Statins are not beneficial as adjunctive therapy when prescribed solely for the diagnosis of HF in the absence of other indications, and routine use of statins for the treatment of HF is not indicated outside of current practice guide- lines for the primary and secondary preven- tion of atherosclerotic vascular disease5,8,273 276 (Class III: No benefit; Level of Evidence A). Metabolic Syndrome and HF: Clustering Risk With Comorbidities The Metabolic Syndrome and Incremental Risk in HF In the earlier sections of this document, the indepen- dent roles of hypertension, diabetes mellitus, and obe- sity in the development of HF and their effect on out- comes in patients with HF are reviewed. In this section, we review whether there is incremental risk when these comorbidities cluster as the metabolic syndrome in patients with HF. The metabolic syndrome constitutes a clustering of risk factors that include elevated glu- cose, hypertension, central obesity, and dyslipidemias, namely hypertriglyceridemia and low high-density lipo- Although the underlying cause of the syn- drome remains poorly understood, insulin resistance and central obesity are thought to play a key role. A variety of organizations have proposed definitions for the metabolic syndrome,288 291 and there are some ca- veats in the application of the various definitions of the metabolic syndrome. The risk factors included in the metabolic syndrome are continuous and may impart varying degrees of risk across the spectrum of values. Instead, the definitions have been used in a dichoto- mous manner with risk assessed as above or below a cut point. In addition, each criterion of the definition is given equal weight toward the diagnosis of the metabol- ic syndrome. Lastly, unmeasured or related conditions such as chronic inflammation, prothrombotic milieu, polycystic ovary syndrome, nonalcoholic steatohepa- titis, cholesterol gallstones, and sleep apnea may be associated with the metabolic syndrome. Impact of the Metabolic Syndrome on Incident HF A number of studies have demonstrated that the pres- ence of the metabolic syndrome translates into an in- creased risk of developing HF. NHANES III (Third National Health and Nutrition Examination Survey; 1988 1994) reported an association between the metabolic syn- drome and HF.292 Participants with the metabolic syn- drome were twice as likely to report HF. The prevalence of HF increased with the number of components of the metabolic syndrome. However, when the homeostasis model assessment was included in the multivariate mod- el, the odds ratio of the metabolic syndrome was no longer significant, suggesting that 90.7% of the associa- tion between the metabolic syndrome and HF was at- tributed to insulin resistance. Interestingly, the strength of this association varied among ethnic groups, with the homeostasis model assessment explaining 85.7% of the association in whites, 95.7% in Mexican Americans, and only 32.7% in blacks. The first prospective study to confirm that the meta- bolic syndrome is a significant predictor of incident HF comes from the Uppsala Longitudinal Study of Adult A cohort of 2314 men (age, 50 years) without HF, MI, or valvular disease at baseline was followed up for 20 years. With the application of a modified ver- sion of the ATP III (Adult Treatment Panel III) criteria (BMI was used instead of waist circumference), the risk of incident HF was 5.3 per 1000 person-years for those with the metabolic syndrome versus 1.7 per 1000 person-years for those without the metabolic syn- drome. The metabolic syndrome increased the risk of developing HF >3-fold and remained significant after adjustment for established risk factors for HF. The inci- dence of HF in those with the metabolic syndrome began Bozkurt et al diverging from those without the syndrome at 10 years of follow-up, suggesting that long-term follow-up may be necessary to truly estimate the impact of the metabolic syndrome. The increased risk of HF with the metabolic syn- drome has consistently been demonstrated in other populations. In assessments of the contribution of the individual metabolic syndrome components to incident HF, the results vary slightly between studies, but over- all, obesity, hypertension, and an increased fasting glucose most strongly predicted incident HF. These risk factors had HRs similar to that of the metabolic syndrome as a whole, suggesting that the metabolic syndrome does not predict HF better than its individual components. Wang et al294 applied the World Health Organization, National Cholesterol Education Program, International Diabetes Federation, and AHA/National Heart, Lung, and Blood Institute definitions to a popu- lation of elderly Finns and found that each of them was predictive of incident HF. Both MESA199 and this study demonstrated that the metabolic syndrome predicts HF independently of MI, suggesting that it is also as- sociated with nonischemic HF. also demonstrate the important contribution of other typically unmeasured components of the metabolic syndrome, including inflammation and microalbuminuria (included in the World Health Organi- zation definition), to the development of HF. In CHS, a C-reactive protein level 3 mg/L and interleukin-6 level 2.21 pg/mL were significant predictors of incident HF and provided additive information when combined with the metabolic syndrome in predicting the development Moreover, in MESA, C-reactive protein, interleu- kin-6, fibrinogen, and microalbuminuria levels were sig- nificantly associated with incident HF. Although obesity ) was also an independent risk factor for the development of HF, its results were attenuated with the addition of interleukin-6 or C-reactive protein to the model, suggesting that the effects of obesity may be partially mediated through inflammatory pathways.199 Role of the Metabolic Syndrome in Patients With Established HF The prevalence and effects of the metabolic syndrome in the established HF population are less well studied. Because the metabolic syndrome is an independent risk factor for the development of HF, it is not surprising that its prevalence in the HF population is higher than in the general adult population. The 2 studies from the United States, 1 study done in a hospitalized HF popula- tion (without restriction of EF with modified ATP III using and the other focused on an outpa- tient population with HFrEF,297 reported a prevalence of 68.3% and 40%, respectively. The prevalence of the metabolic syndrome in a Japanese HF cohort was 37%, which is more than double the prevalence found in the general Japanese population.298 Lastly, a small Turkish study of HFrEF reported a prevalence of 51%.299 These studies uniformly found a higher prevalence of the meta- bolic syndrome in women than in men. Hispanics had the highest prevalence of the metabolic syndrome (78.8%) followed by whites (69.5%) and blacks (60.9%).296 In the 2 studies that did not restrict EF, the prevalence of HF- pEF was higher in those with the metabolic syndrome. The effect of the metabolic syndrome on mortality in the HF population has been assessed in 2 studies with discrepant results. Hassan et al296 reported a lower mortality in patients with HF with compared with those without the metabolic syndrome (43.8% versus 57.6%) in a retrospective cohort of patients (n=625) admitted with HF. There was a nonlinear decrease in mortality with an increasing number of metabolic syndrome criteria: 68.2% in those with no criteria to 37.0% in those with all 5 criteria. Conversely, a prospective cohort of 865 out- patients with HFrEF (EF <40%) demonstrated a mortality of 24% in those with the metabolic syndrome compared with 16% in those without at 2.6 years of follow-up.297 The Kaplan-Meier curves were similar for up to 4 years of follow-up for both groups and diverged thereafter with higher mortality in the metabolic syndrome group. As described for obesity, hypertension, and dia- betes mellitus, a similar paradoxical effect may ex- ist with respect to the metabolic syndrome: Although obesity, higher BP, and elevated cholesterol are risk factors for the development of HF and mortality in the general adult population, these factors are associated with improved survival in patients with established HF. The metabolic syndrome is associated with higher all- cause and cardiovascular mortality in the general adult but as suggested by Hassan et al,296 the metabolic syndrome may exert an inverse associa- tion with improved survival in the HF population. Further studies are warranted to confirm and better understand this paradox. Treatment of the Metabolic Syndrome Given that overweight and obesity, physical inactivity, and an atherogenic diet contribute to the development of the metabolic syndrome, the institution of lifestyle modification is first-line therapy. Lifestyle modification involves the institution of changes in diet, exercise, and behavior to gradually achieve a modest degree of in- tentional weight loss.289,302 In the general population, a realistic weight loss goal is a 7% to 10% reduction in baseline weight over 6 to 12 months. Even if this degree of weight loss does not achieve a normal BMI, it imparts significant metabolic benefits. In general, the diet should be low in saturated fats, trans fats, cholesterol, and simple sugars and incorporate an increased intake of fruits, vegetables, and whole grains. Management of Comorbidities in Chronic Heart Failure CLINICAL STATEMENTS AND GUIDELINES Exercise is an important factor in initiating and maintaining weight loss. A minimum of 30 minutes of moderate-inten- sity physical activity is recommended on most days of the week, with further increases in exercise imparting greater benefits. Implementation of the above lifestyle recommen- dations to achieve a gradual, modest weight loss has sig- nificant benefits in the general population. These include a significant reduction in BP, total cholesterol, triglycerides, and fasting glucose. In addition, there is a 58% reduction in the development of diabetes mellitus.303 A slightly different dietary approach to the metabolic syndrome may be the implementation of a Mediterranean- style diet. In general, the traditional Mediterranean diet consists of a high intake of monounsaturated fatty acids, primarily from olives and olive oil, and PUFAs, particu- larly -linoleic acid from nuts, as well as increased con- sumption of fruits, vegetables, whole grains, legumes, and fish, along with moderation in alcohol intake and lim- ited red meats (Table 12). Kastorini et al305 performed a meta-analysis demonstrating that the Mediterranean diet exerts favorable effects on the components of the meta- bolic syndrome, namely reducing waist circumference, triglycerides, SBP, diastolic BP, glucose, and insulin re- sistance measured by homeostatic model assessment, and increases high-density lipoprotein levels. Lifestyle Modifications and HF Multifactorial Lifestyle Modification Interventions Does Multifactorial Lifestyle Modification Prevent HF? A healthful lifestyle appears to reduce the risk of devel- oping HF. The Physicians Health Study (1982 2008) demonstrated that participants with the healthiest life- styles had the lowest lifetime risk of developing HF.306 Six healthy lifestyle factors were assessed: BMI <25 kg/ , not smoking, regular exercise 5 times/wk, moder- ate drinking (5 14 times/wk), consumption of breakfast cereal, and consumption of fruits and vegetables ( 4 servings/d). During 22.4 years of follow-up in 20900 men, 1200 (5.7%) developed HF. A higher number of healthy lifestyle characteristics was associated with a lower risk of developing HF. The lifetime risk for HF in those without any of the above healthy lifestyle factors was 21.2% compared with only 10.1% in those with 4 lifestyle factors. There are limited data to determine whether the imple- mentation of lifestyle modification in at-risk patients can translate into a reduced risk of HF. The Steno-2 study307 (Intensified Multifactorial Intervention in Patients With Type 2 Diabetes and Microalbuminuria) reported a reduced risk of CVD in patients with type 2 diabetes mellitus who par- ticipated in an intensive, multifactorial intervention that in- cluded quarterly clinic visits; a low-fat diet; 30 minutes of exercise 3 to 5 times/wk; prescription of an ACE inhibitor, a multivitamin, and aspirin; and a step-wise approach to pharmacological therapy for diabetes mellitus, hyperten- sion, and hyperlipidemia. After a mean follow-up of 7.8 years, the intensive therapy group experienced a signifi- cant risk reduction in a combined end point that included cardiovascular mortality, nonfatal MI, coronary artery by- pass surgery, percutaneous coronary intervention, nonfa- tal stroke, amputation, or vascular surgery for peripheral P=0.008). Because the Steno-2 trial used an aggressive lifestyle and pharmacological approach to improving the metabolic risk factors, the study could not assess the contributions of the individual treatment components and specific reduction in HF. In the Look-AHEAD trial (Action in Health in Diabetes), intensive lifestyle intervention focusing on weight loss did not reduce the rate of cardiovascular events in overweight or obese adults with type 2 diabetes Participants (n=5145) were randomized to conventional therapy or an intensive lifestyle modification program that included a hypocaloric, low-fat diet; use of Table 12. Mediterranean Diet Used in the Primary Prevention of Cardiovascular Disease With a Mediterranean Diet Trial Mediterranean Diet Recommended Olive oil* 4 tbsp/d Tree nuts and peanuts 3 servings/wk Fresh fruits 3 servings/d Vegetables 2 servings/d Fish (especially fatty fish), seafood 3 servings/wk Legumes 3 servings/wk Sauce made with tomato and onion, slowly simmered with olive oil White meat Instead of red meat Wine with meals (socially, with moderation) Discouraged Soda drinks <1 drink/d Commercial bakery goods, sweets, and pastries Spread fats <1 serving/d Red and processed meats <1 serving/d CVD indicates cardiovascular disease. *The amount of olive oil includes oil used for cooking and salads and oil consumed in meals eaten outside the home. In the group assigned to the Mediterranean diet with extravirgin olive oil, the goal was to consume 50 g ( 4 tbsp) per day of the polyphenol-rich olive oil supplied, instead of the ordinary refined variety, which is low in polyphenols. Modified from Estruch et al.304 Copyright 2013, Massachusetts Medical Society. Reprinted with permission from Massachusetts Medical Society. Bozkurt et al meal replacement products; 175 min/wk of physical activ- ity; and frequent visits with study personnel. Weight loss was greater in the intervention group than in the control group throughout the study (8.6% versus 0.7% at 1 year; 6.0% versus 3.5% at study end). The intensive lifestyle intervention produced greater reductions in glycated he- moglobin and greater initial improvements in fitness and all cardiovascular risk factors except for low-density-lipo- protein cholesterol levels but did not have a significant impact on cardiovascular events308 310 (Table 13). Does Multifactorial Lifestyle Modification Improve Outcomes in Patients With Established HF? There are few data on the application of a lifestyle modification program in the HF population. A small pilot study (n=20) randomized patients with HFrEF (EF <50%) and the metabolic syndrome to a lifestyle modification program modeled after the Look-AHEAD trial.240 months, the lifestyle group had not lost significantly more weight than the control group ( 0.56 3.7 kg for the control group versus 1.2 4.1 kg for the lifestyle group; P=0.71). Thus, there were no significant altera- tions in metabolic or functional parameters and biomark- ers. Importantly, the intervention, which included a hypo- caloric diet with meal replacement products and a home walking program, was not associated with adverse events related to weight loss or exercise. Current approaches for lifestyle modifications for a HF patient include a variety of approaches such as losing or maintaining normal weight, tracking daily fluid intake, avoiding alcohol, avoiding or limiting caffeine, eating a heart-healthy diet, being physically active, exercising, managing stress, keeping track of and monitoring BP, getting adequate rest, developing support, avoiding flu and pneumonia with vaccinations, and implementing other dietary interventions8 (Table 14). Given their im- portance in lifestyle modification, in the next sections, we focus on specific dietary interventions and exercise regimen. Dietary Lifestyle Interventions in HF Evidence for the effects of dietary patterns among pa- tients with HF is limited. Current dietary recommenda- tions for patients with HF are based largely on data from populations without HF. Dietary Interventions for the Prevention of HF The DASH (Dietary Approaches to Stop Hypertension) diet, which includes high intakes of fruits, vegetables, low-fat dairy, and whole grains, resulting in high potas- sium, magnesium, calcium, and fiber, moderately high protein, and low total and saturated fat, effectively re- duces BP. Current data suggest that the DASH diet is ef- fective in preventing HF.321,322 In a prospective, observa- tional study of 36019 participants without baseline HF, diabetes mellitus, or MI in Sweden, the DASH diet was associated with lower rates of incident HF.321 Similarly, in 38987 participants in a cohort of Swedish men 45 to 79 years of age, the DASH diet was associated with lower rates of HF and HF events.322 The Mediterranean diet emphasizes high consumption of olive oil and a high intake of vegetables, fruits, whole grains, legumes, fish, and nuts and limits unhealthy fats. It has been shown to prevent cardiovascular events.323 The PREDIMED study (Prevenci n con Dieta Mediter- r nea), a multicenter, randomized trial to assess the effects of the Mediterranean diet (components listed in Table 12) on the primary prevention of CVD, randomized Table 13. Recommendation for Lifestyle Modifications in Stages A and B HF: Asymptomatic Patients at Risk for HF or With Structural Heart Disease Recommendation COR LOE Referenced Guideline References Exercise or regular physical activity is beneficial in prevention of cardiovascular disease and HF. I B COR indicates Class of Recommendation; HF, heart failure; and LOE, Level of Evidence. Table 14. Recommendations for Lifestyle Modifications in Stage C HF: Patients With Cardiac Structural Abnormalities or Remodeling With Prior or Current Symptoms of HF, Especially With Clustering Risk or Several Comorbidities at the Same Time Recommendations COR LOE Referenced Guideline References Exercise training (or regular physical activity) is recommended as safe and effective for patients with HF who are able to participate to improve functional status. Sodium restriction is reasonable for patients with symptomatic HF to reduce congestive symptoms. Otherwise, there are no specific recommendations for caloric intake or dietary composition. COR indicates Class of Recommendation; HF, heart failure; and LOE, Level of Evidence. Management of Comorbidities in Chronic Heart Failure CLINICAL STATEMENTS AND GUIDELINES 7447 participants to 1 of 3 groups: the Mediterranean diet with extravirgin olive oil, the Mediterranean diet with 30 g of mixed nuts daily, or a control group with low-fat Participants had either type 2 diabetes mellitus or at least 3 major risk factors of smoking, hyperten- sion, increased low-density lipoprotein cholesterol, low high-density lipoprotein levels, overweight/obesity, or a family history of premature coronary heart disease. After a median follow-up of 4.8 years, there was a significant reduction in the primary end point (a composite of MI, stroke, or death resulting from cardiovascular causes) in both Mediterranean diet groups compared with the control group with a low-fat diet. When the components of the primary end point were assessed individually, there was a significant reduction in the rate of stroke but no significant impact on the risk of MI or mortality (from cardiovascular or all-cause). Although there are no data specifically addressing the impact of the Mediter- ranean diet on the development of HF or established HF, both Mediterranean diets in the PREDIMED diet resulted in significant decreases in plasma N-terminal pro-brain natriuretic peptide levels, suggesting mitigation against Similarly, the Lyon Diet Heart Study, a small, random- ized, secondary prevention trial of the Mediterranean diet performed in patients after first MI (n=423),324 showed that the Mediterranean diet group had fewer cardiac deaths, nonfatal MIs, or HF development compared with the control group after a mean follow-up of 46 months. Although these data are provocative, the Mediterranean diet has not been widely implemented or incorporated into the metabolic syndrome guidelines and needs to be further studied in the HF population. Diet in Patients With Established HF Among Women s Health Initiative participants, higher DASH diet scores were associated with modestly lower mortality rates in women with HF.325 Similarly, there was a trend toward an inverse association between Mediter- ranean diet scores and lower mortality rates among women with HF.325 In a cross-sectional study of 372 con- secutive patients with HF, the Mediterranean diet was as- sociated with beneficial effects on biventricular systolic and diastolic function.326 These data provide support for the concept that di- etary recommendations developed for other cardiovas- cular conditions or general populations may also be ap- propriate in patients with HF. Similarly, in patients with HFpEF with treated hyperten- sion, the sodium-restricted DASH diet has been shown to reduce systemic BP, arterial stiffness, and oxidative and to improve diastolic function, arterial elas- tance, and ventricular-arterial coupling.328 Data on the role of the Mediterranean diet in patients with HF are very limited. Among postmenopausal women enrolled in the Women s Health Initiative trial, there was a nonsignificant trend toward an inverse association be- tween Mediterranean diet scores and mortality in women It should be noted that the major and distinc- tive components of the Mediterranean diet may not have been captured by the food frequency questionnaire used in this study and may have contributed to these nonsig- It is also interesting to note that the DASH-type diet is similar to the Mediterranean diet in its components. Both are high in fruits, vegetables, whole grains, and nuts, and especially when reduced in sodium intake, both seem to be a reasonable nutritional model in HF.329 The above studies related to the DASH and Mediterranean diets provide support for the concept that dietary rec- ommendations developed for other cardiovascular con- ditions or general populations may also be appropriate in patients with HF. Experimental studies have demonstrated inconsis- tent results with a high-protein diet in patients with HF. In some models, a high-protein diet (30% of energy intake) compared with a standard diet with 18% of energy intake from protein failed to affect cardiac mass, LV volumes, LVEF, or myocardial mitochondrial oxidative capacity or did not improve survival.330 A few early clinical studies, on the other hand, demonstrated that a high-protein diet can result in moderate weight loss and reduced adiposity in overweight and obese patients with HF, and these changes were associated with improvements in functional status, lipid profiles, glycemic control, and However, these preliminary findings need to be confirmed in studies with more participants and long Exercise Training and Physical Activity as Lifestyle Intervention in HF Exercise and Physical Activity for the Prevention of HF Physical activity and physical fitness have been associ- ated with a lower incidence of HF in several population- based studies and large-scale cohorts.193,311 315 On the other hand, a sedentary lifestyle and physical inactiv- ity have been associated with an increased risk of the development of HF regardless of BMI category, base- line hypertension status, and prevalent coronary heart Although current HF guidelines focus on the role of exercise training (or regular physical activ- ity) in patients with established HF, the beneficial role of physical activity and exercise in cardiovascular health is clear and supported for the prevention of HF193,311 315 (Table 13). Exercise Training and Physical Activity in Patients With Established HF Of the components of lifestyle modification, exercise is the most studied in HF. Exercise training (or regu- lar physical activity) is recommended by guidelines as Bozkurt et al safe and effective for patients with HF who are able to participate to improve functional status.8,29,317 Exercise has been described to exert the following physiological benefits in HF: decreased plasma norepinephrine levels and inflammation; increased heart rate variability, endo- thelial vasodilatation, coronary blood flow reserve, and anaerobic threshold; and changes in skeletal muscle Meta-analyses and a large, randomized, clinical trial have demonstrated the beneficial effects of an exercise program in patients with established The ExTraMATCH (Exercise Training Meta Analysis of Trials in Chronic Heart Failure Patients) meta-analysis of 9 prospective studies (n=801) dem- onstrated a reduction in overall mortality with exercise that translated into a number needed to treat of 17 to As mentioned in the obesity sec- tion, the HF-ACTION trial randomized 2331 outpatients with HF (EF <35%) to an exercise program or usual The exercise regimen consisted of 36 su- pervised sessions over 3 months followed by home- based training. All-cause mortality and hospitalization were not different between the 2 groups. The Cochrane Database recently published a meta-analysis of 19 tri- als (including the above-mentioned HF-ACTION trial; total n=3647) that assessed the effects of exercise training in HFrEF.319 Exercise interventions reduced HF and improved QOL but did not affect all-cause mortality. Interestingly, when HF-ACTION was excluded, mortality was improved with exercise (relative risk, 0.91; 95% CI, 0.39 0.98; Table 14). Types of Exercise Training Recommended in HF Aerobic exercise training regimens in HF have varied among studies from a low level to a more moderate in- tensity. Interval training at various intensities (50%, 70%, and 80% of maximal capacity) has shown to be beneficial, but training intensity does not seem to directly influence the magnitude of the increase in exercise tolerance.334 The exercise training regimen varied from general exer- cise to isolated muscle training involving major muscle groups; the setting has varied from supervision to home training; the modality has also been variable, more com- monly treadmill or bicycle ergometry; and the length of training program has been as short as several weeks to as long as a year.335 Therefore, agreement on a universal exercise prescription for HF population does not exist, and an individualized approach with guidance of the AHA exercise standards for testing and training statement is Gas exchange measurements can offer an objective assessment of functional capacity and can be used when feasible to derive the exercise prescription and to monitor changes in functional sta- The most frequently used exercise intensity range is 70% to 80% of peak V , usually determined from a symptom-limited exercise test.335 Common ex- ercise regimens include jogging, calisthenics, walking, use of a treadmill, rowing, use of an arm ergometer, step aerobics, or cycling at 60% to 80% of V max or maximum work capacity for 30 to 40 minutes 3 to 4 Very debilitated patients or those who are not accustomed to aerobic activity may need to initiate the program at a lower intensity (60% or 65% of peak V ) and perform interval training with periods of rest.335 The most commonly used exercise duration is 20 to 30 minutes at the desired intensity.335 Progression should be built into the prescription to adjust the exercise inten- sity as the patient becomes better conditioned. Duration of exercise should include an adequate warm-up period, with this period being longer in the most debilitated patients. Most studies have used 3 to 5 times/wk as the optimal training frequency.335 The need for monitor- ing has not been systematically studied, but telemetry monitoring is recommended initially.337 Home training can follow this early supervised period for patients not demonstrating any hemodynamic or rhythm instability. It would be prudent, however, to monitor patients who have demonstrated exercise-induced arrhythmias and those patients with advanced HF.335 Although the safety and efficacy of resistance train- ing have not been established in this population,335 re- sistance training can offer the opportunity to strengthen individual muscle groups and has been shown to be ef- fective without safety issues in small trials with patients Small free weights (1, 2, or 5 lb), elas- tic bands, or repetitive isolated muscle training can be but the safety of resistance training in patients with HF needs to be further established in larger trials.335 Recommendations Harmonized With Existing Guidelines See Tables 13 and 14 for a summary of these recom- mendations. Dietary Guidelines in Patients With HF Typical dietary guidelines for the HF population state that sodium restriction or fluid restriction in patients with severe HF with congestion and with hyponatremia is rea- Otherwise, there are no specific recommenda- tions for caloric intake or dietary composition included in the current AHA/ACCF, Heart Failure Society of America, or European Society of Cardiology HF guidelines8,29,317 other than nutritional supplements not being recom- mended as treatment of HF in patients with current or prior symptoms of HFrEF.8 Guideline Recommendations for Exercise With the above background, the Heart Failure Society of America, European Society of Cardiology, ACC, and AHA recommend exercise training or regular physical activity in patients with HF,8,29,249,317,318 but these guidelines have Management of Comorbidities in Chronic Heart Failure CLINICAL STATEMENTS AND GUIDELINES not addressed the beneficial role of exercise in preven- tion of HF, which we tried to address by adding a rec- ommendation stating the beneficial role of exercise or physical activity for patients with stage A or B HF. In the Heart Failure Society of America guidelines, it is recommended that patients with HF undergo exercise testing before enrollment in an exercise training pro- gram to determine suitability for exercise training and to assess for ischemia or arrhythmias. If deemed safe, exercise training should be considered for patients with HF. Initially, exercise should be supervised to educate the patient on heart rate response and level of exercise and to gradually increase exercise duration and intensity. The exercise goal is 30 minutes of moderate activity 5 d/wk with warm-up and cool-down periods (Strength of In the European Society of Cardiology guidelines, it is recommended that regular aerobic exercise be encour- aged to improve functional capacity and symptoms.317 The 2013 ACCF/AHA HF guidelines indicate that exer- cise training (or regular physical activity) is recommend- ed as safe and effective for patients with HF who are able to participate to improve functional status8,230,319,320 (Level of Evidence A). Stage A or B HF 1. Exercise or regular physical activity is ben- eficial in prevention of CVD and HF (Class I; Level of Evidence B).193,311 316 Stage C HF 1. Exercise training (or regular physical activ- ity) is recommended as safe and effective for patients with HF who are able to participate to improve functional status8,230,319,320 (Class I; Level of Evidence A). Summary and Future Directions As addressed in the earlier sections, lifestyle modifica- tion and the management of comorbidities remain chal- lenging in patients with HF. Despite intensive lifestyle and medical interventions, the prevention and optimal treatment of hypertension, diabetes mellitus, obesity, and metabolic syndrome have often proved difficult in patients with HF. These comorbidities are highly prevalent and are associated with the development of incident HF in the general population. However, in patients with established HF, their contributory roles to clinical outcomes are para- doxical; that is, patients with HF with diabetes mellitus, obesity, and hypertension usually are associated with better outcomes than patients without those comorbidities individually, making their management targets and treatment reasons quite challenging. Participants in clinical trials receive maximally sup- portive and evidence-based interventions, yet adher- ence to standard guideline-directed HF therapy in real-world patients may be limited by the coexis- tence of chronic HF and comorbid conditions. Self-care strategies are limited by HF itself and these competing comorbidities and usually require coordination and different care models.249,341 Treatment options of these chronic comorbidities in HF are limited and usually without large-scale or definitive clinical trial evidence of improved out- comes in patients with HF. Treatment of these comorbidities may be associ- ated with adverse outcomes resulting from over- treatment or side effects of treatment modalities. It should be kept in mind that even modest changes in the prevention of comorbidities and risk factors for HF can greatly affect the development of and outcomes in HF. These underline the importance of prevention strategies, which probably are the most effective approaches to reduce the burden of HF. Furthermore, in recent years, focus has moved from control of a single risk factor to reducing overall car- Greater benefit may be realized by combining a healthy lifestyle with BP lowering; prevention of diabetes mellitus, insulin resistance, obesity, and ischemic events; and avoidance of cardiotoxic exposure (alcohol, cardiotoxic drugs, and chemotherapy) rather than any single approach Although this approach is likely to be valid, it requires evaluation in well-designed trials. New innovative initiatives such as the Life s Simple 7 developed by the AHA emphasize the prevention of CVD and aim to empower individuals on self-care and prevention by concise yet thorough explanation of the AHA s recommendations for healthy living, including guidance on how (1) to get active, (2) to control cholesterol, (3) to eat better, (4) to manage BP, (5) to lose weight, (6) to reduce blood sugar, and The emphasis on prevention is one of the most effective strategies for the 2020 goal of the AHA, defined as to improve the car- diovascular health of all Americans by 20 percent while reducing deaths from CVDs and stroke by 20 percent by the year 2020. 345 Such initiatives with emphasis on prevention are critical in reducing the burden of HF. FOOTNOTES The American Heart Association makes every effort to avoid any actual or potential conflicts of interest that may arise as a result of an outside relationship or a personal, professional, or business interest of a member of the writing panel. Specifical- ly, all members of the writing group are required to complete Bozkurt et al and submit a Disclosure Questionnaire showing all such rela- tionships that might be perceived as real or potential conflicts of interest. This statement was approved by the American Heart As- sociation Science Advisory and Coordinating Committee on September 24, 2015, and the American Heart Association Ex- ecutive Committee on October 27, 2015. A copy of the docu- ment is available at http://professional.heart.org/statements by using either Search for Guidelines & Statements or the Browse by Topic area. To purchase additional reprints, call 843-216-2533 or e-mail kelle.ramsay@wolterskluwer.com. The American Heart Association requests that this docu- ment be cited as follows: Bozkurt B, Aguilar D, Deswal A, Dunbar SB, Francis GS, Horwich T, Jessup M, Kosiborod M, Pritchett AM, Ramasubbu K, Rosendorff C, Yancy C; on behalf of the American Heart Association Heart Failure and Transplan- tation Committee of the Council on Clinical Cardiology; Council on Cardiovascular Surgery and Anesthesia; Council on Cardio- vascular and Stroke Nursing; Council on Hypertension; and Council on Quality and Outcomes Research. Contributory risk and management of comorbidities of hypertension, obesity, diabetes mellitus, hyperlipidemia, and metabolic syndrome in chronic heart failure: a scientific statement from the American Heart Association. Circulation. 2016;134:e535 e578. doi: 10.1161/CIR.0000000000000450. Expert peer review of AHA Scientific Statements is conducted by the AHA Office of Science Operations. For more on AHA statements and guidelines development, visit http://professional.heart.org/statements. Select the Guidelines & Statements drop-down menu, then click Pub- lication Development. Permissions: Multiple copies, modification, alteration, enhancement, and/or distribution of this document are not permitted without the express permission of the American Heart Association. Instructions for obtaining permission are located at http://www.heart.org/HEARTORG/General/Copyright- Permission-Guidelines_UCM_300404_Article.jsp. A link to the Copyright Permissions Request Form appears on the right side of the page. Circulation is available at http://circ.ahajournals.org. Disclosures Writing Group Disclosures Writing Group Member Employment Research Grant Other Research Support Speakers Bureau/ Honoraria Expert Witness Ownership Interest Consultant/ Advisory Board Other Biykem Bozkurt Baylor College of Medicine None None None None None None None David Aguilar Baylor College of Medicine National Heart, Lung, Blood Institute* None None None None Bristol Myers Squibb* Anita Deswal Michael E.DeBakeyVA Medical Center/Baylor College of Medicine NIH None AHA Heart Failure Spotlight Series*; Aurora Health Care Inc.* None None None None Sandra B. Dunbar Emory University None None None None None None None Gary S. Francis University of Minnesota NIH* None None None None Novartis*; Amgen* None Tamara Horwich UCLA None None None None None None None Mariell Jessup University of Pennsylvania None None None None None None None Mikhail Kosiborod Mid America Heart Institute Gilead ; Genentech ; Sanofi Aventis ; AstraZeneca None Amgen* None None AstraZeneca ; Eli Lilly*; Boehringer Ingelheim ; ZS Pharma ; Sanofi-Aventis ; Amgen ; GSK*; Merck*; Novo Nordisk* Gilead (other research support) Allison M. Pritchett Baylor College of Medicine None None None None St. Jude* None None Kumudha Ramasubbu New York Methodist Hospital None None None None None None None (Continued) Management of Comorbidities in Chronic Heart Failure CLINICAL STATEMENTS AND GUIDELINES References 1. Ather S, Chan W, Bozkurt B, Aguilar D, Ramasubbu K, Zachariah AA, Wehrens XH, Deswal A. 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Eckel RH, Jakicic JM, Ard JD, de Jesus JM, Houston Miller N, Hub- bard VS, Lee IM, Lichtenstein AH, Loria CM, Millen BE, Nonas CA, Sacks FM, Smith SC Jr, Svetkey LP, Wadden TA, Yanovski SZ, Ken- dall KA, Morgan LC, Trisolini MG, Velasco G, Wnek J, Anderson JL, Halperin JL, Albert NM, Bozkurt B, Brindis RG, Curtis LH, DeMets D, Hochman JS, Kovacs RJ, Ohman EM, Pressler SJ, Sellke FW, Shen WK, Smith SC Jr, Tomaselli GF. 2013 AHA/ACC guideline on lifestyle management to reduce cardiovascular risk: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines [published corrections appear in Circulation. 2014;129(suppl 2):S100 S101 and Circulation. 10.1161/01.cir.0000437740.48606.d1. 5. Stone NJ, Robinson J, Lichtenstein AH, Bairey Merz CN, Blum CB, Eckel RH, Goldberg AC, Gordon D, Levy D, Lloyd-Jones DM, Mc- Bride P, Schwartz JS, Shero ST, Smith SC Jr, Watson K, Wilson PW, Eddleman KM, Jarrett NM, LaBresh K, Nevo L, Wnek J, An- derson JL, Halperin JL, Albert NM, Bozkurt B, Brindis RG, Curtis LH, DeMets D, Hochman JS, Kovacs RJ, Ohman EM, Pressler SJ, Sellke FW, Shen WK, Smith SC Jr, Tomaselli GF. 2013 ACC/AHA guideline on the treatment of blood cholesterol to reduce athero- sclerotic cardiovascular risk in adults: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines [published corrections appear in Circulation. 2014;129:S46 S48 and Circulation. 2015;132:e396]. Circulation. 2014;129(suppl 2):S1 S45. doi: 10.1161/01.cir.0000437738. 63853.7a. Reviewer Disclosures Reviewer Employment Research Grant Other Research Support Speakers Bureau/ Honoraria Expert Witness Ownership Interest Consultant/ Advisory Board Other Maya Guglin University of South Florida None None None None None None None Douglas Mann Washington University School of Medicine None None None None None None None Lynne Stevenson Brigham and Women s Hospital None None None None None None None W.H. Wilson Tang Cleveland Clinic Foundation NIH* None None None None None None This table represents the relationships of reviewers that may be perceived as actual or reasonably perceived conflicts of interest as reported on the Disclosure Questionnaire, which all reviewers are required to complete and submit.A relationship is considered to be significant if (a) the person receives $10000 or more during any 12-month period, or 5% or more of the person s gross income; or (b) the person owns 5% or more of the voting stock or share of the entity, or owns $10000 or more of the fair market value of the entity. A relationship is considered to be modest if it is less than significant under the preceding definition. *Significant. Clive Rosendorff James J. Peters VA Medical Center None None None None None None None Clyde Yancy Northwestern University None None None None None None None This table represents the relationships of writing group members that may be perceived as actual or reasonably perceived conflicts of interest as reported on the Disclosure Questionnaire, which all members of the writing group are required to complete and submit. A relationship is considered to be significant if (a) the person receives $10000 or more during any 12-month period, or 5% or more of the person s gross income; or (b) the person owns 5% or more of the voting stock or share of the entity, or owns $10000 or more of the fair market value of the entity. A relationship is considered to be modest if it is less than significant under the preceding definition. *Modest. Significant. 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