Pathophysiologic targets for acute heart failure therapy: The ... · Pathophysiologic targets for acute heart failure therapy: The Cardiorenal Syndrome Professor and Co-Head, Dept

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?

Current Estimate of the Number of

Advanced HF Patients

Miller and Guglin JACC 2013

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



•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

Cardiorenal Syndrome


The New Definition of Cardiorenal Syndrome

Ronco C. et al, EHJ 2010

Filippatos G et al. Eur Heart J 2013

Classification and Stages of Acute Kidney

Injury

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

//Ronco et al., JACC 2008

AKI = 1.5-2 x Cr (baseline)

Cardiorenal Syndrome Type 1

Ronco et al., JACC 2008

Cardiorenal Syndrome Type 1

What`s next?

1. Lasix iv

2. Levosimendan

3. Dobutamine

4. Milrinone

5. Norepinephrine

6. Nesiritide

7. LVAD

8. ECMO

9. Hemofiltration

Carubelli Heart Fail Rev 2012

Causes of renal dysfunction in HF

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

Algorithm for the management of AHF

Mebazaa EHJ 2015

Felker NEJM 2011

JACC 2012

Diuretic Strategies in Patients with Acute

Heart Failure. The Dose Trial

Blunted Response to Loop Diuretics in Acute Heart Failure

Braunwald EHJ 2014

Adaptative and maladaptative mechanisms to renal hypoperfusion in heart failure

Ruggenenti and Remuzzi Eur Heart J 2011

Compensated HF Decompensated HF

Carubelli Heart Fail Rev 2012

Causes of resistance to furosemide

Ultrafiltration in Decompensated Heart

Failure with Cardiorenal Syndrome: CARRESS-HF

Bart NEJM 2012

CARRESS Trial: Changes from Baseline

in Serum Creatinine and Body Weight

Bart NEJM 2012

CARRESS-HF: Serious Adverse Events

Bart NEJM 2012

The Dilemma of Drug Therapy in Acute Heart Failure

JJ McMurray EHJ 2012


•Lasix iv boli

•Levosimendan•0.1 to 0.2 μg/kg/min

Hasenfuss and Teerlink, EHJ

2011

Inotropic Therapies

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

Packer JACC HF 2013

Worsening Clinical Status Requiring Rescue

Therapy in REVIVE I and REVIVE II

Mebazaa JAMA 2007

SURVIVE: Survival of Patients With Acute Heart

Failure in Need of Intravenous Inotropic Support

(SURVIVE)

Mebazaa JAMA 2007

SURVIVE: Primary and Secondary Outcomes

So etiology may influence response to milrinone (all inotropes?)

JAMA 2002; JACC 2003

Teerlink, Lancet 2011

Dose-dependent changes in echocardiogram

measures by omecamtiv mecarbil dose

Metra Eur Heart J 2012

Effects of pharmacological agents on renal

function parameters

deGoma JACC 2006

Diuretics and Aquaretics

Rolofylline: Change in Serum Creatinine

Gottlieb Circ 2002

PROTECT: Rolofylline fails to meet PrimaryEndpoint which included renal function!

Massie NEJM 2010

PROTECT: Rolofylline fails to meet PrimaryEndpoint which included renal function

Massie NEJM 2010

deGoma JACC 2006


EVEREST: Primary Endpoints

Konstam JAMA 2007

deGoma JACC 2006


??

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

SIRIUS II: Renal Safety of Urodilatin


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: Patient reported Dyspnea

Teerlink Lancet 2012

RELAX-AHF: CV death or readmission to hospital

for heart or renal failure during 60-day follow-up


RELAX-AHF:

Cardiovascular and All-Cause Death


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

Another 3 days later...


•Lasix iv boli

•Levosimendan•0.1 to 0.2 μg/kg/min

Renal Function pre and post LVAD-

Implantation

pre-LVAD post-LVAD



Kidney Functions Remains Stable 7 years

post Heart Transplantation

Merci

Frank Ruschitzka, MD, FRCP, FESC

President-elect ESC-HFA

University Heart Centre Zürich

[email protected]

Approach to Renal Dysfunction in Acute

Heart Failure

Damman EHJ 2014

Henry Kissinger (1923 - )

The absence of

alternatives clears the

mind marvelously

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 of Cardiorenal Syndrome Type 1

Roubille et al., Blood Purif 2014

Treatment : acute effects of IV diuretics in heartfailure

• Increase heart rate

• Decline cardiac filling pressure

• Rise in plasma renin activity

• Increase NA, renin, vasopressin

//

CRS and Diuretics HF, Diuretics and NGAL

Treatment : Diuretics

Ronco et al.

Algorithm for the management of AHF

Mebazaa EHJ 2015

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: Patient reported Dyspnea


RELAX-AHF: CV death or readmission to hospital

for heart or renal failure during 60-day follow-up


RELAX-AHF:

Cardiovascular and All-Cause Death


Natriuretic Peptides

Cardiovasc Res 2006

NT pro BNP and BNP

Cardiomyocyte

Blood

Corti Circ 2001

Natriuretic Peptides- The Natural Born

Enemies of Angiotensin II

VMAC: Nesiritide vs Nitroglycerin

JAMA 2002

Meta-Analysis can be misleading...

Effect of Nesiritide in Patients with Acute

Decompensated Heart Failure

O’Connor NEJM 2011

Effect of Nesiritide in Patients with Acute

Decompensated Heart Failure

O’Connor NEJM 2011

deGoma JACC 2006


??

Rank Order of Hydrolysis by NEP is

CNP>ANP>BNP>Urodilatin

Cardiovasc Res 2006

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


% p

ati

en

ts

SIRIUS II: Renal Safety of Urodilatin


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


2011

Inotropic Therapies

OPTIME: Long-Term Effects of Inotropes

JAMA 2002

So etiology may influence response to

milrinone (all inotropes?)

JAMA 2002; JACC 2003

Mebazaa JAMA 2007

SURVIVE: Effect of Dobutamine and

Levosimendan on All-Cause Mortality


2011

Mode of action of cardiac myosin

activators

Teerlink, Lancet 2011

Dose-dependent changes in echocardiogram

measures by omecamtiv mecarbil dose

• BP 82/60 mmHg

• HR 90/min/SR

• PC 22 mmHg

• „lukewarm“

• iv Furosemide

•Norepinephrine

•Levosimendan

•CVVHDF

•Bromocriptine

So now what?

1. ECMO

2. IABP

3. LVAD

4. BiVAD

5. CRT

6. high urgency listing

7. 2+5+6

8. 3+6

Circuit Configuration of VA ECMO

Gaffney BMJ 2010

Circuit Configuration for VA vs VV ECMO

Moraca J Card Surg 2012

Strategy for Acute Refractory Cardiac

Failure: Bridge to Decision

ventilation, Systolic BP < 80

mmHg

Wer nur die Chemie versteht,

versteht die auch nicht recht.

Georg Christoph Lichtenberg

1742-1799

Wer nur das Herz versteht,

versteht die Kardiologie nicht recht.

Zürich 2012

Wer das Herz nicht versteht,

ist kein guter Internist.

Zürich 2012

Pathophysiologic targets for acute heart failure therapy: The ... · Pathophysiologic targets for acute heart failure therapy: The Cardiorenal Syndrome Professor and Co-Head, Dept

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