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ARNIs: balancing “the good and the bad” of neuroendocrine response to HF

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Abstract

Background

A new class of drugs—angiotensin receptor, neprylisin inhibitors, ARNI—has shown to be prognostic superior in HFrEF to the sole inhibition of the renin–angiotensin axes with enalapril. The ultimate mechanism of action of ARNIs is unknown.

Aim

We have considered that ARNI exerts a positive modulation of the neuroendocrine balance, with enhancement of the physiological diuresis and dilatation due to neprylisin inhibition by sacubitril. This represents a shift in HF medical therapy always directed to counteract (with inhibitors of the renin–angiotensin system, beta blockers or inhibitors of aldosterone) the so-called “bad” neuroendocrine response. Development of ARNI, on the contrary, has led to consider the neuroendocrine response to HFrEF from a different angle, which is to say that the activation is not always deleterious, but it could also be beneficial. This concept is highlighted by the enhancement of the activity of atrial natriuretic peptide, induced by sacubitril/valsartan in the PARADIGM trial, and found as proof from early studies on untreated patients with constrictive pericarditis. The possibility that sacubitril inhibition of neprylisin acts by enhancing substance P and gene-related calcitonin peptide is also considered, as well as the negative effect of neprylisin inhibition.

Conclusions

The beneficial effects of ARNI are related, in part at least, to a positive modulation of the neuroendocrine response to the disease, resulting in an increase of physiological diuresis and dilatation.

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Acknowledgements

This manuscript has been written in collaboration with the Italian Portuguese Action on Heart Failure: Aurora Andrade (Centro Hospitalar do Tâmega e Sousa, Penafiel, Portugal), Rui Baptista (Serviço de Cardiologia, Cardiologia A, Centro Hospitalar e Universitário de Coimbra, Coimbra, Portugal; Faculty of Medicine, University of Coimbra, Coimbra, Portugal), Paulo Bettencourt (Faculdade de Medicina da Universidade do Porto, Unidade I&D Cardiovascular do Porto and Serviço de Medicina Interna, Hospital CUF Porto, Porto, Portugal), Dulce Brito (Serviço de Cardiologia, Hospital de Santa Maria, Centro Hospitalar de Lisboa Norte, CCUL, Faculdade de Medicina da Universidade de Lisboa, Lisboa, Portugal), Ana Camacho (Centro Hospitalar de Algarve—Faro), Paolo Camici (Vita Salute University and San Raffaele Hospital—Milan—Italy), Fatima Franco (Hospital Universidade de Coimbra, Centro Hospitalar e Universitário de Coimbra, Serviço de Cardiologia, Coimbra, Portugal), Fernando Frioes (Intermediate Care Unit, Department of Internal Medicine, Centro Hospitalar Universitário de São João, Porto, Portugal), Sara Goncalves (Serviço de Cardiologia, Centro Hospitalar de Setúbal, Setúbal, Portugal), Donato Mele (University Cadiological Centre, University Hospital of Ferrara), Joao Morais (Cardiology Department, Centro Hospitalar de Leiria, Portugal), Brenda Moura (Cardiology Department, Hospital de São João, Porto, Portugal), Maria Irene Marques Moreira (Department of Internal Medicine, Centro Hospitalar do Porto, Instituto de Ciências Biomédicas de Abel Salazar, University of Porto, Portugal (I.M.)), Marisa Peres (Hospital Santarém, Santarém, Portugal), Pasquale Perrone Filardi (Department of Advanced Biomedical Science, University Federico II of Naples, Naples, Italy), Joana Pimenta (Department of Internal Medicine, Centro Hospitalar São João, Porto, Portugal; Department of Medicine, University of Porto Medical School, Porto, Portugal), Pedro Morais Sarmento (Internal Medicine Department, Hospital da Luz, Lisbon, Portugal), Petar Seferovic (Faculty of Medicine, University of Belgrade, and Cardiology Department, Clinical Centre Serbia, Belgrade, Serbia). This work was supported by a grant from Fondazione Anna Maria Sechi per il Cuore (FASC), Italy. The funders had no role in the preparation and decision to publish or the preparation of the manuscript.

Author information

Authors and Affiliations

  1. University Cardiologic Centre, University Hospital of Ferrara, Ferrara, Italy

    Roberto Ferrari & A. Fucili

  2. Maria Cecilia Hospital, Cotignola, Italy

    Roberto Ferrari

  3. CINTESIS-Center for Health Technology and Services Research, Porto, Portugal

    J. Cardoso

  4. Department of Cardiology, Faculty of Medicine, University of Porto, Porto, Portugal

    J. Cardoso

  5. São João Medical Centre, Porto, Portugal

    J. Cardoso

  6. Heart Failure Clinic, Hospital São Francisco Xavier, CHLO, Lisbon, Portugal

    M. C. Fonseca

  7. NOVA Medical School, Faculdade de Ciências Médicas, Universidade Nova de Lisboa, Lisbon, Portugal

    M. C. Fonseca

  8. Advanced Heart Failure Unit, Hospital Santa Cruz, Centro Hospitalar Lisboa Ocidental, Lisbon, Portugal

    C. Aguiar

  9. CHTMAD, Hospital S. Pedro, Vila Real, Portugal

    J. I. Moreira

  10. Cardiology, DIMES, Alma Mater-University of Bologna, Bologna, Italy

    C. Rapezzi

  11. Azienda Ospedaliero-Universitaria di Ferrara, Ospedale di Cona, Via Aldo Moro 8, Cona, 44124, Ferrara, Italy

    Roberto Ferrari

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  1. Roberto Ferrari
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  2. J. Cardoso
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  3. M. C. Fonseca
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  4. C. Aguiar
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  5. J. I. Moreira
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  6. A. Fucili
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Consortia

the “Italian-Portuguese Action on Heart Failure” Group

  • Aurora Andrade
  • , Rui Baptista
  • , Paulo Bettencourt
  • , Dulce Brito
  • , Ana Camacho
  • , Paolo Camici
  • , Fatima Franco
  • , Fernando Frioes
  • , Sara Goncalves
  • , Joao Morais
  • , Brenda Moura
  • , Maria Irene Marques Moreira
  • , Marisa Peres
  • , Pasquale Perrone Filardi
  • , Joana Pimenta
  • , Pedro Morais Sarmento
  •  & Petar Seferovic

Corresponding author

Correspondence to Roberto Ferrari.

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RF has received honoraria for steering committee membership and consulting from Novartis and Servier; and speaker fees from Cipla, Lupin, Merck Serono, and Servier International. JC has consulted and received speaker fees, or investigational grants for Abbott, AstraZeneca Pharmaceuticals, Bial, Boehringer Ingelheim, Menarini, Merck Serono, Merck Sharp & Dohme, Novartis, Orion, Pfizer, Sanofi and Vifor M.C.F. has received fees from Novartis, Servier,Orion, Roche, Bayer and Vifor (companies that develop and market tests and/or treatments in the area of HF) for HF consulting, sitting on clinical study steering committees and giving lectures at congresses and other scientific sessions. CA has received lecture fees and honoraria for consultancy from Novartis and Servier. JIM has no conflict of interest. DM has no conflict of interest. CR has received honoraria (as a speaker and board member) from Novartis.

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Ferrari, R., Cardoso, J., Fonseca, M.C. et al. ARNIs: balancing “the good and the bad” of neuroendocrine response to HF. Clin Res Cardiol 109, 599–610 (2020). https://doi.org/10.1007/s00392-019-01547-2

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  • DOI: https://doi.org/10.1007/s00392-019-01547-2

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