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............................................................................................................................................................................. were associated with poorer outcomes in observational studies in patients with HF.670,671 Treatment of thyroid disorders should be guided by general endocrine guidelines. There are no randomized trials evaluating the efficacy of thyroid replacement therapy in subclinical hypothyroidism, but there is a general agreement to correct it when the TSH is >10 mIU/L, particularly in patients <70 years. Correction may also be considered at lower TSH levels (710 mIU/L).672674

13.3 Obesity

Obesity is a risk factor for hypertension and CAD and is also associated with an increased risk of HF. There is possibly a stronger association with HFpEF.258,675677 Once obese patients have HF, an obesity paradox has been described such that overweight or mildly/moderately obese patients have a better prognosis than leaner patients, particularly compared with those who are underweight.678,679 However, other variables may influence this relationship and the obesity paradox is not observed in patients with diabetes.680,681 Second, BMI does not take into account body composition, e.g. the relation between lean skeletal muscle mass and fat mass. Obese patients who are fit and have a preserved skeletal muscle mass have better prognosis than obese sarcopenic patients.682 Waist circumference or the waist-to-hip ratio, measuring visceral obesity, is less influenced by muscle mass and may have a stronger relationship with outcomes than BMI, especially in female patients.683,684 Body fat has a major impact on the diagnostic and prognostic value of multiple parameters. Obese patients with HF have lower NP concentrations due to increased expression of clearance receptors and augmented peptide degradation by the adipose tissue.74 Peak oxygen consumption adjusted for body weight underestimates exercise capacity in obese patients and an adjustment for lean body mass should be used for risk stratification.96 Obesity may be a major cause of HFpEF and obese HFpEF patients display several pathophysiologic mechanisms that differ from nonobese patients with HFpEF.258,675677,685 Caloric restriction and exercise training had additive beneficial effects on exercise capacity and QOL of patients with obesity and HFpEF in a randomized trial.337

13.4 Frailty, cachexia, sarcopenia

Frailty is a multidimensional dynamic state, independent of age, that makes the individual more vulnerable to the effect of stressors.686 HF and frailty are two distinct yet commonly associated conditions. The assessment of frailty in patients with HF is crucial as it is associated with both unfavourable outcomes and reduced access to, and tolerance of, treatments. Several tools have been proposed for frailty screening and assessment in different chronic conditions, including HF. The HFA of ESC has developed a HF-specific tool based on four major domains, clinical, psycho-cognitive, functional, and social.686 Frailty is more prevalent in patients with HF than in the general population and may occur in up to 45% of the patients, according to a recent meta-analysis.687,688 Patients with HF are up to six times more likely to be frail, and frail people have a significantly increased risk of developing HF.689,690 Frailty is associated with a higher risk of death, hospitalizations, and functional decline as well as with a longer duration of hospital stay.691693 The treatment of frailty in HF should be multifactorial and targeted to its main components and may include physical rehabilitation with exercise training, nutritional supplementation as well as an individualized approach to treating comorbidities.686 Cachexia is defined as a ‘complex metabolic syndrome associated with underlying illness and characterized by loss of muscle with or without loss of fat mass’.694 Its major clinical feature is a >5% oedema-free body weight loss during the previous 12 months or less.694,695 Cachexia is a generalized wasting process that may coexist with frailty and may occur in 515% of patients with HF, especially those with HFrEF and more advanced disease status. It is associated with reduced functional capacity and decreased survival.695698 As it is associated with other chronic diseases, such as cancer, alternative, non-cardiac causes for cachexia should always be investigated.699

Sarcopenia is defined by the presence of low muscle mass together with low muscle function, strength, or performance.698 It is usually identified by an appendicular skeletal muscle mass, defined as the sum of the muscle mass of the four limbs, 2 standard deviation below the mean of a healthy reference group aged 1840years with a cut-off value of 7.26 kg/m2 for men.688,700,701 It occurs physiologically with aging. However, it is accelerated by chronic diseases, such as cancer and HF. Sarcopenia can be found in 2050% of patients with HFrEF and is often associated with frailty and increased morbidity and mortality. It is a major determinant of outcomes outweighing the effect of body weight and BMI.684,698,701,702 So far, the most effective strategy for sarcopenia treatment is resistance exercise training, possibly combined with a protein intake of 11.5 g/kg/day.698,703 Drug treatments, including anabolic compounds like testosterone, growth hormone, ghrelin receptor agonists, were tested in small studies, showing favourable results mostly in terms of exercise capacity and muscle strength.697,703705 There are no data showing a favourable impact of sarcopenia treatment on outcomes. However, exercise training has favourable effects in patients with HF (see section 9.4).95,323329

13.5 Iron deficiency and anaemia

Iron deficiency and anaemia are common in patients with HF, being independently associated with reduced exercise capacity, recurrent HF hospitalizations, and high CV and all-cause mortality.706,707 According to the World Health Organization criteria, anaemia is defined as a haemoglobin concentration <12 g/dL in women and <13 g/dL in men. In patients with HF, iron deficiency is defined as either a serum ferritin concentration <100 ng/mL or 100299 ng/ mL with transferrin saturation (TSAT) <20%.708710 Ferritin tissue expression and concentration in the peripheral blood is increased by inflammation and several disorders such as infection, cancer, liver disease, and HF itself. Hence, higher cut-off values have been applied for the definition of iron deficiency in patients with HF.709711 Another marker reflecting depleted intracellular iron can be high serum soluble transferrin receptors, which derives from proteolysis of the membrane transferrin receptor. Its synthesis is increased in case of iron deficiency and is not affected by inflammation. High serum soluble transferrin receptors identify patients at high risk of death beyond standard prognostic variables.711,712 However, its applicability for iron supplementation therapy has not been demonstrated yet. Iron deficiency, which can be present independently of anaemia, is present in up to 55% of chronic HF patients and in up to 80% of those with AHF.713716 It may be caused by increased loss, reduced intake or absorption (i.e. malnutrition, gut congestion) and/or impaired iron metabolism caused by the chronic inflammatory activation of HF, although the exact cause of iron deficiency in HF remains unknown. Iron deficiency may impair functional capacity, precipitate circulatory Downloaded from academic.oup.com/eurheartj/article/42/36/3599/6358045 by guest on 07 October 2026