1. Tomaselli Lab Department of Medicine Division of Cardiology Ross 844 gtomasel@jhmi.edu GFP-LC3 Cx43 MERGE 5 mm WTIQ/AA 1 sec 0 WT IQ/AA IQ/AA + Ranol

2. Areas of Research Interest Cardiac Ion Channel structure-function and regulation – Na, K channels – Connexins Cellular and Molecular Remodeling in the Diseased Heart – Heart failure and CRT Mechanisms of Sudden Cardiac Death – PROSE-ICD

3. Na channel regulation Na channel regulation Channel mutation in a patient WTR526HS528A Na V 1.5 I-II linker PKA:substrate = 1:50 PKA:substrate = 1:1 Total protein WTR526HS528A dsRED-ERNav1.5

4. A CaMKII 0 10 pA/pF 5 ms CaMKII +AIP 0 Control 0 B Membrane potential (mV) Control AIP CaMKII CaM CaMKII +AIP CaM +AIP 0 0.2 0.4 0.6 0.8 1 -120-100-80-60-40 -20 I /Imax -120 50 ms -140 -20 500 ms C 0 1 2 3 4 5 6 7 8 9 10 -60-50-40-30-20-10010 mV tau fast (ms) * * * Membrane Potential * I Na Norm (%) 20 % 100 ms CaMKII Control D E late I Na (% of peak) 0.2 0.4 0.6 0.8 1 1.2 ControlCaMKIICaM CaMKII +AIP PKA * Ca/CaM/CamKII regulation of Na channels

5. Mouse model – defective CaM regulation 5 mm WTIQ/AA #724 (281d) #715 (281d) A WTIQ/AA B Age (months) 20 30 40 50 60 70 036912 WT IQ/AA FS (%) * * Age (months) HW/TL (mg/cm) 60 80 100 120 140 036912 WT IQ/AA * * 100 ms WT IQ/AA WTIQ/AA RR (ms)146140 PR (ms)3839 QRS (ms)13 QT (ms)3855* QTc (ms)103144* 1 sec 0 WT IQ/AA IQ/AA + Ranolazine

6. Remodeling of the diseased heart

7. HF – Ca handling and adrenergic signaling HF-synch * † CaT amplitude (Lateral) F405/485 ContDHFCRT * * * 0.2 0.4 0.6 0.8 1.0 0 baseline ISO FSK 1.0 NFDHFCRT HF-sync 500 ms baseline ISO

8. Transcription Profiling in HF and CRT DHFNF + CRT NF DHF CRT AB C EF (%) 0 10 20 30 40 50 60 70 NFDHF 3wk6wk CRT 3wk6wk p<0.04

9. PROSE-ICD PROSE-ICD Candidate Gene SNPs rs10774048, CACNA1C rs2167385, GPD1L rs9897584, KCNJ2 rs6673954 RYR2 rs6700557 p = 0.05 p = 0.01 - log 10 (P value) Genomic position