Canadian Journal of Cardiology

A Novel Approach to Drug Development in Heart Failure: Towards Personalized Medicine

Published:December 19, 2013DOI:


      Evidence-based treatment has succeeded in improving clinical outcomes in heart failure. Nevertheless, morbidity, mortality, and the economic burden associated with the syndrome remain unsatisfactorily high. Most landmark heart failure studies included broad study populations, and thus current recommendations dictate standardized, universal therapy. While most patients included in recent trials benefit from this background treatment, exceeding this already significant gain has proven to be a challenge. The early identification of responders and nonresponders to treatment could result in improved therapeutic effectiveness, while reduction of unnecessary exposure may limit harmful and unpleasant side effects. In this review, we examine the potential value of currently available information on differential responses to heart failure therapy—a first step toward personalized medicine in the management of heart failure.


      Le traitement fondé sur des données probantes est parvenu à améliorer les résultats cliniques de l’insuffisance cardiaque. Néanmoins, la morbidité, la mortalité et le fardeau économique associés au syndrome demeurent trop élevés. Les études les plus marquantes sur l’insuffisance cardiaque incluaient de vastes populations, donc les recommandations actuelles dictent un traitement universel standardisé. Bien que la plupart des patients inclus dans les récents essais bénéficient de ce traitement de fond, le dépassement de ce gain déjà significatif s’est révélé difficile. L’identification précoce des patients qui répondent au traitement et de ceux qui n’y répondent pas permettrait d’améliorer l’efficacité thérapeutique, alors que la diminution de l’exposition inutile pourrait limiter les effets secondaires néfastes et désagréables. Dans cette revue, nous examinons la valeur potentielle des informations actuellement disponibles sur les effets différentiels du traitement de l’insuffisance cardiaque, une première étape vers la médecine personnalisée utile à la prise en charge de l’insuffisance cardiaque.
      To read this article in full you will need to make a payment

      Purchase one-time access:

      Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online access
      One-time access price info
      • For academic or personal research use, select 'Academic and Personal'
      • For corporate R&D use, select 'Corporate R&D Professionals'


      Subscribe to Canadian Journal of Cardiology
      Already a print subscriber? Claim online access
      Already an online subscriber? Sign in
      Institutional Access: Sign in to ScienceDirect


        • McMurray J.J.
        • Adamopoulos S.
        • Anker S.D.
        • et al.
        ESC guidelines for the diagnosis and treatment of acute and chronic heart failure 2012: the Task Force for the Diagnosis and Treatment of Acute and Chronic Heart Failure 2012 of the European Society of Cardiology. Developed in collaboration with the Heart Failure Association (HFA) of the ESC.
        Eur J Heart Fail. 2012; 14: 803-869
        • Wong C.Y.
        • Chaudhry S.I.
        • Desai M.M.
        • et al.
        Trends in comorbidity, disability, and polypharmacy in heart failure.
        Am J Med. 2011; 124: 136-143
        • Zhou H.H.
        • Koshakji R.P.
        • Silberstein D.J.
        • et al.
        Altered sensitivity to and clearance of propranolol in men of Chinese descent as compared with American whites.
        N Engl J Med. 1989; 320: 565-570
        • Exner D.V.
        • Dries D.L.
        • Domanski M.J.
        • et al.
        Lesser response to angiotensin-converting-enzyme inhibitor therapy in black as compared with white patients with left ventricular dysfunction.
        N Engl J Med. 2001; 344: 1351-1357
        • Carson P.
        • Ziesche S.
        • Johnson G.
        • et al.
        Racial differences in response to therapy for heart failure: analysis of the vasodilator-heart failure trials. Vasodilator-Heart Failure Trial Study Group.
        J Card Fail. 1999; 5: 178-187
        • Rathore S.S.
        • Wang Y.
        • Krumholz H.M.
        Sex-based differences in the effect of digoxin for the treatment of heart failure.
        N Engl J Med. 2002; 347: 1403-1411
        • Felker G.M.
        • Benza R.L.
        • Chandler A.B.
        • et al.
        Heart failure etiology and response to milrinone in decompensated heart failure: results from the OPTIME-CHF study.
        J Am Coll Cardiol. 2003; 41: 997-1003
        • Cleland J.G.
        • Tendera M.
        • Adamus J.
        • et al.
        The perindopril in elderly people with chronic heart failure (PEP-CHF) study.
        Eur Heart J. 2006; 27: 2338-2345
        • Massie B.M.
        • Carson P.E.
        • McMurray J.J.
        • et al.
        Irbesartan in patients with heart failure and preserved ejection fraction.
        N Engl J Med. 2008; 359: 2456-2467
        • Yusuf S.
        • Pfeffer M.A.
        • Swedberg K.
        • et al.
        Effects of candesartan in patients with chronic heart failure and preserved left-ventricular ejection fraction: the CHARM-Preserved Trial.
        Lancet. 2003; 362: 777-781
        • Nieminen M.S.
        • Harjola V.P.
        • Hochadel M.
        • et al.
        Gender related differences in patients presenting with acute heart failure. Results from EuroHeart Failure Survey II.
        Eur J Heart Fail. 2008; 10: 140-148
        • Pina I.L.
        • Kokkinos P.
        • Kao A.
        • et al.
        Baseline differences in the HF-ACTION trial by sex.
        Am Heart J. 2009; 158: S16-S23
        • Meyer S.
        • van der Meer P.
        • van Deursen V.M.
        • et al.
        Neurohormonal and clinical sex differences in heart failure.
        Eur Heart J. 2013; 34: 2538-2547
        • Ghali J.K.
        • Krause-Steinrauf H.J.
        • Adams K.F.
        • et al.
        Gender differences in advanced heart failure: insights from the BEST study.
        J Am Coll Cardiol. 2003; 42: 2128-2134
        • Meyer S.
        • van der Meer P.
        • Massie B.M.
        • et al.
        Sex-specific acute heart failure phenotypes and outcomes from PROTECT.
        Eur J Heart Fail. 2013; 15: 1374-1381
        • Murphy E.
        Estrogen signaling and cardiovascular disease.
        Circ Res. 2011; 109: 687-696
        • Follath F.
        • Cleland J.G.
        • Klein W.
        • et al.
        Etiology and response to drug treatment in heart failure.
        J Am Coll Cardiol. 1998; 32: 1167-1172
        • Sliwa K.
        • Blauwet L.
        • Tibazarwa K.
        • et al.
        Evaluation of bromocriptine in the treatment of acute severe peripartum cardiomyopathy: a proof-of-concept pilot study.
        Circulation. 2010; 121: 1465-1473
        • Murphy C.J.
        • Oudit G.Y.
        Iron-overload cardiomyopathy: pathophysiology, diagnosis, and treatment.
        J Card Fail. 2010; 16: 888-900
        • Huang D.
        • Cheng J.W.
        Pharmacologic management of heart failure with preserved ejection fraction.
        Ann Pharmacother. 2010; 44: 1933-1945
        • Joglar J.A.
        • Acusta A.P.
        • Shusterman N.H.
        • et al.
        Effect of carvedilol on survival and hemodynamics in patients with atrial fibrillation and left ventricular dysfunction: retrospective analysis of the US Carvedilol Heart Failure Trials Program.
        Am Heart J. 2001; 142: 498-501
        • van Veldhuisen D.J.
        • Aass H.
        • El Allaf D.
        • et al.
        Presence and development of atrial fibrillation in chronic heart failure. Experiences from the MERIT-HF Study.
        Eur J Heart Fail. 2006; 8: 539-546
        • Lechat P.
        • Hulot J.S.
        • Escolano S.
        • et al.
        Heart rate and cardiac rhythm relationships with bisoprolol benefit in chronic heart failure in CIBIS II Trial.
        Circulation. 2001; 103: 1428-1433
        • Mulder B.A.
        • van Veldhuisen D.J.
        • Crijns H.J.
        • et al.
        Effect of nebivolol on outcome in elderly patients with heart failure and atrial fibrillation: insights from SENIORS.
        Eur J Heart Fail. 2012; 14: 1171-1178
        • Rienstra M.
        • Damman K.
        • Mulder B.A.
        • et al.
        Beta-blockers and outcome in heart failure and atrial fibrillation. a meta-analysis.
        JACC: Heart Failure. 2013; 1: 21-28
        • Lander E.S.
        • Linton L.M.
        • Birren B.
        • et al.
        Initial sequencing and analysis of the human genome.
        Nature. 2001; 409: 860-921
        • Venter J.C.
        • Adams M.D.
        • Myers E.W.
        • et al.
        The sequence of the human genome.
        Science. 2001; 291: 1304-1351
        • Collins F.S.
        • Green E.D.
        • Guttmacher A.E.
        • et al.
        A vision for the future of genomics research.
        Nature. 2003; 422: 835-847
        • Hershberger R.E.
        • Morales A.
        • Siegfried J.D.
        Clinical and genetic issues in dilated cardiomyopathy: a review for genetics professionals.
        Genet Med. 2010; 12: 655-667
        • Alcalai R.
        • Seidman J.G.
        • Seidman C.E.
        Genetic basis of hypertrophic cardiomyopathy: from bench to the clinics.
        J Cardiovasc Electrophysiol. 2008; 19: 104-110
        • Fang K.C.
        Clinical utilities of peripheral blood gene expression profiling in the management of cardiac transplant patients.
        J Immunotoxicol. 2007; 4: 209-217
        • Srivastava P.K.
        • Duan F.
        Harnessing the antigenic fingerprint of each individual cancer for immunotherapy of human cancer: genomics shows a new way and its challenges.
        Cancer Immunol Immunother. 2013; 62: 967-974
        • Simon R.
        • Roychowdhury S.
        Implementing personalized cancer genomics in clinical trials.
        Nat Rev Drug Discov. 2013; 12: 358-369
        • Borjesson M.
        • Magnusson Y.
        • Hjalmarson A.
        • et al.
        A novel polymorphism in the gene coding for the beta(1)-adrenergic receptor associated with survival in patients with heart failure.
        Eur Heart J. 2000; 21: 1853-1858
        • Magnusson Y.
        • Levin M.C.
        • Eggertsen R.
        • et al.
        Ser49Gly of beta1-adrenergic receptor is associated with effective beta-blocker dose in dilated cardiomyopathy.
        Clin Pharmacol Ther. 2005; 78: 221-231
        • Levin M.C.
        • Marullo S.
        • Muntaner O.
        • et al.
        The myocardium-protective Gly-49 variant of the beta 1-adrenergic receptor exhibits constitutive activity and increased desensitization and down-regulation.
        J Biol Chem. 2002; 277: 30429-30435
        • Troncoso R.
        • Moraga F.
        • Chiong M.
        • et al.
        Gln(27)-->Glubeta(2)-adrenergic receptor polymorphism in heart failure patients: differential clinical and oxidative response to carvedilol.
        Basic Clin Pharmacol Toxicol. 2009; 104: 374-378
        • Kaye D.M.
        • Smirk B.
        • Williams C.
        • et al.
        Beta-adrenoceptor genotype influences the response to carvedilol in patients with congestive heart failure.
        Pharmacogenetics. 2003; 13: 379-382
        • Green S.A.
        • Turki J.
        • Innis M.
        • et al.
        Amino-terminal polymorphisms of the human beta 2-adrenergic receptor impart distinct agonist-promoted regulatory properties.
        Biochemistry. 1994; 33: 9414-9419
        • Littlejohn M.D.
        • Palmer B.R.
        • Richards A.M.
        • et al.
        Ile164 variant of beta2-adrenoceptor does not influence outcome in heart failure but may interact with beta blocker treatment.
        Eur J Heart Fail. 2008; 10: 55-59
        • Lobmeyer M.T.
        • Gong Y.
        • Terra S.G.
        • et al.
        Synergistic polymorphisms of beta1 and alpha2C-adrenergic receptors and the influence on left ventricular ejection fraction response to beta-blocker therapy in heart failure.
        Pharmacogenet Genomics. 2007; 17: 277-282
        • Hein L.
        • Altman J.D.
        • Kobilka B.K.
        Two functionally distinct alpha2-adrenergic receptors regulate sympathetic neurotransmission.
        Nature. 1999; 402: 181-184
        • Rigat B.
        • Hubert C.
        • Alhenc-Gelas F.
        • et al.
        An insertion/deletion polymorphism in the angiotensin I-converting enzyme gene accounting for half the variance of serum enzyme levels.
        J Clin Invest. 1990; 86: 1343-1346
        • Raynolds M.V.
        • Bristow M.R.
        • Bush E.W.
        • et al.
        Angiotensin-converting enzyme DD genotype in patients with ischaemic or idiopathic dilated cardiomyopathy.
        Lancet. 1993; 342: 1073-1075
        • Andersson B.
        • Sylven C.
        The DD genotype of the angiotensin-converting enzyme gene is associated with increased mortality in idiopathic heart failure.
        J Am Coll Cardiol. 1996; 28: 162-167
        • McNamara D.M.
        • Holubkov R.
        • Postava L.
        • et al.
        Pharmacogenetic interactions between angiotensin-converting enzyme inhibitor therapy and the angiotensin-converting enzyme deletion polymorphism in patients with congestive heart failure.
        J Am Coll Cardiol. 2004; 44: 2019-2026
        • Han B.
        • Hasin Y.
        Cardiovascular effects of natriuretic peptides and their interrelation with endothelin-1.
        Cardiovasc Drugs Ther. 2003; 17: 41-52
        • Beta-Blocker Evaluation of Survival Trial Investigators
        A trial of the beta-blocker bucindolol in patients with advanced chronic heart failure.
        N Engl J Med. 2001; 344: 1659-1667
        • Taylor M.R.
        • Slavov D.
        • Humphrey K.
        • et al.
        Pharmacogenetic effect of an endothelin-1 haplotype on response to bucindolol therapy in chronic heart failure.
        Pharmacogenet Genomics. 2009; 19: 35-43
        • Swain S.M.
        • Whaley F.S.
        • Ewer M.S.
        Congestive heart failure in patients treated with doxorubicin: a retrospective analysis of three trials.
        Cancer. 2003; 97: 2869-2879
        • Colombo A.
        • Meroni C.A.
        • Cipolla C.M.
        • et al.
        Managing cardiotoxicity of chemotherapy.
        Curr Treat Options Cardiovasc Med. 2013; 15: 410-424
        • Wojnowski L.
        • Kulle B.
        • Schirmer M.
        • et al.
        NAD(P)H oxidase and multidrug resistance protein genetic polymorphisms are associated with doxorubicin-induced cardiotoxicity.
        Circulation. 2005; 112: 3754-3762
        • Lemieux J.
        • Diorio C.
        • Cote M.A.
        • et al.
        Alcohol and HER2 polymorphisms as risk factor for cardiotoxicity in breast cancer treated with trastuzumab.
        Anticancer Res. 2013; 33: 2569-2576
        • Visscher H.
        • Ross C.J.
        • Rassekh S.R.
        • et al.
        Pharmacogenomic prediction of anthracycline-induced cardiotoxicity in children.
        J Clin Oncol. 2012; 30: 1422-1428
      1. Schmitter D, Cotter G, Voors AA. Clinical use of novel biomarkers in heart failure: towards personalized medicine. Heart Fail Rev 2013 [Epub ahead of print].

        • Preston R.A.
        • Materson B.J.
        • Reda D.J.
        • et al.
        Age-race subgroup compared with renin profile as predictors of blood pressure response to antihypertensive therapy. Department of Veterans Affairs Cooperative Study Group on Antihypertensive Agents.
        JAMA. 1998; 280: 1168-1172
        • Lim P.O.
        • MacFadyen R.J.
        • Struthers A.D.
        Is there a role for renin profiling in selecting chronic heart failure patients for ACE inhibitor treatment?.
        Heart. 2000; 83: 257-261
        • Weir M.R.
        • Saunders E.
        Renin status does not predict the anti-hypertensive response to angiotensin-converting enzyme inhibition in African-Americans. Trandolapril Multicenter Study Group.
        J Hum Hypertens. 1998; 12: 189-194
        • Konstam M.A.
        • Gheorghiade M.
        • Burnett Jr., J.C.
        • et al.
        Effects of oral tolvaptan in patients hospitalized for worsening heart failure: the EVEREST Outcome Trial.
        JAMA. 2007; 297: 1319-1331
        • Lanfear D.E.
        • Sabbah H.N.
        • Goldsmith S.R.
        • et al.
        Association of arginine vasopressin levels with outcomes and the effect of V2 blockade in patients hospitalized for heart failure with reduced ejection fraction: insights from the EVEREST trial.
        Circ Heart Fail. 2013; 6: 47-52
        • Morawiec B.
        • Kawecki D.
        Copeptin: a new marker in cardiology.
        J Cardiovasc Med (Hagerstown). 2013; 14: 19-25
        • Zannad F.
        • Alla F.
        • Dousset B.
        • et al.
        Limitation of excessive extracellular matrix turnover may contribute to survival benefit of spironolactone therapy in patients with congestive heart failure: insights from the randomized aldactone evaluation study (RALES). Rales Investigators.
        Circulation. 2000; 102: 2700-2706
        • Jourdain P.
        • Jondeau G.
        • Funck F.
        • et al.
        Plasma brain natriuretic peptide-guided therapy to improve outcome in heart failure: the STARS-BNP Multicenter Study.
        J Am Coll Cardiol. 2007; 49: 1733-1739
        • Berger R.
        • Moertl D.
        • Peter S.
        • et al.
        N-terminal pro-B-type natriuretic peptide-guided, intensive patient management in addition to multidisciplinary care in chronic heart failure a 3-arm, prospective, randomized pilot study.
        J Am Coll Cardiol. 2010; 55: 645-653
        • Januzzi Jr., J.L.
        • Rehman S.U.
        • Mohammed A.A.
        • et al.
        Use of amino-terminal pro-B-type natriuretic peptide to guide outpatient therapy of patients with chronic left ventricular systolic dysfunction.
        J Am Coll Cardiol. 2011; 58: 1881-1889
        • Troughton R.W.
        • Frampton C.M.
        • Yandle T.G.
        • et al.
        Treatment of heart failure guided by plasma aminoterminal brain natriuretic peptide (N-BNP) concentrations.
        Lancet. 2000; 355: 1126-1130
        • Pfisterer M.
        • Buser P.
        • Rickli H.
        • et al.
        BNP-guided vs symptom-guided heart failure therapy: the Trial of Intensified vs Standard Medical Therapy in Elderly Patients With Congestive Heart Failure (TIME-CHF) randomized trial.
        JAMA. 2009; 301: 383-392
        • Lainchbury J.G.
        • Troughton R.W.
        • Strangman K.M.
        • et al.
        N-terminal pro-B-type natriuretic peptide-guided treatment for chronic heart failure: results from the BATTLESCARRED (NT-proBNP-Assisted Treatment To Lessen Serial Cardiac Readmissions and Death) trial.
        J Am Coll Cardiol. 2009; 55: 53-60
        • Persson H.
        • Erntell H.
        • Eriksson B.
        • et al.
        Improved pharmacological therapy of chronic heart failure in primary care: a randomized Study of NT-proBNP Guided Management of Heart Failure–SIGNAL-HF (Swedish Intervention study–Guidelines and NT-proBNP AnaLysis in Heart Failure).
        Eur J Heart Fail. 2010; 12: 1300-1308
        • Eurlings L.W.
        • van Pol P.E.
        • Kok W.E.
        • et al.
        Management of chronic heart failure guided by individual N-terminal pro-B-type natriuretic peptide targets: results of the PRIMA (Can PRo-brain-natriuretic peptide guided therapy of chronic heart failure IMprove heart fAilure morbidity and mortality?) study.
        J Am Coll Cardiol. 2010; 56: 2090-2100
        • Shah M.R.
        • Califf R.M.
        • Nohria A.
        • et al.
        The STARBRITE trial: a randomized, pilot study of B-type natriuretic peptide-guided therapy in patients with advanced heart failure.
        J Card Fail. 2011; 17: 613-621
        • Karlstrom P.
        • Alehagen U.
        • Boman K.
        • et al.
        Brain natriuretic peptide-guided treatment does not improve morbidity and mortality in extensively treated patients with chronic heart failure: responders to treatment have a significantly better outcome.
        Eur J Heart Fail. 2011; 13: 1096-1103
        • Savarese G.
        • Trimarco B.
        • Dellegrottaglie S.
        • et al.
        Natriuretic peptide-guided therapy in chronic heart failure: a meta-analysis of 2,686 patients in 12 randomized trials.
        PLoS One. 2013; 8: e58287
        • Boyle A.
        • Sobotka P.A.
        Redefining the therapeutic objective in decompensated heart failure: hemoconcentration as a surrogate for plasma refill rate.
        J Card Fail. 2006; 12: 247-249
        • Leypoldt J.K.
        • Cheung A.K.
        • Steuer R.R.
        • et al.
        Determination of circulating blood volume by continuously monitoring hematocrit during hemodialysis.
        J Am Soc Nephrol. 1995; 6: 214-219
        • Davila C.
        • Reyentovich A.
        • Katz S.D.
        Clinical correlates of hemoconcentration during hospitalization for acute decompensated heart failure.
        J Card Fail. 2011; 17: 1018-1022
        • van der Meer P.
        • Postmus D.
        • Ponikowski P.
        • et al.
        The predictive value of short-term changes in hemoglobin concentration in patients presenting with acute decompensated heart failure.
        J Am Coll Cardiol. 2013; 61: 1973-1981
        • Oh J.
        • Kang S.M.
        • Hong N.
        • et al.
        Hemoconcentration is a good prognostic predictor for clinical outcomes in acute heart failure: data from the Korean Heart Failure (KorHF) Registry.
        Int J Cardiol. 2013; 168: 4739-4743
        • Testani J.M.
        • Brisco M.A.
        • Chen J.
        • et al.
        Timing of hemoconcentration during treatment of acute decompensated heart failure and subsequent survival: importance of sustained decongestion.
        J Am Coll Cardiol. 2013; 62: 516-524
        • Bartel D.P.
        MicroRNAs: genomics, biogenesis, mechanism, and function.
        Cell. 2004; 116: 281-297
        • Oliveira-Carvalho V.
        • da Silva M.M.
        • Guimaraes G.V.
        • et al.
        MicroRNAs: new players in heart failure.
        Mol Biol Rep. 2013; 40: 2663-2670
        • van Rooij E.
        • Marshall W.S.
        • Olson E.N.
        Toward microRNA-based therapeutics for heart disease: the sense in antisense.
        Circ Res. 2008; 103: 919-928
        • Zhu H.
        • Fan G.C.
        Extracellular/circulating microRNAs and their potential role in cardiovascular disease.
        Am J Cardiovasc Dis. 2011; 1: 138-149
        • Dickinson B.A.
        • Semus H.M.
        • Montgomery R.L.
        • et al.
        Plasma microRNAs serve as biomarkers of therapeutic efficacy and disease progression in hypertension-induced heart failure.
        Eur J Heart Fail. 2013; 15: 650-659