1. A New Mechanism for Cardiomyopathy Based on Abnormal Rheology.
Tim Jacobson MD & Jonathan Lindner MD
Oregon Health & Science University

2. Case 62 year old F referred in 2006 for management of CAD.
Hx IMI in the late 1990’s.
Paroxysomal atrial fibrillation
Not having angina.
+ LE edema.
+ Intermittent R leg claudication.
Limited functional status due to back pain.

3. Past Medical History Paroxysmal Nocturnal Hemoglobinuria
Hypercoagulable state
Recurrent thromboses on coumadin.
On chronic lovenox.
IMI in late 1990’s.
Transfusion dependant.
Avg of 2 units/month
Insulin requiring DM
Addison’s disease
Hyperlipidemia
Stage 2 renal failure
Peripheral vascular disease.
R ankle ABI 0.59.

4. Fam/Soc Hx, Meds & Exam Meds Exam Carvedilol 12.5 mg BID
Enalapril 2.5 mg BID
Simvastatin 20 mg daily
Enoxaparin 60mg QD bid
Prednisone 10 mg daily
Florinef 0.1 mg daily
Soc HX: non smoker, no EtOH, no drugs.
5’2” 150 lbs /60
Normal carotid upstrokes without bruits.
Normal JVP.
Lungs CTA B
Nl PMI. RRR. No M/R/G.
Normal femoral pulses.
No palpable R DP or PT.
Ext warm, 1+ edema.

5. Labs WBC 8.4 HCT 36.4 PLT 180 TSH 2.2 Ferritin 955 LDH 1300-1800
Na 140
K 4.0
Cl 112
CO2 = 27
BUN 20
Creat 0.8
LFT’s normal
INR 1.07
WBC 8.4
HCT 36.4
PLT 180
TSH 2.2
Ferritin 955
LDH
SPEP/UPEP normal.
HIV negative.

6. Echo 2006

7. Echo 2006

8. Echo 2006

9. Echo Report

10. Further Evaluation Cardiac MRI Coronary Angiography
Normal L main
Mild disease of the LAD and diagonal system.
Mild disease of circ system.
Small dominant RCA with severe stenosis and TIMI 2 flow after small RV branch.
Done to rule out cardiac iron overload.
Prior myocardial infarction involving the basal/mid inferior wall/inferior septum.
No evidence of abnormal iron deposition in the myocardium or liver.

11. What is PNH? Paroxysmal Nocturnal Hemoglobinuria
Paroxysmal hemolytic anemia of varying severity.
“Brown urine in the AM”.
Hypercoagulable state (venous > arterial)
Thrombosis in 28% at 8 years.
Bone marrow aplasia
Pancytopenia in 15% at 8 years.
Progression to myelodysplastic syndrome or acute leukemia
5% at 8 years.
Median survival of years after diagnosis.

12. Nature Biotechnology 2007;25:1256-1264
PNH
Due to an acquired mutation in PIG-A gene.
Causes inability to produce the GPI anchor.
Absence of CD 59
inhibitor of reactive lysis, protectin, and membrane attack complex inhibitory factor
Absence of CD 55
decay accelerating factor
Hemolysis is mediated by complement activation.
Nature Biotechnology 2007;25:

13. Increased Capillary Resistance
Increased blood viscosity.
Hyperlipidemia
Hyperglycemia
Ischemic microvascular injury.
Changes in RBC deformability and charge.

14. Red Cell Deformability and Resistance
Normal
PNH
Relative Apparent Viscosity
Pries, et al., 1996

15. Lindner et al. JASE 2002;15(5):396-403
Evaluation of Microvascular Function with Dipyridamole Stress Perfusion Echo
Fig. 6. A, Examples of sequential intravital microscopy frames obtained 30 ms apart used to measure capillary microbubble velocity (scale bars = 20 μm); B, relation between RBC velocity and microbubble velocity in capillaries (dashed line represents line of identity).
Lindner et al. JASE 2002;15(5):

16. Dipyridamole Stress Perfusion Echo
Baseline Beat beats beats beats beats
Jayaweera et al. Am. J. Physiol (Heart Circ. Physiol. 46): H2363-H2372, 1999.

17. Clinical Course Over the next several months:
Carvedilol uptitrated to mg po bid.
Enalapril uptitrated to 5 mg daily.
Started on Eculizumab (anti C5 therapy).
Hemolysis much reduced. LDH fell to < 250.
Transfusion requirement resolved.

18. Therapy Eculizumab (Soliris)
Monoclonal antibody that binds to C5 and inhibits terminal complement activation.
Reduced hemolysis and transfusion requirements in patients with PNH.
Nature Reviews Drug Discovery ;6:

19. Repeat Echo 11/07

20. Beta Curves
Baseline Beat beats beats beats beats
PRE
POST

21. Echo 6/2008

22. Echo 6/2008

23. Echo 6/2008

24. Repeat Echo June 2008
Simpson’s biplane EF 42%.

25. Conclusions
First known case of significant improvement in LV function in response to treatment of PNH with Eculizumab.
Reduced hemolysis leading to:
Normalization of RBC shape and transit through capillaries.
Reduced blood viscosity.
Improved O2 delivery to myocardium
Culminating in improved global LV function.