1. Treatment Strategies for ADHF Associated AKI John Lynn Jefferies, MD, MPH, FAAP, FACC Director, Cardiomyopathy, Advanced Heart Failure, and Ventricular Assist Device Programs Co-Director, Cardiovascular Genetics Associate Professor, Pediatric Cardiology and Adult Cardiovascular Diseases The Heart Institute Cincinnati Children’s Hospital

2. Jessup et al. Circulation 2009;119:1977-2016.

3. Shah M et al. Rev Cardiovasc Med. 2001;2(suppl 2):S2 Pharmacologies in Heart Failure Management ANP BNP NO Endothelin Aldosterone Vasopressin Angiotensin II Norepinephrine Vasoconstriction Vasodilation Bradykinin Prostacyclin

4. Congestion at Rest Low Perfusion at Rest No Yes Warm & DryWarm & Wet Cold & WetCold & Dry Signs/symptoms of congestion  Orthopnea/PND  JVD  Ascites  Edema  Rales (rare in HF) Possible evidence of low perfusion  Narrow pulse pressure  Sleepy/obtunded  Low serum sodium  Cool extremities  Hypotension with ACE inhibitor  Renal dysfunction (one cause) Stevenson LW. Eur J Heart Fail. 1999;1:251 Hemodynamic Profile Assessment

5. Yes Stevenson LW. Eur J Heart Fail. 1999;1:251 No 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 Congestion at Rest Low Perfusion at Rest No Yes Warm & Wet PCWP elevated CI normal Natriuretic Peptide Nesiritide or Patient Selection and Treatment

6. Proven Outcomes for Heart Failure Therapies Improve Survival – ACE inhibitor – ARB – Beta blocker – Aldosterone receptor antagonist – Hydralazine/long- acting nitrates Reduce Hospitalization – ACE inhibitor – ARB – Beta blocker – Aldosterone receptor antagonist – Hydralazine/long-acting nitrates – Digoxin

7. Intravenous Agents for Heart Failure TherapyCOPCWPBPHR Ar- rhyth- mia Shorter Onset Longer Offset Diure- sis Dopamine (ng/kg/min) Low (<3) Mod (3–7) High (7–15)        +++ +++ +++ 000000 ???? Dobutamine    +++0  Milrinone  +++  Nitroglycerin   +++0  Nesiritide  ++  Nitroprusside    ++++0  Young JB. Rev Cardiovasc Med.2001;2(suppl 2):S19

8. Ventricular Remodeling Ventricular Remodeling After Acute Infarction Ventricular Remodeling in Diastolic and Systolic HF Initial infarct Expansion of infarct (hours to days) Global remodeling (days to months) Normal heart Hypertrophied heart (diastolic HF) Dilated heart (systolic HF) Jessup M et al. N Engl J Med. 2003;348:2007

9. Hemodynamic (balanced vasodilation)  Veins  Arteries  Coronary arteries Neurohormonal   aldosterone   endothelin   norepinephrine Renal   sodium and water excretion Abraham WT et al. J Card Fail. 1998;4:37 Clemens LE et al. J Pharmacol Exp Ther. 1998;287:67 Marcus LS et al. Circulation. 1996;94:3184 Tamura N et al. Proc Natl Acad Sci U S A. 2000;97:4239 Zellner C et al. Am J Physiol. 1999;276(3 pt 2):H1049 Cardiac  Lusitropic  Antifibrotic  Antiremodeling Pharmacologies in Heart Failure Management

10. Sites of Action for HF Therapies Beta blockers Digoxin, inotropes Peripheral Arteries Cardiac- resynchronization therapy ACE inhibitors, angiotensin receptor blockers, aldosterone antagonists Diuretics, aldosterone antagonists, nesiritide Kidney ACE inhibitors, angiotensin receptor blockers, vasodilators, alpha blockade, nesiritide, exercise Heart Jessup M, Brozena S. N Engl J Med. 2003;348:2007

11. Current Heart Failure Strategies “Primum non nacere” (First, do no harm) Factors predicting quality outcomes – Correct diagnosis – Appropriate management strategies Timing is everything – Utilization of available resources thoughtfully – Learn from the adult literature…

12. Management of End-Stage Heart Failure Jessup et al. Circulation 2009;119:1977-2016.

13. Management of End-Stage Heart Failure Jessup et al. Circulation 2009;119:1977-2016.

14. Management of End-Stage Heart Failure Jessup et al. Circulation 2009;119:1977-2016.

15. Patients with Reduced Left Ventricular Function Jessup et al. Circulation 2009;119:1977-2016.

16. Ventricular Assist Devices The Next Frontier

17. Ultrafiltration Ultrafiltration (UF) is a potentially attractive treatment strategy for patients with volume overload with CRS – UF has no effect on serum electrolytes – Results are rapid – Volume removed is easily controlled and predictable – Does not stimulate the neurohormonal system – Restores responsiveness to diuretics in patients with diuretic resistance

18. Costanzo et al. Semin Nephrol 2012;32:100-111.

19. Costanzo et al. J Am Coll Cardiol 2007;49:675-683 Ultrafiltration

20. Costanzo et al. J Am Coll Cardiol 2007;49:675-683.

21. Costanzo et al. Semin Nephrol 2012;32:100-111

22. Bart et al. J Card Fail 2012;18:176-182.

23. Vasopressin Antagonists Arginine vasopressin (AVP) levels are often elevated in heart failure Leads to water retention, hyponatremia, vasoconstriction, and myocardial fibrosis AVP antagonists (Conivaptan and Tolvaptan) are available in the US Enhance free water clearance without electrolyte loss No effect on renal function

24. Udelson et al. J Cardiac Fail 2011;17:973-981.

26. Conclusions Current treatment of decompensated heart failure involves multiple possible therapeutic strategies Many of these are harmful to the kidney and may worsen AKI Newer technologies may favorably impact markers of AKI and result in less long-term morbidity and mortality

27. Conclusions The treatment of acute decompensated heart failure requires recognition that HF is a syndrome involving complex interactions Preservation of kidney function is critical to avoidance of readmission and survival Consultation with Cardiologists that have recognized expertise in the management of HF is strongly recommended