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Preface| Volume 40, ISSUE 2, Pxi-xiv, May 01, 2022

Emerging Comorbidities in Heart Failure

DOI:https://doi.org/10.1016/j.ccl.2022.02.001
Emerging Comorbidities in Heart Failure
Previous ArticleForthcoming Issues
Next ArticleThyroid Abnormalities in Heart Failure
      Figure thumbnail fx1
      Antonio Cittadini, MD, Editor
      Figure thumbnail fx2
      Eduardo Bossone, MD, PhD, Editor
      Figure thumbnail fx3
      Hector O. Ventura, MD, Editor
      Heart failure (HF), a complex clinical syndrome characterized by cardinal symptoms and signs, represents an intriguing clinical challenge for cardiologists and physicians, considering its increase in prevalence, incidence, hospitalizations, and death
      • Tsao C.W.
      • Aday A.W.
      • Almarzooq Z.I.
      • et al.
      Heart disease and stroke statistics–2022 update: a report from the American Heart Association.
      Circulation. 2022; 145 (CIR0000000000001052): e153-e639https://doi.org/10.1161/CIR.0000000000001052
      ; furthermore, the recent COVID-19 outbreak created novel needs in the everyday clinical practice, with the necessity of ideate new strategies of management.
      • Salzano A.
      • D’Assante R.
      • Stagnaro F.M.
      • et al.
      Heart failure management during COVID-19 outbreak in Italy. Telemedicine experience from a heart failure university tertiary referral centre.
      Eur J Heart Fail. 2020; 22: 1048-1050https://doi.org/10.1002/ejhf.1911
      In this context, HF patients display several chronic coexisting diseases,
      • Streng K.W.
      • Nauta J.F.
      • Hillege H.L.
      • et al.
      Non-cardiac comorbidities in heart failure with reduced, mid-range and preserved ejection fraction.
      Int J Cardiol. 2018; 271: 132-139
      strongly impacting on morbidity, mortality, and health-related quality of life.
      • Wolsk E.
      • Claggett B.
      • Køber L.
      • et al.
      Contribution of cardiac and extra-cardiac disease burden to risk of cardiovascular outcomes varies by ejection fraction in heart failure.
      Eur J Heart Fail. 2018; 20: 504-510
      ,
      • Radhoe S.P.
      • Veenis J.F.
      • Linssen G.C.M.
      • et al.
      Diabetes and treatment of chronic heart failure in a large real-world heart failure population.
      ESC Heart Fail. 2022; 9: 353-362
      In addition, the presence of comorbidities determines a more complex clinical management leading to increasing health care costs (Fig. 1).
      • Iorio A.
      • Senni M.
      • Barbati G.
      • et al.
      Prevalence and prognostic impact of non-cardiac co-morbidities in heart failure outpatients with preserved and reduced ejection fraction: a community-based study.
      Eur J Heart Fail. 2018; 20: 1257-1266
      Figure thumbnail gr1
      Fig. 1Impact of emerging comorbidities on HF.
      (Modified from Cittadini A, Bossone E, Ventura HO. Emerging comorbidities in heart failure. Heart Fail Clin 2020;16(1):xiii-xv.)
      The purpose of the present issue of Cardiology Clinics is to review several comorbidities (ie, noncardiac and cardiac), with the aim of helping clinicians in the everyday management of HF patients.

      NONCARDIAC COMORBIDITIES

      Growing evidence suggests that HF patients displaying a hormone disarrangement are characterized by impaired cardiovascular performance and poor prognosis.
      • Arcopinto M.
      • Salzano A.
      • Giallauria F.
      • et al.
      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.
      PLoS One. 2017; 12: e0170058
      , 
      • Arcopinto M.
      • Salzano A.
      • Bossone E.
      • et al.
      Multiple hormone deficiencies in chronic heart failure.
      Int J Cardiol. 2015; 184: 421-423
      , 
      • Salzano A.
      • Marra A.M.
      • Ferrara F.
      • et al.
      Multiple hormone deficiency syndrome in heart failure with preserved ejection fraction.
      Int J Cardiol. 2016; 225: 1-3
      , 
      • Marra A.M.
      • Arcopinto M.
      • Bobbio E.
      • et al.
      An unusual case of dilated cardiomyopathy associated with partial hypopituitarism.
      Intern Emerg Med. 2012; 7: S85-S87
      Recently, this hypothesis has been confirmed by data from the T.O.S.CA. registry,
      • Cittadini A.
      • Salzano A.
      • Iacoviello M.
      • et al.
      Multiple hormonal and metabolic deficiency syndrome predicts outcome in heart failure: the T.O.S.CA. Registry.
      Eur J Prev Cardiol. 2021; 28: 1691-1700
      ,
      • Bossone E.
      • Arcopinto M.
      • Iacoviello M.
      • et al.
      Multiple hormonal and metabolic deficiency syndrome in chronic heart failure: rationale, design, and demographic characteristics of the T.O.S.CA. Registry.
      Intern Emerg Med. 2018; 13: 661-671
      with patients affected by multiple hormone and metabolic deficiency syndrome (defined as 2 or more hormone deficiencies) experienced the worst outcome. In this regard, Danzi and colleagues and Napoli and colleagues reviewed in the present issue the role of thyroid hormones, growth hormone, testosterone, and insulin in HF, also in consideration of their potential therapeutic role.
      • Salzano A.
      • Marra A.M.
      • Arcopinto M.
      • et al.
      Combined effects of growth hormone and testosterone replacement treatment in heart failure.
      ESC Heart Fail. 2019; 6: 1216-1221https://doi.org/10.1002/ehf2.12520
      , 
      • Salzano A.
      • D'Assante R.
      • Lander M.
      • et al.
      Hormonal replacement therapy in heart failure: focus on growth hormone and testosterone.
      Heart Fail Clin. 2019; 15: 377-391
      , 
      • Salzano A.
      • Marra A.M.
      • D'Assante R.
      • et al.
      Growth hormone therapy in heart failure.
      Heart Fail Clin. 2018; 14: 501-515
      , 
      • Arcopinto M.
      • Salzano A.
      • Isgaard J.
      • et al.
      Hormone replacement therapy in heart failure.
      Curr Opin Cardiol. 2015; 30: 277-284
      A novel HF pathophysiologic model, the so-called gut hypothesis (ie, the interplay between HF and the gastrointestinal system), has been reviewed by Salzano and colleagues; specifically, the choline/carnitine derived metabolite trimethylamine N-oxide, strictly linked to the Western diet,
      • Cassambai S.
      • Salzano A.
      • Yazaki Y.
      • et al.
      Impact of acute choline loading on circulating trimethylamine N-oxide levels.
      Eur J Prev Cardiol. 2019; 26 (2047487319831372): 1899-1902https://doi.org/10.1177/2047487319831372
      ,
      • Yazaki Y.
      • Aizawa K.
      • Israr M.Z.
      • et al.
      Ethnic differences in association of outcomes with trimethylamine N-oxide in acute heart failure patients.
      ESC Heart Fail. 2020; 7: 2373-2378https://doi.org/10.1002/ehf2.12777
      appears to be a novel risk predictor as well as a promising therapeutic target in HF.
      • Salzano A.
      • Israr M.Z.
      • Yazaki Y.
      • et al.
      Combined use of trimethylamine N-oxide with BNP for risk stratification in heart failure with preserved ejection fraction: findings from the DIAMONDHFpEF study.
      Eur J Prev Cardiol. 2020; 27 (2047487319870355): 2159-2162https://doi.org/10.1177/2047487319870355
      , 
      • Yazaki Y.
      • Salzano A.
      • Nelson C.P.
      • et al.
      Geographical location affects the levels and association of trimethylamine N-oxide with heart failure mortality in BIOSTAT-CHF: a post-hoc analysis.
      Eur J Heart Fail. 2019; 21: 1291-1294https://doi.org/10.1002/ejhf.1550
      , 
      • Israr M.Z.
      • Bernieh D.
      • Salzano A.
      • et al.
      Association of gut-related metabolites with outcome in acute heart failure.
      Am Heart J. 2021; 234: 71-80
      A recently emerged paradigm shift in HF pathophysiology is the interaction between right HF and pulmonary circulation.
      • Marra A.M.
      • Sherman A.E.
      • Salzano A.
      • et al.
      Right side of the heart pulmonary circulation unit involvement in left-sided heart failure: diagnostic, prognostic, and therapeutic implications.
      Chest. 2022; 161: 535-551https://doi.org/10.1016/j.chest.2021.09.023
      ,
      • D'Alto M.
      • Marra A.M.
      • Severino S.
      • et al.
      Right ventricular-arterial uncoupling independently predicts survival in COVID-19 ARDS.
      Crit Care. 2020; 24: 670
      Indeed, disorders such as chronic obstructive pulmonary disease, sleep breathing disorders, and pulmonary hypertension (ie, when right heart-pulmonary circulation unit is impaired) play a central role in HF progression,
      • Streng K.W.
      • Nauta J.F.
      • Hillege H.L.
      • et al.
      Non-cardiac comorbidities in heart failure with reduced, mid-range and preserved ejection fraction.
      Int J Cardiol. 2018; 271: 132-139
      ,
      • Iorio A.
      • Senni M.
      • Barbati G.
      • et al.
      Prevalence and prognostic impact of non-cardiac co-morbidities in heart failure outpatients with preserved and reduced ejection fraction: a community-based study.
      Eur J Heart Fail. 2018; 20: 1257-1266
      ,
      • Marra A.M.
      • Egenlauf B.
      • Ehlken N.
      • et al.
      Change of right heart size and function by long-term therapy with riociguat in patients with pulmonary arterial hypertension and chronic thromboembolic pulmonary hypertension.
      Int J Cardiol. 2015; 195: 19-26
      as reviewed by Pellicori and colleagues, Coniglio and colleagues, and Marra and colleagues. Intriguingly, right ventricular dysfunction is also linked to cardiac cachexia and sarcopenia, critical turning points in the context of HF, as Valentova and colleagues exposed in their review. In addition, the role of the “obesity paradox” in chronic heart failure has been reviewed by Carbone and colleagues. Specifically, a paradoxical decrease in mortality in those with higher body mass index has been observed in HF patients, in the context of the so-called reverse epidemiology.
      • Aimo A.
      • Januzzi J.L.
      • Vergaro G.
      • et al.
      Revisiting the obesity paradox in heart failure: per cent body fat as predictor of biomarkers and outcome.
      Eur J Prev Cardiol. 2019; 26 (2047487319852809): 1751-1759https://doi.org/10.1177/2047487319852809
      Finally, the amount of renal impairment is a keystone in clinical decision making in HF patients.
      • Melgaard L.
      • Overvad T.F.
      • Skjøth F.
      • et al.
      Risk of stroke and bleeding in patients with heart failure and chronic kidney disease: a nationwide cohort study.
      ESC Heart Fail. 2018; 5: 319-326
      ,
      • Mullens W.
      • Damman K.
      • Harjola V.P.
      • et al.
      The use of diuretics in heart failure with congestion—a position statement from the Heart Failure Association of the European Society of Cardiology.
      Eur J Heart Fail. 2019; 21: 137-155
      In this regard, Costanzo described the cardiorenal syndrome, focusing on the importance of accurate quantitative measurement of fluid volume in patients with HF.

      CARDIOVASCULAR COMORBIDITIES

      In the present issue, Di Palo and colleagues discuss arterial hypertension (ie, “blood pressure paradox”). Indeed, whereas in most of cardiovascular disease high blood pressure has an adverse prognostic role
      • Ventura H.O.
      • Lavie C.J.
      Hypertension: management and measurements.
      Curr Opin Cardiol. 2018; 33: 375-376
      ,
      • Stewart M.H.
      • Lavie C.J.
      • Ventura H.O.
      Future pharmacological therapy in hypertension.
      Curr Opin Cardiol. 2018; 33: 408-415
      ; in HF, the optimal target of blood pressure remains a matter of debate. Furthermore, clinicians are challenged by the management of antithrombotic treatment in patients with coexisting HF and atrial fibrillation
      • Carlisle M.A.
      • Fudim M.
      • DeVore A.D.
      • et al.
      Heart failure and atrial fibrillation, like fire and fury.
      JACC Heart Fail. 2019; 7: 447-456
      ; Obeidat and colleagues, reviewing the role of direct oral anticoagulant, highlight their safety and effectiveness also in HF.
      Sex and gender integration still remains an unmet need in research and clinic,
      • Marra A.M.
      • Benjamin N.
      • Eichstaedt C.
      • et al.
      Gender-related differences in pulmonary arterial hypertension targeted drugs administration.
      Pharmacol Res. 2016; 114: 103-109
      , 
      • Salzano A.
      • Demelo-Rodriguez P.
      • Marra A.M.
      • et al.
      A focused review of gender differences in antithrombotic therapy.
      Curr Med Chem. 2017; 24: 2576-2588
      , 
      • Giannoulis M.G.
      • Boroujerdi M.A.
      • Powrie J.
      • et al.
      Gender differences in growth hormone response to exercise before and after rhGH administration and the effect of rhGH on the hormone profile of fit normal adults.
      Clin Endocrinol (Oxf). 2005; 62: 315-322
      and HF is no exception, as Romiti and colleagues describe in this issue.
      Finally, as highlighted by Di Paolo and colleagues, clinicians should take care also of psychological comorbidities of HF, including depression, anxiety, and insomnia, considering their important burden on patients’ quality of life.
      In conclusion, we are confident that the perspectives reported in this issue of Cardiology Clinics will help clinicians and physician to best understand and manage these comorbidities in HF patients.

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        • Aday A.W.
        • Almarzooq Z.I.
        • et al.
        Heart disease and stroke statistics–2022 update: a report from the American Heart Association.
        Circulation. 2022; 145 (CIR0000000000001052): e153-e639https://doi.org/10.1161/CIR.0000000000001052
        View in Article
        • Salzano A.
        • D’Assante R.
        • Stagnaro F.M.
        • et al.
        Heart failure management during COVID-19 outbreak in Italy. Telemedicine experience from a heart failure university tertiary referral centre.
        Eur J Heart Fail. 2020; 22: 1048-1050https://doi.org/10.1002/ejhf.1911
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        • Streng K.W.
        • Nauta J.F.
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        Non-cardiac comorbidities in heart failure with reduced, mid-range and preserved ejection fraction.
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        • Claggett B.
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        Contribution of cardiac and extra-cardiac disease burden to risk of cardiovascular outcomes varies by ejection fraction in heart failure.
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        • Veenis J.F.
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        Diabetes and treatment of chronic heart failure in a large real-world heart failure population.
        ESC Heart Fail. 2022; 9: 353-362
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        • Senni M.
        • Barbati G.
        • et al.
        Prevalence and prognostic impact of non-cardiac co-morbidities in heart failure outpatients with preserved and reduced ejection fraction: a community-based study.
        Eur J Heart Fail. 2018; 20: 1257-1266
        View in Article
        • Arcopinto M.
        • Salzano A.
        • Giallauria F.
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        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.
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        Multiple hormone deficiencies in chronic heart failure.
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        Multiple hormone deficiency syndrome in heart failure with preserved ejection fraction.
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        • Cittadini A.
        • Salzano A.
        • Iacoviello M.
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        Multiple hormonal and metabolic deficiency syndrome predicts outcome in heart failure: the T.O.S.CA. Registry.
        Eur J Prev Cardiol. 2021; 28: 1691-1700
        View in Article
        • Bossone E.
        • Arcopinto M.
        • Iacoviello M.
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        Multiple hormonal and metabolic deficiency syndrome in chronic heart failure: rationale, design, and demographic characteristics of the T.O.S.CA. Registry.
        Intern Emerg Med. 2018; 13: 661-671
        View in Article
        • Salzano A.
        • Marra A.M.
        • Arcopinto M.
        • et al.
        Combined effects of growth hormone and testosterone replacement treatment in heart failure.
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        View in Article
        • Salzano A.
        • D'Assante R.
        • Lander M.
        • et al.
        Hormonal replacement therapy in heart failure: focus on growth hormone and testosterone.
        Heart Fail Clin. 2019; 15: 377-391
        View in Article
        • Salzano A.
        • Marra A.M.
        • D'Assante R.
        • et al.
        Growth hormone therapy in heart failure.
        Heart Fail Clin. 2018; 14: 501-515
        View in Article
        • Arcopinto M.
        • Salzano A.
        • Isgaard J.
        • et al.
        Hormone replacement therapy in heart failure.
        Curr Opin Cardiol. 2015; 30: 277-284
        View in Article
        • Cassambai S.
        • Salzano A.
        • Yazaki Y.
        • et al.
        Impact of acute choline loading on circulating trimethylamine N-oxide levels.
        Eur J Prev Cardiol. 2019; 26 (2047487319831372): 1899-1902https://doi.org/10.1177/2047487319831372
        View in Article
        • Yazaki Y.
        • Aizawa K.
        • Israr M.Z.
        • et al.
        Ethnic differences in association of outcomes with trimethylamine N-oxide in acute heart failure patients.
        ESC Heart Fail. 2020; 7: 2373-2378https://doi.org/10.1002/ehf2.12777
        View in Article
        • Salzano A.
        • Israr M.Z.
        • Yazaki Y.
        • et al.
        Combined use of trimethylamine N-oxide with BNP for risk stratification in heart failure with preserved ejection fraction: findings from the DIAMONDHFpEF study.
        Eur J Prev Cardiol. 2020; 27 (2047487319870355): 2159-2162https://doi.org/10.1177/2047487319870355
        View in Article
        • Yazaki Y.
        • Salzano A.
        • Nelson C.P.
        • et al.
        Geographical location affects the levels and association of trimethylamine N-oxide with heart failure mortality in BIOSTAT-CHF: a post-hoc analysis.
        Eur J Heart Fail. 2019; 21: 1291-1294https://doi.org/10.1002/ejhf.1550
        View in Article
        • Israr M.Z.
        • Bernieh D.
        • Salzano A.
        • et al.
        Association of gut-related metabolites with outcome in acute heart failure.
        Am Heart J. 2021; 234: 71-80
        View in Article
        • Marra A.M.
        • Sherman A.E.
        • Salzano A.
        • et al.
        Right side of the heart pulmonary circulation unit involvement in left-sided heart failure: diagnostic, prognostic, and therapeutic implications.
        Chest. 2022; 161: 535-551https://doi.org/10.1016/j.chest.2021.09.023
        View in Article
        • D'Alto M.
        • Marra A.M.
        • Severino S.
        • et al.
        Right ventricular-arterial uncoupling independently predicts survival in COVID-19 ARDS.
        Crit Care. 2020; 24: 670
        View in Article
        • Marra A.M.
        • Egenlauf B.
        • Ehlken N.
        • et al.
        Change of right heart size and function by long-term therapy with riociguat in patients with pulmonary arterial hypertension and chronic thromboembolic pulmonary hypertension.
        Int J Cardiol. 2015; 195: 19-26
        View in Article
        • Aimo A.
        • Januzzi J.L.
        • Vergaro G.
        • et al.
        Revisiting the obesity paradox in heart failure: per cent body fat as predictor of biomarkers and outcome.
        Eur J Prev Cardiol. 2019; 26 (2047487319852809): 1751-1759https://doi.org/10.1177/2047487319852809
        View in Article
        • Melgaard L.
        • Overvad T.F.
        • Skjøth F.
        • et al.
        Risk of stroke and bleeding in patients with heart failure and chronic kidney disease: a nationwide cohort study.
        ESC Heart Fail. 2018; 5: 319-326
        View in Article
        • Mullens W.
        • Damman K.
        • Harjola V.P.
        • et al.
        The use of diuretics in heart failure with congestion—a position statement from the Heart Failure Association of the European Society of Cardiology.
        Eur J Heart Fail. 2019; 21: 137-155
        View in Article
        • Ventura H.O.
        • Lavie C.J.
        Hypertension: management and measurements.
        Curr Opin Cardiol. 2018; 33: 375-376
        View in Article
        • Stewart M.H.
        • Lavie C.J.
        • Ventura H.O.
        Future pharmacological therapy in hypertension.
        Curr Opin Cardiol. 2018; 33: 408-415
        View in Article
        • Carlisle M.A.
        • Fudim M.
        • DeVore A.D.
        • et al.
        Heart failure and atrial fibrillation, like fire and fury.
        JACC Heart Fail. 2019; 7: 447-456
        View in Article
        • Marra A.M.
        • Benjamin N.
        • Eichstaedt C.
        • et al.
        Gender-related differences in pulmonary arterial hypertension targeted drugs administration.
        Pharmacol Res. 2016; 114: 103-109
        View in Article
        • Salzano A.
        • Demelo-Rodriguez P.
        • Marra A.M.
        • et al.
        A focused review of gender differences in antithrombotic therapy.
        Curr Med Chem. 2017; 24: 2576-2588
        View in Article
        • Giannoulis M.G.
        • Boroujerdi M.A.
        • Powrie J.
        • et al.
        Gender differences in growth hormone response to exercise before and after rhGH administration and the effect of rhGH on the hormone profile of fit normal adults.
        Clin Endocrinol (Oxf). 2005; 62: 315-322
        View in Article

      Article Info

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      DOI: https://doi.org/10.1016/j.ccl.2022.02.001

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      © 2022 Published by Elsevier Inc.

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