Acute Decompensated Heart Failure : What is New ?

1. Prof. U. C. SAMAL
MD, FICC, FACC, FIACM, FIAE, FISE, FISC, FAPVS
Ex-HOD Medicine & Prof. Cardiology
Patna Medical College, Patna, Bihar
Past President, Indian College of Cardiology
Permanent & Chief Trustee, ICC-HFFI
National Executive Member, Cardiological Society of India
President, CSI Bihar
Acute Decompensated Heart Failure :
What Is New ?

2. Drug failures in acute heart failure
Trial name Drug tested Patients enrolled
VMAC Nesiritide Decompensated CHF
Excluded SBP < 90 mmHg, Mean SBP > 124 mmHg
No LVEF cut point
OPTIME Milrinone Decompensated systolic heart failure,
not requiring inotropes
Excluded SBP < 80 mmHg, Mean SBP = 120 mmHg
Mean LVEF = 23%
VERITAS Tezosentan Acute heart failure
Two out of four-↑BNP, pulmonary oedema, CXR
congestion,
LVEF < 40%, Mean LVEF = 20% in VERITAS I and
28% in VERITAS II
Mean SBP = 131 in VERITAS I and 132 in VERITAS II
SURVIVE Levosimendan Acute decompensated HF requiring inotropes
LVEF < 30%, Mean LVEF = 24$
Mean SBP-116 mmHg

3. Trial name Drug tested Patients enrolled
REVIVE -2 Levosimendan Acute decompensated HF
Symptomatic despite i.v. diuretic
LVEF < 35%, Excluded SBP > 90 mmHg
EVEREST Tolvaptan Hospitalized for decompensated CHF
LVEF ≤ 40%, Excluded SBP < 120 mmHg
Mean LVEF = 27.5%, Mean SBP= 120 mmHg
PROTECT I
and II
Rolofylline Acute heart failure, Impaired renal function
↑BNP
ASCEND-HF Nesiritide Acute decompensated heart failure
Drug failures in acute heart failure

4. Some new therapeutic agents for acute heart
failure and their potential targets
Agent For patients with these
clinical features
Diuretics, vasopressin
antagonists,
adenosine antagonists
Patients with signs of fluid
overload, high BNP
Vasodilators Normal to high SBP, high BNP
Inotropes Low SBP, signs of
Hypoperfusion
Renal preservation agents Renal dysfunction
Myocardial protection agents CAD, or ongoing ischaemia

5. Proposed classification for patients who present with acute
heart failure syndromes
ACCF/AHA
stage
Explanation of stage
Worsening chronic
HF (75%)
Stage C C: structural heart disease with
prior or current symptoms of HF
Advanced HF (5%) Stage D D: refractory HF requiring
specialized interventions
De novo HF (20%) Stage B most
common, but also
Stage A
Also neither A
nor B
B: structural heart disease but
without signs or symptoms of HF
A: at high risk for HF but without
structural heart disease or
symptoms of HF

6. Phases of acute heart failure syndromes management
PHASES
PHASES GOALS AVAILABLE TOOLS
Initial or
emergency
department
phase of
management
Treat life threatening
conditions
Establish the diagnosis
Determine the clinical
profile
Identify and treat
precipitant
Disposition
Examples: STEMI - reperfusion therapy
History, physical exam, EKG, X-ray,
natriuretic peptide level
BP, HR, signs (e.g. pulmonary oedema),
ECG, X-ray,
laboratory analysis, echocardiography
History, physical exam, X-ray, ECG,
laboratory analysis
No universally accepted risk-stratification
method
Frontiers in Cardiovascular Medicine EHJ 2010:31;784-793

7. Phases of acute heart failure syndromes management
PHASES
PHASES GOALS AVAILABLE TOOLS
IN – HOSPITAL
PHASE
Monitoring and
reassessment
Assess right and left
ventricular pressures
Assess and treat (in the
right patient) other cardiac
and non-cardiac conditions
Assess for myocardial
viability
Signs/symptoms, HR, SBP, ECG,
orthostatic changes, body weight,
laboratory analysis (BUN/Cr,
electrolytes), potentially BNP
SBP (orthostatic changes, valsalva
manoeuvre), echocardiography, BNP/NT-
proBNP, PA catheter
Echo-Doppler, cardiac catheterization,
electrophysiology testing
MRI, stress testing, echocardiography,
radionuclear studies
Frontiers in Cardiovascular Medicine EHJ 2010:31;784-793

8. Phases of acute heart failure syndromes management
PHASES
PHASES GOALS AVAILABLE TOOLS
DISCHARGE
PHASE
Assess functional capacity
Re-evaluate exacerbating
factors (e.g. non-
adherance, infection,
anaemia, arrhythmias,
hypertension) and treat
accordingly
Optimize pharmacological
therapy
Establish post-discharge
planning
6 min walk test
Examples: physical therapy, education for
diet control and medication, evaluation for
sleep apnoea
ACCF/AHA and ESC guidelines
Discharge instructions including body
weight monitoring, smoking cessation,
medication adherance, follow-up
Frontiers in Cardiovascular Medicine EHJ 2010:31;784-793

9. Frontiers in Cardiovascular Medicine EHJ 2010:31;784-793
ESC divides pts. Into six clinical profiles
1.Worsening or decompensated chronic HF
2.Pulmonary Oedema
3.Hypertensive HF
4.Cardiogenic shock
5.Isolated right HF
6.ACS and HF with the explicit acknowledgement
that there is overlap between groups
The ACCF/AHA divides patients based on
presenting clinical profile into three main
groups:
(i) volume overload, manifested by pulmonary
and/or systemic congestion, usually due to
increases in blood pressure (BP),
(ii) severely reduced cardiac output often with
hypotension, and
(iii) combined volume overload and cardiogenic
shock
ESC Guidelines

10. Initial Therapeutic Management
Target Therapeutic example Mechanism of action Side effects
Alleviate
congestion
IV furosemide Water and sodium
excretion
Electrolyte abnormalities
Reduce
elevated LV
filling
pressures
IV nitrates Direct relaxation of
vascular smooth muscle
cells through various
mechanisms
Hypotension, decreased
coronary perfusion
pressure
Poor cardiac
performance
Inotropes Activate camp or calcium
sensitization resulting in
improved contractility; also
powerful vasodilators: in
effect, inodilators
Hypotension,
arrhythmias, myocardial
damage, association with
increased morbid events
Tachycardia
and increased
systemic blood
pressure (i.e. in
cases of
excessive
sympathetic
tone
Beta-blockers: IV esmolol
may be used when HF is
related to AF with RVR
and/or severe hypertension
Blockade of beta-1 and
beta-2 receptors
Bradycardia,hypotension,
negative inotropy;
however given short half-
life of esmolol, these side
effects should be short
lived
Frontiers in Cardiovascular Medicine EHJ 2010:31;784-793

11. Short- and long-term novel therapies for AHF syndromes
Short term Long term Both
Levosimendan [LIDO, CASINO, SURVIVE]
Nesiritide[ROSE, DOSE-AHF]
Relaxin [RELAX-AHF]
Myosin Activators Omecamtiv Mecarbil
[ATOMIC-AHF]
RyR2 stabilizers/ rycals
Cinaciguat (UIT)
Adenosine regulating agents
Stresscopin
Istaroxime [HORIZON-HF]
Ularitide [TRUE-AHF, SIRIUS II, URGENT]
Urocrotins [UNICORN]
Hypertonic Saline
Ultrafiltration [RAPID-CHF, UNLOAD]
IABP
EECP [PEECH]
CAFA
IMT
Direct renin
Inhibitors (DRI)
[ASTRONAUT]
Macronutrients
Micronutrients
CRT/AICD
Adenosine Antagonists
[PROTECT, REACH UP rolofylline]
Vasopressin Antagonists
[EVEREST, TACTICS-HF]
Digoxin [DIG]
CD-NP
Frontiers in Cardiovascular Medicine EHJ 2010:31;784-793 modified 2013

12. Clinical RELEVANCE of promising novel biomarkers(AHFS)
Biomarker Diagnosis Prognosis Therapy guidance Cardiac
Production
NT-proBNP and
BNP
++++ ++++ ++ Solely
Serum Sodium ++ ++ ++ No
Serum Creatinine ++ ++ ++ No
MR-proANP +++ ++++ Likely similar to NT-
ProBNP/BNP
Solely
sST2 + ++++ ? Not Exclusively
Hs troponin-I
[EFFECT]
+ ++++ ? Solely
MR-proADM - ++++ ? No
Cystatin C - ++++ ? No
NGAL - ++++ ? No
GDF-15 - +++ ? Not Exclusively
β- Trace protein - +++ ? No
Gal-3 - +++ ? Not exclusively
CRP - ++ ? No
TNF-α - ++ ? No
IL-6 - ++ ? No
PTX3 - ++ ? Unknown
MPO - ++ ? Not exclusively
ET-1 - ++ ? Not exclusively
Copeptin - ++ ? No
PCT ++ ++ ++ No
12
Clinical Chemistry 58:1 127–138 (2012)

13. Summary of the main utility biomarkers in AHFS
Biomarkers Diagnosis & pathophysiology Adverse prognosis
Serum sodium n.v. 136-145mmol/L
AHF –RAA activation
<120mmol/L
Serum creatinine n.v. 0.5 – 1.5mg/dL
Cardiorenal syndrome
> 150µmol/L
Serum uric acid n.V m 3.1 -8.1mg/100ml, 2.2
-7.1mg/100ml
AHF –oxidative stress
>1.5mg/dl
>9.8mg/dl
NPs [blood & serum]
BNP
NT-pro-BNP
MR-pro-ANP
v.n. HF cut off
<100pg/ml; >400pg/ml
<400pg/ml; >2000pg/ml
<120pmol/l; 120pmol/l
AHF left ventricular volume and
pressure overload [heart muscle
stretching]
> 1000pg/ml
> 5000pg/ml
--
ST2 [serum] n.V 1.75 -34.3U/ml
AHF overload
>10ng/ml

14. Summary of the main utility biomarkers in AHFS
Biomarkers Diagnosis & pathophysiology Adverse prognosis
PCT [serum] Cut off 0.05ng/ml 0.05 -0.5ng/ml local infection
0.5-2ng/ml systemic infection
2-10ng/ml SIRS – sepsis
>10ng/ml sepsis
NGAL [serum and
urine]
Cut off 150ng/ml serum, 130ng/ml urine
Cardiorenal syndrome
>100ng/ml
Copeptin [serum] Median 3.7pmol/l
AHF vascular alterations
>54.2pmol/l
MR-proADM [SERUM] AHF vascular alterations >2.15nmol/l
ADMA AHF oxidative stress

15. Modes of presentation of ADHF
Clinical status Heart
rate
SBP
mmHg
Cl L /
min /m3
Pulmonary
capillary
wedge
pressure
mmHg
Conges
tion
killip/for
rester
Diuresis Hypope
rfusion
End organ
hypoperfusion
I acute
decompensated
congestive heart
failure
+ / - Low
normal /
high
Low
normal /
high
Mild elevation K II / F II + +/- _
II Acute heart failure
with hypertension/
hypertensive crisis
Usually
elevated
High +/- >18 K II-IV/ F
II / III
+/- +/- + WITH CNS
symptoms
III Acute heart
failure with
pulmonary edema
+ Low
normal
Low Elevated K III / F II + +/- -
IVa Cardiogenic
shocka/low-output
syndrome
+ Low
normal
Low, <2.2 >16 K III-IV/ F
I-III
Low + +
IVb Severe
cardiogenic shock
>90 <90 <1.8 >18 K IV / F IV Very low ++ +
V High-output
failure
+ +/- + +/- K II / F I-II + - -
VI Right-sided acute
heart failure
Usually
low
Low Low Low F I +/- +/-, acute
onset
+/-

16. Patient presenting with dyspnea
Differential diagnosis
cardiac -- Consider acute
coronary syndrome
Physical exam, chest x-ray,
ECG, BNP level
Treatment option for HF with SBP
<90mmHg or shock –diuretics,
inotropes, vasodilators and /or
nesiritide to follow
BNP <100pg/ml BNP 100-500pg/ml BNP >500pg/ml
HF very unlikely [2%] Clinical suspicion of
HF or past h/o HF
HF very likely [95%]
HF highly probable [90%]
Differential diagnosis
noncardiac -- consider
COPD, pulmonary
embolism, asthma,
pneumonia, sepsis
Treatment option for HF with SBP >
90mmHg -- diuretics with nesritide
esp. with CKD & pulmonary
congestion may consider adding
vasodilators if hypertensive may
consdider adding inotropes for poor
perfusion
Treatment option --
•Diuretics as required
•Consider nesritide if any of the
following - Scr>1.5mg/dl, CrCl
<60ml/min, BUN >10mg/dl,
pulmonary congestion or for border
line hemodynamic instability

17. Comprehensive Assessment
Potential targets Method of assessment
Congestion JVP, Body wt, peripheral edema
LV function, valvular ds, wall
motion abnormalities, aneurysm
ECHO Doppler, MRI, Nuclear
imaging
Ischaemia Pharmacological or exercise
testing with imaging
CAD Cardiac catheterization and
angiography
Ventricular dyssnchrony [wide
QRS]
Electrocardiogram
Viable but dysfunctional
myocardium
Low dose dobutamine ECHO, MRI

18. Myocardium Coronary
arteries
Electrical
system
Valves
•Surgery
•Procedural
•Statins
•Per EDC
guidelines
Pericardium
LV
dysfunction
•ACE-I or ARB
•Beta blockers
•Aldosterone
antagonist
•Hydral / ISDN
•Digoxin
•Macronutrients
•Micronutrients
•Metabolic
modulators
CAD
•Anti platelet
•Statins
•Revascularization
•Other ESC
guideline
recommended
therapy for
secondary
prevention
Sudden cardiac
death
•ICD
•B- blockers
•Aldesterione
antagonist
Ventriculasr
dysschrony
•CRT +/- ICD
Atrial fibrillation
•Rate control – digoxin – b-
blocker, non dihydropyridine ca
channel blockers
•Warfarin
•Rhythm control
•MAZE procedure
Congestion – [ salt restriction, diuretics, ultrafiltarion, vasopressin antagonists]
Hypertension [ACE I or ARB, diuretics, other per ESC guidelines
Enhance adherence [education, disease management, performance improvement system
Cardiac reconstruction
[five overacting thematic targets – myocardium, coronary arteries, electrical system, pericardium, valves]

19. Mortality %

20. AHFS : NOT VERIFIED
Similarities and differences between acute MI & AHFS in
hospitalization in the US
Incidence 1 million per year 1 million per year
Mortality
Pre hospitalization
In hospital
After discharge [ 60-90 d]
High
3-4%
2%
?
3-4%
10%
Myocardial injury Yes Likely
Pathophysiological target Clearly defined
[coronary thrombosis]
Uncertain
Clinical benefits of
interventions in published
clinical trial
Beneficial Minimal / no benefit or
deleterious compared with
placebo
ACC / AHA recommendation LEVEL A NONE
Circulation
Circulation
Special report
Acute Heart Failure Syndrome

21. Omecamtiv Mecarbil (OM) is a
Novel Selective Cardiac Myosin
Activator
Malik FL, et al. Science 2011; 331:1439-43
Teerlink JR, et al. Lancet 201; 378:667-75; Cleland JGF, et al. Lancet
2011; 378:676-83

24. Acute Heart Failure Syndrome(s)
• Acute heart failure (AHF) is defined as a rapid
onset or change in the signs and symptoms of
HF, resulting in the need for urgent therapy.
• Symptoms are primarily the result of severe
pulmonarycongestion due to elevated left
ventricular (LV) filling pressures(with or without
low cardiac output).
• AHFS can occur in patientswith preserved or
reduced ejection fraction (EF).
• Concurrentcardiovascular conditions such as
coronary heart disease (CHD),hypertension,
valvular heart disease, atrial arrhythmias, and/or
noncardiac conditions (including renal
dysfunction, diabetes,anemia) are often present
and may precipitate or contributeto the
pathophysiology of this syndrome

25. EBM in AHFS?
• The first randomizedplacebo-controlled
AHFS trials were published as late as
2002.
Cuffe MS, et al. for the Outcomes of a Prospective Trial of Intravenous Milrinone forExacerbations of Chronic Heart Failure (OPTIME-CHF) Investigators. Effects of short-term,
intravenous milrinone on acute exacerbation of chronic heart failure: a randomized controlled trial. JAMA. 2002; 287: 1541–1547.
PublicationCommittee forthe VMAC Investigators. Intravenous nesiritide vs nitroglycerin fortreatment of decompensated congestive heart failure: a randomized controlled trial.
JAMA. 2002; 287: 1531–1540
• None of the placebo-controlled AHFS
studies conducted to datehas shown
either a consistent improvement of in-
hospital orpostdischarge survival or a

26. AHFS – Goals of treatment
• † Emergency treatment phase
• Improve symptoms
• Restore oxygenation
• Improve organ perfusion and haemodynamics
• Limit cardiac/renal damage
• Minimize ICU length of stay
• † In-hospital management phase
• Stabilize patient and optimize treatment strategy
• Initiate appropriate (life-saving) pharmacological therapy
• Consider device therapy in appropriate patients
• Minimize hospital length of stay
• † Discharge planning phase
• Plan follow-up strategy
• Educate and initiate appropriate lifestyle adjustments
• Provide adequate secondary prophylaxis
• Prevent early readmission
• Improve quality of life and survival

27. AHFS: which appropriate targets
of therapy ?
• Traditionally, reduction in pulmonary
capillary wedge pressure (PCWP)and/or
increase in cardiac output.
• However, other therapeutictargets may
include blood pressure control, myocardial
protection,neurohormonal modulation, and
preservation of renal function.

28. Treatment of AHFS Patients
• The emergencytreatment phase

29. Patient Selection and Treatment
Congestion at Rest
YesNo
Warm & Dry
PCWP normal
CI normal
(compensated)
Cold & Wet
PCWP elevated
CI decreased
Cold & Dry
PCWP low/normal
CI decreased
Vasodilators
Nitroprusside
Nitroglycerin
Inotropic Drugs
Dobutamine
Milrinone
Calcium Sensitizers
Normal
SVR
High
SVR
Low
Perfusion
at Rest
No
Yes
Warm & Wet
PCWP elevated
CI normal
Natriuretic
Peptide
Nesiritide
or
Stevenson LW. Eur J Heart Fail. 1999;1:251.

30. Adverse Drug Effects
• Non-Potassium-Sparing Diuretics
Intravenous loop diuretics may improve symptoms and fluid loss
initially but also may contribute to renal function decline.This may
be related not only to intravascular volume depletionbut also to
further neurohormonal activation resulting in avasomotor
nephropathy.
• Intravenous loop diuretics may be associated with worse
outcomes in AHFS patients.
• Inotropic Therapy
Intravenous inotropes increase myocardial oxygen consumption,
causing myocardial damage in the setting of hibernating
myocardium. Use of inotropes has consistently been associated
with increasedmortality.
• Vasodilators
Excessive vasodilatation in AHFS may lead to blood pressure
decrease, potentially exacerbating myocardial ischemia and renal
hypoperfusion.

31. AHFS: which appropriate targets
of therapy ?
Perspectives
• Managing fluids,
• Preserving renal function

32. • Loop diuretics are an essential component of therapy for patients with acute decompensated
heart failure, but there are few prospective data to guide their use.
• In a prospective, double-blind, randomized trial, we assigned 308 patients with ADHF to
receive furosemide administered intravenously by means of either a bolus every 12 hours or
continuous infusion and at either a low dose (equivalent to the patient’s previous oral dose) or
a high dose (2.5 times the previous oral dose).
• Among patients with ADHF, there were no significant differences in patients’ global
assessment of symptoms or in the change in renal function when diuretic therapy was
administered by bolus as compared with continuous infusion or at a high dose as compared
with a low dose.
Furosemide

33. • The study tests the hypothesis that in patients admitted with acutely decompensated heart failure (ADHF),
achievement of adequate body hydration status with intensive medical therapy, modulated by combined
bioelectrical vectorial impedance analysis (BIVA) and B-type natriuretic peptide (BNP) measurement, may contribute
to optimize the timing of patient’s discharge and to improve clinical outcomes.
• 300 ADHF pts underwent serial BIVA and BNP measurement. Therapy was titrated to reach a BNP value of 250
pg/ml, whenever possible.
• Our study confirms the hypothesis that combined BNP/BIVA sequential measurementshelp to achieve adequate fluid
balance status in patients with ADHF and can be used to drive a ‘‘tailored therapy,’’ allowing clinicians to identify
high-risk patients and possibly to reduce the incidence of complications secondary to fluid management strategies.

34. Ultrafiltration

35. • Small studies have indicated that adenosine A1
receptor antagonists enhance diuresis and may
improve renal function in patients with chronic heart
failure or AHF.
• 2,033 AHF pts, volume overload, eCrCl 20 - 80
ml/min, and elevated BNP randomized (2:1) within 24
h of hospital presentation to rolofylline 30 mg/day or
intravenous placebo for up to 3 days.
• In this large, phase III clinical trial, the adenosine A1
receptor antagonist rolofylline did not prevent
persistent worsening renal function in AHF patients
with volume overload and renal dysfunction.
Rolofylline

36. •Effects of rolofylline on endpoints in relation to baseline renal function.
•The secondary morbidity/mortality endpoint, the risk of death or cardiovascular or renal rehospitalization through
day 60, was lower in the rolofylline group compared with the placebo group only in patients with a baseline eCrCl 30
ml/min (hazard ratio: 0.64; 95% CI: 0.43 to 0.95), but not in the other subgroups
Rolofylline

37. AHFS: which appropriate targets
of therapy ?
• Contractility
• Diastole

38. • Istaroxime is a novel intravenous agent with inotropic and lusitropic properties related to inhibition of Na/K
adenosine triphosphatase (ATPase) and stimulation of sarcoplasmic reticulum calcium ATPase.
• 120 AHF pts and reduced systolic function. Three sequential cohorts of 40 patients each were randomized 3:1
istaroxime:placebo to a continuous 6-h infusion. The first cohort received 0.5 g/kg/min, the second 1.0 g/kg/min, and
the third 1.5 g/kg/min istaroxime or placebo.
• In patients hospitalized with HF, istaroxime improved PCWP and possibly diastolic function. In contrast to available
inotropes, istaroxime increased SBP and decreased HR.
Istaroxime

39. •Urocortins are a recently discovered group of peptide hormones of the corticotropin releasing factor
family. They bind with a strong affinity to the CRH-R2 receptor, which is highly expressed in the
myocardium and in the vascular endothelium.
•Urocortins exhibit potent inotropic and lusitropic effects on rat and sheep hearts and activates a group of
myocyte protective pathways collectively known as ‘reperfusion injury salvage kinase’.
•In healthy humans show that brief intravenous infusions of urocortin 2 in healthy humans induce
pronounced dose-related increases in cardiac output, heart rate, and left ventricular ejection fraction while
decreasing systemic vascular resistance; similar effects were seen in HF patients.
Urocortins

40. AHFS: which appropriate targets
of therapy ?
• Vasomotion

41. • Nesiritide is approved in the United States for early relief of dyspnea in patients with acute heart failure.
Previous meta-analyses have raised questions regarding renal toxicity and the mortality associated with
this agent.
• We randomly assigned 7141 patients
• Coprimary end points were the change in dyspnea at 6 and 24 hours, and the composite end point of
rehospitalization for heart failure or death within 30 days.
• Nesiritide was not associated with an increase or a decrease in the rate of death and rehospitalization
and had a small, nonsignificant effect on dyspnea when used in combination with other therapies.
• It was not associated with a worsening of renal function, but it was associated with an increase in rates
of hypotension. On the basis of these results, nesiritide cannot be recommended for routine use in the
broad population of patients with acute heart failure.
Nesiritide

42. These molecules have been engineered to combine the beneficial aspects of different natriuretic peptides
into a single molecule while minimizing potentially negative actions.
CD-NP is a combination of C-type natriuretic peptide (CNP) and Dendroapsis NP
(DNP).
Although lacking natriuretic effects, CNP is a more selective venodilator than BNP, thus reducing the risk of
significant hypotension. On the other side, DNP possesses significant natriuretic activity, at the expense of
possible hypotensive effects.
The chimeric peptide CD-NP combines the favourable natriuretic effects of DNP with the venodilatory profile
of CNP, reducing the risk for harmful side effects.
Preliminary studies in AHFS patients are ongoing.
Chimeric natriuretic peptides

43. • Cinaciguat (BAY 58-2667) is a soluble guanylate cyclase (sGC, second messenger that internalizes the message
carried by intercellular messengers such as peptide hormones and NO) activator that is being developed as a first-
in-class treatment for acute decompensated heart failure (ADHF). It acts independently of the sGC ligand nitric
oxide.
• Cardioprotective effects in animal models, and pilot clinical studies found that it was well tolerated, unloaded the
heart and increased cardiac output.
• This placebo-controlled, randomized, double-blind, multicenter, international phase IIb study investigated the safety
and efficacy of intravenous cinaciguat (per-protocol) as add-on to standard therapy in 139 patients with ADHF
(NYHA functional class III and IV; pulmonary capillary wedge pressure [PCWP] ≥ 18 mmHg).
• Cinaciguat rapidly and significantly reduced PCWP and PVR and increased cardiac output in patients with ADHF,
without impairing cardiac or renal function. Hypotension occurred in some patients; further dose titration studies
are therefore required to establish the optimal dosing strategy for this promising new therapy.
Cinaciguat

44. Adenosine regulating agents
•This new class of drugs, whose prototype is represented by acadesine, has been developed to mimic the
protective effects of adenosine during ischaemia.
•Acadesine exerts its pharmacological actions by increasing adenosine bioavailability and by activating
50adenosine monophosphate (AMP) signalling cascade via its metabolite 5-aminoimidazole-4-carboxamide
riboside (ZMP).
•The first mechanism leads to multiple anti-ischaemic effects (maintenance of endothelial function and
vasodilation, inhibition of platelet aggregation and neutrophil activation), whereas the latter ameliorates
glucose uptake and free fatty acid oxidation thus increasing ATP synthesis. Importantly, acadesine exerts
its actions only in areas undergoing net ATP catabolism (such as ischaemic tissues) thereby avoiding
potentially harmful peripheral vasodilator effects.
Acadesine

45. First identified as a pregnancy hormone with powerful vascular effects, relaxin is
currently under investigation for its systemic and renal vasodilatory actions.
In AHFS patients with high SBP, data from a Phase II trial have demonstrated an
improvement in dyspnoea with a single dose.
A Phase III clinical trial is currently underway.
Relaxin

46. In-Hospital Management Phase
• This phase begins once the patient is stabilized
and dyspneais improved.
• Because a significant number of patients
continueto have signs and symptoms of HF, the
goals of this phase arecontinued hemodynamic
and symptomatic improvement while preventing
myocardial and renal injury.
• Patients who are not treated withACE inhibitors,
angiotensin receptor blockers, ß-blockers,or
aldosterone antagonists should receive these
therapies, asrecommended by recent guidelines

47. AHFS: in-hospital management
(ADHERE/OPTIMIZE-CHF/EURO-HF)

48. Discharge-Planning Phase
• Despite the clinical evidence supporting the use of
implantablecardiac defibrillators and cardiac
resynchronization therapyin patients with chronic
HF and systolic dysfunction, theirrole in AHFS
patients is not clear.
• The available data suggest that a significant number
of AHFSpatients are not being evaluated for
potential beneficial surgicalprocedures that include
myocardial revascularization, LV reconstruction,
mitral valve surgery, or cardiac transplantation.

49. AHFS where are we? Where are we going?
• AHFS is a complex condition with substantial morbidity and
mortalityand enormous utilization of health resources and cost.
• Thereare numerous challenges in caring for this population.
• UniformAHFS classification is currently lacking, and management
strategiesvary markedly.
• There is a general consensus that to reduce mortality,morbidity, and
the economic burden of AHFS, systematic researchefforts on clinical
application and translation of promisingbasic science results are
needed.
• Pathophysiologically basedinterventions (eg, cardiorenal syndrome)
may be particularlyappealing.
• A special focus should be on choice of appropriatemanagement
strategies, including minimizing the use of drugswith adverse
effects and development and validation of knownprognostic markers
to guide AHFS interventions.

50. …of note, every large published clinical trial conducted in patients with
AHFs has been negative in terms of efficacy, safety, or both.
…However, most international multicenter clinical trials completed to
date were conducted on fairly undifferentiated populations of patients
with AHFs.
….homogeneous pathophysiological disease states within the
heterogeneity of aHFs is of paramount importance to clinical trial design
and aHFs therapy.
… Future trials conducted in aHFs must abandon the ‘one-sizefits- all’
approach in favor of an approach that takes into account the varied and
distinct pathophysiologies of aHFs.

51. Milton Packer 2008 JCF
• … Yet, despite substantial advances in our understanding and
management of heart failure, we have had
• few successes and many failures.
• Nearly 1,000 new drugs and devices have been developed for
the treatment of heart failure duringthe past 20 years, but only
9 have received regulatory approval and are being used in the
clinical setting.
• Most of our efforts to correct fluid retention, stimulate the
inotropic state of the heart, and modulate neurohormonal
systems have not predictably improved the condition of
patients with HF…

52. Apelin

53. rhBNP
D
R I
M
K
R
G
S
S
S
S
G
L
G
F
C
C
S S
G
SGQVM
K V L
R
R
H
KPS
Effects of Nesiritide
Venous, arterial, coronary
VASODILATION
CARDIAC
INDEX
Preload
Afterload
PCWP
Dyspnea
HEMODYNAMIC
CARDIAC
No increase in HR
Not proarrhythmic
Aldosterone
Endothelin
Norepinephrine
SYMPATHETIC AND
NEUROHORMONAL SYSTEMS
Fluid volume
Preload
Diuretic
usage
NATRIURESIS
DIURESIS
RENAL

70. (1) Symptom relief.
(2) Measures of congestion relief (i.e. improvement in
clinical signs).
(3) Index hospitalization data (e.g. length of stay).
(4) Prevention of end-organ damage (heart and
kidney).
(5) Post-discharge: death and rehospitalization data.
Federal Drug Administration (FDA) Study Group as a general
guide for choosing the components of the endpoints to be
included when testing different types of drugs in different patient
subgroups, although not all of them would be necessary in a
single trial
Position Statement European Journal of Heart Failure (2011)

73. Simplified schematic of guanylyl cyclase (GC) pathways, which have cyclic guanosine monophosphate (cGMP) as their second messenger. Nitric
oxide is produced by endothelial cells and activates soluble GC in the target cell. ANP and BNP stimulate GC-A (also called NP receptor A), while
CNP stimulates GC-B (also called NP receptor B). DNP is a GC-agonist first discovered in snake venom. CD-NP is a chimeric peptide composed of
the ring structure and amino terminus of CNP and the carboxyterminus of DNP; it activates both GC-A and GC-B. Natriuretic peptides also bind to
the non-GC-linked natriuretic peptide C receptor, the biological significance of which beyond NP clearance is currently unclear. Cyclic GMP
modulates cGMP-dependent protein kinase G, cGMP-regulated PDEs, and cGMP-regulated cation channels. The cGMP signal is terminated by
PDEs that hydrolyze cGMP to GMP, or by extrusion into the extracellular space. The NPs are degraded by a variety of peptidases. Cyclic GMP
signaling can be enhanced by (1) the use of NO mimetics such as nitrovasodilators, (2) direct sGC stimulators, (3) exogenous NPs, (4) inhibiting
NP degrading enzymes, and (5) inhibiting the activity of cGMP-hydrolyzing PDEs. ANP, atrial natriuretic peptide; BNP, B-type natriuretic peptide;
cGMP, cyclic guanosine monophosphate; GMP, guanosine monophosphate; GC, guanylyl cyclase; DNP, Dendroaspis natriuretic peptide; DPP4,
dipeptidyl peptidase IV; NEP, neutral endopeptidase; NO, nitric oxide; PDE, phosphodiesterase; PKG, protein kinase G; RA, natriuretic peptide
receptor A; sGC, soluble guanylate cyclase.

74. Schematic illustrating three different forms of soluble guanylate cyclase and their respective responsiveness to nitrovasodilators, heme-dependent
sGC stimulators (e.g., BAY 41-2272), and heme-independent sGC activators (e.g., cinaciguat [also known as BAY 58-2667]). Nitric oxide (NO) and
nitrovasodilators only stimulate sGC when it, contains the heme moiety with a ferrous iron (Fe2+
); furthermore, NO and nitrovasodilators have cGMP-
independent actions. BAY 41-2272 also activates only the NO-sensitive sGC but without the cGMP-independent actions of NO and nitrovasodilators.
Cinaciguat activates heme-free sGC, which is insensitive to NO, and also inhibits its degradation. The question marks indicate that little is known
about the transition between the different forms, their prevalence in health and disease, and their potential restoration to the reduced, NO-sensitive
form. cGMP, cyclic guanosine monophosphate; Fe, iron; sGC, soluble guanylate cyclase.
(From Boerrigter G, Burnett JC Jr. Soluble guanylate cyclase: not a dull enzyme. Circulation 2009;119(21):2752-2754.)

75. Mechanism of action of novel contractility-enhancing medications. Levosimendan enhances contractility by increasing responsiveness of
myofilaments to calcium. The cardiac myosin activator CK 1827-452 stimulates myosin adenosine triphosphatase (ATPase), thereby increasing force
generation. Istaroxime inhibits activity of plasma membrane sodium-potassium ATPase and increases the activity of sarcoplasmic/endoplasmic
reticulum calcium ATPase (SERCA). ADP, adenosine diphosphate; ATP, adenosine triphosphate; I-1, protein phosphatase inhibitor-1; P, phosphate;
PLB, phospholamban; PP1, protein phosphatase; RyR2, ryanodine receptor; TnC, troponin C; TnI, troponin I; TnT, troponin T.
(Modified from Tavares M, Rezlan E, Vostroknoutova I, et al. New pharmacologic therapies for acute heart failure. Crit Care Med 2008; 36[Suppl]:S112-
S120.)

76. Forrester Hemodynamic Subsets
Subset Description
I: Warm and dry (normal)
PCWP 15–18 mmHg and CI
>2.2 L/min/m2
II: Warm and wet (congestion)
PCWP >18 mmHg and CI >2.2
L/min/m2
III: Cold and dry (hypoperfusion)
PCWP 15–18 mmHg and CI
<2.2 L/min/m2
IV: Cold and wet (congestion and
hypoperfusion)
PCWP >18 mmHg and CI <2.2
L/min/m2

77. Treatment Goals for ADHF
•Improve symptoms, especially congestion and low-output sympt.
•Restore normal oxygenation
•Optimize volume status
•Identify etiology
•Identify and address precipitating factors
•Optimize chronic oral therapy
•Minimize side effects
•Identify patients who might benefit from revascularization
•Identify patients who might benefit from device therapy
•Identify risk of thromboembolism and need for anticoagulation
•Educate patients concerning medications and self-management of
heart failure
•Consider and, where possible, initiate a disease-mgt. program

78. Subset I: Warm and Dry
• Therapy is the optimization of oral medications
Pharmacotherapy for ADHF
Subset II: Warm and Wet
• Patient has hypervolemia
• IV diuretics and plus or minus vasodilators, nesiritide

79. Subset III: Cold and Dry
• Patient has hypoperfusion
• Therapy:
oIf PCWP <15 mmHg, IV fluids until PCWP 15–18
mmHg
oIf PCWP ≥15 mmHg and MAP <50 mmHg, IV
dobutamine
oIf PCWP ≥15 mmHg, MAP ≥50 mmHg and
compelling indication for inotrope, IV inotrope
oIF PCWP ≥15 mmHg, MAP ≥50 mmHg and no
compelling indication for inotrope, IV vasodilator
Pharmacotherapy for ADHF

80. Subset IV: Cold and Wet
• Patient has hypoperfusion and hypervolemia
• Therapy:
oIV diuretics
oIf MAP <50 mmHg, IV dobutamine
oIf MAP ≥50 mmHg and compelling indication for
inotrope, IV inotrope
oIf MAP ≥50 mmHg and no compelling indication for
inotrope, IV vasodilator
Pharmacotherapy for ADHF

81. Discharge Criteria for Patients With ADHF
•Treat exacerbating factors (i.e., discontinuation of contraindicated
medications)
•Patient is at a "dry" weight
•Oral medication regimen stable for 24 hours
•Patient and family education completed, including clear discharge
instructions
•Left ventricular ejection fraction documented
•Smoking cessation counseling initiated
•Follow-up clinic visit scheduled, 7 to 10 days out
•Optimal pharmacologic therapy achieved or intolerance
documented
•Plans for postdischarge management

82. Ideal properties for an acute heart failure
syndromes therapy
• Improve signs and symptoms (e.g. dyspnoea)
• Improve haemodynamics without adversely effecting heart rate
and blood pressure
• Improve the neurohumoral profile
• Do not cause myocardial and/or kidney damage
• Be effective in the context of current evidence-based therapy
such as ACE-I and beta-blockers
• Demonstrate efficacy in both the acute and chronic setting
• Be affordable
• Reduce both in-hospital and post-discharge morbidity and
mortality.

83. Differential diagnosis include :
• Myocardial infarction
• Congestive HF
• Pneumonia
• COPD exacerbation
• Cardiac tamponade
• Anxiety
• Pulmonary embolism
• Asthma

84. Medicine and dietary non compliance :
Cardiac causes
•Ischemia
•Arrhythmia
•Uncontrolled hypertension
Noncardiac causes
•Infection (pneumonia with or without hypoxia)
•Exacerbation of comorbidity (chronic obstructive
pulmonary disease)
•Pulmonary embolus
Toxins (nonsteroidal anti-inflammatory drugs)
Volume overload

85. Istaroxime: Na/K-ATPase
Inhibitor
Change in left ventricular dP/dtmax comparing istaroxime (PST-
2744) to dobutamine in 5 dogs with chronic ischemic heart
failure. No difference was found between PST-2744 and 5
μg/kg/min dobutamine. Both significantly increased dP/dtmax (p
< 0.05). Reproduced with permission.J Am Coll Cardiol. 2006;48(12):2397-2409.

86. Responses of Natriuretic Peptides, ET-1, and Cortisol
Mean 95% confidence interval of atrial natriuretic peptide (ANP), brain natriuretic peptide (BNP), cortisol,
endothelin-1 (ET-1), and N-terminal pro-brain natriuretic peptide (NT-proBNP) during and after 4-h infusions
(shaded in gray) of placebo (open circles) or urocortin (Ucn2) (solid circles). *p < 0.05 and **p < 0.01 indicate
significant time-by-treatment interaction in the specific time phase.
Chan et al. JACC: Heart Failure Vol. 1,

87. Responses of Ucn-2, PRA, AngII, Aldosterone, and
Ucn-1
Mean 95% confidence interval of plasma aldosterone, angiotensin-II (AngII), plasma renin activity (PRA), urocortin-2
(Ucn2), and urocortin-1 (Ucn1) during and after 4-h infusions (shaded in gray) of placebo (open circles) or Ucn2 (solid
circles). yp < 0.001 indicates significant time-by-treatment interaction in the specific time phase.
Chan et al. JACC: Heart Failure Vol. 1,

88. Pulmonary Pressures, Cardiac Output, and
Calculated
Total Peripheral Resistance Responses
Right heart catheter parameters (mean SEM) during and after 4-h
infusions (shaded in gray) of placebo (open circles) or urocortin-2 (solid
circles). *p < 0.05 and yp < 0.001 indicate significant time-by-treatment
interaction in the specific time phase. cTPR ¼ calculated total peripheralChan et al. JACC: Heart Failure Vol. 1,

89. Congestion at rest
Low
perfustion
at rest
No Yes
Warm &
dry PCWP
normal CI
normal
Warm &
wet PCWP
elevatedCI
normal
Cold & dry
PCWP
low /
normal CI
decreased
Cold & wet PCWP
elevated CI decreased
Normal SVR High SVR
Natriuretic
Peptides
Nesiritide
Or
Vasodilators
Nitroprusside
Nitroglycerine
No
Yes
Inotropic Drugs
Dobutamine
Milrinone
Calcium Sensitizers