Contemporary Management of

Heart Failure : Overview of

Biomarkers and Medical Therapy

Suryono, MD
 Definition of Heart Failure

 ESC 2016: HF is a clinical syndrome characterized

by typical symptoms that may be accompanied by
signs caused by a structural and/or functional
cardiac abnormality, resulting in a reduced cardiac
output and/ or elevated intracardiac pressures at rest
or during stress
 ACCF/AHA 2013: HF is a complex clinical
syndrome that results from any structural or
functional impairment of ventricular filling or
ejection of blood
Mechanism of Biomarkers Secretion
 Natriuretic Peptide
 BNP (B type Natriuretic Peptide) is a neurohormone
synthesized and released primarily from heart ventricle
 Synthesized and released as response to : Pressure
overload, Volume overload
 Result in : vasodilatation, natriuresis, diuresis, inhibition of
RAA, stimulation of symphatetic
 Half life time : 20 minutes (BNP), 1-2 hours (NT pro BNP)
 Both is assisting in : Diagnosis, Prognosis, Management
HF
 The most common use of NP : assisting in the dx of HF in
patients with dyspnea
 Sensitivity : 90% , Specificity : 76%
 Cut off point : BNP : 100 pg/ml, NT pro BNP 300 pg/ml
 Cut off point is depended on age (various) :
< 50 yrs : 450 pg/ml
50-75 yrs : 900 pg/ml
> 75 yrs : 1800 pg/ml
 NP is secreted on blood  bound with NP receptor type C
 will be proteolyzed by Neutral Endo Peptidase (NEP)
eliminated via kidney (so px with renal failure will have
increasing NP level)
 Elevated NP level at discharge reflects a high risk of
readmission, mortality  suggesting up titration therapy
 When do we measure NP :
1. After several days of tx
2. Anticipation of discharge
3. At discharge
 Conclusion of NP clinical use :
1. Dx of HF
2. Assesment of discharge
3. Prognosticate for mortality and readmission
4. Titration of medical therapy (outpatient, potentially
inpatient)
 ST2
 ST2 is a member of interleukin IL1 receptor like
proteins, expressed in fibroblasts and
cardiomyocites in response to mechanical stress

 Expressed in 2 forms :
1. Transmembrane form : ST2L (ST2 Ligand)
2. Solute Circulating form : sST2 (serum ST2)

 If ST2L bound with IL33 : cardioprotective

 If sST2 bound with IL33 : fibrosis, hypertrophy
 Cut off point : 35 ng/ml (for acute/chronic HF)
This value is not depended on age, sex, BMI

 sST2 is the strongest prediction to predict mortality

in HF.

 Conclusion of sST2 clinical use :

1. Prognosticate mortality
2. Potentially guide choice for medical therapy
 HsTn (High Sensitive Troponine)
 Troponin is muscle proteins complex regulates
myocyte contraction, there are 3 isoforms : C,I,T
 High hsTn is associated with high risk of mortality in
in-hospital pastients in acute HF case
 Serial hsTn is also important in predicting :
- Mortality in 90 days
- Readmission
 Recommendation for using hsTn in heart failure:
A. Acute Heart Failure :
1. Exclude type I MI (ACS)
2. May rise/fall even without MI (acute HF  rise,
treatment of HF  fall)
3. Tn>99 percentile  worse outcome
B. Chronic heart failure :
(Data not clear)
 Conclusion of hsTn clinical use :
1. Prognosticate mortality and readmission
2. Prognosticate for developing symptomatic HF
3. Potentially asses response to therapy
 Procalcitonin (PCT)

 Px with “shortness of breath” requires rapid and

accurate assessment Heart failure 0r pneumonia?
 PCT is produced in the C cell of tyroid gland
changed to Calcitonin & few PCT detected in serum
 Pathologic condition PCT is produced in
extratyroid tissues PCT level increases
 PCT increases in bacterial infection, not viral
 Half life time of PCT = 24 hours
 Cut off point : 0,1 ng/ml
 High sensitivity in excluding pneumonia in HF &
tailoring antibiotics
 Conclusion of PCT clinical use:
1. Exclude of pneumonia in heart failure
excacerbation
2. Guide antibiotics use
 Galectin 3 (Gal 3)

 Galectin 3 is a macrophage product, member of

lectin, Found in heart : myocardium matrix,
fibroblast
 Related to :
1. Inflammatory cascade of cardiac injury
2. Formation of fibrosis
 Cut off point : 17,7 ng/ml
 Gal3 = cardiac fibrosis biomarker
 Gal3 able to predict 60 days mortality, superior than
NT pro BNP
 Conclusion of Gal3 clinical use :
Predicting prognosis/mortality in heart failure
Biomarker Diagnostic Capability Prognostic Capability

BNP +++ +++

NT-prroBNP +++ +++

ST2 - ++

Hs-Tn +++ +++

Procalcitonin +++ +++

Galactin 3 - +
 HFrEF management
 Survival rates in chronic HF have improved with the introduction of new therapies 1

ACEI* β-blocker* MRA* ARB*

Reduction in relative risk of
mortality vs placebo

16% 17%
(4.5% ARR; (3.0% ARR;
mean follow up median follow up
of 41.4 months) of 33.7 months)
SOLVD1,2 30% CHARM-
34% (11.0% ARR;
(5.5% ARR; mean follow up Alternative5
mean follow up of 24 months)
of 1.3 years) RALES4
CIBIS-II3

 However, significant mortality remains – ~50% of patients die within 5 years of diagnosis6–7
*On top of standard therapy at the time of study (except in CHARM-Alternative where background ACEI therapy was excluded). Patient populations varied between trials and as such
relative risk reductions cannot be directly compared. SOLVD (Studies of Left Ventricular Dysfunction), CIBIS-II (Cardiac Insufficiency Bisoprolol Study II) and RALES (Randomized
Aldactone Evaluation Study) enrolled chronic HF patients with LVEF≤35%. CHARM-Alternative (Candesartan in Heart failure: Assessment of Reduction in Mortality and Morbidity)
enrolled chronic HF patients with LVEF≤40%
• ACEI=angiotensin-converting-enzyme inhibitor; ARB=angiotensin  1. McMurray et al. Eur Heart J 2012;33:1787–847; 2. SOLVD Investigators. N Engl J Med
receptor blocker; HF=heart failure; ARR=absolute risk reduction; 1991;325:293–302; 3. CIBIS-II Investigators. Lancet 1999;353:9–13; 4. Pitt et al. N Engl J
HFrEF=heart failure with reduced ejection fraction; LVEF=left ventricular Med 1999;341:709-17; 5. Granger et al. Lancet 2003;362:772–66. 6. Yancy et al. Circulation
ejection fraction; MRA=mineralocorticoid receptor antagonist 2013;128:e240–327; 7. Levy et al. N Engl J Med 2002;347:1397–402
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 Landmark trials in patients with HFrEF
SOLVD-T1 (1991) CHARM-Alternative3 (2003) SHIFT5 (2010) PARADIGM-HF7 (2014)
2,569 patients 2,028 patients 6,558 patients 8,442 patients
Key benefits of enalapril (ACEI) Key benefits of candesartan Key benefits of ivabradine Key benefits of (ARNI) vs
vs placebo: (ARB) vs placebo: (If inhibitor) vs placebo: enalapril:
• 16%  all-cause mortality • 23%  CV mortality or HF • 18%  CV death or HF • 20%  CV mortality or
hospitalization hospitalization HF hospitalization

1990s 2000s 2010s

CIBIS-II2 (1999) CHARM-Added4 (2003) EMPHASIS-HF6 (2011)

2,647 patients 2,548 patients 2,737 patients
Key benefits of bisoprolol (BB) Key benefits of Key benefits of eplerenone
vs placebo: candesartan (ARB) vs (MRA) vs placebo:
• 34%  all-cause mortality placebo: • 37%  CV mortality or HF
• 15%  CV mortality or HF hospitalization
hospitalization

Percentages are relative risk reductions vs comparator 1. SOLVD Investigators. N Engl J Med 1991;325:293–302
ACEI=angiotensin-converting enzyme inhibitor; ARB=angiotensin receptor blocker; 2. CIBIS-II Investigators. Lancet 1999;353:9–13; 3. Granger et al. Lancet 2003;362:772−6
ARNI=angiotensin receptor neprilysin inhibitor; BB=beta blocker; CV=cardiovascular; 4. McMurray et al. Lancet 2003;362:767–771; 5. Swedberg et al. Lancet 2010;376:875–85
6. Zannad et al. N Engl J Med 2011;364:11–21; 7. McMurray et al. N Engl J Med 2014;371:993–1004
HF=heart failure; HFrEF=heart failure with reduced ejection fraction;
MRA=mineralocorticoid receptor antagonist. See notes for definitions of study names
 Evolution of pharmacologic
approaches in HF:
ARNI as a new alternative to an ACEI or ARBs in
patients with HFrEF1
β-blockers
SNS
Epinephrine α1, β1, β2
Norepinephrine receptors
Neprilysin Vasoconstriction
inhibitors RAAS activity
Vasopressin
NP system HF SYMPTOMS &
PROGRESSION
Heart rate
Contractility
NPRs NPs

Vasodilation RAAS inhibitors

Blood pressure
RAAS
Sympathetic tone (ACEI, ARB, MRA)
Natriuresis/diuresis
Vasopressin Ang II AT1R
Aldosterone INACTIVE
Fibrosis FRAGMENTS Vasoconstriction
Hypertrophy Blood pressure
Sympathetic tone
ARNI Aldosterone
Hypertrophy
Fibrosis

 ARNI: enhancement of natriuretic and other vasoactive peptides, with simultaneous RAAS suppression
ACEI=angiotensin-converting enzyme inhibitor; Ang=angiotensin;
ARB=angiotensin
receptor blocker; AT1R=angiotensin II type 1 receptor; HF=heart failure; 1. McMurray et al. Eur J Heart Fail 2013;15:1062–73
HFrEF=heart failure with reduced ejection fraction; MRA=mineralocorticoid Figure references: Levin et al. N Engl J Med 1998;339:321–8 Nathisuwan & Talbert. Pharmacotherapy 2002;22:27–42
Kemp & Conte. Cardiovascular Pathology 2012;365–71
receptor antagonist; NP=natriuretic peptide; NPRs=natriuretic peptide receptors; Schrier & Abraham. N Engl J Med 2009;341:577–85
RAAS=renin-angiotensin-aldosterone system; SNS=sympathetic nervous system
 2016 ESC Guideline
Therapeutic algorithm for symptomatic
HFrEF

ACEI = angiotensin-converting enzyme inhibitor; ARB = angiotensin receptor

blocker; ARNI = angiotensin receptor neprilysin inhibitor; BNP = B-type natriuretic
peptide; CRT = cardiac resynchronization therapy; HF = heart failure; HFrEF =
heart failure with reduced ejection fraction; H-ISDN = hydralazine and isosorbide
dinitrate; HR = heart rate; ICD = implantable cardioverter defibrillator; LBBB = left
bundle branch block; LVAD = left ventricular assist device; LVEF = left ventricular
ejection fraction; MR = mineralocorticoid receptor; NT-proBNP = N-terminal pro-B
type natriuretic peptide; NYHA = New York Heart Association; OMT = optimal
medical therapy; VF = ventricular fibrillation; VT = ventricular tachycardia.

. Ponikowski et al. Eur Heart J 2016; 37(27): 2129-2200

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 2016 ACC/AHA/HFSA Focused
Update on New
Pharmacological Therapy for Heart Failure (1)

Recommendations for Renin-Angiotensin System Inhibition

With ACEi / ARB / ARNI
COR LOE Recomendation
I ACEi : A The use of ACE inhibitors is beneficial for patients with prior or current
symptoms of chronic HFrEF to reduce morbidity and mortality
I ARB : A The use of ARBs to reduce morbidity and mortality is recommended in patients
with prior or current symptoms of chronic HFrEF who are intolerant to ACE
inhibitors because of cough or angioedema
I ARNI : B-R In patients with chronic symptomatic HFrEF NYHA class II or III who tolerate
an ACE inhibitor or ARB, replacement by an ARNI is recommended to further
reduce morbidity and mortality
Notes • ARNI should not be administered concomitantly with ACE inhibitors or
within 36 hours of the last dose of an ACE inhibitor (III : Harm, B-R)
• ARNI should not be administered to patients with a history of angioedema
(III Harm, C-EO)

Yancy et al. Circulation 2016;134(13): e282–293

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 Summary

1. HF is a complex clinical syndrome that results from any

structural or functional impairment of ventricular filling or
ejection of blood
2. Biomarkers can assist clinician to diagnose, predict
prognosis, and guide the treatment of heart failure
3. Multiple pharmacological agent are useful in improving
mortality and morbidity.
4. Among them, ARNI was superior to ACEi in reducing the
risks of death and of hospitalization for heart failure

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Thank You