Advertisement

Emerging Comorbidities in Heart Failure

      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.
      ; 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.
      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.
      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.
      ,
      • 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.
      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.
      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.
      • Arcopinto M.
      • Salzano A.
      • Bossone E.
      • et al.
      Multiple hormone deficiencies in chronic heart failure.
      • Salzano A.
      • Marra A.M.
      • Ferrara F.
      • et al.
      Multiple hormone deficiency syndrome in heart failure with preserved ejection fraction.
      • Marra A.M.
      • Arcopinto M.
      • Bobbio E.
      • et al.
      An unusual case of dilated cardiomyopathy associated with partial hypopituitarism.
      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.
      ,
      • 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.
      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.
      • Salzano A.
      • D'Assante R.
      • Lander M.
      • et al.
      Hormonal replacement therapy in heart failure: focus on growth hormone and testosterone.
      • Salzano A.
      • Marra A.M.
      • D'Assante R.
      • et al.
      Growth hormone therapy in heart failure.
      • Arcopinto M.
      • Salzano A.
      • Isgaard J.
      • et al.
      Hormone replacement therapy in heart failure.
      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.
      ,
      • Yazaki Y.
      • Aizawa K.
      • Israr M.Z.
      • et al.
      Ethnic differences in association of outcomes with trimethylamine N-oxide in acute heart failure patients.
      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.
      • 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.
      • Israr M.Z.
      • Bernieh D.
      • Salzano A.
      • et al.
      Association of gut-related metabolites with outcome in acute heart failure.
      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.
      ,
      • D'Alto M.
      • Marra A.M.
      • Severino S.
      • et al.
      Right ventricular-arterial uncoupling independently predicts survival in COVID-19 ARDS.
      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.
      ,
      • 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.
      ,
      • 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.
      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.
      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.
      ,
      • 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.
      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.
      ,
      • Stewart M.H.
      • Lavie C.J.
      • Ventura H.O.
      Future pharmacological therapy in hypertension.
      ; 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.
      ; 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.
      • Salzano A.
      • Demelo-Rodriguez P.
      • Marra A.M.
      • et al.
      A focused review of gender differences in antithrombotic therapy.
      • 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.
      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.

      REFERENCES

        • 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
        • 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
        • 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
        • 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
        • 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
        • 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
        • 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
        • 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
        • 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
        • 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
        • 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
        • 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
        • 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
        • 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
        • 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
        • 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
        • 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