted in the context of the overall risk assessment according to each clinical setting, and is considered a high risk CV marker.^7,525 Given the various clinical scenarios related to CKD, it is worth mentioning systemic arterial hypertension, dyslipidemia and the use of antiplatelet agents in primary prevention.

With regard to systemic arterial hypertension, risk stratification and treatment to prevent events and additional loss of renal function should follow the guidelines published by this Society.¹⁴⁶ It is noteworthy that in this case, CKD is used in the additional risk stratification according to eGFR and urinary albumin-creatinine ratio, and can be interpreted as target organ damage (eGFR 30-60 ml/min/1.73 m² or urinary albumin-creatinine 30-300 mg/g) or as an established disease (eGFR < 30 ml/min / 1.73 m² or urinary albumin-creatinine > 300 mg/g). Similarly, the approach to dyslipidemia in CKD patients should follow the stratification and treatment model proposed in this Society’s specific guideline.⁷ In this case, CKD (eGFR < 60 ml/min/1.73 m²) is considered as a high-risk CV marker for proposed goals and treatments.⁷

Finally, regarding the use of antiplatelet agents in primary prevention, the evidence regarding its benefit is not robust enough to indicate its routine use considering CKD alone. In a meta-analysis of more than 50 studies and more than 27,000 patients, the use of ASA reduced the risk of infarction without, however, reducing overall mortality, CV mortality or stroke, with increased numbers of major and minor bleeds.⁵²⁷ Thus, the use of antiplatelet agents should be assessed according to the overall risk and decision-making should be made on an individual basis when considering their use solely for CKD.

Recommendations for CKD and CV risk can be seen in Table 10.5.

10.8. Obstructive Sleep Apnea

In recent years, much has been debated about obstructive sleep apnea (OSA) as a CV risk factor and, in 2018, the Brazilian Society of Cardiology published a position on this clinical condition and its implications on CV risk.⁵²⁸ OSA is characterized by the temporary narrowing or occlusion of the upper airway during sleep,⁵²⁹ which in turn activates the sympathetic nervous system and triggers a chain of events involving elevation of blood pressure, release of inflammatory mediators, oxidative stress, endothelial dysfunction, reduced insulin sensitivity and activation of the renin-angiotensin-aldosterone system.^528-530 Despite the short duration of events, prolonged repetitive exposure to periods of hypoventilation and hypoxemia can lead to chronic changes in metabolism and circulatory system leading to consequences such as systemic arterial hypertension, pulmonary hypertension, arrhythmias, coronary disease, stroke, heart failure, diabetes, dyslipidemia, and increased mortality CV.^528-533

The prevalence of OSA has increased in recent years^528,529 and some series have reported apnea-hypopnea index equal to or greater than 5 events per hour in 34% of men and 17% of women aged 30 to 70.⁵³⁴ In CVD patients The prevalence of OSA is higher when compared to patients of the same age and sex in the general population, regardless of body mass index.⁵²⁹ Among CVD, hypertension, coronary artery disease, stroke and heart failure with reduced ejection fraction, with reports of associated prevalence of OSA of up to 83%, 58%, 91% and 53%, respectively.^528,529

The treatment of OSA is mainly based on the use of continuous positive airway pressure (CPAP). There is evidence that this treatment modality has beneficial effects on blood pressure control,⁵³⁵ but evidence regarding rigid outcomes such as total and CV mortality is not as robust,^528-530 with data on primary prevention from observational studies.^531,536 In a recent systematic and meta-analysis review, no reduction in major CV events including vascular death or all-cause death was observed.⁵³⁷ It is worth mentioning that in 60% of the studies evaluated CV disease (secondary prevention) was documented and in such cases, with patients undergoing optimal clinical treatment, CPAP treatment may have little additional effect than current treatment when assessing total mortality and CV outcomes,^530,537 despite the benefits of blood pressure control and improvement of extra-cardiac symptoms.⁵³⁰

Finally, CV prevention strategies in OSA patients should consider the higher morbidity and mortality attributed to this condition, emphasizing the control of other associated risk factors and respecting specific treatment indications according to this Society’s position on group 11 of AOS.⁵²⁸

Recommendations for obstructive sleep apnea (OSA) and CV risk are shown in Table 10.6.

10.9. Erectile Dysfunction

Erectile dysfunction (ED) is the recurrent inability to obtain and maintain an erection that allows for satisfactory sexual activity. ED is not a disease but a symptomatic manifestation of isolated or associated pathologies.⁵³⁸ It has a prevalence of just over 50% in men over 40 years of age in the USA and Brazil. Studies have shown a prevalence between 43 and 46% in the same age range.^538-541 The causes of ED can be classified as psychological, organic or a combination of both. Organic factors include vascular, endocrine, neurological, drug-related causes, and urological interventions. Vascular etiology is the most common cause of erectile dysfunction. Arterial traumatic disease, atherosclerosis and SAH are among the main causes of vascular ED. Increasing the prevalence in patients with hypertension and / or diabetes and also with aging, it may reach a prevalence of over 68% in these populations and also be related to therapy with CV action drugs that contribute to the occurrence of ED.^542-544

ED is currently recognized as being of vascular etiology in most men, with endothelial dysfunction as the common denominator. ED often precedes CVD and is often present in men with known CVD, leading to the concept that a man with ED and no CVD symptoms is a patient with CVD until proven otherwise, and a man with known CVD should be routinely asked about your erectile dysfunction. ED also has a significant negative impact on the patient and partner (one man’s problem but a couple’s concern), thus emphasizing the need to approach ED as early as possible.⁵⁴⁵

A meta-analysis of 20 prospective cohort studies involving 36,744 participants suggested that erectile dysfunction significantly increases the risk of ischemic heart disease, stroke and all-cause mortality and concluded that it could play a role in quantifying CV risk based on traditional risk factors.⁵⁴⁶ Another population-based study of 95,038 men aged 45 and over showed that CVD risk is related to the severity of erectile dysfunction in men with and without established CVD, with a relative risk (respectively) of 1.6 and 1.7 for the development of ischemic heart disease.⁵⁴⁷ All men with erectile dysfunction should be considered potential candidates for primary prevention, CV risk stratification and treated according to their risk estimates.

Recommendations for autoimmune diseases and CV risk are listed in Table 10.7.

10.10. Prevention of Rheumatic Heart Disease

Rheumatic heart disease (RHD) is the cardiac consequence of acute rheumatic fever (ARF), an inflammatory disease caused by streptococcal pharyngitis. Its prevalence is closely related to unfavorable sanitary conditions, agglomerations and inadequate access to health systems.⁵⁴⁸ Over the last decades there has been a significant reduction in prevalence and mortality from RHD worldwide (with a reduction in standardized global mortality of 47, 8% from 1990 to 2015²), markedly in developed countries, and even near eradication in some regions. However, the burden of disease remains high in underdeveloped countries and even in poor regions of developed countries.⁵⁴⁸ In 2015, the highest age-standardized mortality rates for RHD prevalence were observed in Oceania, South Asia, and central sub-Saharan Africa, but there is clearly an underestimation of data from Brazil and Latin America, partly due to the scarcity of primary data. It is estimated that in 2015 there were 33.4 million cases and approximately 10.5 million disability-adjusted life years (DALY) attributable to RHD worldwide.⁵⁴⁹

The principal determinant of RF is the admittedly repeated infection with group A beta-hemolytic streptococci (GAS), and some theories attempt to explain the pathophysiology involved in susceptibility to damage, which affects only 6% of individuals exposed to GAS: a) an antigenic similarity between agent structures (M protein surface and GlcNAc epitope) and molecules in host tissues, triggering an exaggerated immune response, and b) generation of a “neo-antigen” through contact between GAS and collagen matrix subendothelial, with consequent binding between M proteins and CB3 region of collagen type IV, inducing an autoimmune response against collagen.⁵⁴⁸

Thus, primary prevention of RF requires early identification and appropriate therapy for GAS pharyngitis. When selecting a treatment regimen, consideration should be given to the bacteriological and clinical efficacy, ease of adherence to the recommended regimen (ie: dosing frequency, duration of therapy and acceptability), cost, spectrum of activity of the selected agent and potential adverse effects. In this context, intramuscular benzathine penicillin G, oral potassium penicillin V and oral amoxicillin are the recommended antimicrobial agents for the treatment of GAS pharyngitis in people without penicillin allergy (Table 10.8). GAS resistance to penicillin has never been documented, and penicillin potentially prevents primary attacks of RF even when started nine days after the onset of infection.^550,551