Comorbidities in chronic heart failure: An update from Italian Society of Cardiology (SIC) Working Group on Heart Failure

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Narrative Review

Comorbidities in chronic heart failure: An update from Italian Society of Cardiology (SIC) Working Group on Heart Failure ⁎

Michele Correalea, , Stefania Paolillob, Valentina Mercurioc, Giuseppe Limongellid,e,f, Francesco Barillàg, Gaetano Ruoccoh, Alberto Palazzuolih, Domenico Scutinioi, Rocco Lagioiai, Carolina Lombardij, Laura Lupik, Damiano Magrìl, Daniele Masaroned, Giuseppe Pacileod, Pietro Scicchitanom, Marco Matteo Cicconem, Gianfranco Paratij, Carlo G Tocchettic, Savina Nodarik a

Department of Cardiology, University Hospital Foggia, Italy Department of Advanced Biomedical Sciences, Federico II University of Naples, Naples, Italy Department of Translational Medical Sciences, Federico II University, Naples, Italy d Heart Failure Unit, AORN dei Colli, Monaldi Hospital, Naples, Italy e Department of Translational Medical Sciences, Luigi Vanvitelli University, Naples, Italy f Institute of Cardiovascular Sciences, University College of London, London, United Kingdom g Department of Cardiovascular, Respiratory, Nephrologic, Anesthesiologic and Geriatric Sciences, Sapienza" University of Rome, Italy h Cardiovascular Diseases Unit Department of Internal Medicine, University of Siena, Siena, Italy i Cardiology Department, IRCCS “S. Maugeri” Cassano (BA), Bari, Italy j Istituto Auxologico Italiano, IRCCS, Sleep Disorders Center & Department of Cardiovascular, Neural and Metabolic Sciences. San Luca Hospital, Milan, Italy k Section of Cardiology, Department of Medical and Surgical Specialties, Radiological Sciences, and Public Health, University of Brescia, Italy l Department of Clinical and Molecular Medicine, University “La Sapienza”, Rome, Italy m Section of Cardiovascular Diseases, Department of Emergency and Organ Transplantation, University of Bari “A. Moro”, Bari, Italy b c

A R T I C LE I N FO

A B S T R A C T

Keywords: Chronic heart failure COPD Cardio-oncology Chronic kidney disease Sleep apnea Hypertension Coronary artery disease Diabetes

The increasing number of patients with heart failure HF and comorbidities is due to aging population and increase of life expectancy of patients with cardiovascular disease. Encouraging results derived by recent trials may suggest some comorbidities as new targets for new drugs, highlighting the need for a better understanding of the comorbidities’ effects in HF patients and the need of a multidisciplinary approach for the management of chronic HF with comorbidities. We report a brief review about main cardiovascular and non-cardiovascular comorbidities in HF patients in order to update physicians and researchers engaged in the HF research or in “fight against heart failure.”

1. Introduction The Prevalence of Heart Failure (HF) in the western world is around 1-2% and more than 10% over 70 years of age and the incidence is about 5–10 per 1000 persons per year, representing the leading cause of outpatient visits and the most frequent reason of hospitalization for patients over 65 years of age [1]. Comorbidities are a major issue in HF, leading to poor outcomes, excessive hospitalization and mortality. Comorbidities may be subdivided into cardiovascular (CV) and non-CV. HF in elderly patients is associated with more widespread symptoms and signs due to the presence of non-CV comorbidities. This can cause

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difficulties in assessing the correct diagnosis and initiating appropriate therapy. Some comorbidities (chronic obstructive pulmonary disease, diabetes mellitus, anemia, and obesity) are more prevalent in HF with preserved ejection fraction (HFPEF) patients [2]. Furthermore, the new paradigm for HFPEF [3] identifies a systemic proinflammatory state induced by comorbidities as the main cause of myocardial structural and functional alterations. This underlines the different role and impact of comorbidities in HFPEF and the importance of treating comorbidities in both HFPEF and HF patients with reduced EF (HFrEF) in order to slow the HF progression and reduce the acute decompensation

Corresponding author at: Viale Pinto 1, 71122 Foggia, Italy. E-mail address: [email protected] (M. Correale).

https://doi.org/10.1016/j.ejim.2019.10.008 Received 23 March 2019; Received in revised form 27 July 2019; Accepted 5 October 2019 0953-6205/ © 2019 European Federation of Internal Medicine. Published by Elsevier B.V. All rights reserved.

Please cite this article as: Michele Correale, et al., European Journal of Internal Medicine, https://doi.org/10.1016/j.ejim.2019.10.008

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Fig. 1. Comorbidities in HF patients. CV (blue arrows) and no-CV (red arrows) comorbidities. Heart failure is at the center of all comorbidities. CV and no-Cv comorbidities contribute to HF development, progression and prognosis. CKD: Chronic Kidney Disease; COPD: Chronic Obstructive Pulmonary Disease. (For interpretation of the references to color in this figure legend, the reader is referred to the web version of this article.)

combination: heart failure; Chronic obstructive pulmonary disease; cancer; chronic kidney disease; obstructive and central sleep apnea; hypertension; coronary artery disease; diabetes; hypothyroidism and hyperthyroidism; hyperuricemia; vitamin D deficiency; anabolic hormones; sarcopenia; cachexia; iron deficiency; depression; cognitive impairment; peripheral artery disease and atrial fibrillation. Only articles in English were selected for the review, which focused on the most consistent and relevant trials and original papers, preferentially involving humans.

episodes. The most frequently occurring CV and non-CV comorbidities in HF are discussed in the present paper (Fig. 1 and Table 1). We highlight the need of specific skills in the management of these comorbidities.

2. Methods An extensive online search on PubMed was performed until January 2019 by using the following main keywords alone or in logic

Table 1 CV and no-CV comorbidities in HF patients: Unmet needs. Table summarizes CV and no-Cv comorbidities in HF patients, reporting for each one, some unclear points in the managements (clinical “unmet needs”). CV: cardiovascular; HF: heart failure; LVEF: left ventricle ejection fraction; CKD: Chronic Kidney Disease; COPD: Chronic Obstructive Pulmonary Disease; DM: diabetes mellitus. CV comorbidities

Clinical unmet needs

Hyperthension Coronary heart disease Atrial Fibrillation

Improvement in LV diastolic function by antihypertensive drugs might improve CV prognosis in HF In presence of viable myocardium whether and when the revascolarization is associated to any benefits. To establish the best therapeutic approach in terms of rhythm control or rate control. Accurate balance of thrombotic and bleeding risk. To better understand how to prevent endothelial disfunction

Peripheral artery disease CV No-comorbidities Cancer Sleep-Disorder Breathing COPD Glucose metabolism disorders Other metabolism disorders

Diabetes Mellitus Hypothyroidism and Hyperthyroidism Vitamin D deficiency Hyperuricemia Anabolic Hormones

Sarcopenia and Cachexia Chronic kidney disease Iron deficiency Depression and cognitive impairment .

Optimal cardioprotective and surveillance strategies during chemiotherapy Value of cut-off for LVEF in order to start or to stop chemiotherapy To evaluate the utility of Adaptative Servo-Ventilation Diagnosing and staging COPD in HF patients Greater use of selective beta-blockers in co-existing COPD in HF To evaluate the using empagliflozin in HF patients independently from the presence of DM To know the effect of T3 supplementation in HF patients with low T3 syndrome To know the influence of vitamin D in HF To better understand Febuxostat effects in patients with HF and hyperuricemia. To better understand the effects of testosterone and growth hormone therapy in HF patients. Real prevalence of cardiac cachexia, assessed on the basis of more recent criteria, in order to better understand its real prognostic value in HF patients. The need to better contextualize the clinical meaning of CKD in HF looking at congestion and haemodynamic status. To address the potential benefit of intravenous iron in HF associated with iron deficiency. Assessment of cognitive functioning, should be part of routine clinical examination in HF

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3. Cancer in heart failure

of the pathophysiology of this comorbidity, is needed to address the challenging, clinically important questions posed by co-existing COPD in HF patients.

The incidence of most cancers increases with age. A new cancer diagnosis in HF patients is not infrequent, and an increased incidence of cancer in patients with established HF has been suggested [4]. In HF patients, cancer diagnosis has important implications in terms of prognosis and both CV and anti-tumor treatments [5]. A close collaboration between cardiologists and oncologists is fundamental to improve management of these patients, with both specialists understanding the benefits of HF and antineoplastic therapies, and the risks of withholding or suboptimally treating either or both diseases [6]. The prognostic impact of each disease should always be well defined and considered in decision-making. Such multidisciplinary approach should also include other healthcare professionals, among which cardiac rehabilitation, psychology and palliative care. The SAFE-HEaRT trial has been recently designed to assess whether patients with mildly reduced ejection fraction can undergo anti-HER2 drugs in the setting of ongoing cardiac treatment [7]. Further studies will clarify the thresholds at which cancer treatment should not be administered in HF patients, and the optimal cardioprotective and surveillance strategies for patients affected by these two diseases [3].

6. Glucose metabolism disorders Glucose metabolism disorders are high prevalent in HF patients and significantly impact on disease progression and on long-term morbidity and mortality. The relationship between these two conditions is bidirectional since each disease independently and negatively influences the other. Prevalence of diabetes mellitus (DM) ranges from 10 to 30% up to 40% in hospitalized HF patients [24,25]; similarly, insulin resistance (IR) is common in HF with an estimated prevalence of about 60% even in absence of overt DM [26,27]. In the future, these records are expected to grow due to the ageing of the population at risk for both glucose metabolism abnormalities and HF. Data form the ESC-HFA Heart Failure Long-Term Registry [28] showed that CHF outpatients with overt or undiagnosed diabetes had higher 1-year rates of all-cause death, CV death, and first hospitalization for worsening HF than those without diabetes. Similar data were reported for patients with acute HF [29]. A post-hoc analysis of the GISSI-HF Trial [30] confirmed these data in a longer follow-up (3.9 years) reporting that patients with DM had higher incidence rates of allcause death (34.5% versus 24.6%) and the composite of all-cause death or CV hospitalization (63.6% versus 54.7%) and that higher hemoglobin A1 c was independently related with and increased risk of both study outcomes. Also IR seems to be an independent predictor of adverse prognosis in HF with some pathophysiological implications in disease progression and representing a potential new therapeutic target [31]. DM and IR lead to functional, metabolic and structural changes, responsible of myocardial damage and HF progression. In particular, hyperglycemia activates several cellular pathways abnormalities leading to oxidative stress; DM and IR are responsible of neurohormonal and sympathetic nervous system activation, abnormalities in contractile proteins, change in substrate utilization, cellular injury, microvascular and endothelial dysfunction (ED) [32]. Thus, a strict control is needed in patients exhibiting both HF and glucose metabolism disorders, with a continuous update of the treatment to improve prognosis. In the last few years, novel antihyperglycemic agents demonstrated a beneficial effect on CV and HF outcomes. The EMPA-REG Outcome Trial [33] demonstrated that the sodium–glucose cotransporter 2 (SGLT2) empagliflozin, significantly reduced the risk of death from CV causes (38% relative risk reduction), hospitalization for HF (35% relative risk reduction), and death from any cause (32% relative risk reduction). The pathophysiological mechanisms leading to the beneficial effect of empagliflozin on CV outcomes are not still completely understood. A post-hoc analysis of the study [34] reported that the overall effect of empagliflozin on the outcomes was not mainly driven by the presence of HF at baseline. Two trials are underway in patients with HFpEF and HFrEF using empagliflozin independently from the presence of DM (ClinicalTrials.gov Identifier: NCT03057977 and NCT03057951) [35,36].

4. Sleep-disordered breathing Sleep-related breathing (SBD) disorders are frequently reported in HF patients and are associated with poor prognosis. Recently the results of PROMISES Study [8] (with a large multidisciplinary database of clinical and instrumental data, including sleep data, derived from overnight unattended cardio-respiratory polysomnography in HF patients, with either moderate-severe reduced ejection fraction (EF) or with clinical decompensation) have shown that Obstructive sleep apnea (OSA) was the most frequent form of SBD observed. A markedly reduced left ventricular (LV) EF was the most important factor associated with central sleep apneas (CSA) (OR= = 7.7 for AHI cutoff= = 15 and LVEF ≤ 35%) together with male gender and increasing age. Conversely conventional risk factors for OSA (BMI, age and gender) did not identify HF patients affected by this condition. These findings could suggest that history and physical examination cannot easily characterize HF patients' risk of OSA and this would represent a strong indication for performing a polysomnography more frequently. Results from the randomized Treatment of Sleep-Disordered Breathing with Predominant Central Sleep Apnea by Adaptive Servo-Ventilation in Patients with Heart Failure (SERVE-HF) trial [9] in stable HFrEF and predominantly CSA, showed CV and all-cause mortality were increased in the auto-servoventilation arm [10]. In hospitalized HF patients with moderate-to-severe sleep apnea, adding ASV to OMT did not improve 6month cardiovascular outcomes [11]. These results, inconsistent with earlier smaller studies, require results from ongoing studies [12]. 5. Chronic obstructive pulmonary disease Chronic obstructive pulmonary disease (COPD) is among the most common comorbidities in HF, with one third of the patients presenting with co-exiting COPD [13]. Diagnosing and staging COPD in HF patients may be challenging. Instead, the prevalence of HF in COPD patients often is under-diagnosed (COPD may interfere with the diagnostic process of HF). There is general agreement that COPD is associated with increased morbidity and mortality risk in chronic HF (CHF) [14–16] and in acute HF [17–19]. Concerns regarding potential bronchoconstriction remain the main reason for underutilization of beta-blockers in these patients [20] particularly after a hospitalization for HF [21,22]. HF Guidelines clearly stated that COPD “is not a contra-indication” to beta-blocker treatment [1]. The benefits of treatment with cardio-selective betablockers in HF outweigh any potential risk associated with treatment even in patients with severe COPD [23]. Major progress in knowledge

7. Others endocrinological disorders 7.1. Hypothyroidism and hyperthyroidism Thyroid dysfunction states (hyperthyroidism and hypothyroidism) have a recognized negative impact in patients with HF [37]. Thyroid function test should be recommended every 6–12 months in patients with HF (3 months in patients using amiodarone) [38]. Both overt and subclinical hypothyroidism are associated to increased mortality and hospitalization rate in patients with HF [39,40]. Treatment of hypothyroidism is required in all patients with HF and TSH levels > 5 mIU/L [41]. It is best accomplished by oral T4 administration, 3

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with a starting dose of 50–75 μg/die, and with an increase of 25 μg every 10–12 weeks [42]. Hyperthyroidism is a well know enemy of the heart muscle and its function, since it may cause or exacerbates preexisting HF [43,44]. To date, no data are available regarding its impact on prognosis. Management of hyperthyroidism in HF patients is indicated for all patients with a TSH < 0.01 mIU/L.

episodes and more advanced stages [63,64]. Therefore, some pathophysiological pathways appear common in the two organs: activation of neuro-endocrine system, oxidative stress and inflammatory activity [65,66]. Renal function (RF) deterioration in the setting of acute HF is still questioned: it could be a direct consequence of neurohormonal overdrive and vasoconstriction, it could be related to arterial underfilling, venous congestion, kidney status before the acute event or a consequence of aggressive decongestant therapy [67]. Although CKD criteria and stages are well established by universally recognized laboratory parameters (ie eGFR, serum creatinine, albuminuria), there is no agreement upon definition of CKD criteria (KDIGO, KDOQI, CKDEPI) and eGFR calculation method. Therefore patients with CKD tend to be excluded in clinical trials [68]. The last metanalysis in this field evidenced CKD has an impaired prognosis with respect to worsening RF (WRF), and subjects affected by more severe degree experienced poorer outcome [69]. Predisposing conditions such as diabetes, smoking, metabolic disorders and hypertension, may amplify cardiac and kidney atherosclerosis process, and increase neurohormonal overdrive (norepinephrine and angiotensin II with their vasoconstrictive and profibrotic properties) leading to a final systemic and renal hemodynamic derangement [70,71]. Patients with CKD may develop a further RF deterioration related to the HF drug therapy: angiotensin-converting enzyme (ACE) inhibitors and mineral corticoid receptor antagonists (MRA) are often withdrawn because of RF risk deterioration [72]. Therefore, many patients develop diuretic resistance with needing of high loop diuretic dose and consequent electrolyte unbalance, hypotension and increased arrhythmic risk. Taken together all these remarks highlight the need to better contextualize the clinical meaning of CKD in HF looking at congestion and haemodynamic status, primitive organ disease, and concomitant risk factors.

7.2. Amiodarone- induced thyroid disease Thyroid dysfunction (hyperthyroidism and hypothyroidism) is a relatively frequent complication of amiodarone therapy [45]. Two main mechanisms can be responsible of amiodarone induced hyperthyroidism (AIH): an accelerated synthesis of thyroid hormone due to iodide load (type 1), or destructive thyroiditis (type 2) [46,47]. In both cases, amiodarone therapy should be stopped (with the exception of patients with life-threatening ventricular arrhythmias responsive to the drug), with the adjunct of thionamides (e.g. methimazole 40–60 mg/ die) in the type 1AIH, and corticosteroid (e.g. prednisone dose is about 0.5–0.7 mg/kg/die) in the type 2 AIH [48]. Amiodarone induced hypothyroidism is presumably related to the Wolff–Chaikoff effect (i.e. reduction in thyroid hormone levels caused by ingestion of a large amount of iodine), and it is easily treated with T4. In these patients, there is no need to discontinue amiodarone, if considered essential for the underlying clinical state [49]. 7.3. Euthyroid sick syndrome HF may alter thyroid metabolism resulting in T3 decrease, with a negative impact on functional status and patient prognosis. To date, it is not clear the effect of T3 supplementation in HF patients with low T3 syndrome [50].

9. Sarcopenia and cachexia 7.4. Hyperuricemia Among extracardiac factors driving HF progression, the role of skeletal muscle disorders and cachexia has been recently recognized. Incidence and prevalence of these conditions in HF studies are different because of definition disagreement. Sarcopenia affects only skeletal muscle and is commonly defined as muscle loss which reduces subject walking speed ≤1 m/s or walking distance <400 m during a 6-min walking test distance [73]. The prevalence of sarcopenia in HF patients is 19,5% [74]. Cachexia is defined as unintentional non-edematous weight loss of > 5% over at least 6 months. Recently, this definition was improved with the following new criteria: 1) decreased muscle strength 2) fatigue 3) anorexia 4) low fat free mass index 5) abnormal biochemistry [anemia (Hb < 120 g/L), low serum albumin (<32 g/L), increased inflammatory markers (CRP > 5 mg/L, IL-6 > 4 pg/mL) [75,76]. Mitochondrial dysfunction represents the first actor leading to muscle wasting. In HF, reduced mitochondrial function due to peripheral hypoxia causes fiber-type changes and subsequent atrophy. The consequence of this process is the reduction in exercise capacity leading to increased muscle wasting and catabolic dominance in bone and fat districts [77,78]. However, the pathophysiological crosstalk of cardiac cachexia is multifactorial including increased circulating levels of proinflammatory cytokines, IR (leading also to sarcopenia), increased oxidative stress, protein degradation and inhibition of muscle regeneration through sympathetic nervous system (increased serum levels of epinephrine and norepinephrine) and renin-angiotensin and aldosterone system activation [79]. These mechanisms may induce altered immune system activation encouraging infections and consequent worsening of HF. The consequence of intestinal congestion is reduced arterial blood flow which contributes to an excessive growth of iuxtamucosal bacteria with consequent malabsorption and pro-inflammatory cytokines production. HF patients present appetite loss with subsequent reduction of nutritive substance intake leading to electrolyte unbalance, anemia and decrease of serum albumin and protein levels, with reduced oncotic

Hyperuricemia is common in patients with HF and may be due to the upregulation of the xanthine oxidase [51]. Despite the detrimental effects of hyperuricemia on CV system, clinical trials with xanthine oxidase inhibitors failed to improve clinical outcome in HF patients [52,53]. A trial [54] with febuxostat is ongoing in patients with HF and hyperuricemia. 7.5. Vitamin D deficiency Recent observation linked Vitamin D deficiency and HF, but pathogenetic mechanisms of this association remain poorly understood [55]. Irrespective of some epidemiological observation that showed an association between vitamin D deficiency and clinical outcome in HF patients [56], clinical trials assessing the influence of vitamin D supplementation have been inconclusive, [57] or more recently unfavorable in patients with advanced HF (not reduced mortality and greater need for mechanical circulatory support implants) [58]. 7.6. Anabolic hormones There is increasing evidence that a reduction of anabolic hormones (i.e. growth hormone and testosterone) is common in HF patients and it is associated with impaired functional capacity and clinical outcome [59,60]. There are clinical evidences that both testosterone and growth hormone therapy may be useful in HF patients [61,62]. However, more robust data from randomized controlled trials are needed. 8. Chronic kidney disease The association between Chronic Kidney Dysfunction (CKD) and HF is steadily increasing and will further rise in relation to ageing in community cohort and particularly in patients with recurrent HF 4

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pressure and circulating fluid overload [80,81]. Each comorbidities may lead to cachexia development; venous congestion could lead to WRF which increases diuretic resistance, DM could amplify catabolic processes which induce to protein degradation and consequent muscle wasting and cachexia, gastro-intestinal discomfort could cause diarrhea or vomit which lead to electrolyte unbalance and increased risk of arrhythmias. The final consequence is an increased hemodynamic congestion with inadequate diuretic response [82]. Recently, a post-hoc analysis of GISSI-HF and Val-Heft demonstrated that unintentional weight loss ≥2 Kg was related to mortality and adverse CV and non-CV events [83]. Cachectic state was related to mortality independently from NYHA class, LVEF and peak oxygen consumption [84]. Finally, CHARM registry revealed that patients with 5% or greater weight loss in 6 months had over a 50% increase in hazard compared with those with stable weight [85]. COPERNICUS trial [86] results showed carvedilol may attenuate the development of cachexia in patients with CHF. Future studies should evaluate the prevalence of cardiac cachexia, assessed on the basis of more recent criteria, in order to better understand its real prognostic value in HF patients.

and is known to be associated with poor outcome. The highest prevalence, up to 80%, is reported in patients hospitalized due to acute decompensation. Vascular CI is already present in the early stage of HF, even before LV systolic dysfunction [106]. Numerous factors contribute to CI in HF, but hypertension, atrial fibrillation (AF), stroke and impaired haemodynamics are the most relevant. Cerebral hypoperfusion, disruption of blood-brain barrier, oxidative damage, platelet hyperreactivity, brain-endothelium inflammatory activation and adrenergic system alterations are main mechanisms. White matter hyperintensities, lacunar infarcts and generalized volume loss are common features revealed by neuroimaging. Both vitamin D deficiency and poor sleep quality are associated with CI in older adults with HF [107]. Sixminute walk distance, but not LVEF or NYHA functional class, was an important predictor of CI in outpatients with HFrEF [108]. In HF patients, CRT-D and exercise are associated with an improvement in CI [109]. Assessment of cognitive functioning, should be part of routine clinical examination in HF. The Montreal Cognitive Assessment seems to be a better screening tool than Mini-Mental Status Exam for mild CI in HF patients [110].

10. Iron deficiency in heart failure

12. Hypertension

Iron deficiency (ID) is a clinical condition in which iron stores are not sufficient to satisfy the body's metabolic needs. Frequently affects HF patients and may leads to increase in the hemodynamic instability, rehospitalization and mortality rates [87]. Iron can acquire or yield electrons, passing from a Fe++ ion to a Fe +++ ion. This element is essential for the hemoglobin synthesis as well as for enzymatic processes where oxidation-reduction reactions occur, such as the mitochondrial respiratory chain [88,89]. Hepcidin is the enzyme that regulates the iron metabolism [90,91]. In HF patients the chronic inflammatory process leads to an increase in production of Hepcidin. Clinically we distinguish between absolute and functional ID, both with or without anemia [92,93]. In the first, the ferritin levels are <100 µg/mL. In the second, occurring in chronic inflammatory processes and in renal failure, ferritin is normal with a Transferrin Saturation (TSAT) <20% [94,95]. New evidence reports that ferric carboxymaltose i.v. administration can improve both ID and symptoms in HF patients [96,97]. The FAIRHF trial showed an improvement of functional class and reduced impairment of RF after 24 weeks of treatment with ferric carboxymaltose [98,99]. Recently, the CONFERM-HF trial [100] demonstrated improved exercise capacity and a significant reduction in the hospitalization rate after 12 months of ferric carboxymaltose treatment in HF patients with ID and normal hemoglobin values [101]. In conclusion, ID affects HF patients and causes an increase in morbidity and mortality. However, it is probable that ID will become a new therapeutic target for the treatment of HF. The ongoing FAIR-HF 2 trial (ClinicalTrials.gov Identifier: NCT03036462) is underway to further address the potential benefit of intravenous iron in HF associated with iron deficiency.

Hypertension is one of the most powerful determinants of HF progression, accounting for the 74% increase in first hospitalizaion for acute heart decompensation [111]. The increase in cardiac after-load and LV wall tension, the hyperactivation of renin-angiotensin-aldosterone pathway and the subsequent deregulation of molecular and biochemical ways of regulating cardiac muscle cells are the premixes for the development of heart remodelling leading to diastolic and/or systolic heart impairment [112,113]. The tight connection among hypertension and HF has been receipted from international guidelines [114]1: all of them advise for a correct use of anti-hypertensive drugs for the correct management of patients suffering from HF. Meta-analyses evaluating the effects of ACEinhibitors and angiotensin II receptor blockers in HF patients clearly outlined [115] the net benefit deriving from the clinical use of these drugs in preventing HF progression and mortality, showing a mean reduction of 11% in all-cause mortality and 14% in CV mortality rate [116]. Arterial hypertension, the most important risk factor for LV diastolic dysfunction, represents a precipitating cause of HF in patients with LV dysfunction. Antihypertensive drugs may improve LV diastolic function; however, it is still unclear whether this improvement in LV diastolic function can also improve CV prognosis [117]. 13. Coronary artery disease Coronary artery disease (CAD) plays a pivotal role in the etiology of the HF syndrome [118]. The presence of CAD (previous myocardial infarction (MI) or clinically silent coronary ischemia) has been described in over the 50% of all HF cases [119]. Furthermore, acute coronary events represent well known triggers in the decompensation of CHF patients. Besides the epicardial artery involvement, also the microvascular coronary disease is often present in these patients but under-recognized [120]. All above mentioned data strongly support the role of CAD (epicardial/microvascular; clinically overt/silent) in promoting the HF development and progression. The identification of a clear ischemic substrate has enormous implications with respect to both the treatment and the prognosis of HF patients. An ischemic LV dysfunction may be partially or completely reversible by revascularization in the presence of viable myocardium [121], the assessment of myocardial viability is central to the management of ischemic cardiomyopathy. A re-evaluation of coronary perfusion is important in the followup of ischemic HF patients. Observational analyses have provided positive evidence for the role of revascularization in hibernating myocardium in improving survival. However, the Surgical Treatment for

11. Depression and cognitive impairment Depression is a common comorbidity of HF. Its large prevalence in HF could be due to the deamination of monoamines linked with monoamine oxidase activity [102]. In HF, depression is related to increased all-cause mortality, rehospitalization and reduced quality of life [103]. Pharmacological management of depression in HF has not been shown to improve major outcomes. Support from relatives may decrease anxiety and depression. Vitamin D supplements predicted lower depressive symptoms and reduced cardiac events for patients with moderate to severe depressive symptoms [104]. The spectrum of Cognitive impairment (CI) in HF may range from delirium to isolated memory or non-memory-related deficits to dementia [105]. CI is highly prevalent in both HFrEF and HFpEF patients 5

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species concentrations in vascular beds as well as a reduction in enzymes able to counteract reactive radicals [138,139]. The reduced oxygen delivery to the peripheral circulation due to the impairment in heart function can promote the increase in oxidative stress. In HF patients, alterations in autonomic nervous system and neurohormonal network can account for the possible impairment in vascular walls actions and promote ED [140]. Finally, the lack of physical activities in HF patients is a further cause for alterations in vascular walls performances [141] and exercise training in CHF is associated with enhanced flow-mediated dilation suggestive of improvement in endothelial function [142]. ED can also promote HF development. All the main comorbidities able to promote the development of ED (dyslipidaemia, hypertension, smoking habits, age, etc) are all able to influence the development of HF [137]. Recently new evidences demonstrated the correlation between renal artery resistance index (RRI) and HF stages [143]. The RRI predicts the WRF in CHF outpatients. Early detection of ED can identify HF patients at higher risk for death, thus promoting the increase in therapeutic approaches in order to slow the progression of HF.

Ischaemic Heart Failure (STICH) trial [122] has challenged this belief, highlighting the noninferiority of optimal medical therapy (OMT) over revascularization and OMT. STICH has not ended the question over the benefit of revascularization in ischaemic HF. Nowadays, it remains unclear in presence of viable myocardium whether and when the revascolarization is associated to any benefits. 13.1. Atrial fibrillation The risk of AF increases from 4.5- to 5.9-fold in the presence of HF and HF patients develop AF at a rate of 6% to 8% per year [123]. The increasing number of HF patients and AF is due to aging population and increase of life expectancy of patients with CV disease. AF and HF are so closely related, mainly because they share the same CV risk factors (advanced age, hypertension, diabetes, obesity, ischemic and non-ischemic structural heart disease) [124], and because are included in a pathophysiological vicious circle in which one favors the occurrence of the other. AF may favor the development of HF through several mechanisms. AF is the most common cause of tachycardia-induced cardiomyopathy; the degree of induced ventricular dysfunction is related to the duration of tachycardia and restoration of sinus rhythm is usually associated with recovery of LV systolic function [125]. Even HF through several mechanisms can contribute to the onset and persistence of AF. Atrial stretch, consequent to the increase of cardiac filling pressures, results in activation of stretch-activated ionic currents, leading to dispersion of refractoriness and changes in atrial conduction and anisotropy, and so favoring AF development [126]. HF is also associated with generation of interstitial fibrosis, that can lead to abnormal conduction through the atria, creating a substrate for AF [127]. The prognostic significance of AF in HF patients is controversial. The theory that AF may be a marker of advanced disease is supported by epidemiological data showing that AF is more prevalent in advanced stages of HF [128]. The following issues need to be considered in HF patients with AF: identification of potentially correctable cause (hypothyroidism or hyperthyroidism, electrolyte disorders, uncontrolled hypertension, mitral valve disease), assessment of need of anticoagulant therapy (after an accurate balance of thrombotic and bleeding risk) and establish the best therapeutic approach in terms of rhythm control or rate control [129,130]. The rhythm control strategy is probably the best choice for patients with a reversible secondary cause of AF (e.g. hyperthyroidism) or an obvious precipitant factor (e.g. recent pneumonia) and in patients with hemodynamic instability [131]. The strategy of ventricular rate control is based on controlling the ventricular response to AF by the modulation of the atrio-ventricular node function, with drug therapy (betablockers, digoxin, or non-dihydropyridines calcium-channel blocker only in patients with HFpEF) or with ablation technique [132].

15. Conclusion Comorbidities are common in HF, and differences in co-occurrence of conditions exist by type of HF and sex. Encouraging results, derived by trials, may suggest some comorbidities as new pharmacological targets in HF, highlighting the need for a better understanding of the clinical consequences of multiple chronic conditions in HF patients. These new discoveries suggest anymore a multidisciplinary approach for the management of chronic HF with comorbidities and we strongly recommend it. Declaration of Competing Interest The authors have no financial or other interest in the product or distributor of the product. Furthermore, they have no other kinds of associations, such as consultancies, stock ownership, or other equity interests or patent-licensing arrangements. Reference [1] Ponikowski P, Voors AA, Anker SD, Bueno H, Cleland JG, Coats AJ, Falk V, Gonzalez-Juanatey JR, Harjola VP, Jankowska EA, Jessup M, Linde C, Nihoyannopoulos P, Parissis JT, Pieske B, Riley JP, Rosano GM, Ruilope LM, Ruschitzka F, Rutten FH, van der Meer P, Authors/Task Force M, Document R. 2016 ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure: The Task Force for the diagnosis and treatment of acute and chronic heart failure of the European Society of Cardiology (ESC). Developed with the special contribution of the Heart Failure Association (HFA) of the ESC. Eur J Heart Fail 2016;18(8):891–975. [2] Mentz RJ, Kelly JP, von Lueder TG, Voors AA, Lam CS, Cowie MR, Kjeldsen K, Jankowska EA, Atar D, Butler J, Fiuzat M, Zannad F, Pitt B, O'Connor CM. Noncardiac comorbidities in heart failure with reduced versus preserved ejection fraction. J Am Coll Cardiol 2014;64(21):2281–93. Dec 2. [3] Paulus WJ, Tschöpe C.A novel paradigm for heart failure with preserved ejection fraction: comorbidities drive myocardial dysfunction and remodeling through coronary microvascular endothelial inflammation. J Am Coll Cardiol. 2013Jul 23;62(4):263–271. [4] Meijers WC, Maglione M, Bakker SJL, Oberhuber R, Kieneker LM, de Jong S, Haubner BJ, Nagengast WB, Lyon AR, van der Vegt B, van Veldhuisen DJ, Westenbrink BD, van der Meer P, Silljé HHW, de Boer RA. The failing heart stimulates tumor growth by circulating factors. Circulation 2018. Feb 19pii: CIRCULATIONAHA.117.030816 https://doi.org/10.1161/CIRCULATIONAHA. 117.030816. [Epub ahead of print] PMID: 29459363. [5] Ameri P, Canepa M, Anker MS, Belenkov Y, Bergler-Klein J, Cohen-Solal A, Farmakis D, López-Fernández T, Lainscak M, Pudil R, Ruschitska F, Seferovic P, Filippatos G, Coats A, Suter T, Von Haehling S, Ciardiello F, de Boer RA, Lyon AR, Tocchetti CG. Heart Failure Association Cardio-Oncology Study Group of the European Society of Cardiology. Cancer diagnosis in patients with heart failure: epidemiology, clinical implications and gaps in knowledge. Eur J Heart Fail 2018;20(5):879–87. https://doi.org/10.1002/ejhf.1165. [6] Zamorano JL, Lancellotti P, Rodriguez Munoz D, Aboyans V, Asteggiano R,

14. Peripheral artery disease Peripheral artery diseases (PAD) are tightly connected to HF [133]. The prevalence of PAD in HF patients varies from 6.8% to 20% [134]. These data might be underestimated because the clinical symptoms of HF can disguise the PAD [135]. The presence of PAD can increase the mortality risk of 3% and 2% respectively, in HFrEF and HFpEF patients. The higher prevalence of this association and its negative prognostic role is mainly related to the common pathogenetic background (dyslipidemia, hypertension, diabetes, CKD, dietary habits, etc.) [136], and all of these factors are effectively able to promote the original source of both HF and PAD: the endothelial disfunction (ED). The role of endothelial function in HF syndrome is complex because the link between endothelial function and HF is bidirectional [137]. HF promotes the increase in oxidative radical 6

European Journal of Internal Medicine xxx (xxxx) xxx–xxx

M. Correale, et al.

[7]

[8]

[9] [10]

[11]

[12]

[13]

[14]

[15]

[16]

[17]

[18]

[19]

[20] [21]

[22]

[23]

[24] [25]

Galderisi M, Habib G, Lenihan DJ, Lip GY, Lyon AR, Lopez Fernandez T, Mohty D, Piepoli MF, Tamargo J, Torbicki A, Suter TM, Authors/Task Force M. Guidelines ESCCfP. 2016 ESC Position Paper on cancer treatments and cardiovascular toxicity developed under the auspices of the ESC Committee for Practice Guidelines: The Task Force for cancer treatments and cardiovascular toxicity of the European Society of Cardiology (ESC). Eur J Heart Fail 2017;19(1):9–42. https://doi.org/10. 1002/ejhf.654. Jan. Lynce F, Barac A, Tan MT, Asch FM, Smith KL, Dang C, Isaacs C, Swain SM. SAFEHEaRt: rationale and design of a pilot study investigating cardiac safety of HER2 targeted therapy in patients with HER2-positive breast cancer and reduced left ventricular function. Oncologist 2017;22(5):518–25. Lombardi C, Faini A, La Rovere M, Fanfulla F, Mattaliano P, Caravita S, Contini M, Agostoni P, Perrone-Filardi P, Parati G. PROMISES Investigators. Heart failure and sleep related breathing disorders: Data from PROMISES (Progetto Multicentrico Italiano Sonno e Scompenso Cardiaco) study. Int J Cardiol. 2018;271:140–5. Nov 15. Cowie MR, Woehrle H, Wegscheider K, et al. Adaptive servo-ventilation for central sleep apnea in systolic heart failure. New Engl J Med 2015;373(12):1095–105. Cowie MR, Woehrle H, Wegscheider K, Vettorazzi E, Lezius S, Koenig W, Weidemann F, Smith G, Angermann C, d'Ortho MP, Erdmann E, Levy P, Simonds AK, Somers VK, Zannad F, Teschler H. Adaptive servo-ventilation for central sleep apnoea in systolic heart failure: results of the major substudy of SERVE-HF. Eur J Heart Fail 2018;20(3):536–44. Mar. O'Connor CM, Whellan DJ, Fiuzat M, Punjabi NM, Tasissa G, Anstrom KJ, Benjafield AV, Woehrle H, Blase AB, Lindenfeld J, Oldenberg O. Cardiovascular outcomes with minute ventilation-targeted adaptive servo-ventilation therapy in heart failure: the CAT-HF trial. J Am Coll Cardiol 2017;69(12):1577–87. Mar 28. Lyons OD, Floras JS, Logan AG, Beanlands R, Cantolla JD, Fitzpatrick M, Fleetham J, John Kimoff R, Leung RS, Lorenzi Filho G, Mayer P, Mielniczuk L, Morrison DL, Ryan CM, Series F, Tomlinson GA, Woo A, Arzt M, Parthasarathy S, Redolfi S, Kasai T, Parati G, Delgado DH, Bradley TD. ADVENT-HF Investigators. Design of the effect of adaptive servo-ventilation on survival and cardiovascular hospital admissions in patients with heart failure and sleep apnoea: the ADVENT-HF trial. Eur J Heart Fail 2017;19(4):579–87. Apr. Yancy CW, Jessup M, Bozkurt B, Butler J, Casey Jr DE, Drazner MH, Fonarow GC, Geraci SA, Horwich T, Januzzi JL, Johnson MR, Kasper EK, Levy WC, Masoudi FA, McBride PE, McMurray JJ, Mitchell JE, Peterson PN, Riegel B, Sam F, Stevenson LW, Tang WH, Tsai EJ, Wilkoff BL. American College of Cardiology Foundation/ American Heart Association Task Force on Practice Guidelines. 2013 ACCF/AHA guideline for the management of heart failure: a report of the American College of Cardiology Foundation/American Heart Association Task Force on practice guidelines. Circulation 2013;128:e240–327. Canepa M, Temporelli PL, Rossi A, Rossi A, Gonzini L, Nicolosi GL, Staszewsky L, Marchioli R, Maggioni AP, Tavazzi L, Investigators GISSI-HF. Prevalence and prognostic impact of chronic obstructive pulmonary disease in patients with chronic heart failure: data from the GISSI-HF trial. Cardiology 2017;136:128–37. Chioncel O, Lainscak M, Seferovic PM, Anker SD, Crespo-Leiro MG, Harjola VP, Parissis J, Laroche C, Piepoli MF, Fonseca C, Mebazaa A, Lund L, Ambrosio GA, Coats AJ, Ferrari R, Ruschitzka F, Maggioni AP, Filippatos G. Epidemiology and one-year outcomes in patients with chronic heart failure and preserved, mid-range and reduced ejection fraction: an analysis of the ESC Heart Failure Long-Term Registry. Eur J Heart Fail 2017;19:1574–85. Canepa M, Straburzynska-Migaj E, Drozdz J, Fernandez-Vivancos C, Pinilla JMG, Nyolczas N, et al. Characteristics, treatments and 1-year prognosis of hospitalized and ambulatory heart failure patients with chronic obstructive pulmonary disease in the European Society of Cardiology Heart Failure Long-Term Registry. Eur J Heart Fail 2018;20:100–10. Mentz RJ, Schmidt PH, Kwasny MJ, Ambrosy AP, O'Connor CM, Konstam MA, et al. The impact of chronic obstructive pulmonary disease in patients hospitalized for worsening heart failure with reduced ejection fraction: an analysis of the EVEREST trial. J Card Fail 2012;18:515–23. Mentz RJ, Fiuzat M, Wojdyla DM, Chiswell K, Gheorghiade M, Fonarow GC, et al. Clinical characteristics and outcomes of hospitalized heart failure patients with systolic dysfunction and chronic obstructive pulmonary disease: findings from OPTIMIZE-HF. Eur J Heart Fail 2012;14:395–403. Jacob J, Tost J, Ò Miró, Herrero P, Martín-Sánchez FJ, Llorens P, Research Group ICA-SEMES. Impact of chronic obstructive pulmonary disease on clinical course after an episode of acute heart failure. EAHFE-COPD study. Int J Cardiol. 2017;227:450–6. Lipworth B, Wedzicha J, Devereux G, Vestbo J, Dransfield MT. Beta-blockers in COPD: time for reappraisal. Eur Respir J 2016;48:880–8. Lipworth B, Skinner D, Devereux G, Thomas V, Ling Zhi Jie J, Martin J, et al. Underuse of β-blockers in heart failure and chronic obstructive pulmonary disease. Heart 2016;102:1909–14. Tavazzi L, Swedberg K, Komajda M, Böhm M, Borer JS, Lainscak M, Robertson M, Ford I, Investigators SHIFT. Clinical profiles and outcomes in patients with chronic heart failure and chronic obstructive pulmonary disease: an efficacy and safety analysis of SHIFT study. Int J Cardiol 2013;170:182–8. Vestbo J, Hurd SS, Agustí AG, Jones PW, Vogelmeier C, Anzueto A, et al. Global strategy for the diagnosis, management, and prevention of chronic obstructive pulmonary disease: GOLD executive summary. Am J Respir Crit Care Med 2013;187:347–65. Soläng L, Malmberg K, Rydén L. Diabetes mellitus and congestive heart failure. Further knowledge needed. Eur Heart J 1999;20:789–95. Dei Cas A, Khan SS, Butler J, Mentz RJ, Bonow RO, Avogaro A, Tschoepe D, Doehner W, Greene SJ, Senni M, Gheorghiade M, Fonarow GC. Impact of diabetes

[26]

[27]

[28]

[29]

[30]

[31] [32] [33]

[34]

[35]

[36]

[37] [38] [39]

[40] [41]

[42] [43] [44] [45]

[46] [47] [48]

[49] [50] [51]

[52]

7

on epidemiology, treatment, and outcomes of patients with heart failure. JACC Heart Fail 2015;3:136–45. AlZadjali MA, Godfrey V, Khan F, Choy A, Doney AS, Wong AK, Petrie JR, Struthers AD, Lang CC. Insulin resistance is highly prevalent and is associated with reduced exercise tolerance in nondiabetic patients with heart failure. J Am Coll Cardiol 2009;53:747–53. Paolillo S, Rengo G, Pellegrino T, Formisano R, Pagano G, Gargiulo P, et al. Insulin Resistance is associated with impaired cardiac sympathetic innervation in patients with heart failure. Eur Heart J Cardiovasc Imaging 2015;16:1148–53. Dauriz M, Targher G, Laroche C, Temporelli PL, Ferrari R, Anker S, Coats A, Filippatos G, Crespo-Leiro M, Mebazaa A, Piepoli MF, Maggioni AP, Tavazzi L, Heart Failure Long-Term Registry ESC-HFA. Association between diabetes and 1year adverse clinical outcomes in a multinational cohort of ambulatory patients with chronic heart failure: results from the ESC-HFA Heart Failure Long-Term Registry. Diabetes Care 2017;40:671–8. Targher G, Dauriz M, Laroche C, Temporelli PL, Hassanein M, Seferovic PM, Drozdz J, Ferrari R, Anker S, Coats A, Filippatos G, Crespo-Leiro MG, Mebazaa A, Piepoli MF, Maggioni AP, Tavazzi L. ESC-HFA HF Long-Term Registry investigators. In-hospital and 1-year mortality associated with diabetes in patients with acute heart failure: results from the ESC-HFA Heart Failure Long-Term Registry. Eur J Heart Fail 2017;19:54–65. Dauriz M, Targher G, Temporelli PL, Lucci D, Gonzini L, Nicolosi GL, Marchioli R, Tognoni G, Latini R, Cosmi F, Tavazzi L, Maggioni AP. GISSI‐HF investigators. Prognostic impact of diabetes and prediabetes on survival outcomes in patients with chronic heart failure: a post-hoc analysis of the GISSI-HF (Gruppo Italiano per lo Studio della Sopravvivenza nella Insufficienza Cardiaca-Heart Failure) trial. J Am Heart Assoc 2017;6(7). Jia G, DeMarco VG, Sowers JR. Insulin resistance and hyperinsulinaemia in diabetic cardiomyopathy. Nat Rev Endocrinol 2016;12(3):144–53. Mar. Perrone-Filardi P, Paolillo S, Costanzo P, Savarese G, Trimarco B, Bonow RO. The role of metabolic syndrome in heart failure. Eur Heart J 2015;36:2630–4. Zinman B, Wanner C, Lachin JM, Fitchett D, Bluhmki E, Hantel S, Mattheus M, Devins T, Johansen OE, Woerle HJ, Broedl UC, Inzucchi SE. EMPA-REG OUTCOME investigators. Empagliflozin, cardiovascular outcomes, and mortality in type 2 diabetes. N Engl J Med 2015;373:2117–28. Fitchett D, Zinman B, Wanner C, Lachin JM, Hantel S, Salsali A, Johansen OE, Woerle HJ, Broedl UC, Inzucchi SE. EMPA-REG OUTCOME® trial investigators. Heart failure outcomes with empagliflozin in patients with type 2 diabetes at high cardiovascular risk: results of the EMPA-REG OUTCOME® trial. Eur Heart J 2016;37:1526–34. A phase III randomised, double-blind trial to evaluate efficacy and safety of once daily empagliflozin 10 mg compared to placebo, in patients with chronic heart failure with reduced ejection fraction (HFrEF). Boehringer Ingelheim, 2017. https://clinicaltrials.gov/ct2/show/NCT03057977. A phase III randomised, double-blind trial to evaluate efficacy and safety of once daily empagliflozin 10 mg compared to placebo, in patients with chronic Heart Failure with preserved Ejection Fraction (HFpEF). Boehrigner Ingelheim, 2017. https://clinicaltrials.gov/ct2/show/NCT03057951. Biondi B. Mechanisms in endocrinology: heart failure and thyroid dysfunction. Eur J Endocrinol 2012;167:609–18. Grais IM, Sowers JR. Thyroid and the heart. Am J Med 2014;127:691–8. Triggiani V, Iacoviello M. Thyroid disorders in chronic heart failure: from prognostic set-up to therapeutic management. Endocr Metab Immune Disord Drug Targets 2013;13:22–37. Mitchell JE, Hellkamp AS, Mark DB, et al. Thyroid function in heart failure and impact on mortality. JACC Heart Fail 2013;1:48–55. Garber JR, Cobin RH, Gharib H, Hennessey JV, Klein I, Mechanick JI, PessahPollack R, Singer PA, Woeber KA. American Association of Clinical Endocrinologists and American Thyroid Association Taskforce on hypothyroidism in adults. Clinical practice guidelines for hypothyroidism in adults: cosponsored by the American Association of Clinical Endocrinologists and the American Thyroid Association. Thyroid 2012;22:1200–35. Almandoz JP, Gharib H. Hypothyroidism: etiology, diagnosis, and management. Med Clin North Am 2012;96(2):203–21. Mar. Klein I, Danzi S. Thyroid disease and the heart. Curr Probl Cardiol 2016;41:65–92. Martinez F. Thyroid hormones and heart failure. Heart Fail Rev 2016;21(4):361–4. Elnaggar MN, Jbeili K, Nik-Hussin N, Kozhippally M Pappachan JM. AmiodaroneInduced thyroid dysfunction: a clinical update. Exp Clin Endocrinol Diabetes 2018;126:333–41. Danzi S, Klein I. Amiodarone-induced thyroid dysfunction. J Intensive Care Med 2015;30:179–85. Bogazzi F, Bartalena L, Martino E. Approach to the patient with amiodarone-induced thyrotoxicosis. J Clin Endocrinol Metab 2010;95:2529–35. Bartalena L, Bogazzi F, Chiovato L, Hubalewska-Dydejczyk A, Links TP, Vanderpump M. 2018 European Thyroid Association (ETA) guidelines for the management of amiodarone-associated thyroid dysfunction. Eur Thyroid J 2018;7:55–66. Narayana SK, Woods DR, Boos CJ. Management of amiodarone-related thyroid problems. Ther Adv Endocrinol Metab 2011;2:115–26. Grais IM, Sowers JR. Thyroid and the heart. Am J Med 2014;127:691–8. Gustafsson D, Unwin R. The pathophysiology of hyperuricaemia and its possible relationship to cardiovascular disease, morbidity and mortality. BMC Nephrol 2013;14:164–72. Givertz MM, Anstrom KJ, Redfield MM, Deswal A, Haddad H, Butler J, Tamg WHW, Dunlap ME, LeWinter MM, Mann DL, Felker GM, O'Connor CM, Goldsmith SR, Ofili EO, Saltzberg MT, Marguiles KB, Cappola TP, Konstam MA, Semigran MJ,

European Journal of Internal Medicine xxx (xxxx) xxx–xxx

M. Correale, et al.

[53]

[54]

[55] [56]

[57]

[58]

[59]

[60]

[61]

[62]

[63]

[64]

[65]

[66] [67]

[68]

[69]

[70] [71]

[72] [73]

[74]

[75]

[76]

McNulty SE, Lee KL, Shah MR, Hernandez AF. Effects of xanthine oxidase inhibition in hyperuricemic heart failure patients: the Xanthine Oxidase Inhibition for Hyperuricemic Heart Failure Patients (EXACT-HF) study. Circulation 2015;131:1763–71. Hare JM, Mangal B, Brown J, Fisher Jr. C, Freudenberger R, Colucci WS, Mann DL, Liu P, Givertz MM, Schwarz RP. OPT-CHF Investigators. Impact of oxypurinol in patients with symptomatic heart failure: results of the OPT-CHF study. J Am Coll Cardiol. 2008;51:2301–9. Yokota T, Fukushima A, Kinugawa S, Okumura T, Murohara T, Tsutsui H. Randomized trial of effect of urate-lowering agent febuxostat in chronic heart failure patients with hyperuricemia (LEAF-CHF). Int Heart J. 2018;59(5):976–82. Sep 26. Marshall Brinkley D, Ali OM, Zalawadiya SK, Wang TJ. Vitamin D and heart failure. Curr Heart Fail Rep 2017;14:410–20. Gotsman I, Shauer A, Zwas DR, Hellman Y, Keren A, Lotan C, Admon D. Vitamin D deficiency is a predictor of reduced survival in patients with heart failure; vitamin D supplementation improves outcome. Eur J Heart Fail 2012;14(4):357–66. Apr. Dalbeni A, Scaturro G, Degan M, Minuz P, Delva P. Effects of six months of vitamin D supplementation in patients with heart failure: a randomized double-blind controlled trial. Nut Met Cardio Dis 2014;24:861–8. Zittermann A, Ernst JB, Prokop S, Fuchs U, Dreier J, Kuhn J, Knabbe C, Birschmann I, Schulz U, Berthold HK, Pilz S, Gouni-Berthold I, Gummert JF, Dittrich M, Börgermann J. Effect of vitamin D on all-cause mortality in heart failure (EVITA): a 3-year randomized clinical trialwith 4000 IU vitamin D daily. Eur Heart J 2017;38(29):2279–86. Aug 1. Arcopinto M, Salzano A, Giallauria F, Bossone E, Isgaard J, Marra AM, Bobbio E, Vriz O, Åberg DN, Masarone D, De Paulis A, Saldamarco L, Vigorito C, Formisano P, Niola M, Perticone F, Bonaduce D, Saccà L, Colao A, Cittadini A. T.O.S.CA. Growth hormone deficiency is associated with worse cardiac function, physical performance, and outcome in chronic heart failure: insights from the T.O.S.CA. GHD Study Intern Emerg Med 2018;4:1844–8. Yoshihisa A, Suzuki S, Sato Y, Kanno Y, Abe S, Miyata M, Sato T, Oikawa M, Kobayashi A, Yamaki T, Kunii H, Nakazato K, Ishida T, Takeishi Y. Relation of testosterone levels to mortality in men with heart failure. Am J Cardiol 2018;121:1321–7. Malkin CJ, Pugh PJ, West JN, van Beek EJ, Jones TH, Channer KS. Testosterone therapy in men with moderate severity heart failure: a double-blind randomized placebo controlled trial. Eur Heart J 2006;27:57–64. Cittadini A, Marra AM, Arcopinto M, Bobbio E, Salzano A, Sirico D, Napoli R, Colao A, Longobardi S, Baliga RR, Bossone E, Saccà L. Growth hormone replacement delays the progression of chronic heart failure combined with growth hormone deficiency: an extension of a randomized controlled single-blind study. JACC Heart Fail 2013;1:325–30. Smith GL, Lichtman JH, Bracken MB, Shlipak MG, Phillips CO, DiCapua P, Krumholz HM. Renal impairment and outcomes in heart failure: systematic review and meta-analysis. J Am Coll Cardiol 2006;47:1987–96. Palazzuoli A, Beltrami M, Nodari S, McCullough PA, Ronco C. Clinical impact of renal dysfunction in heart failure. Rev Cardiovasc Med 2011;12(4):186–99. https://doi.org/10.3909/ricm0581. Zoccali C, Vanholder R, Massy ZA, Ortiz A, Sarafidis P, Dekker FW, Fliser D, Fouque D, Heine GH, Jager KJ, Kanbay M, Mallamaci F, Parati G, Rossignol P, Wiecek A, London G. The systemic nature of CKD. Nat Rev Nephrol 2017;13(6):344–58. https://doi.org/10.1038/nrneph.2017.52. Damman K, Testani JM. The kidney in heart failure: an update. Eur Heart J 2015;36:1437–44. Palazzuoli A, Lombardi C, Ruocco G, et al. Chronic kidney disease and worsening renal function in acute heart failure: different phenotypes with similar prognostic impact. Eur Heart J Acute Cardiovasc Care 2016;5:534–48. Coca SC, Krumholtz HM, Garg AX, Parikh CR. Under representation of renal disease in randomized controlled trials of cardiovascular diseases. JAMA 2006;296:1377–84. Damman K, Valente MA, Voors AA, O'Connor CM, van Veldhuisen DJ, Hillege HL. Renal impairment, worsening renal function, and outcome in patients with heart failure: an updated meta-analysis. Eur Heart J 2014;35:455–69. Schiffrin EL, Lipman ML, Mann JFE. Chronic kidney disease effects on the cardiovascular system. Circulation 2007;116:85–97. Brewster UC, Setaro JF, Perazella MA. The renin-angiotensin-aldosterone system: cardiorenal effects and implications for renal and cardiovascular disease states. Am J Med Sci 2003;326:15–24. Metra M, Cotter G, Gheroghiade M, Dei Cas L, Voors AA. The role of kidney in heart failure. Eur Heart J 2012;33:2135–43. Morley JE, Abbatecola AM, Argiles JM, Baracos V, Bauer J, Bhasin S, Cederholm T, Coats AJ, Cummings SR, Evans WJ, Fearon K, Ferrucci L, Fielding RA,Guralnik JM, Harris TB, Inui A, Kalantar-Zadeh K, Kirwan BA, Mantovani G, Muscaritoli M, Newman AB, Rossi-Fanelli F, Rosano GM, Roubenoff R, Schambelan M, Sokol GH, Storer TW, Vellas B, von Haehling S, Yeh SS, Anker SD. Society on Sarcopenia, Cachexia and Wasting Disorders Trialist Workshop Sarcopenia with limited mobility: an international consensus. J Am Med Dir Assoc 2011;12:403–9. Fülster S, Tacke M, Sandek A, Ebner N, Tschöpe C, Doehner W, Anker SD, von Haehling S. Muscle wasting in patients with chronic heart failure: results from the studies investigating co-morbidities aggravating heart failure (SICA-HF). Eur Heart J 2013;34:512–9. Argilés JM, Anker SD, Evans WJ, Morley JE, Fearon KC, Strasser F, Muscaritoli M, Baracos VE. Consensus on cachexia definitions. J Am Med Dir Assoc 2010;11:229–30. Bahls M, Felix SB. Cachexia and right ventricular dysfunction in chronic heart

[77] [78] [79] [80]

[81]

[82] [83]

[84]

[85]

[86]

[87] [88]

[89]

[90] [91]

[92] [93]

[94]

[95]

[96]

[97]

[98]

[99]

[100]

8

failure: what is the chicken and what the egg?Eur Heart J. 2016 Apr 12. pii: ehw118. [Epub ahead of print]. Kinugawa S, Takada S, Matsushima S, Okita K, Tsutsui H. Skeletalmuscle abnormalities in heart failure. Int Heart J 2015;56:475–84. Von Haehling S. The wasting continuum in heart failure: from sarcopenia to cachexia. Proc Nutr Soc 2015;74:367–77. Loncar G, Springer J, Anker M, Doehner W, Lainscak M. Cardiac cachexia: hic et nunc: “hic et nunc” – here and now. Int J Cardiol 2015;201:e1–12. Rahman A, Jafry S, Jeejeebhoy K, Nagpal AD, Pisani B, Agarwala R. Malnutrition and cachexia in heart failure. JPEN J Parenter Enteral Nutr 2015. Jan 29. pii: 0148607114566854. [Epub ahead of print]. Valentova M, von Haehling S, Bauditz J, Doehner W, Ebner N, Bekfani T, Elsner S, Sliziuk V, Scherbakov N, Murín J, Anker SD, Sandek A. Intestinal congestion and right ventricular dysfunction: a link with appetite loss, inflammation, and cachexia in chronic heart failure. Eur Heart J 2016. Feb 9. pii: ehw008. [Epub ahead of print]. Arques S, Ambrosi P. Human serum albumin in the clinical syndrome of heart failure. J Card Fail 2011;17:451–8. Rossignol P, Masson S, Barlera S, Girerd N, Castelnovo A, Zannad F, Clemenza F, Tognoni G, Anand IS, Cohn JN, Anker SD, Tavazzi L, Latini R. GISSI-HF and ValHeFT Investigators. Loss in body weight is an independent prognostic factor for mortality in chronic heart failure: insights from the GISSI-HF and Val-HeFT trials. Eur J Heart Fail 2015;17:424–33. Anker SD, Ponikowski P, Varney S, Chua TP, Clark AL, Webb-Peploe KM, Harrington D, Kox WJ, Poole-Wilson PA, Coats AJ. Wasting as independent risk factor for mortality in chronic heart failure. Lancet 1997;349:1050–3. Pocock SJ, McMurray JJ, Dobson J, Yusuf S, Granger CB, Michelson EL, Ostergren J, Pfeffer MA, Solomon SD, Anker SD, Swedberg KB. Weight loss and mortality risk in patients with chronic heart failure in the candesartan in heart failure: assessment of reduction in mortality and morbidity (CHARM) programme. Eur Heart J 2008;29:2641–50. Clark AL, Coats AJS, Krum H, Katus HA, Mohacsi P, Salekin D, Schultz MK, Packer M, Anker SD. Effect of beta-adrenergic blockade with carvedilol on cachexia in severe chronic heart failure: results from the COPERNICUS trial. J Cachexia Sarcopenia Muscle 2017;8(4):549–56. von Haehling S, Jankowska EA, van Veldhuisen DJ, Ponikowski P, Anker SD. Iron deficiency and cardiovascular disease. Nat Rev Cardiol 2015;12(11):659–69. Hoes MF, Beverborg NG, Kijlstra JD, Kuipers J, Swinkels DW, Giepmans BNG, Rodenburg RJ, van Veldhuisen GJ, Rudolf A, de Boer RA, van der Meer P. Iron deficiency impairs contractility of human cardiomyocytes through decreased mitochondrial function. Eur J Heart Fail 2018;20:910–9. Haddad S, Wang Y, Galy B, Korf-Klingebiel M, Hirsch V, Baru AM, Rostami F, Reboll MR, Heineke J, Flögel U, Groos S, Renner A, Toischer K, Zimmermann F, Engeli S, Jordan J, Bauersachs J, Hentze MW, Wollert KC, Kempf T. Iron-regulatory proteins secure iron availability in cardiomyocytes to prevent heart failure. Eur Heart J 2017;38(5):362–72. Hentze MW, Muckenthaler MU, Andrews NC. Balancing acts: molecular control of mammalian iron metabolism. Cell 2004;117(3):285–97. Reichert CO, da Cunha J, Levy D, Maselli LMF, Bydlowski SP, Spada C. Hepcidin: homeostasis and diseases related to iron metabolism. Acta Haematol 2017;137(4):220–36. Anand IS, Gupta P. Anemia and iron deficiency in heart failure: current concepts and emerging therapies. Circulation 2018;138(1):80–98. Jankowska EA, von Haehling S, Anker SD, Macdougall IC, Ponikowski P. Iron deficiency and heart failure: diagnostic dilemmas and therapeutic perspectives. Eur Heart J 2013;34(11):816–29. Mar. von Haehling S, Gremmler U, Krumm M, Mibach F, Schön N, Taggeselle J, Dahm JB, Angermann CE. Prevalence and clinical impact of iron deficiency and anaemia among outpatients with chronic heart failure: The PrEP Registry. Clin Res Cardiol 2017;106(6):436–43. Jun. Tkaczyszyn M, Comín-Colet J, Voors AA, van Veldhuisen DJ, Enjuanes C, MolinerBorja P, Rozentryt P, Poloński L, Banasiak W, Ponikowski P, van der Meer P, Jankowska EA. Iron deficiency and red cell indices in patients with heart failure. Eur J Heart Fail 2018;20(1):114–22. Jan. Kulnigg S, Stoinov S, Simanenkov V, Dudar LV, Karnafel W, Garcia LC, Sambuelli AM, D'Haens G, Gasche C. A novel intravenous iron formulation for treatment of anemia in inflammatory bowel disease: the ferric carboxymaltose (FERINJECT) randomized controlled trial. Am J Gastroenterol 2008;103(5):1182–92. May. Toblli JE, Angerosa M. Optimizing iron delivery in the management of anemia: patient considerations and the role of ferric carboxymaltose. Drug Des Devel Ther 2014;8:2475–91. Dec 11. Anker SD, Comin Colet J, Filippatos G, Willenheimer R, Dickstein K, Drexler H, Lüscher TF, Bart B, Banasiak W, Niegowska J, Kirwan BA, Mori C, von Eisenhart Rothe B, Pocock SJ, Poole-Wilson PA, Ponikowski P. FAIR-HF Trial Investigators. Ferric carboxymaltose in patients with heart failure and iron deficiency. N Engl J Med 2009;361(25):2436–48. Dec 17. Ponikowski P, Filippatos G, Colet JC, Willenheimer R, Dickstein K, Lüscher T, Gaudesius G, von Eisenhart Rothe B, Mori C, Greenlaw N, Ford I, Macdougall I, Anker SD. FAIR-HF trial investigators. The impact of intravenous ferric carboxymaltose on renal function: an analysis of the FAIR-HF study. Eur J Heart Fail 2015;17(3):329–39. Mar. Ponikowski P, van Veldhuisen DJ, Comin-Colet J, Ertl G, Komajda M, Mareev V, McDonagh T, Parkhomenko A, Tavazzi L, Levesque V, Mori C, Roubert B, Filippatos G, Ruschitzka F, Anker SD. CONFIRM-HF Investigators. Beneficial effects of long-term intravenous iron therapy with ferric carboxymaltose in patients with symptomatic heart failure and iron deficiency. Eur Heart J

European Journal of Internal Medicine xxx (xxxx) xxx–xxx

M. Correale, et al.

heart disease. Circulation 2012;125:945–57. [124] Kareti KR, Chiong JR, Hsu SS, Miller AB. Congestive heart failure and atrial fibrillation: rhythm verus rate control. J Card Fail 2005;11:164–72. [125] Gentlesk PJ, Sauer WH, Gerstenfeld EP, Lin D, Dixit S, Zado E, Callans D, Marchlinski FE. Reversal of left ventricular dysfunction following ablation of atrial fibrillation. J Cardiovasc Electrophysiol 2007;18:9–14. [126] Solti F, Vecsey T, Kékesi V, Juhàsz-Nagy A. The effect of atrial dilatation on the genesis of atrial arrhythmias. Cardiovasc Res 1989;23:882–6. [127] Li D, Fareh S, Leung TK, Nattel S. Promotion of atrial fibrillation by heart failure in dogs: atrial remodeling of a different sort. Circulation 1999;100:87–95. [128] Maisel WH, Stevenson LW. Atrial fibrillation in heart failure: epidemiology, pathophysiology, and rationale for therapy. Am J Cardiol 2003;91:2D–8D. [129] Kirchhof P, Benussi S, Kotecha D, Ahlsson A, Atar D, Casadei B, Castella M, Diener HC, Heidbuchel H, Hendriks J, Hindricks G, Manolis AS, Oldgren J, Popescu BA, Schotten U, Van Putte B, Vardas P, Agewall S, Camm J, Baron Esquivias G, Budts W, Carerj S, Casselman F, Coca A, De Caterina R, Deftereos S, Dobrev D, Ferro JM, Filippatos G, Fitzsimons D, Gorenek B, Guenoun M, Hohnloser SH, Kolh P, Lip GY, Manolis A, McMurray J, Ponikowski P, Rosenhek R, Ruschitzka F, Savelieva I, Sharma S, Suwalski P, Tamargo JL, Taylor CJ, Van Gelder IC, Voors AA, Windecker S, Zamorano JL, Zeppenfeld K. 2016 ESC Guidelines for the management of atrial fibrillation developed in collaboration with EACTS. Eur J Cardiothorac Surg 2016;50(5):e1–88. Nov. [130] January CT, Wann LS, Alpert JS, Calkins H, Cigarroa JE, Cleveland Jr JC, Conti JB, Ellinor PT, Ezekowitz MD, Field ME, Murray KT, Sacco RL, Stevenson WG, Tchou PJ, Tracy CM, Yancy CW. American College of Cardiology/American Heart Association Task Force on Practice Guidelines. 2014 AHA/ACC/HRS guideline for the management of patients with atrial fibrillation: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines and the Heart Rhythm Society. J Am Coll Cardiol 2014;64(21):e1–76. Dec 2. [131] Wyse DG, Waldo AL, DiMarco JP, Domanski MJ, Rosenberg Y, Schron EB, Kellen JC, Greene HL, Mickel MC, Dalquist JE, Corley SD. Atrial Fibrillation Follow–up Investigation of Rhythm Management (AFFIRM) investigators. A comparison of rate control and rhythm control in patients with atrial fibrillation. N Engl J Med 2002;347(23):1825. [132] Dorian P. Rate control in atrial fibrillation. N Engl J Med 2010;362(15):1439–41. Apr 15. [133] Metra M, Zacà V, Parati G, Agostoni P, Bonadies M, Ciccone M, Cas AD, Iacoviello M, Lagioia R, Lombardi C, Maio R, Magrì D, Musca G, Padeletti M, Perticone F, Pezzali N, Piepoli M, Sciacqua A, Zanolla L, Nodari S, Filardi PP. Dei Cas L; Heart Failure Study Group of the Italian Society of Cardiology. Cardiovascular and noncardiovascular comorbidities in patients with chronic heart failure. J Cardiovasc Med (Hagerstown) 2011;12:76–84. [134] Inglis SC, Hermis A, Shehab S, Newton PJ, Lal S, Davidson PM. Peripheral arterial disease and chronic heart failure: a dangerous mix. Heart Fail Rev 2013;18:457–64. [135] Hiatt WR. Heart failure and peripheral artery disease: an unappreciated association. JACC Heart Fail 2014;2:455–6. [136] Mattioli AV, Palmiero P, Manfrini O, Puddu PE, Nodari S, Dei Cas A, Mercuro G, Scrutinio D, Palermo P, Sciomer S, Di Francesco S, Novo G, Novo S, Pedretti RFE, Zito A, Parati G, Pedrinelli R, Farinetti A, Maiello M, Moscucci F, Tenaglia RL, Sucato V, Triggiani M, Cugusi L, Scicchitano P, Saba PS, Ciccone MM. Mediterranean diet impact on cardiovascular diseases: a narrative review. J Cardiovasc Med (Hagerstown) 2017;18:925–35. [137] Areas GPT, Mazzuco A, Caruso FR, Jaenisch RB, Cabiddu R, Phillips SA, Arena R, Borghi-Silva A. Flow-mediated dilation and heart failure: a review with implications to physical rehabilitation. Heart Fail Rev. 2018Jul 11. 10.1007/s10741-0189719-7. [Epub ahead of print]. [138] Miller JD, Peotta VA, Chu Y, Weiss RM, Zimmerman K, Brooks RM, Heistad DD. MnSOD protects against COX1-mediated endothelial dysfunction in chronic heart failure. Am J Physiol Heart Circ Physiol 2010;298. H1600-7. [139] Zuo L, Chuang CC, Hemmelgarn BT, Best TM. Heart failure with preserved ejection fraction: Defining the function of ROS and NO. J Appl Physiol (1985) 2015;119:944–51. [140] Sheng Y, Zhu L. The crosstalk between autonomic nervous system and blood vessels. Int J Physiol Pathophysiol Pharmacol 2018;10:17–28. [141] Wray DW, Amann M, Richardson RS. Peripheral vascular function, oxygen delivery and utilization: the impact of oxidative stress in aging and heart failure with reduced ejection fraction. Heart Fail Rev 2017;22:149–66. [142] Erbs S, Höllriegel R, Linke A, Beck EB, Adams V, Gielen S, Möbius-Winkler S, Sandri M, Kränkel N, Hambrecht R, Schuler G. Exercise training in patients with advanced chronic heart failure (NYHA IIIb) promotes restoration of peripheral vasomotor function, induction of endogenous regeneration, and improvement of left ventricular function. Circ Heart Fail 2010;3(4):486–94. Jul. [143] Ciccone MM, Iacoviello M, Gesualdo L, Puzzovivo A, Antoncecchi V, Doronzo A, Monitillo F, Citarelli G, Paradies V, Favale S. The renal arterial resistance index: a marker of renal function with an independent and incremental role in predicting heart failure progression. Eur J Heart Fail 2014;16:210–6.

2015;36(11):657–68. Mar 14. [101] Anker SD, Kirwan BA, van Veldhuisen DJ, Filippatos G, Comin-Colet J, Ruschitzka F, Lüscher TF, Arutyunov GP, Motro M, Mori C, Roubert B, Pocock SJ, Ponikowski P. Effects of ferric carboxymaltose on hospitalisations and mortality rates in irondeficient heart failure patients: an individual patient data meta-analysis. Eur J Heart Fail 2018;20(1):125–33. Jan. [102] Corbineau S1, Breton M2, Mialet-Perez J3. Costemale-lacoste JF4. Major depression and heart failure: Interest of monoamine oxidase inhibitors. Int J Cardiol 2017;247:1–6. Nov 15. [103] Mbakwem A1, Aina F1, Amadi C1. Expert opinion-depression in patients with heart failure: is enough being done? Card Fail Rev 2016;2(2):110–2. Nov. [104] Song EK1, Wu JR2, Moser DK3, Kang SM4. Lennie TA3 Vitamin D supplements reduce depressive symptoms and cardiac events in heart failure patients with moderate to severe depressive symptoms. Eur J Cardiovasc Nurs 2018;17(3):207–16. Mar. [105] Alagiakrishnan K, Mah D, Ahmed A, Ezekowitz J. Cognitive decline in heart failure. Heart Fail Rev 2016;21(6):661–73. Nov. [106] 6,7 Adamski MG1, Sternak M2, Mohaissen T2, Kaczor D2, Wierońska JM3, Malinowska M4, Czaban I4, Byk K5, Lyngsø KS6, Przyborowski K2, Hansen PBL, Wilczyński G4, Chlopicki S. 1,8 Vascular cognitive impairment linked to brain endothelium inflammation in early stages of heart failure in mice. J Am Heart Assoc 2018;7(7):e007694. Mar 26pii. [107] Song EK1, Wu JR.Associations of vitamin D intake and sleep quality with cognitive dysfunction in older adults with heart failure. J Cardiovasc Nurs. 2018Mar 29. 10. 1097/JCN.0000000000000469. [Epub ahead of print]. [108] Graham S1, Ye S2, Qian M3, Sanford AR3, Di Tullio MR2, Sacco RL4, Mann DL5, Levin B3, Pullicino PM6, Freudenberger RS7, Teerlink JR8, Mohr JP9, Labovitz AJ10, Lip GY11, Estol CJ12, Lok DJ13, Ponikowski P14, Anker SD15, Thompson JL3, Homma S3. WARCEF investigators. Cognitive function in ambulatory patients with systolic heart failure: insights from the warfarin versus aspirin in reduced cardiac ejection fraction (WARCEF) trial. PLoS One 2014;9(11):e113447. Nov 26. [109] Duncker D1, Friedel K1, König T1, Schreyer H1, Lüsebrink U1, Duncker M2, Oswald H1, Klein G3, Gardiwal A4. Cardiac resynchronization therapy improves psycho-cognitive performance in patients with heart failure. Europace 2015;17(9):1415–21. Sep. [110] K1 Alagiakrishnan, D2 Mah, JR3 Dyck, A4 Senthilselvan, J5 Ezekowitz. Comparison of two commonly used clinical cognitive screening tests to diagnose mild cognitive impairment in heart failure with the golden standard European Consortium Criteria. Int J Cardiol 2017;228:558–62. Feb 1. [111] Lamblin N, Meurice T, Tricot O, de Groote P, Lemesle G, Bauters C. First hospitalization for heart failure in outpatients with stable coronary artery disease: determinants, role of incident myocardial infarction, and prognosis. J Card Fail 2018;S1071–9164(18):31053–8. https://doi.org/10.1016/j.cardfail.2018.09.013. Oct 5pii[Epub ahead of print]. [112] Pfeffer MA. heart failure and hypertension: importance of prevention. Med Clin North Am 2017;101(1):19–28. [113] Perkovic V, Rodgers A. Redefining blood-pressure targets–SPRINT starts the marathon. N Engl J Med 2015;373(22):2175–8. [114] Yancy CW, Jessup M, Bozkurt B, Butler J, Casey Jr DE, Colvin MM, Drazner MH, Filippatos GS, Fonarow GC, Givertz MM, Hollenberg SM, Lindenfeld J, Masoudi FA, McBride PE, Peterson PN, Stevenson LW, Westlake C. 2017 ACC/AHA/HFSA focused update of the 2013 ACCF/AHA guideline for the management of heart failure: a report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines and the Heart Failure Society of America. J Am Coll Cardiol. 2017;70(6):776–803. [115] Komajda M, Böhm M, Borer JS, Ford I, Tavazzi L, Pannaux M, Swedberg K. Incremental benefit of drug therapies for chronic heart failure with reduced ejection fraction: a network meta-analysis. Eur J Heart Fail 2018;20(9):1315–22. [116] Tai C, Gan T, Zou L, Sun Y, Zhang Y, Chen W, Li J, Zhang J, Xu Y, Lu H, Xu D. Effect of angiotensin-converting enzyme inhibitors and angiotensin II receptor blockers on cardiovascular events in patients with heart failure: a meta-analysis of randomized controlled trials. BMC Cardiovasc Disord 2017;17(1):257. [117] Nadruz W, Shah AM, Solomon SD. Diastolic dysfunction and hypertension. Med Clin North Am 2017;101(1):7–17. Jan. [118] Lala A, Desai AS. The role of coronary artery disease in heart failure. Heart Fail Clin 2014;10(2):353–65. [119] Gheorghiade M, Bonow RO. Chronic heart failure in the United States: a manifestation of coronary artery disease. Circulation 1998;97(3):282–9. [120] Mohri M, Takeshita A. Coronary microvascular disease in humans. Jpn Heart J 1999;40(2):97–108. [121] Gurunathan S, Ahmed A, Senior R. The benefits of revascularization in chronic heart failure. Curr Heart Fail Rep 2015;12(2):112–9. Apr. [122] Velazquez EJ, Lee KL, Deja MA, Jain A, Sopko G, Marchenko A, Ali IS, Pohost G, Gradinac S, Abraham WT, Yii M, Prabhakaran D, Szwed H, Ferrazzi P, Petrie MC, O'Connor CM, Panchavinnin P, She L, Bonow RO, Rankin GR, Jones RH, Rouleau JL, Investigators STICH. Coronary-artery bypass surgery in patients with left ventricular dysfunction. N Engl J Med 2011;364(17):1607–16. Apr 28. [123] Darby AE, Dimarco JP. Management of atrial fibrillation in patients with structural

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