Tomaselli Lab

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

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 Channel mutation in a patient R526H S528A NaV1.5 I-II linker WT PKA:substrate= 1:50 WT R526H S528A PKA:substrate= 1:1 Total protein Nav1.5 dsRED-ER

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

5. 5 mm A IQ/AA * 70 140 0 WT 60 120 * 50 * HW/TL (mg/cm) FS (%) 100 * 40 WT IQ/AA + Ranolazine 80 WT WT 30 IQ/AA 60 IQ/AA WT IQ/AA 1 sec 20 #724 (281d) #715 (281d) 0 3 6 9 12 0 3 6 9 12 Age (months) Age (months) B IQ/AA 100 ms WT IQ/AA Mouse model – defective CaM regulation

6. Remodeling of the diseased heart

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

8. DHF NF + CRT A B 70 60 50 p<0.04 EF (%) 40 30 20 10 NF DHF CRT 0 3wk 6wk 3wk 6wk C NF DHF CRT Transcription Profiling in HF and CRT

9. PROSE-ICD Candidate Gene SNPs rs10774048, CACNA1C rs6673954RYR2 rs6700557 rs2167385, GPD1L rs9897584, KCNJ2 - log10(P value) p = 0.01 p = 0.05 Genomic position