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Investigating Cardiac Ion Channel Regulation and Remodeling in Heart Disease

This research focuses on the structure-function relationships and regulatory mechanisms of cardiac ion channels, specifically sodium (Na) and potassium (K) channels, and connexins. We explore cellular and molecular remodeling in heart failure, the implications for cardiac resynchronization therapy (CRT), and the mechanisms contributing to sudden cardiac death. We utilize mouse models with specific channel mutations to examine channel regulation by proteins like CaMKII and PKA, and we profile candidate gene SNPs linked to heart disease outcomes.

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Investigating Cardiac Ion Channel Regulation and Remodeling in Heart Disease

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  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

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