New Drugs for the Hypertensive Failing Heart

  • Victor VoicuEmail author
  • Maria Dorobantu
Part of the Updates in Hypertension and Cardiovascular Protection book series (UHCP)


A few important and relevant aspects revealed during a series of basic and clinical research studies have changed the view on hypertension, its treatment, and the prophylaxis of its complications, in particular heart failure.

It has been observed that heart failure prevalence is on the rise, with high mortality rates, including in those undergoing complex therapy for hypertension. Moreover, recent clinical trials have reached surprising conclusions, lowering the threshold for blood pressure readings that have been a reference point to guide hypertension treatment, thus far.

Furthermore, it has been noted that despite the various possibilities to counteract the renin-angiotensin-aldosterone system effects through angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin receptor blockers (ARBs), these agents do not have the expected efficacy on aldosterone secretion. On the contrary, the endogenous secretion of aldosterone increases under treatment with angiotensin-converting enzyme inhibitors or angiotensin receptor blockers, giving rise to new challenges.

The relatively new focus on efficiently counteracting the cardiovascular effects of aldosterone is based on the fundamental discoveries from the past decades.

Regardless of aldosterone serum levels (normal or high), aldosterone antagonists are essential agents in the treatment of hypertension, irrespective of the association with heart failure (HF). Moreover, the aldosterone escape phenomenon, meaning the increase in aldosterone secretion sometime after initiating treatment with ACEIs or ARBs, has been also observed after treatment with mineralocorticoid receptor antagonists (MRAs). Consequently, a need to introduce selective inhibitors of aldosterone synthase in the treatment of hypertension was obviated. These agents would prevent both cortisol synthesis inhibition and the increase in the synthesis of particular enzymes that control cortisol secretion. Currently, there is compelling evidence such a compound can be produced and validated in clinical practice. Thus, the 2016 ESC guidelines for diagnosis and treatment of HF mentioned the role of the angiotensin receptor-neprilysin inhibitor (ARNI) where ACEIs/ARBs are not efficient or not well tolerated.


Hypertension Heart failure New mechanisms New drugs 


  1. 1.
    Campbell NR, Khalsa T, Lackland DT, Niebylski ML, Nilsson PM, Redburn KA, Orias M, Zhang X-H, Burrell L, Horiuchi M, Poulter NR, Prabhakaran D, Ramirez AJ, Schiffrin EL, Touyz RM, Wang J-G, Weber MA. High blood pressure 2016: why prevention and control are urgent and important. The World Hypertension League, International Society of Hypertension, World Stroke Organization, International Diabetes Foundation, International Council of Cardiovascular Prevention and Rehabilitation, International Society of Nephrology. J Clin Hypertens (Greenwich). 2016;18(8):714–7.Google Scholar
  2. 2.
    Worley SL. Experts provide a glimpse of the new post-SPRINT era of hypertension. PT. 2017;42(2):118–23.Google Scholar
  3. 3.
    Braunwald E. Heart failure. JACC Heart Fail. 2013;1(1):1–20.PubMedGoogle Scholar
  4. 4.
    Rahimi K, Emdin CA, MacMahon S. The epidemiology of blood pressure and its worldwide management. Circ Res. 2015;116(6):925–36.PubMedGoogle Scholar
  5. 5.
    Zanchetti A, Thomopoulos C, Parati G. Randomized controlled trials of blood pressure lowering in hypertension: a critical reappraisal. Circ Res. 2015;116(6):1058–73.PubMedGoogle Scholar
  6. 6.
    Freis ED. Historical development of antihypertensive treatment. In: Laragh JH, Brenner BM, editors. Hypertension: pathophysiology, diagnosis and management. 2nd ed. New York: Raven Press, Ltd.; 1996. p. 2741–51.Google Scholar
  7. 7.
    Anand IS, Claggett B, Liu J, Shah AM, Rector TS, Shah SJ, Desai AS, O’Meara E, Fleg JL, Pfeffer MA, Pitt B, Solomon SD. Interaction between spironolactone and natriuretic peptides in patients with heart failure and preserved ejection fraction: from the TOPCAT trial. JACC Heart Fail. 2017;5(4):241–52.PubMedGoogle Scholar
  8. 8.
    Mancia G, De Backer G, Dominiczak A, Cifkova R, Fagard R, Germano G, Grassi G, Heagerty AM, Kjeldsen SE, Laurent S, Narkiewicz K, Ruilope L, Rynkiewicz A, Schmieder RE, Boudier HAJS, Zanchetti A, Vahanian A, Camm J, De Caterina R, Dean V, Dickstein K, Filippatos G, Funck-Brentano C, Hellemans I, Kristensen SD, McGregor K, Sechtem U, Silber S, Tendera M, Widimsky P, Zamorano JL, Erdine S, Kiowski W, Agabiti-Rosei E, Ambrosioni E, Lindholm LH, Viigimaa M, Adamopoulos S, Agabiti-Rosei E, Ambrosioni E, Bertomeu V, Clement D, Erdine S, Farsang C, Gaita D, Lip G, Mallion J-M, Manolis AJ, Nilsson PM, O’Brien E, Ponikowski P, Redon J, Ruschitzka F, Tamargo J, van Zwieten P, Waeber B, Williams B. 2007 Guidelines for the Management of Arterial Hypertension: The Task Force for the Management of Arterial Hypertension of the European Society of Hypertension (ESH) and of the European Society of Cardiology (ESC). J Hypertens. 2007;25(6):1105–87.PubMedGoogle Scholar
  9. 9.
    Mancia G, Fagard R, Narkiewicz K, Redon J, Zanchetti A, Bohm M, Christiaens T, Cifkova R, De Backer G, Dominiczak A, Galderisi M, Grobbee DE, Jaarsma T, Kirchhof P, Kjeldsen SE, Laurent S, Manolis AJ, Nilsson PM, Ruilope LM, Schmieder RE, Sirnes PA, Sleight P, Viigimaa M, Waeber B, Zannad F. 2013 ESH/ESC Guidelines for the management of arterial hypertension: the Task Force for the management of arterial hypertension of the European Society of Hypertension (ESH) and of the European Society of Cardiology (ESC). J Hypertens. 2013;31(7):1281–357.PubMedGoogle Scholar
  10. 10.
    Schulz M, Krueger K, Schuessel K, Friedland K, Laufs U, Mueller WE, Ude M. Medication adherence and persistence according to different antihypertensive drug classes: a retrospective cohort study of 255,500 patients. Int J Cardiol. 2016;220:668–76.PubMedGoogle Scholar
  11. 11.
    Laurent S, Steckelings UM. Chapter 29—New drugs under development for cardiovascular prevention BT—early vascular aging (EVA). Boston: Academic Press; 2015. p. 323–34.Google Scholar
  12. 12.
    Braunwald E. The path to an angiotensin receptor antagonist-neprilysin inhibitor in the treatment of heart failure. J Am Coll Cardiol. 2015;65(10):1029–41.PubMedGoogle Scholar
  13. 13.
    Santese G, Stefanio C, Belletti G, Boiani M, Schipani A, Trane R, Zacà F. The role of aldosterone receptor blocker therapy in hypertension and heart failure. IJC Metab Endocr. 2015;8(Suppl C):34–7.Google Scholar
  14. 14.
    Wal P, Wal A, Rai AK, Dixit A. Aliskiren: an orally active renin inhibitor. J Pharm Bioallied Sci. 2011;3(2):189–93.PubMedPubMedCentralGoogle Scholar
  15. 15.
    Vaidyanathan S, Camenisch G, Schuetz H, Reynolds C, Yeh C-M, Bizot M-N, Dieterich HA, Howard D, Dole WP. Pharmacokinetics of the oral direct renin inhibitor aliskiren in combination with digoxin, atorvastatin, and ketoconazole in healthy subjects: the role of P-glycoprotein in the disposition of aliskiren. J Clin Pharmacol. 2008;48(11):1323–38.PubMedGoogle Scholar
  16. 16.
    Funder JW. Reconsidering the roles of the mineralocorticoid receptor. Hypertension. 2009;53(2):286–90.PubMedGoogle Scholar
  17. 17.
    Jaisser F, Farman N. Emerging roles of the mineralocorticoid receptor in pathology: toward new paradigms in clinical pharmacology. Pharmacol Rev. 2016;68(1):49–75.PubMedGoogle Scholar
  18. 18.
    Deinum J, Riksen NP, Lenders JWM. Pharmacological treatment of aldosterone excess. Pharmacol Ther. 2015;154:120–33.PubMedGoogle Scholar
  19. 19.
    Pitt B, Pfeffer MA, Assmann SF, Boineau R, Anand IS, Claggett B, Clausell N, Desai AS, Diaz R, Fleg JL, Gordeev I, Harty B, Heitner JF, Kenwood CT, Lewis EF, O’Meara E, Probstfield JL, Shaburishvili T, Shah SJ, Solomon SD, Sweitzer NK, Yang S, McKinlay SM. Spironolactone for heart failure with preserved ejection fraction. N Engl J Med. 2014;370(15):1383–92.PubMedGoogle Scholar
  20. 20.
    Zannad F, Gattis Stough W, Rossignol P, Bauersachs J, McMurray JJV, Swedberg K, Struthers AD, Voors AA, Ruilope LM, Bakris GL, O’Connor CM, Gheorghiade M, Mentz RJ, Cohen-Solal A, Maggioni AP, Beygui F, Filippatos GS, Massy ZA, Pathak A, Pina IL, Sabbah HN, Sica DA, Tavazzi L, Pitt B. Mineralocorticoid receptor antagonists for heart failure with reduced ejection fraction: integrating evidence into clinical practice. Eur Heart J. 2012;33(22):2782–95.PubMedGoogle Scholar
  21. 21.
    Funder JW. Mineralocorticoid receptor antagonists: emerging roles in cardiovascular medicine. Integr Blood Press Control. 2013;6:129–38.PubMedPubMedCentralGoogle Scholar
  22. 22.
    Struthers AD. The clinical implications of aldosterone escape in congestive heart failure. Eur J Heart Fail. 2004;6(5):539–45.PubMedGoogle Scholar
  23. 23.
    Struthers AD, Unger T. Physiology of aldosterone and pharmacology of aldosterone blockers. Eur Heart J Suppl. 2011;13(Suppl_B):B27–30.Google Scholar
  24. 24.
    Pitt B, Remme W, Zannad F, Neaton J, Martinez F, Roniker B, Bittman R, Hurley S, Kleiman J, Gatlin M. Eplerenone, a selective aldosterone blocker, in patients with left ventricular dysfunction after myocardial infarction. N Engl J Med. 2003;348(14):1309–21.PubMedGoogle Scholar
  25. 25.
    Ruilope LM, Tamargo J. Renin-angiotensin system blockade: Finerenone. Nephrol Ther. 2017;13(Suppl 1):S47–53.PubMedGoogle Scholar
  26. 26.
    Schrier RW. Aldosterone ‘escape’ vs ‘breakthrough’. Nat Rev Nephrol. 2010;6(2):61.PubMedGoogle Scholar
  27. 27.
    Azizi M, Amar L, Menard J. Aldosterone synthase inhibition in humans. Nephrol Dial Transplant. 2013;28(1):36–43.PubMedGoogle Scholar
  28. 28.
    Hargovan M, Ferro A. Aldosterone synthase inhibitors in hypertension: current status and future possibilities. JRSM Cardiovasc Dis. 2014;3:2048004014522440.PubMedPubMedCentralGoogle Scholar
  29. 29.
    Oparil S, Schmieder RE. New approaches in the treatment of hypertension. Circ Res. 2015;116(6):1074–95.PubMedGoogle Scholar
  30. 30.
    Bogman K, Schwab D, Delporte M-L, Palermo G, Amrein K, Mohr S, De Vera Mudry MC, Brown MJ, Ferber P. Preclinical and early clinical profile of a highly selective and potent Oral inhibitor of aldosterone synthase (CYP11B2). Hypertension. 2017;69(1):189–96.PubMedGoogle Scholar
  31. 31.
    Volpe M, Carnovali M, Mastromarino V. The natriuretic peptides system in the pathophysiology of heart failure: from molecular basis to treatment. Clin Sci (Lond). 2016;130(2):57–77.Google Scholar
  32. 32.
    Burnett H, Earley A, Voors AA, Senni M, McMurray JJV, Deschaseaux C, Cope S. Thirty years of evidence on the efficacy of drug treatments for chronic heart failure with reduced ejection fraction: a network meta-analysis. Circ Heart Fail. 2017;10(1)Google Scholar
  33. 33.
    Iborra-Egea O, Gálvez-Montón C, Roura S, Perea-Gil I, Prat-Vidal C, Soler-Botija C, Bayes-Genis A. Mechanisms of action of sacubitril/valsartan on cardiac remodeling: a systems biology approach. NPJ Syst Biol Appl. 2017;3:12.PubMedPubMedCentralGoogle Scholar
  34. 34.
    Laurent S, Schlaich M, Esler M. New drugs, procedures, and devices for hypertension. Lancet. 2012;380(9841):591–600.PubMedGoogle Scholar
  35. 35.
    Corti R, Burnett JCJ, Rouleau JL, Ruschitzka F, Luscher TF. Vasopeptidase inhibitors: a new therapeutic concept in cardiovascular disease? Circulation. 2001;104(15):1856–62.PubMedGoogle Scholar
  36. 36.
    Dive V, Chang C-F, Yiotakis A, Sturrock ED. Inhibition of zinc metallopeptidases in cardiovascular disease—from unity to trinity, or duality? Curr Pharm Des. 2009;15(31):3606–21.PubMedGoogle Scholar
  37. 37.
    Daull P, Jeng AY, Battistini B. Towards triple vasopeptidase inhibitors for the treatment of cardiovascular diseases. J Cardiovasc Pharmacol. 2007;50(3):247–56.PubMedGoogle Scholar
  38. 38.
    Pellicori P, Urbinati A, Shah P, MacNamara A, Kazmi S, Dierckx R, Zhang J, Cleland JGF, Clark AL. What proportion of patients with chronic heart failure are eligible for sacubitril-valsartan? Eur J Heart Fail. 2017;19(6):S47–53.Google Scholar
  39. 39.
    McMurray JJV, Packer M, Desai AS, Gong J, Lefkowitz MP, Rizkala AR, Rouleau JL, Shi VC, Solomon SD, Swedberg K, Zile MR. Angiotensin–neprilysin inhibition versus enalapril in heart failure. N Engl J Med. 2014;371(11):993–1004.PubMedGoogle Scholar
  40. 40.
    Voicu V. Antihypertensive drugs. In: Pharmacology. Craiova: The Medical Publishing Company; 2008. p. 232–47.Google Scholar

Copyright information

© Springer Nature Switzerland AG 2019

Authors and Affiliations

  1. 1.Faculty of Medicine, Department of Pharmacology, Toxicology and Clinical PsychopharmacologyUniversity of Medicine and Pharmacy “Carol Davila”BucharestRomania
  2. 2.Medical Sciences SectionRomanian AcademyBucharestRomania
  3. 3.Clinical Emergency Hospital of BucharestBucharestRomania
  4. 4.Cardiology Department‘Carol Davila’ University of Medicine and Pharmacy in BucharestBucharestRomania

Personalised recommendations