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

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Presentation transcript:

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

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

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

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 I /Imax ms ms C mV tau fast (ms) * * * Membrane Potential * I Na Norm (%) 20 % 100 ms CaMKII Control D E late I Na (% of peak) ControlCaMKIICaM CaMKII +AIP PKA * Ca/CaM/CamKII regulation of Na channels

Mouse model – defective CaM regulation 5 mm WTIQ/AA #724 (281d) #715 (281d) A WTIQ/AA B Age (months) WT IQ/AA FS (%) * * Age (months) HW/TL (mg/cm) WT IQ/AA * * 100 ms WT IQ/AA WTIQ/AA RR (ms) PR (ms)3839 QRS (ms)13 QT (ms)3855* QTc (ms)103144* 1 sec 0 WT IQ/AA IQ/AA + Ranolazine

Remodeling of the diseased heart

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

Transcription Profiling in HF and CRT DHFNF + CRT NF DHF CRT AB C EF (%) NFDHF 3wk6wk CRT 3wk6wk p<0.04

PROSE-ICD PROSE-ICD Candidate Gene SNPs rs , CACNA1C rs , GPD1L rs , KCNJ2 rs RYR2 rs p = 0.05 p = log 10 (P value) Genomic position