Tomaselli Lab

Department of MedicineDivision of Cardiology

Ross 844gtomasel@jhmi.eduGFP-LC3

Cx43

MERGE

5 mm

WT IQ/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 Channel mutation in a patient

WT R526HS528A

NaV1.5 I-II linker

PKA:substrate = 1:50

PKA:substrate = 1:1

Total protein

WT R526H S528A

dsRED-ERNav1.5

A

CaMKII0

10 pA/pF

5 ms

CaMKII +AIP0

Control0

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 /Im

ax

　　 　　　　　　　　　　　　

-12050 ms-140

-20 -20500 ms

C

0

1

2

3

4

56

7

8

9

10

-60 -50 -40 -30 -20 -10 0 10

mV

tau

fast

(m

s)

*

* *

Membrane Potential

*

I Na N

orm

(%

)

20 %

100 msCaMKII

ControlD

E

late

I Na (

% o

f pea

k) 0.2

0.4

0.6

0.8

1

1.2

Control CaMKII CaMCaMKII+AIP PKA

*

Ca/CaM/CamKII regulation of Na channels

Mouse model – defective CaM regulation5 mm

WT IQ/AA#724 (281d) #715 (281d)

A

WT IQ/AA

B

Age (months)

20

30

40

50

60

70

0 3 6 9 12

WT

IQ/AA

FS

(%

)

**

Age (months)

HW

/TL

(m

g/c

m)

60

80

100

120

140

0 3 6 9 12

WT

IQ/AA

*

*

100 ms

WT

IQ/AA

WT IQ/AA

RR (ms) 146 140

PR (ms) 38 39

QRS (ms) 13 13

QT (ms) 38 55*

QTc (ms) 103 144*

1 sec

0 WTIQ/AA

IQ/AA + Ranolazine

Remodeling of the diseased heart

HF – Ca handling and adrenergic signaling

HF-synch

*†

CaT amplitude (Lateral)

F405

/485

Cont DHF CRT

*

**

0.2

0.4

0.6

0.8

1.0

0

baselineISOFSK

1.0

NF DHF CRT HF-sync

500 msbaseline

ISO

Transcription Profiling in HF and CRTDHF NF + CRT

NF DHF CRT

A B

C

EF (%

)

0

10

20

30

40

50

60

70

NF DHF3wk 6wk

CRT3wk 6wk

p<0.04

PROSE-ICD Candidate Gene SNPs

0 50,000,000 100,000,000 150,000,000 200,000,000 250,000,0000

0.5

1

1.5

2

2.5

3

3.5

4

rs10774048, CACNA1C

rs2167385, GPD1L

rs9897584, KCNJ2

rs6673954 RYR2rs6700557

p = 0.05

p = 0.01

- lo

g1

0(P

val

ue)

Genomic position