Key Points
- •
Heart failure prevalence continues to rise in the United States and is projected to become worse with aging of the population.
- •
Recent therapeutic advances in heart failure have translated into only modest improvement in outcomes at the community level.
- •
Prevention efforts for heart failure have significantly lagged behind research for new treatment options.
- •
Optimal risk stratification strategies for incident heart failure continue to evolve.
- •
Hypertension and coronary heart disease remain the most prominent risk factors for heart failure, although cardiometabolic risk factors (e.g., obesity and diabetes) are rapidly increasing in importance.
- •
Several individual risk factor treatments have been shown to reduce the risk for development of heart failure.
- •
Further research is needed to assess optimal multiple risk factor interventions, behavior modification strategies, and novel therapeutic approaches to reduce heart failure risk in individuals with risk factors.
- •
Population-based promotion of healthy lifestyle at the primordial prevention level is likely to have an impact on the largest at-risk population.
The concept of “prevention” encompasses a vast spectrum ranging from primordial to primary, secondary, and tertiary prevention. For heart failure, an example of primordial prevention is avoidance of behaviors that enhance (e.g., weight gain) and embracing of behaviors that mitigate (e.g., active lifestyle) the risk for development of heart failure. Primary prevention includes control of heart failure risk factors (e.g., hypertension). Secondary prevention efforts institute interventions to reduce the risk of worsening of existing heart failure (e.g., treatment with beta blockers). Finally, tertiary prevention interventions in advanced heart failure are implemented to reduce the chances of imminent mortality (e.g., implantation of mechanical circulatory assist devices).
Most heart failure quality improvement efforts (e.g., the Get With The Guidelines program by the American Heart Association) are currently targeted at secondary prevention. Similarly, most of the research efforts in heart failure are also targeted to treatment. During the last two decades, an intensified focus on the prevention of coronary artery disease has included the development of risk prediction models, assessment of novel biomarkers, identification of subclinical markers of coronary risk, design of therapeutic trials for coronary disease prevention, and establishment of specific guidelines. Despite the worsening epidemic of heart failure, however, prevention efforts in this area remain rudimentary.
Given the current and projected societal toll of heart failure, both clinically and economically, a more concentrated effort on heart failure prevention is needed. In this chapter, we focus on the primordial and primary prevention of heart failure. In recognition of the emphasis of this text, we will not discuss interventions to improve outcomes in individuals with manifest heart failure.
Heart Failure Epidemiology
Incidence, Prevalence, Outcomes, and Costs
It is estimated that more than 5.5 million subjects in the United States have heart failure, and more than 650,000 are diagnosed for the first time each year. Current evidence suggests that the two major clinical subsets of heart failure (i.e., patients with impaired versus preserved left ventricular systolic function) each composes about half of the overall burden of heart failure in the community. However, various studies have suggested that the proportion of heart failure with preserved ejection fraction ranges from 13% to 74% of all heart failure. These studies are heterogeneous and differ considerably in patient selection criteria, diagnostic criteria for heart failure, and quantitative methods for assessment of ventricular systolic function. A common finding among these studies, however, is that the proportion of heart failure with preserved ejection fraction increases with age. Not surprisingly, there is a secular trend toward increased prevalence of heart failure with preserved ejection fraction among patients hospitalized for heart failure.
Heart failure is the primary reason for 12 to 15 million office visits and 6.5 million hospital days annually. Recurrent hospitalization is a major quality of life and cost issue; the annual number of hospitalizations now exceeds more than 1 million for heart failure as a primary diagnosis and 2.4 to 3.6 million as a primary or secondary diagnosis. Heart failure patients are particularly prone to rehospitalizations, and readmission rates are near 50% within 6 months of discharge. The number of heart failure cases and deaths attributable to heart failure has increased steadily despite advances in treatment and a decline in other major cardiovascular disease during the same interval. Heart failure remains the most common Medicare diagnosis–related group, and more Medicare dollars are spent on heart failure than for any other diagnosis. It has been estimated that the total direct and indirect cost of heart failure in the United States exceeds $30 billion.
Despite this, the outcomes of these patients continue to remain suboptimal at the population level, with only approximately 50% of the individuals surviving past 5 years after diagnosis. Quality of life remains poor. Some temporal improvement trends in outcomes have been restricted primarily to individuals with systolic dysfunction, with no major advances in therapy for either patients with heart failure and preserved ejection fraction or those who are hospitalized for decompensated heart failure.
Future Projections
Heart failure prevalence is rising, and this trend is expected to continue. This is attributed to the increasing elderly population, improved care of acute heart diseases, and increasing prevalence of several cardiovascular risk factors like diabetes and obesity. According to the White House Conference on Aging, aging of the 78 million baby boomers will result in 1 in 5 Americans older than 65 years by 2050. This trend will have a significant effect on health, health care, and health care economics because the use of formal and informal services is strongly correlated with age.
Heart failure incidence and prevalence are highest among the elderly. The incidence rate approaches 10 per 1000 population annually after the age of 65 years; 80% of patients hospitalized with heart failure are older than 65 years. Thus, the increasing age of the population is expected to significantly worsen the current heart failure epidemic. Much of heart failure research to date has focused on treatment. Considering the current epidemiologic trends and the future projections, it is imperative to further heart failure prevention efforts aggressively.
Risk Factors for Heart Failure
Many studies have described various risk factors for development of heart failure ranging from lifestyle factors to comorbidities, medications, laboratory and imaging characteristics, and novel biomarkers and genomic markers ( Table 10-1 ). Heart failure risk increases proportionally with advancing age. Male gender is associated with a higher risk and may in part be explained by the higher prevalence of coronary disease in men. Behavioral risk factors for heart failure include lower levels of physical activity, coffee consumption, and increased dietary salt intake. Low socioeconomic status has been associated with increased risk. Older age, hypertension, diabetes, obesity, and coronary artery disease are risk factors for heart failure with either reduced or preserved ejection fraction. In general, patients with preserved ejection fraction are older, are more likely to be female, and are more likely to be obese. In heart failure with preserved ejection fraction, hypertension is a more common risk factor ; however, a substantial proportion of patients with reduced ejection fraction have a history of hypertension also. In heart failure with reduced ejection fraction, ischemic heart disease is the most common etiology, but it is also a comorbid condition among many patients with preserved ejection fraction. Among patients admitted for decompensated heart failure, 63% of patients with reduced ejection fraction and 54% of patients with preserved ejection fraction have coronary artery disease. Thus, from a prevention perspective, the major target risk factors for possible modification are common in both subsets of heart failure.
| Demographics | Lifestyle factors |
| Older age | Cocaine Tobacco use Excess alcohol consumption Excess caffeine Excess sodium consumption |
| Male gender | |
| Socioeconomic status | |
| Education | |
| Comorbidities | Echocardiographic parameters |
| Hypertension | Ventricular dimension |
| Left ventricular hypertrophy | Ventricular mass |
| Prior myocardial infarction | Ventricular dysfunction |
| Obesity | Diastolic filling impairment |
| Diabetes mellitus Valvular heart disease | Biochemical markers Albuminuria |
| Renal insufficiency | |
| Dyslipidemia | Homocysteine |
| Sleep apnea | Tumor necrosis factor-α |
| Tachycardia | Interleukin-6 |
| Impaired lung function | C-reactive protein |
| Depression, excess stress | Insulin-like growth factor 1 Natriuretic peptides |
| Pharmacologic exposures Chemotherapeutic agents | |
| Genetic risk factors Adrenergic receptors α 2C Del322-325 deletion | |
| Nonsteroidal anti-inflammatory drugs | |
| Thiazolidinediones Doxazosin | Adrenergic receptors β 1 Arg389 change |
| Overexpression of protein kinase C-α ACE and Ang II type 1 receptor gene polymorphisms |
Hypertension and coronary artery disease are the most common and strongest risk factors, conferring a twofold to threefold increased risk for heart failure. Both elevated systolic blood pressure and elevated diastolic blood pressure have been associated with increased risk for heart failure. Diabetes mellitus is associated with a higher risk, both with and without the presence of simultaneous coronary heart disease. Valvular heart disease increases risk through hemodynamic alterations on the ventricles, with either volume or pressure overload leading to myocardial dysfunction.
Obesity, through multiple mechanisms, predisposes individuals to heart failure. Excessive alcohol intake increases blood pressure and is a direct myocardial toxin ; however, light to moderate alcohol consumption has been inversely associated with heart failure risk, especially in men. Smoking promotes several cardiovascular risk factors and is associated with heart failure development. Dyslipidemia predisposes to heart failure; however, it is unclear if this is primarily related to atherosclerosis or if there are alternative effects. High total cholesterol, low high-density lipoprotein cholesterol, and high triglyceride levels have all been correlated with greater left ventricular mass and impaired diastolic function. However, observational studies investigating the association of total cholesterol with incident heart failure in individuals without prior coronary heart disease have yielded inconsistent results.
Complications of renal dysfunction, including anemia, hypertension, arterial stiffening, sodium and water retention, endothelial dysfunction, and alteration in biomarkers profiles, are associated with elevation of the risk for development of heart failure. Anemia and sleep-disordered breathing are associated with heart failure. An increased heart rate increases heart failure odds; whether this represents a compensatory response to lower stroke volume and underlying asymptomatic systolic dysfunction or neurohumoral activation, or both, is not clearly known. Finally, several abnormalities of pulmonary function, including reduced forced vital capacity and forced expiratory volume in the first second of expiration, are associated with heart failure risk.
Microalbuminuria is associated with a threefold increased heart failure hospitalization risk. Levels of homocysteine, insulin-like growth factor, proinflammatory cytokines (e.g., tumor necrosis factor-α, interleukin-6, and C-reactive protein), and B-type natriuretic peptide are associated with an increased risk. Recently, serum resistin, lipoprotein-associated phospholipase A 2 , and myeloperoxidase levels have been associated with increased risk also.
Several chemotherapeutic agents (e.g., doxorubicin, cyclophosphamide, and 5-fluorouracil) are associated with heart failure. Doxorubicin-induced cardiotoxicity is dose related, especially when the cumulative dose exceeds 550 mg/m 2 . Recent data show a higher risk with the use of trastuzumab. Cyclooxygenase 2 inhibitors may increase risk of myocardial infarction, raising heart failure risk concerns. Thiazolidinediones have been associated with edema and precipitation of heart failure. Recently, the Rosiglitazone Evaluated for Cardiac Outcomes and Regulation of Glycaemia in Diabetes (RECORD) study showed that thiazolidinedione use is associated with a small but clinically relevant increased risk of heart failure. However, the debate continues as to whether these drugs truly predispose individuals to development of heart failure or only promote fluid retention in individuals with prevalent left ventricular dysfunction. Recreational drugs (e.g., cocaine abuse) may precipitate heart failure.
Several cardiac anatomic and physiologic measures are associated with a higher risk, including ventricular chamber dilation with an increase in end-diastolic or end-systolic dimensions, increased left ventricular mass, left ventricular diastolic filling impairment, left atrial enlargement, and asymptomatic systolic dysfunction.
Finally, there is growing interest in discovering the genomic predictors of heart failure. Genetic alterations in functional pathways, such as energy production and regulation (e.g., mitochondrial mutations), calcium cycling abnormalities (e.g., RYR2 mutations), and mutations in transcriptional regulators (e.g., Nkx2.5 leading to ventricular hypertrophy), may lead to heart failure risk. Genetic polymorphisms in sympathetic receptors, such as the genes coding for alpha 2C -adrenergic receptors (α 2C Del322-325) or beta 1 -adrenergic receptors (ß 1 Arg389), are associated with heart failure risk. Interestingly, homozygous blacks for α 2C Del322-325 have a fivefold higher risk. If this polymorphism is associated with homozygosity for β 1 Arg389, the risk increases by 10-fold. Other polymorphisms associated with heart failure risk factors (e.g., hypertension and vascular stiffness) are angiotensin-converting enzyme and AT 1 receptor gene polymorphisms, which in turn may affect heart failure risk.
Predicting Incident Heart Failure
Identification of High-Risk Individuals
For implementation of cost-effective preventive interventions, identification of high-risk individuals is essential. Although many heart failure risk factors have been described, determination of their role in predicting a future event is nevertheless challenging. A variable associated with a disease may be a risk marker or a risk factor. A risk factor’s relative importance may change over time as the population characteristics change (e.g., secular trends in age, treatment modalities of other risk factors, and prevalence of competing risk factors). The “independent” prognostic power of any risk factor depends largely on what it is compared against. Importantly, despite strong etiologic association with a disease, a risk factor may be limited in its prognostic role.
A risk factor must have a much stronger association with disease than the usual etiologic research if it is to provide a basis for detection and prediction in an individual patient. If the distributions of the risk factor differ between two groups of patients with differing outcomes, the risk factor may be statistically associated with the outcome. However, for the risk factor to perform well as a prognostic test, the distributions in the two groups must be sufficiently separated to permit selection of a cutoff value that will discriminate between the two groups with high sensitivity and specificity.
The American College of Cardiology and the American Heart Association (ACC/AHA) recently proposed a new heart failure classification scheme that includes stage A patients, those who do not have any structural heart disease but are at risk for heart failure. This new classification is presented in Figure 10-1 . Although individual risk factors for heart failure (e.g., hypertension) are well described, how to quantify individual risk in patients with various combinations of risk factors is not clearly described.
Multiple risk factor prediction schemes, such as the Framingham risk score, have been developed and validated for coronary events. However, the heart failure syndrome represents a spectrum ranging from ischemic to nonischemic causes and normal to depressed ejection fraction. Heart failure may develop in elderly subjects as a result of age-related cardiovascular changes in the absence of traditional risk factors. High-risk subjects therefore may not be detected by coronary risk schemes. For example, in the Cardiovascular Health Study, 66% incident heart failure cases developed in subjects without baseline history of coronary heart disease, and more than half of them never had a preceding coronary event before development of heart failure.
Heart Failure Risk Prediction Models
Most studies of heart failure risk factors have targeted individual risk factors. Table 10-2 summarizes the nine studies that have assessed independent risk factors for incident heart failure comparing multiple risk factors ; only two of them developed a prediction model for incident heart failure. The Framingham heart failure risk score assessed the probability of development of heart failure during a 38-year period in which there were 6354 person-examinations in men and 8913 in women. Although regression coefficients differed among men and women somewhat, overall predictors were similar (see Table 10-2 ). Interestingly, systolic blood pressure was predictive only in men and diabetes mellitus in women.
| Reference | Cohort | Risk Factors |
|---|---|---|
| Eriksson, et al | Göteborg, Sweden | Hypertension, smoking, weight, heart size, T wave abnormality, heart rate variability, peak expiratory flow rate, and psychological stress |
| Chen, et al | EPESE | Gender, age, diabetes, pulse pressure, and body mass index |
| Kannel, et al | Framingham Heart Study | Age, blood pressure, LVH, vital capacity, heart rate, CHD, murmurs, diabetes, cardiomegaly, and body mass index |
| Gottdiener, et al | Cardiovascular Health Study | Age, gender, cerebrovascular disease, diabetes, blood pressure, FEV 1 , creatinine, C-reactive protein, ankle-arm index, atrial fibrillation, LVH, abnormal ejection fraction, electrocardiographic ST-T abnormality |
| He, et al | NHANES I | Gender, education, physical activity, smoking, weight, hypertension, diabetes, valvular disease, and CHD |
| Wilhelmsen, et al | Göteborg, Sweden | Age, family history of infarction, diabetes, history of chest pain, smoking, coffee consumption, alcohol abuse, blood pressure, and body mass index |
| Bibbins-Domingo, et al | Heart and Estrogen/Progestin Replacement Study | Diabetes, atrial fibrillation, myocardial infarction, creatinine clearance, blood pressure, smoking, body mass index, left bundle branch block, and LVH |
| Carr, et al | RENAAL and LIFE studies | Age, history of myocardial infarction, vascular disease, atrial fibrillation, urinary albumin/creatinine ratio, alcohol abuse, Cornell product, and body mass index |
| Butler, et al | Health ABC | Age, CHD, smoking, blood pressure, heart rate, serum creatinine, fasting glucose, albumin level, and LVH on electrocardiogram |
The investigators subsequently developed a 4-year event score with an event rate averaging 3.97 per 100 person-year examinations in men and 2.63 in women with a 37% increment per decade of age. There are several limitations to the use of this score. The chest radiograph and pulmonary function test requirement makes it more difficult to implement it in large population settings for screening. The model was drawn primarily on white populations, and its performance in other racial groups is not known. The model was derived on a restricted group of subjects with a known history of hypertension, coronary heart disease, or valvular heart disease; such characteristics represented less than 50% of the population in other cohorts, such as the Health, Aging, and Body Composition (Health ABC) Study, limiting the model’s generalizability. Finally, this model was not externally validated in independent cohorts.
Recently, the Health ABC heart failure risk model was developed with the data from 2935 individuals participating in the Health ABC Study. The mean age of the population was 73.6 years, with 52% females and 41% blacks. Independent predictors of heart failure included age, history of coronary heart disease and smoking, systolic blood pressure and heart rate, serum glucose concentration, creatinine and albumin levels, and electrocardiographic left ventricular hypertrophy; the model has good discrimination (C-statistic 0.73 in the derivation data set and 0.72 by internal validation with optimism-correction) and good calibration. A simple point score was created to predict incident heart failure risk in four risk groups corresponding to <5%, 5% to 10%, 10% to 20%, and >20% 5-year risk ( Fig. 10-2 ).
The investigators subsequently externally validated the model in the Cardiovascular Health Study; the model retained adequate predictive capabilities. The model predicted risk equally well in both men and women and in white and black races ( Fig. 10-3 ). The utility of the Framingham heart failure risk score in predicting incident heart failure in the overall Health ABC cohort and the subcohorts in which the original score were developed (i.e., subjects with known baseline history of hypertension, coronary heart disease, or valvular heart disease) was also assessed. The Framingham heart failure risk score performance was inferior compared with the Health ABC heart failure risk model.
Challenges in Predicting Incident Heart Failure
Several unique issues make heart failure risk assessment challenging. Heart failure is a clinical diagnosis and cannot be easily diagnosed with a “test.” This leads to diversity in opinions and diagnostic uncertainty in a certain proportion of cases. The most common clinical criteria used to diagnose heart failure are the Framingham criteria, which require the presence of at least two major criteria or one major criterion and two minor criteria. Major criteria include paroxysmal nocturnal dyspnea, neck vein distention, rales, radiographic cardiomegaly, acute pulmonary edema, S 3 gallop, increased central venous pressure >16 cm H 2 O, circulation time ≥25 seconds, hepatojugular reflux, or pulmonary edema or visceral congestion or cardiomegaly at autopsy. Minor criteria include bilateral ankle edema, nocturnal cough, dyspnea on ordinary exertion, hepatomegaly, pleural effusion, reduced vital capacity by one third from maximum, and heart rate ≥120 beats/min. Investigators from the Cardiovascular Health Study developed alternative criteria that included medication use and imaging modalities. When both sets of criteria were compared, only half the patients were adjudicated to have heart failure by both criteria, whereas the other half were labeled with either one or the other but not both criteria. Similar discordance has also been shown between administrative discharge diagnoses and designation based on detailed chart review.
Part of this discordance is related to diagnosis of heart failure with preserved ejection fraction. Many of the heart failure symptoms (e.g., shortness of breath) and signs (e.g., edema) are nonspecific and can be seen in other conditions (e.g., obesity and chronic lung disease). The European Society of Cardiology developed a consensus statement for diagnosis of this condition by use of biomarker- and imaging-based detailed protocols. Similarly, another set of detailed clinical criteria to diagnose incident heart failure in clinical trials was recently published. These criteria may be of limited usefulness from a population health perspective because of cost and logistics. Thus, these guidelines are likely to be used primarily in the clinical and research setting and not in the screening and population prevention arena.
Any clinical prediction rule is unlikely to diagnose “niche” heart failure, such as amyloidosis and hypertrophic cardiomyopathy, disorders with a distinct natural history. Similarly, whether risk prediction for heart failure differs for low versus preserved ejection fraction or stage A versus stage B heart failure is not known.
Risk Factors and Population Attributable Risk
Assessment of the population attributable risk for the common risk factors for any disease is key to prioritize prevention efforts cost-effectively. Population attributable risk represents the proportional reduction in disease risk that would be achieved by eliminating the risk factor from the population, assuming a causal relationship. The relative importance of risk factors in the population can help plan public health interventions; however, the absolute estimates for the population attributable risk of the various risk factors are highly dependent on the definition of risk factors and inclusion of other risk factors in the model used to derive the population attributable risks.
In a recent report from the Health ABC Study, a cohort of well-functioning, community-dwelling older adults, coronary heart disease and uncontrolled blood pressure were the leading causes of heart failure in whites and blacks and in men and women. A substantial proportion of heart failure, however, was also attributed to metabolic and cardiorenal factors, including glucose and renal abnormalities. Several previous investigations have reported substantial sex- and race-related differences in population attributable risks, disease development and progression, and prognosis for heart failure. Understanding and quantifying of these differences are important for planning appropriate preventive interventions.
The higher incidence of heart failure in black compared with white participants in the Health ABC Study was simultaneously accompanied by a higher prevalence of risk factors in black participants ( Table 10-3 ). Interestingly, the black participants had a higher proportion not only of overall risk factors but also specifically of those risk factors that are potentially amenable to intervention, which translated the population attributable risk in general to a higher modifiable fraction in black individuals (68% versus 49% in whites). These data provide valuable information into race-based differences and help prioritize interventions, set targets, and assess the feasibility of novel therapies.
| Risk Factors | White (n = 1686) | Black (n = 1167) | ||
|---|---|---|---|---|
| RR (95% CI) | PAR (%) | RR (95% CI) | PAR (%) | |
| Modifiable | ||||
| Systolic blood pressure ≥140 mm Hg | 1.80 (1.27-2.55) | 21.3 | 1.95 (1.33-2.84) | 30.1 |
| Coronary heart disease | 2.72 (1.89-3.90) | 23.9 | 3.31 (2.26-4.85) | 29.5 |
| Glucose ≥126 mg/dL | 2.08 (1.35-3.22) | 11.3 | 1.37 (0.88-2.14) | 7.3 |
| Left ventricular hypertrophy | 0.90 (0.44-1.84) | — | 2.20 (1.47-3.30) | 19.5 |
| Current smoking | 2.04 (1.15-3.64) | 5.5 | 2.08 (1.37-3.16) | 15.0 |
| Modifiable Fraction | 48.9 | 67.8 | ||
| Potentially Modifiable | ||||
| eGFR <60 mL/min/1.73m 2 | 1.29 (0.88-1.87) | 6.8 | 2.14 (1.42-3.24) | 16.2 |
| Albumin <3.8 g/dL | 1.46 (0.98-2.16) | 8.5 | 1.63 (1.09-2.44) | 12.7 |
| Heart rate >75 beats/min | 1.45 (0.94-2.23) | 6.7 | 1.97 (1.30-2.99) | 15.7 |
| Potentially Modifiable Fraction | 20.5 | 38.6 | ||
Incident Heart Failure Risk Modulation
Incident heart failure risk modulation is currently targeted primarily toward risk factor management individually. For coronary artery disease, the patient’s treatment plan is targeted on the basis of the individualized risk profile related to the various combinations of risk factors (e.g., blood pressure goals or low-density lipoprotein level). On the contrary, no such paradigm for heart failure risk modulation currently exists. Many heart failure risk factors (e.g., age and gender) cannot be intervened on. Other risk factors like proinflammatory states may be targets for intervention in the future. This section describes currently known interventions that directly or indirectly reduce the risk for incident heart failure. Most of these also affect other cardiovascular adverse outcomes; however, this section is focused primarily on heart failure–related data.
Lifestyle
Several studies have reported reduced risk for incident heart failure with healthy lifestyle. Maintaining healthy weight, avoiding smoking, engaging in regular exercise, and maintaining a healthy diet have been shown to favorably influence heart failure risk factors, including coronary heart disease, diabetes mellitus, and hypertension. Recently, the Physicians’ Health Study investigators reported that healthy lifestyle habits (i.e., normal body weight, not smoking, regular exercise, moderate alcohol intake, consumption of breakfast cereals, and consumption of fruits and vegetables) were associated with a lower lifetime risk of heart failure, with the highest risk of 21.3% in men adhering to none of these lifestyle habits and the lowest risk of 10.1% in men adhering to four or more of these habits.
Overweight and Obesity
Body mass index is associated with heart failure in a positive and linear fashion in both sexes. Although body mass index in the obese range (≥30 kg/m 2 ) is clearly associated with an increased risk for heart failure, there is controversy about body mass index in the overweight range (25 to 29.9 kg/m 2 ). Recent data, however, support that overweight is also associated with heart failure. Abdominal obesity may be a stronger predictor for heart failure than total obesity, even in the absence of coronary heart disease. In population studies, a strong association has been found between abdominal adiposity and features of metabolic syndrome, insulin resistance, and inflammation, all of which have been related to heart failure. Individuals with abdominal obesity have more elevated sympathetic neural activation, and visceral adipose tissue has higher expression of angiotensinogen than subcutaneous adipose tissue does.
The anatomic location of excess fat in the abdominal cavity may also be important as there is emerging evidence that increased intra-abdominal pressure leads to cardiac abnormalities that predispose to heart failure. On the contrary, however, there are also data supporting no predictive differences between total and abdominal obesity (as evaluated by waist circumference), and the association between obesity (total or abdominal) and incident heart failure may be mediated partly by insulin resistance. In addition, the relation of obesity and risk of heart failure appears to become less important with age. This age-related attenuation of the obesity and heart failure association needs further investigation.
Several mechanisms by which elevated body mass index increases the risk of heart failure have been proposed. Figure 10-4 summarizes these mechanisms.
- •
Alterations in cardiac loading. Obesity is associated with hemodynamic overload with increased blood volume and cardiac output. In addition, left ventricular afterload is elevated because of both increased peripheral resistance and greater arterial stiffness.
- •
Changes in cardiac structure and function. Both overweight and obesity are associated with increased left ventricular mass, wall thickness, and dimensions, whereas longer duration and severity of increased weight accelerate remodeling. Obese individuals may fail to increase their ejection fraction with exercise secondary to abnormal diastolic function. Right ventricular afterload may be increased because of sleep-disordered breathing and left ventricular changes. Obesity is also associated with left atrial enlargement and atrial fibrillation. Hypertension is common in obesity and further worsens heart failure risk. In experimental studies, obesity causes lipotoxicity with myocardial steatosis and lipoapoptosis, which have been linked to cardiac dilation, reduced contractility, and diastolic dysfunction. Cardiac metabolic changes include reduced glucose and increased fatty acid oxidation; these changes increase myocardial oxygen consumption and decrease cardiac efficiency.
- •
Activation of neurohumoral and inflammatory pathways. Obesity is associated with neurohumoral activation, renal sodium retention, and increased systemic and myocardial oxidative stress. Sympathetic and renin-angiotensin activation directly through adipose tissue signals is common in obesity. Adipose tissue is a source of proinflammatory cytokines, such as tumor necrosis factor-α, interleukin-6, and C-reactive protein; these cytokines, which suppress cardiac function, have been associated with incident heart failure.
- •
Promotion of atherogenic conditions. Obesity is associated with hypertension, insulin resistance, diabetes mellitus, and dyslipidemia, all of which enhance the risk of myocardial infarction and also mediate or directly cause heart failure.
- •
Predisposition to sleep-disordered breathing. Along with right ventricular changes, obstructive sleep apnea could also lead to left ventricular hypertrophy related to exacerbation of hypertension, increased sympathetic tone, chronic hypoxemia, and exaggerated intrathoracic pressure during obstructive episodes.
- •
Chronic kidney disease. Obesity is associated with an increased risk of proteinuria and renal insufficiency, presumably caused by glomerular hyperfiltration, glomerular hyperperfusion, glomerular hypertrophy, hyperlipidemia, and increased expression of vasoactive and fibrogenic substances (such as angiotensin II, insulin, leptin, and transforming growth factor-β1), all factors associated with heart failure risk.
Interventions
The principal approach to cardiovascular risk reduction in obese patients should include weight control, physical activity, and control of the associated risk factors, such as hypertension, diabetes mellitus, sleep disorders, and components of the metabolic syndrome. Myocardial changes with nonsurgical or surgical weight loss are feasible, and minor weight loss is efficacious; a 10% weight reduction ameliorates systolic dysfunction, and weight loss of 8 to 10 kg produces a significant decrease in left ventricular dimensions and mass index and improves diastolic function.
Substantial weight loss reduces left ventricular wall thickness and volume and filling pressures, and improves diastolic measures and left ventricular systolic function. The hemodynamic benefits of weight reduction are important and further improve ventricular structure and function related to improved ventricular loading conditions. The role of metabolic and neurohumoral modification may take precedence over the hemodynamic effects as left ventricular mass or functional improvement occurs independently of loading alterations. Although many metabolic and neurohumoral interventions have been implicated in animal models, the roles of the renin-angiotensin-aldosterone system antagonists, lipid-lowering therapy, and insulin-sensitizing drugs in obese humans need further study.
Sedentary Exercise Habits
Physical inactivity is an important risk factor for cardiovascular diseases including heart failure. Evidence suggests that regular physical activity has important and wide-ranging health benefits like reduction in risk of cardiovascular diseases, hypertension, and diabetes. Sitting more and performing less nonexercise activity push the risk curve upward to the left as shown in Figure 10-5 , where there is the most risk for disease. Interestingly, emerging evidence indicates that maintaining a high level of daily low-intensity activity may be important independently of moderate to vigorous physical activity for several risk factors for coronary heart disease, such as elevated glucose, type 2 diabetes mellitus, and lipids such as triglyceride and high-density lipoprotein cholesterol levels, all of which predispose to new-onset heart failure. Studies have linked prolonged sitting with cardiovascular risk independently of age or recreational energy expenditure.
Physical activity is a key determinant of good health and an important component of weight reduction and weight maintenance, improved lipoprotein profile, and reduced risk of hypertension, diabetes mellitus, and coronary artery disease. These favorable influences on cardiovascular risk profile in turn reduce the likelihood of heart failure.
Physical activity could also reduce left ventricular hypertrophy independent of body weight or blood pressure because of reduction in vascular resistance and blood volume, improved endothelial function, suppression of the renin-angiotensin and sympathetic nervous system activity, and reduction of insulin resistance. Chronic physical activity reduces cytokine production by adipose tissue, skeletal muscles, endothelial cells, and blood mononuclear cells and upregulates antioxidant enzymes. These modifying effects on heart failure risk factors or intermediate pathways leading to heart failure can reduce incident heart failure.
Interventions
The integration of physical activity into the daily lives of the population has proved challenging. In the United States, from 2001 to 2005, the prevalence of regular physical activity increased by 8.6% (from 43.0% to 46.7%) among women and by 3.5% (from 48.0% to 49.7%) among men. The recommendations of the American College of Sports Medicine and the American Heart Association for regular physical activity in healthy adults from 18 to 65 years currently include the following.
- •
Aerobic activity. Moderate-intensity aerobic physical activity for a minimum of 30 minutes on 5 days each week or vigorous-intensity aerobic activity for a minimum of 20 minutes on 3 days each week. A combination of moderate- and vigorous-intensity activity can be performed to meet this recommendation.
- •
Muscle strengthening activity. It is recommended that 8 to 10 exercises be performed on two or more nonconsecutive days each week using the major muscle groups. To maximize strength development, a resistance (weight) should be used that allows 8 to 12 repetitions of each exercise resulting in volitional fatigue. Muscle strengthening activities include a progressive weight-training program, weight-bearing calisthenics, stair climbing, and similar resistance exercises that use the major muscle groups.
- •
Activity dose. Vigorous-intensity activities may have greater benefit than moderate-intensity physical activity.
Because walking is the preferred activity among sedentary individuals embracing physical activity and the effects of walking have been reported as beneficial in primary prevention, this should be adopted by individuals who do not adhere to the current recommendations.
Alcohol Consumption
Excessive alcohol consumption regardless of beverage type is associated with alcoholic cardiomyopathy. This entity is characterized by left ventricular dilation, increased mass, and reduced or normal wall thickness among patients with a lasting history of heavy alcohol consumption. Limited data are available on the amount and duration of consumption; most studies report that patients with symptomatic heart failure had 10 years or more of exposure to heavy drinking.
In animal models, excessive alcohol consumption is associated with left ventricular myocyte loss, negative inotropic effects and dysfunction of myocytes through abnormalities in calcium homeostasis, and hypertrophy through activation of cardiac beta-adrenoceptors from the elevated levels of norepinephrine. In humans, acute ethanol ingestion may also lead to depressed contractility. However, besides the direct myocardial toxicity, excessive alcohol consumption increases the risk of heart failure by promoting hypertension, myocardial infarction, and diabetes.
Interestingly, other data are consistent with possible benefits of moderate alcohol consumption on the risk of heart failure. The New Haven Epidemiologic Study of the Elderly program and the Cardiovascular Health Study reported a 47% and a 34% lower heart failure risk, respectively. The Framingham Heart Study reported a 59% lower risk among men who consumed 8 to 14 drinks per week compared with abstainers and only a modest and nonsignificant association in women. Moreover, it has been reported that light to moderate alcohol consumption is associated with 40% to 50% lower risk of heart failure with previous myocardial infarction, whereas the risk of heart failure without antecedent myocardial infarction among heavy drinkers was 1.7-fold higher than in abstainers in the same study.
Similar findings were reported in the Physicians’ Health Study. Beneficial effects of alcohol have also been reported on risk for hypertension, myocardial infarction, and diabetes mellitus, whereas alcohol seems to raise high-density lipoprotein cholesterol, to improve insulin sensitivity, to lower plasma levels of inflammatory markers and coagulation factors, and to raise plasma levels of adiponectin. Furthermore, alcohol consumption has diuretic effects, which could prevent volume overload and delay onset of signs and symptoms of heart failure. Beneficial effects of light to moderate alcohol consumption on incidence of heart failure seem to be independent of the reduced incidence of myocardial infarction and could be linked to lower pulmonary artery wedge pressure, reduced afterload, systemic arterial vasodilation, and improved endothelial function.
Current evidence does not support a major role for nonethanol components of beverages on the risk of heart failure, whereas drinking patterns play an important role. Binge drinking (defined as consumption of three or more alcoholic drinks within 1 to 2 hours) has deleterious health effects, whereas light to moderate alcohol consumption (one or two drinks per day for men and one drink per day for women spread on several days of the week) appears to yield most of the beneficial health effects. Thus, for a given volume of alcohol within the moderate drinking range, it is better to be distributed evenly throughout the week than to be consumed more rapidly.
Dietary Habits
In the Dietary Approaches to Stop Hypertension (DASH) diet, individuals are encouraged to consume more (1) fruits and vegetables, (2) grains and grain products, (3) lean meats, fish, and poultry, (4) low-fat or nonfat dairy foods, and (5) nuts, seeds, and legumes and to reduce the consumption of red meat, fat, and sugar while maintaining a low-sodium intake. Initially, this diet was promoted for hypertension; however, recent evidence supports its beneficial effects on reduction of heart failure risk, with an observed 37% lower heart failure rate in women who adhere to the DASH diet.
The DASH diet may contribute to heart failure prevention in some cases because of reduction in blood pressure and incident coronary heart disease. Particularly women with the highest values of a score designed to measure consistency with DASH had a 24% lower risk of coronary heart disease and an 18% lower risk of stroke ; using a different DASH score, Folsom and colleagues did not find statistically significant associations with cardiovascular events. However, women with diets most consistent with DASH had an 18% lower rate of death from coronary heart disease and a 14% lower rate of death from stroke that is similar to the projected effect from the DASH trial. Significantly, the DASH diet reduces low-density lipoprotein cholesterol levels and oxidative stress and exerts additional beneficial physiologic effects like estrogenic effects of phytochemicals.
The relationship between several components of the DASH diet and heart failure has been investigated in human and animal studies. In prospective studies of free-living individuals, daily consumption of whole-grain breakfast cereals was associated with a 30% lower rate of heart failure compared with no consumption, consumption of eggs more than twice per day was associated with a 64% higher rate, consumption of fish was associated with a 20% to 31% lower heart failure rate depending on the frequency of consumption, and consumption of 100 mmol or more of sodium was associated with a 26% higher rate ; only nut consumption was not associated with an increase or decrease in heart failure. In rat models of heart failure, macronutrient intake modified the course of cardiac dysfunction. High-fat diets reduced cardiac remodeling and contractile dysfunction; however, animals fed diets high in linoleic acid survived longer than those fed diets high in carbohydrates or lard. When high-starch, high-fructose, and high-fat diets were compared, animals fed the high-fructose diet demonstrated more cardiac remodeling and worse survival.
There are several mechanisms by which whole-grain cereals can protect against heart failure risk, partially through effects on weight, hypertension, myocardial infarction, and diabetes mellitus. Nutrients contained in whole-grain cereals (e.g., potassium) may lower blood pressure, phytoestrogens may improve lipid levels and insulin sensitivity, and other constituents exert beneficial effects on lipid and homocysteine levels or possess antioxidant properties. Slowing of starch digestion or absorption and promotion of satiety are possible mechanisms by which whole-grain cereals may help control body weight.
Fish consumption exerts beneficial effects on heart failure risk, with about a 20% lower risk associated with an intake of one or two times per week and about a 30% lower risk with intake of three or more times per week, compared with intake less than one time per month. Estimated intake of marine n-3 fatty acids was associated with 37% lower heart failure risk in the highest quintile of intake compared with the lowest. Fish oil favorably affects hemodynamics and reduces blood pressure, inflammation, vascular responses, and myocardial oxygen consumption at given workloads; it increases contractile recovery after ischemia-reperfusion, augments left ventricular response to exercise, prevents left ventricular remodeling, and improves left ventricular indices and diastolic filling.
Short-term trials of fish oil supplementation of 3 to 5 g/day may also reduce risk, whereas dietary doses of about 0.5 g/day may result in more modest effects that during the long term may reduce heart failure risk. The beneficial associations were most pronounced among persons consuming broiled or baked fish at least three times per week, the equivalent of about 500 mg/day of eicosapentaenoic acid and docosahexaenoic acid; fried fish intake does seem not to exert this benefit on heart failure risk. It has been reported that broiled or baked fish consumption is inversely associated with systolic blood pressure, C-reactive protein levels, and carotid intimal medial thickness, whereas fried fish intake is positively associated with them, indicating that the type of cooking could have an impact on the effects.
Historically, human ancestors consumed less than 0.25 g of salt per day; humans may therefore be genetically programmed to this amount of salt. The recent change to the high-salt intake of 10 to 12 g/day presents a major challenge to the physiologic systems to excrete these large amounts of salt, resulting in a rise in blood pressure, increase in the risk for cardiovascular and renal disease, bone demineralization, and stomach cancer. The Department of Health and Human Services and the Department of Agriculture currently recommend that adults consume no more than 2300 mg/day of sodium (equal to approximately 1 tablespoon of salt), but specific groups (i.e., all persons with hypertension, all middle-aged and older adults, and all blacks) should consume no more than 1500 mg/day of sodium. Overall, 69.2% of U.S. adults, approximately 145.5 million persons, met the criteria for the risk groups.
There is overwhelming evidence for a causal relationship between salt intake and blood pressure from epidemiology, intervention, treatment, animal, and genetic studies. Salt intake is also associated with increased risk for overall cardiovascular diseases. A reduction in salt intake may have other beneficial effects on the cardiovascular system, independent of and additive to its effect on blood pressure, including regression of left ventricular hypertrophy, delay in deterioration of renal function, and reduction in proteinuria. Salt intake is also associated with incident heart failure in overweight individuals. A high dietary intake of sodium could lead to heart failure because of increased blood pressure (pressure overload) or extracellular fluid (volume overload) and left ventricular hypertrophy.
Specific strategies should be implemented to target an intake of 1500 mg/day of sodium. The food industry should be encouraged to reduce sodium used for food preparation. A public health campaign to educate consumers about the dangers of high salt intake and the need to make wise and healthy choices in the sodium content of their foods is of paramount importance. If consumers become more attuned to the sodium content of their foods and the detrimental health effects of a high-salt intake, they could demand low-sodium products, encouraging manufacturers to reduce the sodium content of their products, and they could also prepare their food with less salt. Finally, the responsibility to use fresh products and to avoid canned and other high-salt food eventually falls on individuals.
Smoking
Tobacco use is the single most prevalent preventable cause of disease and premature death in the United States. Smoking is a strong and independent predictor of incident heart failure in both men and women, with 45% and 88% increased risk, respectively, after adjustment for coronary heart disease, implying a more direct effect of smoking on development of heart failure. In the Coronary Artery Surgery Study, current smokers had 47% higher risk for heart failure. Similarly, a cohort study in Sweden showed that smokers have a 60% higher risk for heart failure, and in the Health ABC Study, current smokers had a twofold higher risk for heart failure.
Smoking is carrying a considerable population attributable risk for heart failure: 17% as reported in the First National Health and Nutrition Examination Survey Epidemiologic Follow-up Study and 5.5% in whites and 15% in blacks as reported in the Health ABC Study. The deleterious effect of tobacco seems to be independent of the form of use (smoked or not); increased risk for cardiovascular diseases is reported in nonsmoking use of tobacco. There is no “safe” level of smoking; a single cigarette may stiffen the left ventricle, and as few as one to four cigarettes a day double the risk of having a myocardial infarction. Moreover, cigarettes with lower yields of tar and nicotine have not been shown to lower risk of heart disease and should not be considered lower risk alternatives to regular cigarettes.
Mechanisms leading to heart failure in smokers include indirect effects (i.e., by causing or aggravating comorbidities that are strongly related with heart failure) and direct effects on the myocardium. Smoking is associated with coronary vasoconstriction, abnormal coronary endothelial function, increased ischemic burden, oxidative stress, increased peripheral vascular resistance, insulin resistance, and type 2 diabetes. Cigarette smoke contains superoxide and other reactive oxygen species, which could cause oxidative damage in endothelial cells and cell death. Acute inhalation of nicotine decreases nitrate, nitrite, and serum antioxidant concentrations in the plasma and increases arterial stiffness. Cigarettes with high- or low-nicotine content or nicotine-free cigarettes composed of synthetic material increase blood carboxyhemoglobin levels, which in turn decreases the amount of oxygen available to the myocardium. In animal models, nicotine exposure induces interstitial fibrosis in the ventricles. Besides nicotine, carbon monoxide is also a significant component of tobacco smoke and causes overexpression of growth-related proteins (such as calmodulin, calcineurin, and vascular endothelial growth factor), impaired cardiac contraction-relaxation cycle, impairment in calcium handling associated with the dysfunction of the SERCA-2a calcium pump, increased cardiomyocyte cGMP, and reduction of T-tubule density, which in turn decreases the synchrony of activation and reduces the rate of calcium release during systole. In healthy humans, smoking is associated with higher left ventricular mass, lower stroke volume, and lower ejection fraction and impaired ventricular diastolic function. All these affected pathways underscore the impact of smoking on myocardial status.
Interventions
All individuals should be asked about tobacco use, and smokers should be counseled to quit. Patients should be referred to formal cessation programs, and pharmacologic therapy should be offered to increase the success rate. Current recommended strategies include the following.
- •
Medications . Several effective medications are available for tobacco dependence, and clinicians should encourage their use by all patients attempting to quit smoking. Seven first-line medications reliably increase long-term smoking abstinence rates, including bupropion SR, nicotine gum or inhaler or lozenge or nasal spray or patch, and varenicline. Notably, none of these medications is contraindicated if cardiovascular disease exists; however, nicotine replacement therapy should be used with caution among particular cardiovascular patient groups.
- •
Counseling and psychosocial support . Individual, group, and telephone practical counseling (problem solving, skills training) and social support are effective, and their effectiveness increases with treatment intensity.
- •
Combination . The combination of counseling and medication, however, is more effective than either alone. Therefore, clinicians should encourage all individuals making a quit attempt to use both counseling and medication.
Quitting tobacco is associated with reduced morbidity and mortality. In the Studies of Left Ventricular Dysfunction trials, ex-smokers had a 30% lower mortality than that of current smokers, a benefit that accrued within 2 years after smoking cessation. This survival rate was similar to that of nonsmokers; the risk for heart failure hospitalizations and myocardial infarctions also reduced after quitting. Women’s risk of heart disease is reduced by one third within 2 years of quitting and by about two thirds within 5 years.
Obstructive Sleep Apnea
Obstructive sleep apnea is characterized by abnormal collapse of the pharyngeal airway during sleep, causing repetitive arousals. Obesity is a major risk factor for this condition, partly because layering of fat adjacent to the pharynx narrows its lumen. The Wisconsin Sleep Cohort Study, a large population-based study, reported that obstructive sleep apnea affects approximately 15% of men and 5% of women between the ages of 30 and 60 years when sleep apnea is defined as an apnea-hypopnea index of ≥10 events per hour. Other studies reported similar findings or an even higher prevalence, especially in women. Several well-conducted studies provided compelling evidence that obstructive sleep apnea is related to hypertension and worsening blood pressure control, coronary artery disease, and diabetes. In addition, obstructive sleep apnea seems to induce left ventricular dysfunction independently of hypertension and in established heart failure results in worse outcomes. In the Sleep Heart Health Study, obstructive sleep apnea was found to be an independent risk factor for heart failure and was associated with a 2.38 relative risk of heart failure when the apnea-hypopnea index was ≥11 events per hour.
Obstructive sleep apnea may lead to heart failure through (1) development and worsening of comorbidities that predispose to heart failure and (2) neurohormonal abnormalities and mechanical modifications. Sleep is normally a period of cardiac rest. Apart from brief bursts of sympathetic activity in rapid eye movement (REM) sleep, sleep is characterized by decreased sympathetic and increased vagal activity, which lowers heart rate and blood pressure. In patients with obstructive sleep apnea, however, negative intrathoracic pressure generated by the inspiratory effort during obstructed breathing increases left ventricular afterload, changes venous return affecting preload and stroke volume, and increases cardiac muscle work index. In addition, sympathetic activation secondary to hypoxia increases blood pressure and heart rate, thus increasing cardiac afterload, and reduces myocardial perfusion, leading to myocardial ischemia. On the other hand, the increased venous return accompanied by acute hypoxic pulmonary vasoconstriction increases right ventricular volume and pressure and also may compromise left ventricular filling. Sleep apnea treatment with devices that provide continuous positive airway pressure has been shown to improve left ventricular structure and function in patients with established left ventricular dysfunction or to reverse functional ventricular abnormalities.
Hypertension
Hypertension is an antecedent condition in the majority of individuals developing heart failure. Systolic blood pressure increases almost linearly with age, as does the overall prevalence of hypertension and the proportion of patients with isolated systolic hypertension. By the age of 75 years, almost all hypertensive individuals have isolated systolic hypertension. Diastolic hypertension is more prevalent before the age of 50 years, whereas prevalent systolic hypertension increases with age and after the age of 50 years represents the most common form of hypertension. Diastolic blood pressure is a more potent cardiovascular risk factor than systolic blood pressure until the age of 50 years, and thereafter systolic blood pressure becomes more important. Clinical trials have demonstrated that controlling systolic hypertension reduces heart failure rates. The population attributable risk of hypertension for heart failure in the general population is reported to be 39% in men and 59% in women by the Framingham investigators, whereas the population attributable risk of uncontrolled blood pressure in the elderly was reported to be 21.3% in whites to 30.1% in blacks in the Health ABC Study. This risk increases in a continuous fashion with increase in blood pressure.
The lifetime risk for heart failure doubles in subjects with blood pressure >160/100 mm Hg versus those with <140/90 mm Hg, and this gradient of risk is seen in both sexes in every decade from 40 to 70 years. Considering that the prevalence of hypertension is estimated to range from 25% to 60% and that this proportion will likely increase with aging of the population and a sedentary lifestyle, the importance of hypertension in development of heart failure cannot be overemphasized.
The progression from hypertension to structural ventricular changes and systolic and diastolic ventricular dysfunction is well established; Figure 10-6 summarizes this process. Increases in cardiac afterload, left ventricular mass, and wall stress accompanied by impairment of diastolic filling properties occur in the chronic setting. Increased peripheral vascular resistance places a greater myocardial burden leading to an increase in myocardial muscle mass. The development of hypertrophy is associated with progressive degenerative changes in the myocytes and an abnormal accumulation of collagen in the interstitial spaces. Initially, this leads to diastolic dysfunction with increased myocardial stiffness. Also, the disproportionately increased left ventricular mass leads to inadequate microvasculature to perfuse the hypertrophied myocardium, resulting in subendocardial hypoperfusion and ischemia. Hypertension also contributes to ischemia by increasing myocardial oxygen demand due to increased workload and is associated with endothelial dysfunction, oxidative stress, and development of atherosclerosis. These changes increase the risk for coronary thrombosis and myocardial infarction characterized by loss of contractile function, neurohormonal activation, and ventricular remodeling, leading to the development of systolic dysfunction.
