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. + LE edema. + Intermittent R leg claudication. Limited functional status due to back pain.

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.

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 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.

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 1300-1800 SPEP/UPEP normal. HIV negative.

Echo 2006

Echo 2006

Echo 2006

Echo Report

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.

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.

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;25:1256-1264

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

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

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):396-403

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.

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.

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

Repeat Echo 11/07

Beta Curves Baseline 1 Beat 2 beats 3 beats 5 beats 8 beats PRE POST

Echo 6/2008

Echo 6/2008

Echo 6/2008

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

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.