Pathophysiologic targets for acute heart failure therapy: The ... · Pathophysiologic targets for...
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Pathophysiologic targets for acute heart failure
therapy: The Cardiorenal Syndrome
Professor and Co-Head, Dept of Cardiology
President-elect ESC-HFA
University Heart Center
Zürich, Switzerland
Frank Ruschitzka, MD, FRCP, FESC
Conflict of interest: Abbott, Aventis, Bayer, Biotronik, Cardiorentis, Merck, Novartis, Pfizer,
SJM, Servier
Interest in Conflict: none
Acute
Acute
Acute
Acute
Allen L A et al. Circulation 2012;125:1928-1952
A depiction of the clinical course of heart failure
Chronic
Chronic
Chronic
What Are We Talking About?
Ekman Circ CV Outcomes 2010
Heart Failure is Moving Center Stage in Cardiology
-Twice as many hospitilizations than all Cancers
Heart Failure is Taking Center Stage
Deutscher Herzbericht 2014, Statistisches Bundesamt
Fatal MI Heart Failure
Acute Heart Failure: Clinical challenges
AHF ACS
Incidence ~ 1.000.000/y ~ 1.000.000/y
Mortality:
pre-hospital
in-hospital
60-90 days
?
3 – 6%
10%
high
3 – 4%
2 %
Targets of therapy Unclear Clearly defined
Clinical trials results
Guidelines (level of
evidence)
Minimal /no benefit
/harmful
A/B – minimal
mostly C
Beneficial
A/B – mostly
Weintraub Circ 2010
CardioRenal Syndrome
With patients‘ permission for publication
• 53y., banker
• Ischemic cardiomyopathy
• 3 HF hosp. in the last year
• Lisinopril 10mg 0-0-1
• Carvedilol 12.5mg 1-0-1
• Eplerenone 25mg 0-0-1
• Lasix 40mg 2-2-0
CardioRenal Syndrome
With patients‘ permission for publication
•NYHA IV, Dyspnea at rest
•170 cm, 76 kg (weight gain 4 kg in last 7 days)
•RR right arm, supine: 92/66mmHg
•Heart rate: 84/min/SR
•Cardiac auscultation:
• gallop
• 3/6 murmur, pm apex (MR)
• HJR pos.
• Pulmo: respiratory rate 18/min, right pleural effusion
• liver 11 cm in MCL
• peripheral edema
The Cardiorenal Syndrome
Decreased
cardiac
performance
Increased
water and Na+
retention
Impaired renal
function
Decreased
cardiac output
Neurohormonal
activation
Diminished
blood flow
Decreased renal
perfusion
What`s next?
1. Lasix iv
2. Levosimendan
3. Dobutamine
4. Milrinone
5. Norepinephrine
6. Nesiritide
7. LVAD
8. ECMO
9. Hemofiltration
Approach to Acute Therapy in Volume
Overloaded Heart Failure Patients
IV Diuretics
Adequate Perfusion
IV Diuretics
plus
IV Vasodilators
Reduced Perfusion
IV Diuretics
IV Inotropes
Cardiogenic Shock
Clinical Congestion
MCS
RR<85mmHgRR 85-110 mmHgRR >110mmHg
mod. JJ McMurray EHJ 2012
The Dilemma of Drug Therapy in Acute Heart Failure:
Patients with Pulmonary Edema/without shock
JJ McMurray EHJ 2012
Adaptative and maladaptative mechanisms to renal hypoperfusion in heart failure
Ruggenenti and Remuzzi Eur Heart J 2011
Compensated HF Decompensated HF
Packer JACC HF 2013
Baseline Characteristics in REVIVE I/II
Hospitalized ADHF but remained dyspneic at rest despite
treatment with intravenous diuretics
Packer JACC HF 2013
Outcomes in REVIVE I/II
Time to Death for Any Reason
During First 90 DaysHazard Ratio for All-Cause
Mortality
Mebazaa JAMA 2007
SURVIVE: Survival of Patients With Acute Heart
Failure in Need of Intravenous Inotropic Support
(SURVIVE)
mod. Forssmann Cardiovasc Res 2006
Urodilatin
• Synthesized in distal tubular cells
• Binds downstream in IMC duct to NPR-A
• Increases Renal Plasma Flow (via cGMP)
• Increases GFR:
• Dilates Vas afferens
• Constricts Vas efferens
• Relaxes mesangials cells
• Decreases sodium reabsorption in PCT and CD
via cGMP dependent phosphorylation of ENaC
• Inhibits renin, aldosterone, and vasopressin secretion
• NOT degraded by NEP inhibition
ANP, BNPUrodilatin/ularitide
Neprilysin
degrades NPs
Natriuretic Peptides and Receptors
Second messenger mediated effects of ularitide
↑cGMP
NPRA NPRBNPRC
GCGC
ANP, BNPUrodilatin/ularitide CNP
PDEProtein-
kinase G
cGMP-
gated ion
channels
NPRA-triggered effects
renin and
aldosterone
inhibiting
vasodilating
Anti-fibrotic
Anti-
hypertrophic
lusitropic
Anti-
apoptotic
Vascular
regeneration
Ularitide in the Kidney
Physiological and pharmacological effects
Physiology
Pharmacology
1
2
1
Synthesis of Urodilatin
as response to ↑Na+
2 Inhibition of sodium and
water reabsorption,
↑ diuresis and ↑ natriuresis
Meyer M, et al., Am J Physiol, 1996; 271(40);F489-497
Lenz W, et al., Kidney Int, 1999; 55:91-99.
1 2
3
4
1
2
3
Pre-glomerular vasodilation
Post-glomerular vasoconstriction
Endlich K, et al., Kidney Int, 1995 Jun;47(6):1558-68
↑ GFRCarstens J, et al., Clin Sci, 1997, 92(4):397-407
4
5
Less susceptible to NEP degradation
Kenny AJ et al. Biochem J, 1993;291:83-8
↑ diuresis and ↑ natriuresis
Abassi ZA, et al., Am J Physiol. 1992;262:F615-21
Villarreal D, et al, Am J Hypertens 1991;4(6):508-15
5
SIRIUS II: Patient-assessed Dyspnea
Moderately or Markedly Better
Mitrovic Eur Heart J 2006
% p
ati
en
ts
TRUE–AHF: TRial of Ularitide`s Efficacy in Patients with Acute Heart Failure
•Co-primary Efficacy Endpoints:• Improvement in a hierarchical clinical composite• All-cause mortality
clinicaltrials.gov
Relaxin
• Peptide hormone
• Similar in size and shape to insulin (MW 5963)
• Found in men and women
• Normal hormone of pregnancy
• Women “exposed” for 9 months to increased plasma concentrations:0.8-1.6 ng/ml pregnancy*
Szlachter et al, Obstet & Gynecol 1982;59:167-70
Stewart et al, J Clin Endocrinol Metab 1990;70:1771-3.
Relaxin
RELAX-AHF: CV death or readmission to hospital
for heart or renal failure during 60-day follow-up
Teerlink Lancet 2012
clinicaltrials.gov
Primary Outcome Measures:
•Time to confirmed cardiovascular (CV) death during the follow-up
period of 180 days
•Time to worsening of heart failure (WHF) through Day 5
RELAX-AHF-2
Therapy of Acute Heart Failure
DiuresisVasodilators
Inotrope
MCS
Vasoconstricted
(no real criteria)
Admission Low output
(No real criteria) or
refractory symptoms
10-15% of Patients
Nitro/Vasodilators
Relaxin?
Urodilatin?
Congestion
Loop
Diuretics
> 80% of
Patients
< 5% of patients
Levosimendan
Dobutamine
Milrinone
MCS
mod. Gheorghiade&Ruschitzka EHJ 2012
Merci
Frank Ruschitzka, MD, FRCP, FESC
President-elect ESC-HFA
University Heart Centre Zürich
Prevalence and Impact of Worsening Renal
Function in Patients with Acute Heart Failure:
POSH trial
Cowie EHJ 2006
Prevalence and Impact of Worsening Renal
Function in Patients with Acute Heart Failure:
POSH trial
Cowie EHJ 2006
BUN and Death or HF Rehospitalization
Log-Rank Test
P-Value = 0.0005
PR
OP
OR
TIO
N O
F R
EM
AIN
ING
IN
ST
UD
Y
0.5
0.6
0.7
0.8
0.9
1.0
DAYS IN STUDY
0 10 20 30 40 50 60 70
BUN > 40 mg/dL
BUN < 18 mg/dL
BUN 19-26 mg/dL
BUN 27-39 mg/dL
Filippatos G et al .J Cardiac Failure 2007
Baseline BUN and 60-day probability of death
Klein Circ Heart Failure 2008
Death /CTX Death /CTX/HF Rehosp.
Worsening Renal Function and Residual
Congestion Increase the Hazard for Death or
HF Rehospitalization
Metra Circ Heart Failure 2012
Death /CTX Death /CTX/HF Rehosp.
Determinants and forms of worsening
renal function in heart failure
Filippatos G et al. Eur Heart J 2013
Peacock, W. F. et al. J Am Coll Cardiol 2010;56:343-351
Risk Stratification Data Points in ED Patients With
Suspected Acute Heart Failure
Treatment : acute effects of IV diuretics in heartfailure
• Increase heart rate
• Decline cardiac filling pressure
• Rise in plasma renin activity
• Increase NA, renin, vasopressin
Relaxin
• Peptide hormone
• Similar in size and shape to insulin
(MW 5963)
• Found in men and women
• Normal hormone of pregnancy
• Women “exposed” for 9 months to
increased plasma concentrations:
0.8-1.6 ng/ml pregnancy*
Szlachter et al, Obstet & Gynecol 1982;59:167-70
Stewart et al, J Clin Endocrinol Metab 1990;70:1771-3.
Relaxin
RELAX-AHF: CV death or readmission to hospital
for heart or renal failure during 60-day follow-up
Teerlink Lancet 2012
mod. Forssmann Cardiovasc Res 2006
Urodilatin
• Synthesized in distal tubular cells
• Binds downstream in IMC duct to NPR-A
• Increases Renal Plasma Flow (via cGMP)
• Increases GFR:
• Dilates Vas afferens
• Constricts Vas efferens
• Relaxes mesangials cells
• Decreases sodium reabsorption in PCT and CD
via cGMP dependent phosphorylation of ENaC
• Inhibits renin, aldosterone, and vasopressin secretion
• NOT degraded by NEP inhibition
Differential Processing of ANP and Urodilatin – Cleavage of the signal peptide is different in heart and kidney
mod. Forssmann CVR 2006 and Histochem Cell Biol 1998
SIRIUS II: Patient-assessed Dyspnea
Moderately or Markedly Better
Mitrovic Eur Heart J 2006
% p
ati
en
ts
Outcome in SIRIUS-II
Mortality in SIRIUS II
13.2
3.3 3.8
1.8
0
5
10
15%
of
pat
ien
ts
Placebo 7.15 15 30Ularitide, ng/kg/min
European Heart Journal (2006) 27, 2823–2832
TRUE–AHF: TRial of Ularitide`s
EFFICACY IN PATIENTS with ACUTE HEART
FAILURE
STUDY DESIGN
Primary Efficacy: Global composite score (superiority)
Primary Safety: All-cause mortality and cardiovascular rehospitalisation and other significant cardiovascular events at 30 days / 3 months (non-inferiority)
Status: recruiting
clinicaltrials.gov
• BP 86/60 mmHg
• HR 90/min/SR
• PC 22 mmHg
• „lukewarm“
• iv Furosemide
•Dobutamine
•Levosimendan
Bromocriptine
• BP 82/60 mmHg
• HR 90/min/SR
• PC 22 mmHg
• „lukewarm“
• iv Furosemide
•Norepinephrine
•Levosimendan
•CVVHDF
•Bromocriptine
Moraca J Card Surg 2012
Strategy for Acute Refractory Cardiac
Failure: Bridge to Decision
ventilation, Systolic BP < 80
mmHg