1

Cardiorenal Syndromes: New Insights into Combined Heart

and Kidney Failure

Peter A. McCullough, MD, MPH FACC, FACP, FAHA, FCCP, FNKF

History

•1913: Sir Thomas Lewis gave a clinical lecture on paroxysmal dyspnoea in cardiocardio--renalrenal patients with special reference to “cardiac” and “u remic” asthma•1951: the term cardiorenal syndromes (CRS) was coin ed by Ledoux [i]

•1997 to present: Schrier in multiple papers summar ized the impact of salt and water retention combined with neurohormonal activat ion in the pathogenesis of CRS.[ii] [iii] [iv]

•2003: Brammah and colleagues pointed out that treat ment of bilateral renal arterial disease could result in improvement of bot h heart and kidney function. [v]

•2005: Braam demonstrated in animals that organ dysf unction in one system influences that in the other. [vi]

•2008: Ronco and colleagues proposed five distinct CRS according to the temporal sequence of organ injury and failure as we ll as the clinical context. [vii]

•2008: Acute Dialysis Quality Initiative (ADQI) inv olving nephrology, critical care, cardiac surgery, and cardiology was convened. [viii]

•2011: Karger launches “Cardiorenal Medicine” James Sowers, MD, Editor•2012: ADQI conducted a second consensus conference to review the spectrum of pathophysiologic mechanisms involved in CRS [i] University College Hospital, London, November 12th, 1913. BMJ 2: 1417–1420. Ledoux P. [Cardiorenal syndrome]. Avenir Med. 1951 Oct;48(8):149-53.[ii] Blair JE, Manuchehry A, Chana A, Rossi J, Schrier RW, Burnett JC, Gheorghiade M. Prognostic markers in heart failure-congestion, neurohormones, and the cardiorenal syndrome. Acute Card Care. 2007;9(4):207-13.[iii] Sarraf M, Masoumi A, Schrier RW. Cardiorenal syndrome in acute decompensated heart failure. Clin J Am Soc Nephrol. 2009 Dec;4(12):2013-26.[iv] Sarraf M, Schrier RW. Cardiorenal syndrome in acute heart failure syndromes. Int J Nephrol. 2011[v] Brammah A, Robertson S, Tait G, Isles C. Bilateral renovascular disease causing cardiorenal failure. BMJ. 2003 Mar 1;326(7387):489-91.[vi] Bongartz LG, Cramer MJ, Doevendans PA, Joles JA, Braam B. The severe cardiorenal syndrome: 'Guyton revisited'. Eur Heart J. 2005 Jan;26(1):11-7.[vii] Ronco C, Haapio M, House AA, Anavekar N, Bellomo R. Cardiorenal syndrome. J Am Coll Cardiol. 2008 Nov 4;52(19):1527-39.[viii] Ronco C, McCullough PA, Anker SD, Anand I, Aspromonte N, Bagshaw SM, Bellomo R, Berl T, Bobek I, Cruz DN, Daliento L, Davenport A, Haapio M, Hillege H, House A, Katz NM, Maisel A, Mankad S, Zanco P, Mebazaa A, Palazzuoli A, Ronco F, Shaw A, Sheinfeld G, Soni S, Vescovo G, Zamperetti N, Ponikowski P; Acute Dialysis Quality Initiative (ADQI) consensus group. Cardiorenal syndromes: an executive summary from the consensus conference of the Acute Dialysis Quality Initiative (ADQI). Contrib Neph rol. 2010;165:54-67.

Outline

� Definitions

� Complex, bidirectional pathogenesis

� Novel diagnostic targets

� Therapy

� Putting it all together

Outline

� Definitions

� Complex, bidirectional pathogenesis

� Novel diagnostic targets

� Therapy

� Putting it all together

2

Cardiorenal Syndrome (CRS) General Definition:A pathophysiologic disorder of the heart and kidneys whereby acute or chronic dysfunction inone organ may induce acute or chronic dysfunction in the other organ

CRS Type I (Acute Cardiorenal Syndrome)Abrupt worsening of cardiac function (acutely decompensated congestive heart failure) leading to acute kidney injury

CRS Type II (Chronic Cardiorenal Syndrome)Chronic abnormalities in cardiac function (chronic congestive heart failure) causing progressive and permanent chronic kidney disease

CRS Type III (Acute Renocardiac Syndrome)Abrupt worsening of renal function (acute kidney ischaemia or tubular injury) causing acute cardiac disorder (new or decompensated heart failure)

CRS Type IV (Chronic Renocardiac Syndrome)Chronic kidney disease (diabetic nephropathy) contributing to decreased cardiac function, cardiac hypertrophy and/or increased risk of adverse cardiovascular events

CRS Type V (Secondary Cardiorenal Syndrome)Systemic condition (e.g. sepsis) causing both cardiac and renal dysfunction

Five Cardiorenal Syndromes

Ronco C, McCullough PA, Anker SD, et al; Acute Dialysis Quality Initiative (ADQI) consensus group. Cardiorenal syndromes: an executive summary from the consensus conference of the Acute Dialysis Quality Initiative (ADQI). Contrib Nephrol. 2010;165:54-67.

Recognition of Cardiorenal Syndrome

Definition of Acute Kidney Injury (KDIGO Guidelines 2012)

3

0.0

1.0

2.0

3.0

4.0

5.0

6.0

1 2 3 4 5

Ris

k of

WR

F(%

)

No. of Risk Factors

24%

38%

53%

29%

16%

Krumholz HM et al. Am J Cardiol. 2000;85:1110.

≤

Risk of Worsening Renal Function (WRF) by Number of Risk Factors

≥

N=1,681, WRF, defined as a rise in serum creatinine of >0.3 mg/dl (26.5 µmol/l).

Characteristics Adjusted OR

Women 1.41

HTN 1.64

Rales>Bases 1.28

HR >100 bpm 1.34

SCr ≥1.5 mg/dL 1.77

SBP >200 mm Hg 1.63

Outline

� Definitions

� Complex, bidirectional pathogenesis

� Novel diagnostic targets

� Therapy

� Putting it all together

4

Cardio-Renal Syndrome Pathophysiology

DM+HTN + other CKD

Renal hypoperfusion

Decreased GFR

Resistence to diuretics

Resistance to ANP/BNP

Na + H2O retention

Necrosis / apoptosis

Fibrosis

Biomarkers

↑BNP/NT-proBNP

↑ N-GAL

↑ KIM-1

↑IL-18

Catalytic iron

↑Cysta,n-C

↑Crea,nine

Urine albuminMany others

Altered Intra-renal Hemodynamics

Humoral

signallingCytokine

secretion

Precipitators

Diuretics

Vasodilators

Procedures Acute on

Chronic

Kidney

Injury

IL-1, TNF-

Alpha

↓Tubulo-

Glomerular

Function

Increased

venous

pressure

Chronic Neurohormonal

↑SNS, RAS, Aldosterone

↓Vitamin D

↑PTH

↑PO4

Hypotestesteronism

↓EPO

↓Fe u,liza,on

↓Na-K ATPase

Inciting Events

↓Medical compliance

↑Sodium intake

Ischemia

Arrhythmias (AF)

OSAS

Added Insults

NSAIDS, TZDs

Decreased Perfusion

Renal

Congestion

Toxicity

Vascocostriction

ANP/

BNP Natruretic Peptides

Leukocyte

ActivationEndothelial

Dysfunction

Blocked

Natriuresis

Acute on Chonic

Cardiac

Disease

McCullough PA, Diez J, KDIGO 2010 Workshopt, Adapted, Courtesy Ronco, C 2009

↑Cytokines, ↑Adhesion Molecules, ↑Enzyma,c Ac,va,on, ↑Oxida,ve Stress

Anemia/Rela,ve ↓Epo/Fe transport blocked

Acute Neurohoromonal Activation

SNS+RAS+Aldosterone+ Endothelin+ADH+, renal

vasoconstriction (adenosine)+prostaglandin

dysregulation

CKD-Associated Myocardial Changes

Myocyte hypertrophy

Myocyte dysfunction

↑↑Inters,,al Fibrosis

↓Capillary density

↑↑LV Mass

Elevated serum troponin levels

CKD-Associated Vascular Changes

Accelerated atherosclerosis

↑Vascular s,ffness

↓Smooth muscle density

Osteoblastic VSMC transformation

Intra-and extracellular calcification

LV Failure Mechanisms

• Pressure overload• Volume overload• Cardiomyopathy

Systolic or Diastolic Dysfunction or Both

High Central Venous Pressure and Cardiorenal Syndro me

JACC Vol. 53, No. 7, 2009

Venous Congestion and Glomerular Filtration

5

Tubular Recovery and Renal Reserve in AKI

Adapted fromThadhani et al., N Engl J Med 1996

~30% of In-hospital AKI results in permanent loss i n eGFR (~5% ESRD)~70% must have had tubular recovery or compensation by the remaining nephrons

Clinical EvaluationAnd Biomarkers

Advanced Imaging

Positron Emission Tomography

Power Doppler

BOLD MRI

Outline

� Definitions

� Complex, bidirectional pathogenesis

� Novel diagnostic targets

� Therapy

� Putting it all together

History of Urine in Western Medicine

� Ancient Babylonian and

Sumerian physicians

first inscribed their

evaluations of urine into

clay tablets as early as

4,000 B.C.

Figure: People showing for a diagnose

a sample of their urine to the physician

Constantine the African.

Yoquinto, My Health Daily News, Aug 15 2011

6

Blood and Urine Biomarkers of Acute Kidney Injury

Adapted from Geraghty et al. Am J Physiol Renal Physiol.1992; 263: 958-962, Westhuyzen, et al, NDT 2003, Endre Z, 2008, Kashani Crit Care 2013

Tubular EnzymuriaGGT, AlkPhos, LDH NAG, α/πGST,

NGAL, IL-18, KIM-1, L-FABP

Cr, Cystatin-C

G1 cell cycle arrest markers ([TIMP-2].[IGFBP7])

Predicted AKI DetectionMultimarker Panel Approach

AKI

0 h 4 h 8 h 12 h 24 h 48 h

Cystatin CCystatin C

IL 18IL 18KIMKIM--11

NGALNGAL

CreatinineCreatinine

Diagnostic value of biomarker Single CombinationLiangos et al., Biomarkers 2008 0.50-0.66 0.78Han et al., Clin JASN 2009 0.59-0.68 0.80-0.84Kashani K et al, Crit Care 2013 0.76-0.79 0.80

Adapted Courtesy Herget-Rosenthal 2010

Inducers of G1 cell cycle arrest (Urine [TIMP-2].[I GFBP7])

24

7

NEPHROCHECK® Test System: (TIMP-2 x IGFBP-7 Product in Spot Urine): Sapphire Study

25

the Astute Medical NEPHROCHECK® Test System has received 510(k) clearance through FDA’s de novo classification process. On 9/5/14 FDA: “Current laboratory tests can only assess whether a patient may already have AKI; often, the patient has progressed to moderate to severe AKI before the test results confirm the clinical diagnosis. NephroCheck detects the presence of insulin-like growth-factor binding protein 7 (IGFBP7) and tissue inhibitor of metalloproteinases (TIMP-2) in the urine, which are associated with acute kidney injury. Within 20 minutes, the test provides a score based on the amount of the proteins present that correlates to the patient’s risk of developing AKI within 12 hours of the test being performed. No other tests currently on the market are FDA-approved or cleared to assess the risk of developing AKI in at-risk patients.”

Baseline Samples and Prediction of AKI

Urinary [TIMP-2]•[IGFBP7] Discriminates Patients With

AKI From Those Without AKI

(Topaz Study)

Bihorac et al, AJRCCM 2014

8

Day 1 Day 2 Day 3 Day 4 Day 5

12 hrs. after

NEPHROCHECK® Test

PositivePositiveAKIRisk™

Score = 2.6

NEPHROCHECK®

Test Performed

NEPHROCHECK®

Test Performed

Urine

Output(UO, mL/h)

Serum

Creatinine(SCr, mg/dL)

Fluid Balance(Cumulative)

Therapies

Hours 0 12 24 36 48 60 72 84 96 108

Case #1

+6.4L

3x SCr Baseline

3x SCr Baseline

AKI<0.5ml/kg/h for ≥12h

0.5 ml/kg/h

Cardiac Surgery: 6 hrs.

Pump time: 1.5 hrs.

No Transfusion

+11.2L+9.5L +12.5L

1.3 SCr 1.3 SCr Baseline

Goetz et al. Mol Cell 2002

NGAL

Siderophore

Iron

NGALControl

Neutrophil Gelatinase-Associated Lipocalin (NGAL) – a specific biomarker of acute kidney injury

Neutrophil Gelatinase-Associated Lipocalin (NGAL) – a specific biomarker of acute kidney injury

NGAL is an endogenous bacteriostatic protein by reducing available catalytic iron

NGAL is an endogenous bacteriostatic protein by reducing available catalytic iron

Goetz et al. Mol Cell 2002

NGAL Siderophore

Iron

E. coli

X

with NGAL

without NGALbacterial growth curves

NGAL

Siderophore

Labile Iron

·O 2

-

Haber Weiss

Fe3+

Fe2+

O 2

OH · H 2 O 2Fenton

Ferric Iron = Fe3

+ ; Ferrous iron= Fe2

+ ; hydrogen peroxide = H2

O2

;

Hydroxyl radical = OH . ; Hydroxide anion = OH - ; oxygen = O2 ;

superoxide anion = . O2

-

ACS

AKIOxidative Stress Reactions

OH -H2O++

9

33

NGAL for the Diagnosis of AKI in the Emergency Department

Nickolas TL, et al. Ann Intern Med. 2008;148:810-819.

N = 635

0

250

500

750

1000

1250

1500

*

*

*

* *

*

AKI PrerenalAzotemia

CKD NormalKidney

Function

Uri

ne N

GA

L, µ

g/g

0.00

2.00

4.00

6.00

8.00

10.00

12.00

14.00

16.00

18.00

20.00

*

*

*

**

***

*

AKI PrerenalAzotemia

CKD NormalKidney

Function

Pre

sent

ing

Ser

um C

reat

inin

e, m

g/dL

NGAL Serum Creatinine

32% of NGAL > 130 µg/g required

dialysis

N=635 adults admitted to hospital,

mean age 60,

30 (4.7%) developed AKI:

•Cardiogenic shock (40%)

•Urinary obstruction (16.7%)

•Multiple myeloma (10%)

•sepsis (6.7%)

•HTN emergency (6.7%)

•NSAIDS (6.7%)

•SLE nephritis (3.3%)

•Interstitial nephritis(3.3%)•Glomerulonephritis (3.3%)•Rhabdomyolysis (3.3%)

Meta-Analysis: Accuracy of NGAL in AKI

� Meta-analysis of 19 diagnostic studies (2538 patients)

� NGAL was a valuable and early predictor of AKI, both overall and across a diverse range of clinical settings

� The cutoff NGAL value for optimum sensitivity and specificity across all settings was >100 ng/mL

� A more consistent cutoff value of >150 ng/mL was identified when using standardized platforms

Haase M, et al. Am J Kidney Dis. 2009;54:1012-1024.

Setting Specificity AUC-ROC

Diagnostic

Odds Ratio

AKI across settings 85.1 0.815 18.6

AKI after cardiac surgery 75.1 0.775 13.1

AKI in critically ill patients 75.5 0.728 10.0

AKI after contrast infusion 96.3 0.894 92.0

AKI prediction using serum NGAL

86.6 0.775 17.9

AKI prediction using urine NGAL

84.3 0.837 18.6

Diagnostic and Prognostic Accuracy of NGAL

Event=30 day HF rehospitalization or death

10

NO DAMAGE DAMAGE PRESENT

NO FUNCTIONAL

CHANGE

No functional No functional

changes or changes or

damage damage

Damage without Damage without

loss of functionloss of function

Damage with Damage with

loss of functionloss of function

Loss of function Loss of function

without without damagedamage

FUNCTIONAL

CHANGE

New Spectrum of AKI based on Combination of Functional and Damage Biomarkers

Based on Serum Creatinine

Based on NGAL

New Criteria for AKI Diagnosis and Staging Using Biomarkers

Based on Serum

Creatinine and Urine

Output

Based on Nephroheck®

, NGAL, L-FABP

Outline

� Definitions

� Complex, bidirectional pathogenesis

� Novel diagnostic targets

� Therapy

� Putting it all together

ModerateHF

SevereHF

MildHF

Post-MILV Dysfunction

SOLVD Treatment(enalapril) CONSENSUS

(enalapril)

AIRE/SAVE(ramipril/captopril)

US Carvedilol/MERIT(carvedilol/metoprolol)

COPERNICUS(carvedilol)

CAPRICORN(carvedilol)

RALES(spironolactone)

EPHESUS/EMPHASIS-HF(eplerenone)

CHARM/Val-HeFT(candesartan/valsartan)

CRT and/or ICD

Pharmacologic Therapy and CRT for HF

A-HeFTLong-acting nitrate/hydralazine

CHARM(candesartan)

Val-HeFT(valsartan)

VALIANT(valsartan)

11

Treatment Patterns and Mortality in Advanced HF

Neuberg GW et al. Am Heart J. 2002;144:31-38.

Group Diuretic dose ACE inhibitor dose

A High…………………………… Low n=240B High…………………………… High n=160C Low……….…………………… Low n=526D Low……………………………. High n=224

0 6 12 18 24 30 36

1.0

0.8

0.6

0.4

0.2

0.0

A

BCD

Chi-square=33.83P = .0001

Months from Randomization

Tota

l Mor

talit

y

Risk of Developing Renal Insufficiency on ACEI Therapy: Results From SOLVD

Clinical VariableEnalapril

RR (95% CI)Placebo

RR (95% CI)

Age (per 10 yrs) 1.42 (1.32-1.52) 1.18 (1.12-1.25)

Baseline EF(per 5% increment)

0.93 (0.91-0.96) 0.93 (0.91-0.96)

Diuretics 1.89 (1.70-2.08) 1.35 (1.09-1.66)

Diabetes 1.33 (1.13-1.53) 1.96 (1.57-2.44)

ß Blockers 0.70 (0.57-0.85) 0.70 (0.57-0.85)

EF, ejection fraction; SOLVD, Studies of Left Ventr icular Dysfunction.Knight EL et al. Am Heart J. 1999;138:849-855.

Prevention of Type I Cardiorenal Syndrome: Lessons Learned from

Clinical Trials and Registries� Programmatic use of PA catheter (Nohria JACC 2008)

� Programmatic use of inotropes/indodilators (ACC/AHA Guidelines)

� High-dose loop diuretics (DOSE Trial 2011)

� Beta-blocker withdrawal (Fonarow, JACC 2008)

� ACEI/ARB withdrawal (Shukla, CIRC, 2008)

� Digoxin withdrawal (Packer, NEJM, 1993)

� Rolophylline (PROTECT, ESC, 2009)

� Endothelin receptor antagonists (Forbes KI 2001)

� Argnine vasopressin receptor antagonists (Konstam JAMA 2007)

� Nesiritide (Yancy, ASCEND HF, 2011, ROSE-HF 2014)

� Ultrafiltration after AKI (Pavlesky, CARRESS 2013)

Drug/Strategy Ineffective/Harmful

OR

Have not identified the ideal patient

subset for benefit

12

Acute Heart Failure (1 symptom AND 1 sign)<24 hours after admission

2x2 factorial randomization

Low Dose (1 x oral)Q12 IV bolus

48 hours

1) Change to oral diuretics2) continue current strategy3) 50% increase in dose

Co-primary endpoints

High Dose (2.5 x oral)Q12 IV bolus

Low Dose (1 x oral)Continuous infusion

High Dose (2.5 x oral)Continuous infusion

72 hours

DOSE Trial: Study Design

Clinical endpoints

60 days

N Engl J Med. 2011 Mar 3;364(9):797-805.

Acute Kidney Injury (AKI) in DOSE Trial

Diuretic Strategy

AK

I Cr

Ris

e >

0.3

mg/

dl P = 0.04

N Engl J Med. 2011 Mar 3;364(9):797-805.

Continuous Infusion Bolus P value

Acute kidney injuryNa↓ use of hypepertonic salineInotrope InfusionLength of hospital stay (days)Death or rehospitalization

22%33%35%

14 + 558%

15%18%23%

11 + 523%

0,300,010,02

<0,030,001

Continuous versus Bolus Intermittent Loop Diuretic Infusion in Acutely Decompensated Heart Failure: A Prospective Randomized TrialAlberto Palazzuoli MD PhD*, Marco Pellegrini MD*, G aetano Ruocco MD*, Giuseppe Martini MD*, Beatrice Franci PhD*, Maria Stella Campagna PhD*, Marilyn Gilleman MD*, P eter A. McCullough, MD, MPH,† Claudio Ronco MD ♦, Ranuccio Nuti MD*.

Manuscript accepted 2014

13

Physical Exam Findings at Admission and Discharge

0%

10%

20%

30%

40%

50%

60%

70%

JVD Rales Edema

AdmissionDischarge

JVD=jugular venous distention.The OPTIMIZE-HF Registry [database]. Final Data Rep ort. Duke Clinical Research Institute. July 2005.

• In theory removes fluid from the blood at the same rate that fluid can be naturally recruited from the tissue

• Transient removal of blood illicits compensatory mechanisms, termed plasma or intravascular refill 1,2

• Ultrafiltrate is isotonic with plasma,

• Removes more sodium than diuretic therapy

• Decreases ECF volume more than a comparable volume of diuretic-induced fluid loss without neurohormonal activation

Fluid Removal by Ultrafiltration

1. Lauer et al. Arch Intern Med. 1983;99:455-460. 2. Marenzi et al. J Am Coll Cardiol. 2001;38:4.

VascularSpace

Ultrafiltrate

VascularSpace

InterstitialSpace (edema)

Na

Na

Na

Na

K

P

H2O

K

P

PR

Effects of Ultrafiltration vs IV Furosemide

+ 80 –

+ 40 –

% 0 –

-140 –

d 0 1d 2d 3d 4d 5d 3m

Neurohormones

Triangles = UltrafiltrationSquares = Furosemide

Agostoni et al. Am J Med. 1994;96:191-199.

Norepinephrine Plasma Renin Activity

+ 170 –

+ 80 –

+ 40 –

% 0 –

- 40 -

Aldosterone

+ 80 –

+ 40 –

% 0 –

-140 –

d 0 1d 2d 3d 4d 5d 3md 0 1d 2d 3d 4d 5d 3m

0

20

40

60

80

100

0 10 20 30 40 50 60 70 80 90

% P

atie

nts

Fre

e F

rom

R

ehos

pita

lizat

ion

UNLOAD Trial: N=200, RCT UF Started before AKI Dev elops, Freedom From Heart Failure Rehospitalization Within 90 Days After Discharge

Costanzo, M. et al., J Am Coll Cardiol 2007;49:675-83.

Ultrafiltration Arm (16 Events)

P = 0.037

Standard Care Arm (28 Events)

14

Mean Changes from Baseline Serum Creatinine Levels at Various Time Points in Ultrafiltration/Standard Car e Group

Costanzo, M. et al., J Am Coll Cardiol 2007;49:675-83.

Ser

um C

reat

inin

e C

hang

e (m

g/dl

)

8 hrs 24 hrs 48 hrs 72 hrs Discharge 10 days

30 days

90 days

Ultrafiltration Arm Standard Care A rm

P > 0.05 at all time points

0.0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1.0

*Trial of UF after AKI has developed

*

Characteristic Pharmacologic Therapy(N=94)

Ultrafiltration(N=94)

Age (yrs)-Median-Interquartile range

6657-78

6961-78

Ejection fraction-Median-Interquartile range

35%25-55%

30%20-52%

Baseline creatinine (mg/dL)-Median-Interquartile range

2.091.71-2.65

1.901.57-2.37

Increase in creatinine (mg/dL)-Median-Interquartile range

0.460.37-0.70

0.430.35-0.60

Outcome Pharmacologic Therapy(N=94)

Ultrafiltration(N=94)

P-value

Death 13 (14%) 16 (17%) 0.55

Hospitalization-All cause-Heart failure

24 (26%)37 (40%)

23 (26%)46 (51%)

0.970.12

Unscheduled emergency department or clinic visits

13 (14%) 19 (21%) 0.21

A

C D

B

Volume Depletion Fluid Balance

Ris

k of

Car

dior

enal

Syn

drom

e

DiureticsUltrafiltration

Liberal Intake Positive Balance

Volume Overload

HypotensionTachycardiaShockOrgan HypoperfusionOliguria

Optimal Status

HypertensionPeripheral Edema

Impaired Oxygenation Organ Congestion

Normal Heart

Diseased Heart

ManagementWindow

Acute Decompensation

Volume DepletionArterial Underfilling

Blood PressureLow High

At-Risk Kidneys

Normal Kidneys

15

Clinical Actions for Acute Kidney Injury

Novel Therapies in TrialsAcutely Decompensated Heart FailureOmecamtiv mecarbil Serelaxin (RLX030) (recombinant form of human relaxi n-2)Ularitide (modified natriuretic peptide)Caperitide (atrial natriuretic peptide)Cinaciguat (activates soluble guanylate cyclase (sGC ))Istaroxime (stimulates SERCA)

Acute Kidney InjuryABT-719 (alpha MSH receptor analogue)THR-184 (agonist for renal BMP receptors (ALK2, 3, and BMPR-II) AC607 (stem cells)BCT197 (anti-inflammatory)CMX-2043 (small molecule adduct of lipoic acid)

Ezekowitz Current Cardiol Rep 2013, Courtesy Shaw A, ADQI 2013

Selective Cardiac Myosin Activator: Omecamtiv Meca rbil

Science 18 March 2011: Vol. 331 no. 6023 pp. 1439-1443

Serelaxin is a recombinant form of human relaxin-2, a naturally occurring peptide pregnancy hormone

Serelaxin IV for up to 48 h, started within 16 h of presentation, with placebo in patients hospitalized for AHF

16

Outline

� Definitions

� Complex, bidirectional pathogenesis

� Novel diagnostic targets

� Therapy

� Putting it all together

Heart Failure Goals

Adapted from: Hunt SA et al. ACC/AHA 2005 CHF Guide line Update. Circulation 2005;112:e154-235.

Pharmaceuticals and Devices

Early Recognitionand Treatment

Revised Staging System

Stage DStage CStage BStage A

Preserve Renal Function

Baptist HealthContinuing Medical Education

8900 N. Kendall Drive

Miami, Florida

Phone ■ 786-596-2398 Fax ■ 786-533-9821

CME@BaptistHealth.net

BaptistHealth.net/CME