Heart Failure

Pembekalan PPDS Angkatan 20

Definition
• Heart failure (HF) is a complex clinical syndrome resulting from
structural and functional impairment of ventricular filling or ejection
of blood.
• Although the clinical syndrome of HF may result from abnormalities
or disorders involving all aspects of cardiac structure and function,
most patients have impairment of myocardial function, ranging from
normal ventricular size and function to marked dilation and reduced
function.

Braunwald's Heart Disease: Textbook of Cardiovascular

Medicine 11th ed
ACC/AHA Stages of HF vs NYHA
Functional Classification

Braunwald's Heart Disease: Textbook of Cardiovascular

Medicine 11th ed
Pathophysiology of HF

Langenickel TH, Dole WP. Drug Discovery Today 2012;9:131–9.

Potential Therapeutic Role of The Neurohumoral Blockade

Cardiac structure/function abnormality

Activation of compensatory mechanisms to maintain

cardiac output and organ perfusion1

SNS RAAS NP system

β blocker RAAS blocker ?

ACEi : captopril, Lisinopril
bisoprolol, carvedilol, nebifolol ARB : valsartan, candesartan
MRA : spironolactone

Activated in response to reduced cardiac output1 Release of NPs in response to cardiac stress3
Short-term effects are beneficial in early HF1 Opposes the actions of the RAAS3 and SNS4,5
Long-term activation exerts unfavourable effects2
The Renin Angiotensin
Aldosterone System

ATII receptor1
The Sympathetic Nervous System

• HF is characterized by heightened
sympathetic tone
• Imbalances in baroreceptor reflexes
and AngII- dependent SNS activation
play an important role in adverse
haemodynamic and cardiac responses
• Stimulation of SNS in HF results in
• Heart rate
• Contractility
• Na reabsorption
• Renal and peripheral vascular
resistance

Ach=acetylcholine; AngII= angiotensin II;

Floras, JACC, 2009, 34: 375-85.
CV=cardiovascular; E=epinephrine; HF=heart failure;
NE=norepinephrine; SNS=sympathetic nervous system Lymperopoulos et al. Circ Res 2013;113:739–53.
 The Natriuretic Peptides
Atrial natriuretic peptide (ANP) B-type natriuretic peptide (BNP) C-type natriuretic peptide (CNP)
H2N H2N
H2N

HOOC-

HOOC-

HOOC-

 Expressed in the atria  Expressed in atrial and ventricular tissue  Expressed in vascular endothelial
 Measurable in plasma  Measurable in plasma cells
and central nervous system
 Not detectable in plasma: primarily
synthesized in vasculature, acting locally
in tissues

t½ in circulation = ~2 mins t½ in circulation = ~20 mins t½ in circulation = ~3 mins

Effects: Effects: Effects:
 Vasorelaxation  Vasorelaxation  Vasorelaxation
 ↑ Diuresis/natriuresis  ↑ Diuresis/natriuresis  More potent dilation of veins than ANP and
 ↓ Proliferation  ↓ RAAS activation (including aldosterone) BNP
 ↓ Hypertrophy  ↓ Sympathetic tone  Bone growth regulation
 ↓ Fibrosis  ↑ RBF and GFR  ↓ Proliferation
 ↓ RAAS activation (including aldosterone)  Myocardial relaxation  ↓ Hypertrophy
 ↓ Sympathetic tone  Lipid mobilization, metabolic effects  ↓ Fibrosis
 ↓ Cardiac preload  ↓ Inflammation
 ↑ Venous capacitance  ↓ Thrombosis
 ↑ RBF and GFR
 Myocardial relaxation
 Lipid mobilization, metabolic effects

ANP=atrial natriuretic peptide; BNP=B-type natriuretic peptide; CNP= Levin et al. N Engl J Med 1998;339;321–8; Gardner et al. Hypertension 2007;49:419–26;

11 C-type natriuretic peptide; GFR=glomerular filtration rate; RAAS=renin- Pandey. J Am Soc Hypertens 2008;2:210–16; Von Lueder et al. Pharmacol Ther 2014;144:41–9; Potter. FEBS J 2011;278:1808–17; Lumsden et al. Curr Pharm Des 2010;16:4080–
8;
angiotensin-aldosterone system; RBF=renal blood flow; t1/2=half-life Mangiafico et al. Eur Heart J 2013;34:886–93; Kousholt. Dan Med J 2012;59:B4469 Potter et al. Handb Exp Pharmacol 2009;191:341–66
Natriuretic peptides mediate a wide range of physiological effects via their receptors

Cardiomyocytes1 Endothelial cells1

ANP and BNP

CNP
NPR-A NPR-B NPR-C

GTP GTP Receptor

cGMP cGMP
Endocytosis
recycling

• Vasodilation1,2 • Vasodilation1,2 Inactivation

• Antihypertrophy1,2 • Antihypertrophy1,2 of NPs1,2,5
• Antiproliferation2 • Antiproliferation2
• Vascular regeneration1 • Vascular regeneration1
• Myocardial relaxation1 • Venodilation1
• Diuresis, natriuresis1,2 • Antifibrosis1
• Antiapoptosis1
• Anti-aldosterone1
• Renin secretion inhibition1,3
• Reduced sympathetic tone4
• Lipolysis1

ANP=atrial natriuretic peptide; BNP=B-type natriuretic peptide; 1. Mangiafico et al. Eur Heart J 2013;34:886–93; 2. Gardner et al.
cGMP=cyclic guanosine monophosphate; CNP=C-type natriuretic peptide; Hypertension 2007;49:419–26; 3. Pandey. J Am Soc Hypertens
14 GTP=guanosine triphosphate; NP=natriuretic peptide; NPR=natriuretic 2008;2:210–26; 4. Levin et al. N Engl J Med 1998;339;321–8;
peptide receptor 5. Von Lueder et al. Pharmacol Ther 2014 [Epub ahead of print]
The Natriuretic Peptides
Release of ANP and BNP from heart and CNP in vasculature1,2

 Sympathetic outflow2
 Vasopressin2 ANP/BNP2
 Salt appetite and water intake2
CNP
(endothelium)3

Relaxation;  arterial stiffness4

 Hypertrophy2,5–6
 Fibroblast proliferation4,7,8

 Na+/H2O loss2 Vasodilation2,3,4

 Aldosterone 2
 Systemic vascular resistance4
 Renin2  Pulmonary artery pressure4
 Pulmonary capillary wedge pressure4
 Right atrial pressure4
1. Mangiafico et al. Eur Heart J 2013;34:886–93; 2. Levin et al. N Engl J Med 1998;339;321–8; 3. Lumsden et al. Curr Pharm Des 2010;16:4080–8;
4. Langenickel & Dole. Drug Discovery Today: Ther Strateg 2012;9:e131–9; 5. Gardner et al. Hypertension 2007;49:419–26; 6. Tokudome et al.
Circulation 2008;117;2329–39; 7.Horio et al. Hypertension 2000;35:19–24; 8. D'Souza et al. Pharmacol Ther 200101:114;3–29

ANP=atrial natriuretic peptide;

BNP=B-type natriuretic peptide;
CNP=C-type natriuretic peptide;
HF=heart failure
Interaction between the action of Neprilysin and RAAS activation
The CV and renal effects of the NP system oppose to RAAS

Natriuretic peptide RAAS

Natriuretic peptide degradation and clearance over-activation
signaling and effects in HF

ANP ANP
ANP
CNP BNP BNP Inactive Ang II
BNP cleavage
CNP products
NPR-A NPR-B NPR-C CNP
AT1 receptor
Neprilysin

GTP GTP
Receptor
Endocytosis Signaling
recycling
cascades
cGMP
Inactivation of
NPs

Vasodilation Vasoconstriction
 Cardiac fibrosis/hypertrophy  Cardiac fibrosis/hypertrophy
 Natriuresis/diuresis  Sodium/water retention

ANP=atrial natriuretic peptide; Ang=angiotensin; AT1=angiotensin II type 1; BNP=B-type Levin et al. N Engl J Med 1998;339;321–8; Gardner et al. Hypertension 2007;49:419–26;

natriuretic peptide; cGMP=cyclic guanosine monophosphate; CNP=C-type natriuretic peptide; Molkentin. J Clin Invest 2003;111:1275–77; Nishikimi et al. Cardiovasc Res 2006;69:318–28;

18 GTP=guanosine triphosphate; NP=natriuretic peptide; NPR=natriuretic peptide receptor;

RAAS=renin-angiotensin-aldosterone system Guo et al. Cell Res 2001;11:165–80; Von Lueder et al. Circ Heart Fail 2013;6:594–605;
Yin et al. Int J Biochem Cell 2003;35:780–3; Mehta and Griendling. Am J Physiol Cell Physiol 2007;292:C82–97; Mangiafico et al. Eur Heart J 2013;34:886–93; Potter. FEBS J 2011;278:1808–17
Kalra PR, Angnostopoulos C, Bolger AP, Coats AJ, Anker SD. The regulation and measurement of plasma volume in
heart failure. J Am Coll Cardiol 2002;39:1901–08
Summary of Heart Failure patophysiology
Sympathetic
nervous system
Epinephrine α1, β1, β2
Norepinephrine receptors
Vasoconstrictio
n RAAS
Natriuretic peptide activity
system HF SYMPTOMS
&
Vasopressin
Heart rate
PROGRESSION Contractility
NPRs NPs

Vasodilation Renin-angiotensin-
Blood pressure
Sympathetic tone aldosterone system
Natriuresis/diure
sis Ang II
Vasopressin
Aldosterone
Fibrosis AT1R
Hypertrophy
Vasoconstrictio
n Blood pressure
Sympathetic
tone
Aldosterone

Ang=angiotensin; AT1R=angiotensin II type 1 receptor; HF=heart failure;
NPs=natriuretic peptides; NPRs=natriuretic peptide receptors; RAAS=renin-
19 angiotensin-aldosterone system
Hypertrophy
Fibrosis& Talbert.
Levin et al. N Engl J Med 1998;339:321–8; Nathisuwan
Pharmacotherapy 2002;22:27–42; Kemp & Conte. Cardiovascular Pathology
2012;365–71; Schrier & Abraham. N Engl J Med 2009;341:577–85
HOW TO DEAL WITH HF
Guideline ESC 2016

ARNI
• New concept in blood
pressure maintenance and
systems
• ARNI+ARB  diberikan
pada pasien HF dengan
reduce EF <35% dengan
pemberian adekuat
ACE+BB+MR antagonist
• ARNI berperan di brain
natriuretic pathway.
• Kombinasi obat yang ada
di pasar:
• Sacubitril dan Valsartan
Acute Heart Failure
Definition
• AHF is defined as rapid onset of symptoms and signs, secondary to
abnormal cardiac function

• Acute heart failure was historically described as a pump failure

causing downstream hypoperfusion and upstream congestion

Understanding acute heart failure: pathophysiology and diagnosis, Eur Heart J Suppl (2016)
Trigger of AHF

Ponikowski. ESC Guidelines for the diagnosis and

treatment of acute and chronic heart failure. 2016
Goals of treatment in acute heart failure
CLASSIFICATIONS
• AHF is classified :
depends on whether patients have a past history of heart
failure or not
1. Acutely decompensated chronic heart failure (ADCHF), in
patients with a heart failure history
2. De novo AHF, in individuals without a past history of heart
failure

• 2016 ESC Guidelines for the diagnosis and treatment of acute and chronic heart
failure: Eur J Heart Fail. 2016; 18: 891–975
• The ESC Textbook of Intensive and AcuteCardiovascular Care (2 ed.), 2018
• European Journal of Heart Failure (2010) 12, 423–433
CLASSIFICATIONS
• AHF is classified :
depends on the level of systolic blood pressure
(SBP) at presentation
1. Hypertensive AHF: SBP >140mmHg
2. Normotensive AHF: SBP falls between 90 and 140 mmHg
3. Hypotensive AHF: SBP < 90 mmHg

• 2016 ESC Guidelines for the diagnosis and treatment of acute and chronic heart
failure: Eur J Heart Fail. 2016; 18: 891–975
• The ESC Textbook of Intensive and AcuteCardiovascular Care (2 ed.), 2018
• European Journal of Heart Failure (2010) 12, 423–433
 usually a hx of prog.
Classification of AHF worsening of known chronic HF on Rx,
and evidence of systemic/pulmonary
congestion.

high BP, +/- preserved LV systolic fxn;

increased sympathetic tone with ↑HR,
vasoconstriction; may be euvolaemic or
only mildly hypervolemic, and frequently
with signs of pulmonary or systemic
congestion

Severe respiratory distress, ↑RR,

orthopnea, rales. O2 sats <90% RA prior
to O2

Clinical and lab evidence of an ACS;

~15% of patients with an ACS have
signs and symptoms of HF. Episodes
of AHF are frequently assoc w/ or
precipitated by arrhythmia
(bradycardia, AF, VT).
Usually sys BP <90 mmHg or drop in
MAP >30 mmHg and absent/low
urine output. Organ hypoperfusion
and pulmonary congestion develop
rapidly
low output in absence of
pulmonary congestion with
increased JVP, w/ or w/out HSM,
and low LV filling pressures
ESC 2008
ECG (low specificity)
• ARRHYTMIA
• ISCHEMIA
• HF is unlikely, in a completely normal ECG (sensitivity
• 89%) --> the routine ECG --> recommended to rule out HF.
Radiology feature of AHF

• 20% ~
NORMAL
ECHOCARDIOGRAPHY
BNP and NT Pro-BNP

in the acute setting, higher values should be used

BNP >100 pg/mL ;
NT-proBNP > 300 pg/ mL
mid-regional pro A-type natriuretic peptide (MR-proANP) > 120
pmol/L]

AHF as the cause for the presenting symtoms suspicious of AHF

Management
MANAGEMENT
ACUTE
HEART
FAILURE

Ponikowski P, et al. Eur Heart J

doi:10.1093/eurheartj/ehw128
Flowchart to diuretic use in acute heart failure

Mullens et al. European Journal of Heart Failure (2019) 21, 137–155

Ponikowski P, et al. Eur Heart J
doi:10.1093/eurheartj/ehw128
 Intravenous diuretic and ultrafiltration

• Regularly monitor renal function and electrolytes

• Ultrafiltration should be considered in patients with refractory volume

overload and acute kidney injury and may be considered in patients

with refractory congestion who fail to respond to diuretic-based therapy

Ponikowski P, et al. Eur Heart J doi:10.1093/eurheartj/ehw128
 Intravenous vasodilators

Ponikowski P, et al. Eur Heart J doi:10.1093/eurheartj/ehw128

Ponikowski P, et al. Eur Heart J doi:10.1093/eurheartj/ehw128
Ponikowski P, et al. Eur Heart J doi:10.1093/eurheartj/ehw128
 Synergistic effect

Diuretics works in Diuretics works in

channel electrolyte channel water
Management of patients with cardiogenic shock
Cardiogenic shock is defined as hypotension (SBP <90 mmHg)
despite adequate filling status with signs of hypoperfusion
THYROID HEART FAILURE
 The Interactions Between Thyroid
Hormones and the Cardiovascular
System
The main effects of
thyroid
hormones :
The heart (by influencing rate, rhythm,
myocardial contraction, and risk of
coronary artery disease)

The vascular tree (through regulating

blood pressure via smooth muscle tone
and endothelial function)

Direct effects on cardiovascular risk

factors (via lipid metabolism and
modulation of inflammatory pathways)
Effect of thyroid hormones on the cardiomyocyte via
genomic and nongenomic actions
Commonly Defined Categories of Thyroid
Status

These definitions Levels are

of thyroid deemed
dysfunction are abnormal when
based on the they are below or
distribution of above the 2.5th
serum TSH and and 97.5th
free T4 percentiles,
concentrations. respectively.

Cappola AR et al. Circulation. 2019;139:2892–2909.

 Guidelines With Recommendations for Management of
Thyroid Dysfunction Coexistent With CVD
• Thyroid testing for a first episode and when ventricular rate is
Atrial fibrillation difficult to control

Heart failure • Thyroid testing at initial presentation

Dilated • Thyroid testing at initial presentation

cardiomyopath
y
• Thyroid testing before, within 3 mo of initiation, and every 3–
Amiodarone use 6 mo or thyroid testing before, at 1 and 3 mo after initiation,
and every 3–6 mo.

Cappola AR et al. Circulation. 2019;139:2892–2909.

Mechanistic Effects of Duration of
Hyperthyroidism on the Evolution of
Heart Failure
Hyperthyroidism
Characterized biochemically by a
low TSH level and elevated T4, T3,
or both. Commonly due to Grave’s
disease, toxic adenoma, and toxic
multinodular
goiter.
This congestive circulation results
from the increases in the blood
volume and heart rate, and the
associated pulmonary arterial
hypertension.

Salman Razvi et al. JACC 2018;71:1781-

 Subclinical Hyperthyroidism
SHyper grade 1 : low, but detectable serum TSH levels
[e.g., TSH 0.1 to 0.39 mU/l])

SHyper grade 2 : suppressed serum TSH levels < 0.1

mU/l

Patients with Subclinical Hyperthyroidism may have an increased risk of AF, HF, and
CV disease.

Management of SHyper should include control of thyroid function and prevention of

CV complications.

Salman Razvi et al. JACC 2018;71:1781-

HF in
Hypothyroidism

Hernando and Eliana, Endocrinol Metab Synd 2015,

4:2
Cardiovascular Concequences
Overt hypothyroidism : reduction in cardiac output, a
decrease in heart rate, and an increase in peripheral
vascular resistance and diastolic dysfunction

Significant changes in modifiable atherosclerotic risk factors

: hypercholesterolemia, diastolic hypertension, increased
carotid intimal-media thickness, and reduced endothelial
nitric oxide

Subclinical Hypothroidsm : diastolic dysfunction due to

impaired ventricular filling and relaxation. Impaired
relaxation of vascular smooth muscle cells, inducing
increases in systemic vascular resistance and arterial
stiffness.
Salman Razvi et al. JACC 2018;71:1781-
 Management Cardiovascular Disease in
Hypothyroidism
Thyroid replacement therapy is beneficial in patients
with subclinical hypothyroidism.

Great caution is needed in treating such patients with

thyroid hormone replacement. The key is to “go low
and go slow.”

The goal of therapy is a euthyroid state with normal

TSH.

And, of course, improvement in myocardial ischemia

and cardiac function.
HEART FAILURE AND DIABETES
MELLITUS
Shannon M. Dunlay. Circulation. Type 2 Diabetes Mellitus and Heart Failure: A Scientific
Statement From the American Heart Association and the Heart Failure Society of America:
This statement does not represent an update of the 2017 ACC/AHA/HFSA heart failure
guideline update, Volume: 140, Issue: 7, Pages: e294-e324, DOI:
(10.1161/CIR.0000000000000691)
© 2019 by the American Heart Association, Inc., and the
Heart Failure Society of America.
Systemic interdependence of heart failure and type 2 diabetes mellitus.

European Heart Journal, Volume 39, Issue 48, 21 December 2018, Pages 4243–4254,
https://doi.org/10.1093/eurheartj/ehy596
What the Guidelines
Says

72
Cosentio F, et al., European Heart Journal (2019) 00, 1¾69 doi:10.1093/eurheartj/ehz486
 73
Cosentio F, et al., European Heart Journal (2019) 00, 1¾69 doi:10.1093/eurheartj/ehz486
What the Guidelines
Says

74
Cosentio F, et al., European Heart Journal (2019) 00, 1¾69 doi:10.1093/eurheartj/ehz486
HEART FAILURE due to HYPERTENSION
Iriarte M, Murga N, Sagastagoitia D, et al. Classification of hypertensive cardiomyopathy. Eur Heart J 1993;14 Suppl J:95–101.
NICE Guidelines on Hypertension, 2019
HEART FAILURE WITH RENAL
IMPAIRMENT
Acute heart failure with renal impairment
ANAEMIA IN HEART FAILURE
THANK YOU