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A number of etiologies for HF have been defined (Table 69–4). Coronary artery disease is often cited as the most common cause of HF.77 Recent data from Norway indicate that 15% to 25% of patients with an acute myocardial infarction develop HF over a 3-year period, with the highest risk in the first 6 months after infarction.78 However, there is race- and sex-related variation in the etiologies for HF. For example, in the Health, Aging, and Body Composition study, among white individuals, the population-attributable risks for incident HF were 23.9% and 21.3% for coronary artery disease and hypertension, respectively. Among black individuals, hypertension accounted for 30.1% of incident HF, whereas coronary artery disease accounted for 29.5%.79 In the Framingham Heart Study, hypertension, rather than coronary artery disease, was the most common risk factor for HF in both men and women, accounting for approximately 60% of HF cases in women and approximately 40% in men.80 Findings from Olmsted County, Minnesota, support sex-related differences in HF risk factors, with coronary artery disease being a major contributor for HF risk in men, whereas hypertension was a greater risk factor in women.81
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The relative contributions of different etiologies for HF also vary geographically. The International Congestive HF Study included nearly 6000 individuals with prevalent HF from South America, Africa, the Middle East, and Asia (Table 69–5).82 In South America, coronary artery disease and hypertension were the etiologies for HF in 26% and 21% of cases, respectively. Chagas disease is also an important cause for HF in South America.83 In contrast, in Africa, hypertension was a major etiologic factor for HF in 35% of cases, whereas coronary artery disease accounted for 20%.82 In Asia and the Middle East, half of HF cases were attributed to coronary artery disease, whereas hypertension caused 10% to 15% of cases. Rheumatic valvular disease was the etiology for HF in 6% to 9% of cases in Asia and the Middle East, accounting for a larger proportion than seen in North America and Europe.82
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Although coronary artery disease and hypertension may be the leading causes of HF worldwide, individual patients frequently have multiple comorbidities that contribute to the syndrome of HF.67,84 Cardiometabolic disorders such as obesity and diabetes mellitus are increasing in prevalence, with greater contributions to HF incidence.67,84 Although modifiable cardiometabolic risk factors account for the majority of causes of HF, less common causes include dilated cardiomyopathy, hypertrophic cardiomyopathy, hemochromatosis, amyloidosis, and human immunodeficiency virus (HIV) infection, among others (see Table 69–4). An increasingly recognized cause of HF is cardiotoxic medications, such as some cancer chemotherapies (eg, anthracyclines and novel biologics).85
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HF appears to cluster within families. For instance, parental HF has been associated with greater left ventricular mass, internal dimension, systolic dysfunction, and incident HF in offspring.86 Nonetheless, no robust genetic variant has, as yet, been identified for “common” HF, or that caused by typical risk factors such as hypertension, diabetes mellitus, and coronary artery disease.87 Some of the familial risk may be mediated through modifiable risk factors, particularly those present in middle age, which contribute substantially to the development of HF later in life. Modifiable risk factors include blood pressure, body mass, cholesterol, diet, glucose, physical activity, and smoking. The greatest cardiovascular impact of blood pressure lowering in hypertensive individuals is on the reduction in risk of HF, even more so than stroke or atherosclerotic coronary artery disease.88 Higher body mass index and obesity are associated with increased risk of HF, and weight loss reduces this risk.89,90,91 Alcohol, when chronically consumed in large amounts, is a recognized etiology for cardiomyopathy. However, recent observations from the ARIC study suggest that light-to-moderate alcohol consumption (seven or fewer drinks per week) lowered the risk of HF in men and, to a lesser extent, in women.92 Similar findings were reported from the Norwegian Nord-Trøndelag Health Study.93 Hyperglycemia and insulin resistance, even in the absence of overt diabetes mellitus, have been associated with increased risk for incident HF.94,95 Diabetes mellitus is also an established risk factor for incident HF.96,97,98,99 However, glucose-lowering therapies for diabetes mellitus have demonstrated mixed results regarding the risk of HF. A number of medications for the treatment of diabetes mellitus have been associated with increased risk of HF, such as the thiazolidinediones (rosiglitazone and pioglitazone) and the dipeptidyl peptidase-4 inhibitor (saxagliptin).100,101 In contrast, glucose lowering with the sodium-glucose cotransporter 2 inhibitor empagliflozin was recently demonstrated to reduce the risk of HF among individuals with prevalent diabetes mellitus.102 Higher amounts of physical activity have been associated with reduced risk of incident HF.103,104 Further, among middle-aged to elderly individuals, smoking is an established risk factor for incident HF.97,98
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The AHA recognized the importance of modifiable risk factors to cardiovascular risk and developed a concept known as the Simple 7 (blood pressure, body mass, cholesterol, diet, glucose, physical activity, and smoking). In the ARIC study, individuals with high Simple 7 scores (indicating more healthy behaviors) were at lower lifetime risk for incident HF (14%), compared with individuals with average (27%) or poor (49%) scores.105 These findings were corroborated by recent observations from the Framingham Heart Study.106 Data from the Physicians’ Health Study suggest that optimal modifiable risk factor profiles can lower the lifetime risk of HF by as much as 50%.107
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Modifiable risk factors and comorbidities contribute to the risk of HF, regardless of LVEF. However, the relative risk associated with risk factors for HF with a preserved versus a reduced LVEF may differ. In the Framingham Heart Study, a history of hypertension, diastolic dysfunction, atrial fibrillation, female sex, and lower ratio of forced expiratory volume in 1 second to forced vital capacity were associated with greater risk for symptomatic HFpEF compared with HFrEF.76,108 Patients with HFpEF often demonstrate exaggerated blood pressure responses to exercise, increased vascular stiffness, chronotropic incompetence, and increased baroreceptor sensitivity, and are exquisitely sensitive to excess preload reduction. In this context, atrial fibrillation appears to be a particularly strong risk factor for HFpEF.109 In the Framingham Heart Study, prior myocardial infarction, left bundle branch block, asymptomatic left ventricular systolic dysfunction, higher serum creatinine, and lower total blood hemoglobin concentration were significantly associated with greater risk for HFrEF.76,108
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Asymptomatic abnormalities of cardiac structure and function are associated with increased risk for the development of HF. Several population-based studies from the United States, Europe, and Australia have examined the prevalence of asymptomatic left ventricular systolic dysfunction, typically defined by LVEF, with estimates ranging from 1% to 12.9% (pooled 4.8%) (Fig. 69–4).110,111,112,113,114,115,116,117,118,119,120 The risk of incident HF associated with asymptomatic left ventricular systolic dysfunction compared with preserved left ventricular function has been reported from the Cardiovascular Health Study, Framingham Heart Study, and Multi-Ethnic Study of Atherosclerosis, with hazard ratios of 1.60 (95% confidence interval [CI], 1.35-1.91), 4.7 (95% CI, 2.7-8.1), and 8.69 (95% CI, 4.90-15.45), respectively.110,111,114 In a meta-analysis of older (≥ 60 years) adults, the median prevalence of asymptomatic left ventricular diastolic dysfunction was 36%.121 The presence, severity, and progression of diastolic dysfunction have been demonstrated in both clinical and community-based populations to be associated with increased risk for incident HF.108,122,123,124 In the Framingham Heart Study, left ventricular hypertrophy was associated with increased risk of incident HF, with eccentric hypertrophy portending a greater risk for HFrEF, whereas concentric hypertrophy was associated with greater risk for HFpEF.125,126 Increased arterial stiffness and vascular remodeling have also been associated with greater risk of HF.127,128,129
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Lifetime Risk and Risk Prediction Models
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The lifetime risk for the development of HF is high. In the Framingham Heart Study, the overall lifetime risk among white men and women was 20%.130 Even among individuals without a history of myocardial infarction, the lifetime risk of HF was substantial, estimated at one in nine men and one in six women.130 Estimates for lifetime risk using data pooled from the Chicago Heart Association, ARIC, and Cardiovascular Health Studies corroborated the high lifetime risks of HF observed in the Framingham Heart Study and extended the findings to black individuals.131 The lifetime risks for HF ranged from 30% to 42%, 20% to 29%, 32% to 39%, and 24% to 46% in white men, black men, white women, and black women, respectively.131 The lifetime risk of HF also differed according to the presence of modifiable risk factors in the ARIC study, as previously mentioned.105
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Heart failure risk prediction models from community cohorts have been developed (Table 69–6). Factors included in the risk prediction models vary by study, but typically include age, sex, heart rate, systolic blood pressure, body mass index, and diabetes mellitus. Other factors, such as smoking status, serum creatinine, coronary heart disease, antihypertensive medication use, left ventricular hypertrophy, and valvular disease, are included to varying extents. The c-statistics for model performance are good, ranging from 0.73 to 0.87.96,97,98,132,133 Further attention has been given to the use of circulating biomarkers for risk prediction. Although a number of candidate biomarkers have been studied, the natriuretic peptides (eg, B-type natriuretic peptide [BNP] and N-terminal pro-BNP [NT-proBNP]) are the most robust biomarker predictors of incident HF after adjusting for clinical factors.97,98,134,135 It is also noteworthy that prediction algorithms that can quantify risk of developing cardiovascular disease incidence in general seem to work reasonably well for predicting incidence of HF.136
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