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
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