A peripheral blood transcriptome biomarker test to diagnose functional recovery potential in advanced heart failure

Mario C Deng, Mario C Deng

Abstract

Heart failure (HF) is a complex clinical syndrome that causes systemic hypoperfusion and failure to meet the body's metabolic demands. In an attempt to compensate, chronic upregulation of the sympathetic nervous system and renin-angiotensin-aldosterone leads to further myocardial injury, HF progression and reduced O2 delivery. This triggers progressive organ dysfunction, immune system activation and profound metabolic derangements, creating a milieu similar to other chronic systemic diseases and presenting as advanced HF with severely limited prognosis. We hypothesize that 1-year survival in advanced HF is linked to functional recovery potential (FRP), a novel clinical composite parameter that includes HF severity, secondary organ dysfunction, co-morbidities, frailty, disabilities as well as chronological age and that can be diagnosed by a molecular biomarker.

Keywords: advanced heart failure; biomarker; functional recovery potential; heart transplantation; mechanical circulatory support; relational medicine; revascularization; shared decision-making; valve replacement; ventricular tachycardia ablation.

Conflict of interest statement

Financial & competing interests disclosure

The author is co-founding equity holder of LeukoLifeDx, Inc., the developer of MyPLeukoMAP™ biomarker test conceptualized in this manuscript. The author has received funding from UCLA NIH R21 1R21HL120040–01 (MCD; PI Deng), UCLA R01 (PI Weiss, Joint PI Deng), UCLA R01 (PI Ping, Co-I Deng), UCLA DOM Internal Funds and the Advanced HF Research Gift to Columbia University (P Geier, J Tocco and R Milo), Advanced HF Research Gift to UCLA (L Layne, J Mulder and P Schultz). The author has no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

No writing assistance was utilized in the production of this manuscript.

Figures

Figure 1. . Functional recovery potential is…
Figure 1.. Functional recovery potential is an novel integrated clinical parameter, defined as a clinical composite parameter that includes chronological age as well as personal biological age, measurable by established and validated heart failure, secondary organ dysfunction, co-morbidities, frailty and disability instruments.
Functional recovery potential (FRP) represents the instantaneous potential of the person with advanced heart failure (AdHF) to cope with stressors such as AdHF surgical/interventional therapies and is a surrogate parameter for a long-term survival benefit. Heart failure severity tools include HFSS, Seattle Heart Failure Model and University of California Los Angeles scores. Organ dysfunction severity tools include Sequential Organ Failure Assessment and Model of Endstage Liver Disease Except INR scores. Co-morbidity burden tools include Society of Thoracic Surgeons and EuroSCORE. Frailty tools include the FRIED scale. Disabilities can be measured by the Activities-of-Daily-Living scale. A high FRP is defined as the composite score improving after AdHF interventions. A low FRP is defined as the composite score not improving after AdHF interventions. Our central postulate is that the FRP can be diagnosed, i.e. that functional recovery can be predicted, by a molecular biomarker.

References

    1. Yancy CW, Jessup M, Bozkurt B, et al. 2017 ACC/AHA/HFSA focused update of the 2013 ACCF/AHA Guideline for the management of heart failure: a report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines and the Heart Failure Society of America. Circulation. 2017;136(6):e137–e161.
    1. Yancy CW, Jessup M, Bozkurt B, et al. 2013 ACCF/AHA guideline for the management of heart failure: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines. J. Am. Coll. Cardiol. 2013;62(16):e147–e239.
    1. Levine B, Kalman J, Mayer L, Fillit HM, Packer M. Elevated circulating levels of tumor necrosis factor in severe chronic heart failure. N. Engl. J. Med. 1990;323(4):236–241.
    1. Deng MC, Dasch B, Erren M, Mollhoff T, Scheld HH. Impact of left ventricular dysfunction on cytokines, hemodynamics, and outcome in bypass grafting. Ann. Thorac. Surg. 1996;62(1):184–190.
    1. The Economist. The joys of living to 100.
    1. Lowsky DJ, Olshansky SJ, Bhattacharya J, Goldman DP. Heterogeneity in healthy aging. J. Gerontol. A Biol. Sci. Med. Sci. 2014;69(6):640–649.
    1. Jylhävä J, Pedersen NL, Hagg S. Biological age predictors. EBioMedicine. 2017;21:29–36.
    1. Bondar G, Togashi R, Cadeiras M, et al. Association between preoperative peripheral blood mononuclear cell gene expression profiles, early postoperative organ function recovery potential and long-term survival in advanced heart failure patients undergoing mechanical circulatory support. PLoS ONE. 2017;12(12):e0189420.
    1. Adigopula S, Vivo RP, Depasquale EC, Nsair A, Deng MC. Management of ACCF/AHA stage C heart failure. Cardiol. Clin. 2014;32(1):73–93. viii.
    1. Goda A, Lund LH, Mancini D. The Heart Failure Survival Score outperforms the peak oxygen consumption for heart transplantation selection in the era of device therapy. J. Heart Lung Transplant. 2011;30(3):315–325.
    1. Jhund PS, Fu M, Bayram E, et al. Efficacy and safety of LCZ696 (sacubitril-valsartan) according to age: insights from PARADIGM-HF. Eur. Heart J. 2015;36(38):2576–2584.
    1. Ouwerkerk W, Zwinderman AH, Ng LL, et al. Biomarker-guided versus guideline-based treatment of patients with heart failure: results from BIOSTAT-CHF. J. Am. Coll. Cardiol. 2018;71(4):386–398.

    2. • Quantitates the potential benefit of adding a biomarker to the best available clinical information in the individual encounter for optimal treatment of heart failure patients.

    1. Petrie MC, Jhund PS, She L, et al. Ten-year outcomes after coronary artery bypass grafting according to age in patients with heart failure and left ventricular systolic dysfunction: an analysis of the extended follow-up of the STICH trial (surgical treatment for ischemic heart failure) Circulation. 2016;134(18):1314–1324.
    1. Velazquez EJ, Lee KL, Deja MA, et al. Coronary-artery bypass surgery in patients with left ventricular dysfunction. N. Engl. J. Med. 2011;364(17):1607–1616.
    1. Carson P, Wertheimer J, Miller A, et al. The STICH trial (surgical treatment for ischemic heart failure): mode-of-death results. JACC Heart Failure. 2013;1(5):400–408.
    1. Velazquez EJ, Lee KL, Jones RH, et al. Coronary-artery bypass surgery in patients with ischemic cardiomyopathy. N. Engl. J. Med. 2016;374(16):1511–1520.
    1. Holmes DR, Jr, Brennan JM, Rumsfeld JS, et al. Clinical outcomes at 1 year following transcatheter aortic valve replacement. JAMA. 2015;313(10):1019–1028.
    1. Leon MB, Smith CR, Mack M, et al. Transcatheter aortic-valve implantation for aortic stenosis in patients who cannot undergo surgery. N. Engl. J. Med. 2010;363(17):1597–1607.
    1. Smith CR, Leon MB, Mack MJ, et al. Transcatheter versus surgical aortic-valve replacement in high-risk patients. N. Engl. J. Med. 2011;364(23):2187–2198.
    1. Leon MB, Smith CR, Mack MJ, et al. Transcatheter or surgical aortic-valve replacement in intermediate-risk patients. N. Engl. J. Med. 2016;374(17):1609–1620.
    1. Whitlow PL, Feldman T, Pedersen WR, et al. Acute and 12-month results with catheter-based mitral valve leaflet repair: the EVEREST II (endovascular valve edge-to-edge repair) high risk study. J. Am. Coll. Cardiol. 2012;59(2):130–139.
    1. Chiarito M, Pagnesi M, Martino EA, et al. Outcome after percutaneous edge-to-edge mitral repair for functional and degenerative mitral regurgitation: a systematic review and meta-analysis. Heart. 2018;104(4):306–312.
    1. Tung R, Vaseghi M, Frankel DS, et al. Freedom from recurrent ventricular tachycardia after catheter ablation is associated with improved survival in patients with structural heart disease: an International VT Ablation Center Collaborative Group study. Heart Rhythm. 2015;12(9):1997–2007.
    1. Vakil K, Garcia S, Tung R, et al. Ventricular tachycardia ablation in the elderly: an International Ventricular Tachycardia Center Collaborative Group analysis. Circ. Arrhythm. Electrophysiol. 2017;10(12) pii:e005332.
    1. Vergara P, Tung R, Vaseghi M, et al. Successful ventricular tachycardia ablation in patients with electrical storm reduces recurrences and improves survival. Heart Rhythm. 2018;15(1):48–55.
    1. Kirklin JK, Pagani FD, Kormos RL, et al. Eighth annual INTERMACS report: Special focus on framing the impact of adverse events. J. Heart Lung Transplant. 2017;36(10):1080–1086.
    1. Lund LH, Khush KK, Cherikh WS, et al. The Registry of the International Society for heart and lung transplantation: thirty-fourth adult heart transplantation report-2017; Focus theme: allograft ischemic time. J. Heart Lung Transplant. 2017;36(10):1037–1046.
    1. Xiong TY, Liao YB, Zhao ZG, et al. Causes of death following transcatheter aortic valve replacement: a systematic review and meta-analysis. J. Am. Heart Assoc. 2015;4(9):e002096.
    1. Risk Scoring System.
    1. EuroSCORE.
    1. O'brien SM, Shahian DM, Filardo G, et al. The Society of Thoracic Surgeons 2008 cardiac surgery risk models: part 2–isolated valve surgery. Ann. Thorac. Surg. 2009;88(1 Suppl.):S23–S42.
    1. Nishimura RA, Otto CM, Bonow RO, et al. 2017 AHA/ACC focused update of the 2014 AHA/ACC guideline for the management of patients with valvular heart disease: a report of the American College of Cardiology/American Heart Association Task Force on clinical practice guidelines. J. Am. Coll. Cardiol. 2017;70(2):252–289.
    1. Baumgartner H. The 2017 ESC/EACTS guidelines on the management of valvular heart disease: what is new and what has changed compared with the 2012 guidelines? Wiener Klinische Wochenschrift. 2017;130(5–6):168–171.
    1. Kodali SK, Williams MR, Smith CR, et al. Two-year outcomes after transcatheter or surgical aortic-valve replacement. N. Engl. J. Med. 2012;366(18):1686–1695.
    1. Wu AH, Aaronson KD, Bolling SF, Pagani FD, Welch K, Koelling TM. Impact of mitral valve annuloplasty on mortality risk in patients with mitral regurgitation and left ventricular systolic dysfunction. J. Am. Coll. Cardiol. 2005;45(3):381–387.
    1. Acker MA, Parides MK, Perrault LP, et al. Mitral-valve repair versus replacement for severe ischemic mitral regurgitation. N. Engl. J. Med. 2014;370(1):23–32.
    1. Goldstein D, Moskowitz AJ, Gelijns AC, et al. Two-year outcomes of surgical treatment of severe ischemic mitral regurgitation. N. Engl. J. Med. 2016;374(4):344–353.
    1. Feldman T, Kar S, Elmariah S, et al. Randomized comparison of percutaneous repair and surgery for mitral regurgitation: 5-year results of EVEREST II. J. Am. Coll. Cardiol. 2015;66(25):2844–2854.
    1. Taramasso M, Denti P, Buzzatti N, et al. Mitraclip therapy and surgical mitral repair in patients with moderate to severe left ventricular failure causing functional mitral regurgitation: a single-centre experience. Eur. J. Cardiothorac. Surg. 2012;42(6):920–926.
    1. Nashef SA, Roques F, Hammill BG, et al. Validation of European System for Cardiac Operative Risk Evaluation (EuroSCORE) in North American cardiac surgery. Eur. J. Cardiothorac. Surg. 2002;22(1):101–105.
    1. Shroyer AL, Coombs LP, Peterson ED, et al. The Society of Thoracic Surgeons: 30-day operative mortality and morbidity risk models. Ann. Thorac. Surg. 2003;75(6):1856–1864. discussion 1864–1855.
    1. Moss AJ, Hall WJ, Cannom DS, et al. Improved survival with an implanted defibrillator in patients with coronary disease at high risk for ventricular arrhythmia. Multicenter Automatic Defibrillator Implantation trial investigators. N. Engl. J. Med. 1996;335(26):1933–1940.
    1. Goonewardene M, Barra S, Heck P, et al. Cardioverter-defibrillator implantation and generator replacement in the octogenarian. Europace. 2015;17(3):409–416.
    1. Goldenberg I, Vyas AK, Hall WJ, et al. Risk stratification for primary implantation of a cardioverter-defibrillator in patients with ischemic left ventricular dysfunction. J. Am. Coll. Cardiol. 2008;51(3):288–296.
    1. European Heart Rhythm A; European Society Of C; Heart Rhythm S. 2012 EHRA/HRS expert consensus statement on cardiac resynchronization therapy in heart failure: implant and follow-up recommendations and management. Heart Rhythm. 2012;9(9):1524–1576.
    1. Briceno DF, Gupta T, Romero J, et al. Catheter ablation of ventricular tachycardia in nonischemic cardiomyopathy: a propensity score-matched analysis of in-hospital outcomes in the United States. J. Cardiovasc. Electrophysiol. 2018 Epub ahead of print.
    1. Baratto F, Pappalardo F, Oloriz T, et al. Extracorporeal membrane oxygenation for hemodynamic support of ventricular tachycardia ablation. Circulation. 2016;9(12) pii:e004492.
    1. Deng MC, De Meester JM, Smits JM, Heinecke J, Scheld HH. Effect of receiving a heart transplant: analysis of a national cohort entered on to a waiting list, stratified by heart failure severity. Comparative Outcome and Clinical Profiles in Transplantation (COCPIT) Study Group. BMJ. 2000;321(7260):540–545.

    2. •• Outlines for the first time in a national cohort of advanced heart failure (AdHF)/transplant patients the time-dependent comparative dynamic hazard modeling necessary to estimate comparative survival benefit between two competing AdHF therapies.

    1. Vucicevic D, Honoris L, Raia F, Deng M. Current indications for transplantation: stratification of severe heart failure and shared decision-making. Ann. Cardiothorac. Surg. 2018;7(1):56–66.
    1. Moons KG, Kengne AP, Woodward M, et al. Risk prediction models: I. Development, internal validation, and assessing the incremental value of a new (bio)marker. Heart. 2012;98(9):683–690.
    1. Gardner RS, Ozalp F, Murday AJ, Robb SD, Mcdonagh TA. N-terminal pro-brain natriuretic peptide. A new gold standard in predicting mortality in patients with advanced heart failure. Eur. Heart J. 2003;24(19):1735–1743.
    1. Doust JA, Pietrzak E, Dobson A, Glasziou P. How well does B-type natriuretic peptide predict death and cardiac events in patients with heart failure: systematic review. BMJ. 2005;330(7492):625.
    1. Aaronson KD, Schwartz JS, Chen TM, Wong KL, Goin JE, Mancini DM. Development and prospective validation of a clinical index to predict survival in ambulatory patients referred for cardiac transplant evaluation. Circulation. 1997;95(12):2660–2667.
    1. Levy WC, Mozaffarian D, Linker DT, et al. The Seattle Heart Failure Model: prediction of survival in heart failure. Circulation. 2006;113(11):1424–1433.
    1. Sartipy U, Dahlstrom U, Edner M, Lund LH. Predicting survival in heart failure: validation of the MAGGIC heart failure risk score in 51,043 patients from the Swedish heart failure registry. Eur. J. Heart Fail. 2014;16(2):173–179.
    1. Sartipy U, Goda A, Mancini DM, Lund LH. Assessment of a University of California, Los Angeles 4-variable risk score for advanced heart failure. J. Am. Heart Assoc. 2014;3(3):e000998.
    1. Sartipy U, Goda A, Yuzefpolskaya M, Mancini DM, Lund LH. Utility of the Seattle Heart Failure Model in patients with cardiac resynchronization therapy and implantable cardioverter defibrillator referred for heart transplantation. Am. Heart J. 2014;168(3):325–331.
    1. Flint KM, Matlock DD, Lindenfeld J, Allen LA. Frailty and the selection of patients for destination therapy left ventricular assist device. Circ. Heart Fail. 2012;5(2):286–293.

    2. •• Raises the provocative hypothesis that not all frailty biology is secondary to heart failure and therefore cannot be reversed in a monocausal mechanical circulatory support AdHF paradigm.

    1. Chyu J, Fonarow GC, Tseng CH, Horwich TB. Four-variable risk model in men and women with heart failure. Circ. Heart Fail. 2014;7(1):88–95.
    1. Cowger J, Sundareswaran K, Rogers JG, et al. Predicting survival in patients receiving continuous flow left ventricular assist devices: the HeartMate II risk score. J. Am. Coll. Cardiol. 2013;61(3):313–321.
    1. Kamath PS, Wiesner RH, Malinchoc M, et al. A model to predict survival in patients with end-stage liver disease. Hepatology. 2001;33(2):464–470.
    1. Collins LV, Hajizadeh S, Holme E, Jonsson IM, Tarkowski A. Endogenously oxidized mitochondrial DNA induces in vivo and in vitro inflammatory responses. J. Leukoc. Biol. 2004;75(6):995–1000.
    1. Vincent JL, De Mendonca A, Cantraine F, et al. Use of the SOFA score to assess the incidence of organ dysfunction/failure in intensive care units: results of a multicenter, prospective study. Working group on “sepsis-related problems” of the European Society of Intensive Care Medicine. Crit. Care Med. 1998;26(11):1793–1800.
    1. Vincent JL, Moreno R, Takala J, et al. The SOFA (Sepsis-related Organ Failure Assessment) score to describe organ dysfunction/failure. On behalf of the Working Group on Sepsis-Related Problems of the European Society of Intensive Care Medicine. Intensive Care Med. 1996;22(7):707–710.
    1. Matthews JC, Pagani FD, Haft JW, Koelling TM, Naftel DC, Aaronson KD. Model for end-stage liver disease score predicts left ventricular assist device operative transfusion requirements, morbidity, and mortality. Circulation. 2010;121(2):214–220.
    1. Abe S, Yoshihisa A, Takiguchi M, et al. Liver dysfunction assessed by model for end-stage liver disease excluding INR (MELD-XI) scoring system predicts adverse prognosis in heart failure. PLoS ONE. 2014;9(6):e100618.
    1. Mancini DM, Eisen H, Kussmaul W, Mull R, Edmunds LH, Jr, Wilson JR. Value of peak exercise oxygen consumption for optimal timing of cardiac transplantation in ambulatory patients with heart failure. Circulation. 1991;83(3):778–786.
    1. Goda A, Williams P, Mancini D, Lund LH. Selecting patients for heart transplantation: comparison of the Heart Failure Survival Score (HFSS) and the Seattle Heart Failure Model (SHFM) J. Heart Lung Transplant. 2011;30(11):1236–1243.
    1. Gilard M, Eltchaninoff H, Iung B, et al. Registry of transcatheter aortic-valve implantation in high-risk patients. N. Engl. J. Med. 2012;366(18):1705–1715.
    1. Adams DH, Popma JJ, Reardon MJ, et al. Transcatheter aortic-valve replacement with a self-expanding prosthesis. N. Engl. J. Med. 2014;370(19):1790–1798.
    1. Popma JJ, Adams DH, Reardon MJ, et al. Transcatheter aortic valve replacement using a self-expanding bioprosthesis in patients with severe aortic stenosis at extreme risk for surgery. J. Am. Coll. Cardiol. 2014;63(19):1972–1981.
    1. Reardon MJ, Van Mieghem NM, Popma JJ, et al. Surgical or transcatheter aortic-valve replacement in intermediate-risk patients. N. Engl. J. Med. 2017;376(14):1321–1331.
    1. Barili F, Pacini D, Capo A, et al. Does EuroSCORE II perform better than its original versions? A multicentre validation study. Eur. Heart J. 2013;34(1):22–29.
    1. Osnabrugge RL, Speir AM, Head SJ, et al. Performance of EuroSCORE II in a large US database: implications for transcatheter aortic valve implantation. Eur. J. Cardiothorac. Surg. 2014;46(3):400–408. discussion 408.
    1. Ben-Dor I, Gaglia MA, Jr, Barbash IM, et al. Comparison between Society of Thoracic Surgeons score and logistic EuroSCORE for predicting mortality in patients referred for transcatheter aortic valve implantation. Cardiovasc. Revasc. Med. 2011;12(6):345–349.
    1. Durand E, Borz B, Godin M, et al. Performance analysis of EuroSCORE II compared with the original logistic EuroSCORE and STS scores for predicting 30-day mortality after transcatheter aortic valve replacement. Am. J. Cardiol. 2013;111(6):891–897.
    1. Makkar RR, Fontana GP, Jilaihawi H, et al. Transcatheter aortic-valve replacement for inoperable severe aortic stenosis. N. Engl. J. Med. 2012;366(18):1696–1704.
    1. Pilotto A, Addante F, Franceschi M, et al. Multidimensional Prognostic Index based on a comprehensive geriatric assessment predicts short-term mortality in older patients with heart failure. Circ. Heart Fail. 2010;3(1):14–20.
    1. Stortecky S, Schoenenberger AW, Moser A, et al. Evaluation of multidimensional geriatric assessment as a predictor of mortality and cardiovascular events after transcatheter aortic valve implantation. JACC Cardiovasc. Interv. 2012;5(5):489–496.
    1. Schoenenberger AW, Stortecky S, Neumann S, et al. Predictors of functional decline in elderly patients undergoing transcatheter aortic valve implantation (TAVI) Eur. Heart J. 2013;34(9):684–692.
    1. Green P, Woglom AE, Genereux P, et al. The impact of frailty status on survival after transcatheter aortic valve replacement in older adults with severe aortic stenosis: a single-center experience. JACC Cardiovasc. Interv. 2012;5(9):974–981.
    1. Arnold SV, Spertus JA, Lei Y, et al. How to define a poor outcome after transcatheter aortic valve replacement: conceptual framework and empirical observations from the placement of aortic transcatheter valve (PARTNER) trial. Circ. Cardiovasc. Qual. Outcomes. 2013;6(5):591–597.
    1. Teuteberg JJ, Ewald GA, Adamson RM, et al. Risk assessment for continuous flow left ventricular assist devices: does the destination therapy risk score work? An analysis of over 1,000 patients. J. Am. Coll. Cardiol. 2012;60(1):44–51.
    1. Joseph SM, Rich MW. Targeting frailty in heart failure. Curr. Treat. Options Cardiovasc. Med. 2017;19(4):31.
    1. Dunlay SM, Park SJ, Joyce LD, et al. Frailty and outcomes after implantation of left ventricular assist device as destination therapy. J. Heart Lung Transplant. 2014;33(4):359–365.
    1. Harjola VP, Mullens W, Banaszewski M, et al. Organ dysfunction, injury and failure in acute heart failure: from pathophysiology to diagnosis and management. A review on behalf of the Acute Heart Failure Committee of the Heart Failure Association (HFA) of the European Society of Cardiology (ESC) Eur. J. Heart Fail. 2017;19(7):821–836.
    1. Charlson ME, Pompei P, Ales KL, Mackenzie CR. A new method of classifying prognostic comorbidity in longitudinal studies: development and validation. J. Chronic Dis. 1987;40(5):373–383.
    1. Fried LP, Tangen CM, Walston J, et al. Frailty in older adults: evidence for a phenotype. J. Gerontol. A Biol. Sci. Med. Sci. 2001;56(3):M146–M156.
    1. Freiheit EA, Hogan DB, Patten SB, et al. Frailty trajectories after treatment for coronary artery disease in older patients. Circ. Cardiovasc. Qual. Outcomes. 2016;9(3):230–238.
    1. Heberton GA, Nassif M, Bierhals A, et al. Usefulness of Psoas Muscle area determined by computed tomography to predict mortality or prolonged length of hospital stay in patients undergoing left ventricular assist device implantation. Am. J. Cardiol. 2016;118(9):1363–1367.
    1. Afilalo J, Lauck S, Kim DH, et al. Frailty in older adults undergoing aortic valve replacement: the FRAILTY-AVR study. J. Am. Coll. Cardiol. 2017;70(6):689–700.
    1. Soysal P, Veronese N, Thompson T, et al. Relationship between depression and frailty in older adults: a systematic review and meta-analysis. Ageing Res. Rev. 2017;36:78–87.
    1. Gill TM, Gahbauer EA, Han L, Allore HG. The relationship between intervening hospitalizations and transitions between frailty states. J. Gerontol. A Biol. Sci. Med. Sci. 2011;66(11):1238–1243.
    1. Mitnitski A, Rockwood K. The rate of aging: the rate of deficit accumulation does not change over the adult life span. Biogerontology. 2016;17(1):199–204.
    1. Xue QL. The frailty syndrome: definition and natural history. Clin. Geriatr. Med. 2011;27(1):1–15.
    1. Myers V, Drory Y, Gerber Y. Clinical relevance of frailty trajectory post myocardial infarction. Eur. J. Prev. Cardiol. 2014;21(6):758–766.
    1. Theou O, Stathokostas L, Roland KP, et al. The effectiveness of exercise interventions for the management of frailty: a systematic review. J. Aging Res. 2011;2011:569194.
    1. Maurer MS, Horn E, Reyentovich A, et al. Can a left ventricular assist device in individuals with advanced systolic heart failure improve or reverse frailty? J. Am. Geriatr. Soc. 2017;65(11):2383–2390.
    1. Blaha MJ, Hung RK, Dardari Z, et al. Age-dependent prognostic value of exercise capacity and derivation of fitness-associated biologic age. Heart. 2016;102(6):431–437.
    1. Southwick SM, Bonanno GA, Masten AS, Panter-Brick C, Yehuda R. Resilience definitions, theory, and challenges: interdisciplinary perspectives. Eur. J. Psychotraumatol. 2014;5:10.
    1. Ornish D, Magbanua MJ, Weidner G, et al. Changes in prostate gene expression in men undergoing an intensive nutrition and lifestyle intervention. Proc. Natl Acad. Sci. USA. 2008;105(24):8369–8374.
    1. Gilstrap LG, Snipelisky D, Abouezzeddine O, et al. Unanswered questions in contemporary heart failure. J. Card. Fail. 2017;23(10):770–774.
    1. Conrad CC. The president's council on physical fitness and sports. Am. J. Sports Med. 1981;9(4):199–202.
    1. Chung CJ, Wu C, Jones M, et al. Reduced handgrip strength as a marker of frailty predicts clinical outcomes in patients with heart failure undergoing ventricular assist device placement. J. Card. Fail. 2014;20(5):310–315.
    1. Jha SR, Ha HS, Hickman LD, et al. Frailty in advanced heart failure: a systematic review. Heart Fail. Rev. 2015;20(5):553–560.
    1. Lindman BR, Pibarot P, Arnold SV, et al. Transcatheter versus surgical aortic valve replacement in patients with diabetes and severe aortic stenosis at high risk for surgery: an analysis of the PARTNER Trial (Placement of Aortic Transcatheter Valve) J. Am. Coll. Cardiol. 2014;63(11):1090–1099.
    1. Furukawa H, Tanemoto K. Frailty in cardiothoracic surgery: systematic review of the literature. Gen. Thorac. Cardiovasc. Surg. 2015;63(8):425–433.
    1. Jha SR, Hannu MK, Chang S, et al. The prevalence and prognostic significance of frailty in patients with advanced heart failure referred for heart transplantation. Transplantation. 2016;100(2):429–436.
    1. Valentova M, Von Haehling S, Krause C, et al. Cardiac cachexia is associated with right ventricular failure and liver dysfunction. Int. J. Cardiol. 2013;169(3):219–224.
    1. De Martinis M, Franceschi C, Monti D, Ginaldi L. Inflammation markers predicting frailty and mortality in the elderly. Exp. Mol. Pathol. 2006;80(3):219–227.
    1. Joyce E. Frailty in advanced heart failure. Heart Fail. Clin. 2016;12(3):363–374.
    1. Loncar G, Springer J, Anker M, Doehner W, Lainscak M. Cardiac cachexia: hic et nunc . J. Cachexia, Sarcopenia Muscle. 2016;7(3):246–260.
    1. Dorshkind K, Montecino-Rodriguez E, Signer RA. The ageing immune system: is it ever too old to become young again? Nat. Rev. Immunol. 2009;9(1):57–62.
    1. Larbi A, Fulop T. From “truly naïve” to “exhausted senescent” T cells: when markers predict functionality. Cytometry Part A. 2014;85(1):25–35.
    1. Wherry EJ. T cell exhaustion. Nat. Immunol. 2011;12(6):492–499.
    1. Burton DG, Faragher RG. Cellular senescence: from growth arrest to immunogenic conversion. Age. 2015;37(2):27.
    1. Fried LP, Kronmal RA, Newman AB, et al. Risk factors for 5-year mortality in older adults: the Cardiovascular Health Study. JAMA. 1998;279(8):585–592.
    1. Partridge JS, Harari D, Dhesi JK. Frailty in the older surgical patient: a review. Age Ageing. 2012;41(2):142–147.
    1. Bagnall NM, Faiz O, Darzi A, Athanasiou T. What is the utility of preoperative frailty assessment for risk stratification in cardiac surgery? Interact. Cardiovasc. Thorac. Surg. 2013;17(2):398–402.
    1. Afilalo J, Mottillo S, Eisenberg MJ, et al. Addition of frailty and disability to cardiac surgery risk scores identifies elderly patients at high risk of mortality or major morbidity. Circ. Cardiovasc. Qual. Outcomes. 2012;5(2):222–228.
    1. Schoenenberger AW, Moser A, Bertschi D, et al. Improvement of risk prediction after transcatheter aortic valve replacement by combining frailty with conventional risk scores. JACC Cardiovasc. Interv. 2018;11(4):395–403.

    2. •• Proposes a multilevel risk prediction concept to account for a real-life biology assessment in the practice of modern medicine.

    1. Sondergaard L, Kirk BH, Jorgensen TH. Frailty: an important measure in patients considered for transcatheter aortic valve replacement. JACC Cardiovasc. Interv. 2018;11(4):404–406.
    1. Bouillon K, Batty GD, Hamer M, et al. Cardiovascular disease risk scores in identifying future frailty: the Whitehall II prospective cohort study. Heart. 2013;99(10):737–742.
    1. Medicine IO. Disability in America: Toward a National Agenda for Prevention. The National Academies Press; Washington DC, USA: 1991.
    1. Fried LP, Ferrucci L, Darer J, Williamson JD, Anderson G. Untangling the concepts of disability, frailty, and comorbidity: implications for improved targeting and care. J. Gerontol. A Biol. Sci. Med. Sci. 2004;59(3):255–263.
    1. Ferrucci L, Guralnik JM, Simonsick E, Salive ME, Corti C, Langlois J. Progressive versus catastrophic disability: a longitudinal view of the disablement process. J. Gerontol. A Biol. Sci. Med. Sci. 1996;51(3):M123–M130.
    1. Turner JE. Is immunosenescence influenced by our lifetime “dose” of exercise? Biogerontology. 2016;17(3):581–602.
    1. Spielmann G, Mcfarlin BK, O'connor DP, Smith PJW, Pircher H, Simpson RJ. Aerobic fitness is associated with lower proportions of senescent blood T-cells in man. Brain, Behav., Immun. 2011;25(8):1521–1529.
    1. Schaenman JM, Rossetti M, Korin Y, et al. T cell dysfunction and patient age are associated with poor outcomes after mechanical circulatory support device implantation. Hum. Immunol. 2018;79(4):203–212.
    1. 5 July 2017. USPTO Application No 62/528,748.
    1. Osler T, Baker SP, Long W. A modification of the injury severity score that both improves accuracy and simplifies scoring. J. Trauma Acute Care Surg. 1997;43(6):922–926.
    1. Knaus WA, Draper EA, Wagner DP, Zimmerman JE. APACHE II: a severity of disease classification system. Crit. Care Med. 1985;13(10):818–829.
    1. Ketchum ES, Moorman AJ, Fishbein DP, et al. Predictive value of the Seattle Heart Failure Model in patients undergoing left ventricular assist device placement. J. Heart Lung Transplant. 2010;29(9):1021–1025.
    1. Martinez-Selles M, Vidan MT, Lopez-Palop R, et al. End-stage heart disease in the elderly. Rev. Esp. Cardiol. 2009;62(4):409–421.
    1. Smits JM, De Vries E, De Pauw M, et al. Is it time for a cardiac allocation score? First results from the Eurotransplant pilot study on a survival benefit-based heart allocation. J. Heart Lung Transplant. 2013;32(9):873–880.
    1. Kormos RL, Teuteberg JJ, Pagani FD, et al. Right ventricular failure in patients with the HeartMate II continuous-flow left ventricular assist device: incidence, risk factors, and effect on outcomes. J. Thorac. Cardiovasc. Surg. 2010;139(5):1316–1324.
    1. Deng MC, Eisen HJ, Mehra MR, et al. Noninvasive discrimination of rejection in cardiac allograft recipients using gene expression profiling. Am. J. Transplant. 2006;6(1):150–160.

    2. •• Describes for the first time a peripheral blood mononuclear cell gene expression profiling biomarker to assist in ruling organ transplant rejection, thereby obviating routine invasive endomyocardial biopsies.

    1. Deng MC. The AlloMap™ genomic biomarker story: 10 years after. Clin. Transplant. 2017;31(3) Epub ahead of print.
    1. Holmes DR, Jr, Mack MJ, Kaul S, et al. 2012 ACCF/AATS/SCAI/STS expert consensus document on transcatheter aortic valve replacement. J. Am. Coll. Cardiol. 2012;59(13):1200–1254.
    1. Lindman BR, Alexander KP, O'Gara PT, Afilalo J. Futility, benefit, and transcatheter aortic valve replacement. JACC Cardiovasc. Interv. 2014;7(7):707–716.
    1. Charles C, Gafni A, Whelan T. Shared decision-making in the medical encounter: what does it mean? (or it takes at least two to tango) Soc. Sci. Med. 1997;44(5):681–692.
    1. Brunner-La Rocca HP, Rickenbacher P, Muzzarelli S, et al. End-of-life preferences of elderly patients with chronic heart failure. Eur. Heart J. 2012;33(6):752–759.
    1. Raia F, Deng MC. Artificial heart pumps: bridging the gap between science, technology and personalized medicine by relational medicine. Future Cardiol. 2017;13(1):23–32.

    2. • Describes the blueprint of a practice of high-tech modern medicine, incorporating cutting-edge scientific and technological achievements in the context of philosophically and humanistically sound foundations, termed relational medicine.

Source: PubMed

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