Co-Morbidities in Heart Failure Beginning to Sprout—and no end in Sight?

The list of co-morbidities in patients with heart failure (HF) is very long, starting with chronic kidney disease,1 diabetes, or chronic obstructive pulmonary disease,2 each of which affect about 30% to 50% of all patients with HF. Other co-morbidities embrace arterial hypertension, obesity, anaemia, and atrial fibrillation. In many patients, particularly in patients with HF with preserved ejection fraction (HFpEF), treatment of co-morbidities is one of the mainstays of therapy. Still, we are only starting to understand the importance of adequate treatment of co-morbidities, and their recognition is of utmost importance. The most recent additions to the list providing more insight into possible treatment modalities include iron deficiency, skeletal muscle wasting, and sleep disordered breathing (Figure 1). Iron deficiency has received tremendous attention recently after it became clear that the co-morbidity has to be diagnosed using different cut-offs values for ferritin and transferrin saturation (TSAT) in patients with HF as compared with patients who do not have a chronic inflammatory disease. Indeed, HF is associated with underlying (subclinical) inflammation rendering iron uptake in the duodenum difficult.3 The first large scale trial named FAIR-HF demonstrated that patients with iron deficiency diagnosed based on ferritin <100 mg/L or ferritin 100–299 mg/L in the presence of a TSAT <20% were likely to show functional improvement at 24 weeks of follow-up after administration of intravenous ferric carboxymaltose.4 More recent insight has been gained from the CONFIRM-HF trial showing that functional benefit from such treatment is maintained out to 52 weeks of follow-up and that intravenous administration of ferric carboxymaltose is safe in patients with HF.5 Publication of this study yielded a higher class of recommendation and a higher level of evidence in the most recent version of the ESC guidelines recommending that ferric carboxymaltose should be considered in patients with HF and iron deficiency.6 The EFFECT-HF study has recently shown that patients with HF and iron deficiency also show an increase in their peak oxygen consumption (VO2) as assessed by spiroergometry after 24 weeks of follow-up. At 24 weeks, average peak VO2 values had decreased in the control group but were maintained in the group that received ferric carboxymaltose.7 Still, we only partly understand the benefit derived from iron administration. Using cardiac magnetic resonance T2* sequence analysis performed before and after a median of 43 days after administration of intravenous ferric carboxymaltose, a pilot study recently found that a borderline increase in median left ventricular ejection fraction was registered [40% (interquartile range 36–45%) to 49% (39–53%), P=0.09]. This result also persisted after adjusting for anaemia at baseline, and the authors concluded that myocardial iron repletion was associated with positive effects on left ventricular remodelling.8 Very recent data have shown that patients with HF who are iron deficient are unlikely to benefit from oral iron administration, because data from the IRONOUT HF study have shown that oral iron is poorly absorbed in the duodenum and its prescription not associated with an increase in the patients' peak VO2 value.9 However, further studies are well under way to strengthen our views and positive evaluations of treating iron deficiency in patients with HF, for example, the PRACTICE-ASIA-HF study,10 the FAIR-HF 2 trial, or the FAIR-HFpEF trial.11 Skeletal muscle wasting, also known as sarcopenia, is likewise very prevalent in patients with HF, as these patients are usually of advanced age. Advanced age per se is associated with a higher prevalence of sarcopenia, a phenomenon encountered around the world.12-14 However, as yet unidentified mechanisms appear to increase the loss in muscle mass and strength in patients with HF. Sarcopenia is defined as low appendicular skeletal muscle mass, i.e. skeletal muscle mass in the arms and legs combined below two standard deviations of the mean value of a healthy reference group of younger age.15 Recent data have estimated the prevalence of sarcopenia among patients with HF to be between 20% and 50% depending on the patient cohort investigated and the underlying aetiology.16-18 Much of the increased prevalence of sarcopenia has been deemed to be due to increased activity of the ubiquitin–proteasome system as a consequence of chronic inflammation.19-21 Management recommendations remain scarce, and smaller studies have been restricted to nutritional therapies, anabolic drugs as well as exercise training.22 Novel drugs are currently in development to treat muscle wasting. Such drugs include myostatin antibodies,23 ghrelin receptor agonists like anamorelin,24, 25 and selective androgen receptor modulators like stamulumab, however their use has mostly seen testing in trials in geriatric patients or in patients with muscular dystrophy or cancer. HF may be somewhat unique, as at least some skeletal muscle weakness may also be related to insulin resistance, another frequent co-morbidity.26 Another co-morbidity that remains largely under-recognized and under-treated in HF is sleep disordered breathing.27, 28 Even though a large number of studies has been published in recent years, screening (polygraphy, questionnaires) and monitoring (e.g. SleepMinderTM)29 tools remain under-utilized. Unfortunately, one of the few larger randomized controlled trials, the SERVE-HF trial,30 ended in disappointment, and it appears unlikely that adaptive servo-ventilation will be used in patients with HF in future trials or in clinical practice.31 However, it is now understood that a shift takes place from a higher prevalence of obstructive sleep apnoea in less symptomatic patients with HF to more frequent central sleep apnoea in patients with more advanced HF in NYHA classes III and IV.32 Increased mortality rates, however, have been recognized in patients with an apnoea–hypopnoea index of >5 per hour of sleep.33 Studies are ongoing as it is now understood that sleep disordered breathing is an independent risk factor of death in patients with HF, and treating sleep disordered breathing may help to improve patients' prognosis.34 Finally, acute HF is receiving increasing attention in recent years. The prevalence of acute HF, however, is difficult to assess, and estimates range between 1% and 12% in the general population.35 In-hospital mortality rates remain high between 4% and 18%, but the definitions of acute HF have varied largely over different study populations.36 Arrigo et al.37 recently studied the effects of precipitating factors on acute HF admissions and long-term mortality and found that such precipitating factors including co-morbidities such as atrial fibrillation having substantial impact on the outcome after hospitalization. In particular, atrial fibrillation and acute coronary syndrome were associated with higher readmission rates after a first admission for acute HF. Patients with acute pulmonary disease showed associations with fewer readmissions, however, they had higher mortality rates, particularly so in patients who were aged 75 years or younger. What we need is a more thorough understanding of the co-morbidities of HF, of their impact on physical well-being, exercise capacity, survival, and their effect on decompensation as well as less ignorance of their importance. Patients require tailor-made therapies, not only for their hearts, but also for the rest of their body. Conflict of interest: S.vH. has been a paid consultant to Vifor, Amgen, BRAHMS/Thermo Fisher, Roche, Novartis, Boehringer Ingelheim, and Respicardia.