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A New Mechanism for Cardiomyopathy Based on Abnormal Rheology.

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

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A New Mechanism for Cardiomyopathy Based on Abnormal Rheology.

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  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 5’2” 150 lbs 62 110/60 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. • 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. Labs • 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 1300-1800 • SPEP/UPEP normal. • HIV negative.

  6. Echo 2006

  7. Echo 2006

  8. Echo 2006

  9. Echo Report

  10. Further Evaluation Coronary Angiography Cardiac MRI 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. • 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.

  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 14 - 19 years after diagnosis.

  12. 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;25:1256-1264

  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. 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):396-403

  16. Dipyridamole Stress Perfusion Echo Baseline 1 Beat 2 beats 3 beats 5 beats 8 beats Jayaweera et al. Am. J. Physiol. 277 (Heart Circ. Physiol. 46): H2363-H2372, 1999.

  17. Clinical Course • Over the next several months: • Carvedilol uptitrated to 18.75 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 . 2007;6:515-516

  19. Repeat Echo 11/07

  20. Beta Curves Baseline 1 Beat 2 beats 3 beats 5 beats 8 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.

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