From Bench to Practice: Cardiac Resynchronisation Therapy Molecular Changes in the Dyssynchronous Heart and Cardiac Resynchronisation Therapy Gordon F. Tomaselli, M.D. Professor of Medicine and Molecular Medicine Michel Mirowski, M.D. Professor of Cardiology Johns Hopkins University September 27, 212 The authors have no financial conflicts of interest to disclose concerning this presentation Research Grant Support NIH NHLBI
Outline Cellular & tissue electrophysiology and Ca 2+ handling alterations in HF Remodeling in CRT cellular electrophysiology and Ca 2+ handling regional gene expression profiling cellular metabolism
HF & CRT Scope of the Problem 5.8 x 1 6 patients with HF in the US ( < ) 67, new diagnoses (adults > 35 yrs) >1.1 x 1 6 hospitalizations (NHDS, NHLBI) >$39 billion estimated annual cost >6, deaths ( > ), ~5% SCD (NCHS) b-ar agonists increase contractility and mortality CRT improves symptoms, ventricular performance and myocardial efficiency AHA Heart Disease and Stroke Statistics 21 Update. Circulation 121:e46, 21
Membrane voltage (mv) Cellular electrophysiological features of heart failure 3-4 Weeks of rapid (24bpm) RV pacing LVEDP 3-45 mmhg 5 endocardial midmyocardial epicardial -5-1 1 5-5 CONTROL HF D APD 9 6 5 4 3 2 1 Class III AAD action 12 1 8 6 4 2 APD 9-1 2 4 6 8 2 4 6 8 msec 2 4 6 8 1 2 3 4 5 6 Cycle Length (sec)
repolarizing depolarizing Current clone mrna protein I Na I Ca,L I Na/Ca SCN5A DHP receptor NCX voltage time I K1 I to,1 Kir2.x Kv4.x /KChIP2 I to,2 I Kr I Ks I Kp HERG/MiRP-1 KvLQT1/minK
A.U. CV (cm/sec) CV (cm/sec) HF - conduction slowing Normal Epicardium HF 45 Cx43 N-cad NL 4 35 3 S1 S1 25 2 NL HF HF Endocardium Normal HF p <.1 45 S1 S1 S1 4 35 3 25 2 NL HF 14 12 1 8 6 Epi Endo p <.1 4 2 NL HF NL HF Akar et al. Circ Res 95:717, 24 Hesketh et al. Circ Res 16:1153, 21
Fiber stress LV Pressure (mmhg) Strain Cardiac dyssynchrony influences regional & global function Normal Heart Dyssynchronous Failing Heart 8 NSR Dyssynchrony 4 Anterior Lateral 2 Area = Regional Work 2 3 6 9 LV Volume (ml). 1. 1 -. 1. 1 Fiber strain Fiber strain
Week Mechanical treatment of HF: What molecular/cellular changes are induced? Animal model of CRT Left Bundle Ablation (QRS > 12 msec) 3 RA pacing (2 bpm) 3 weeks 6 RA pacing (2 bpm) 3 weeks BiV pacing (2 bpm) 3 weeks Dyssynchronous Heart Failure () Resynchronization Heart Failure (CRT) Tissue isolation from epi/endocardium of lateral wall and septum Protein and enzyme analysis
Strain (%) CRT restores synchronous contraction. Control Septum Lateral II -2. -4. -6. 1. NSR 1 mv DEF (3 wk vs 6 wk) -4.4 ± 2.7% CRT 2.8 ± 1.8%. RAP -1. -2..5 -.5-1.5-2.5 CRT 1 ms BiV apoptosis regional heterogeneity of expression: CaMKII, MAPK p38 Time (s) Aiba et al. Circulation 119:122-3, 29; Chakir et al. Circulation 117:1369-77, 28. 1. sec
Cellular Structural Remodeling WGA (t-tubes) RyR (jsr) 5 μm overlay deconvolution 3-D horizontal vertical Sachse et al. Circ Res 11:588,212
Control 5 μm LAT LAT LAT CRT LAT Sachse et al. Circ Res 11:588,212
APD (ms) CRT remodeling cellular AP effects are regional LBBB + RA pacing (2 ppm) 6 wks 3 wks 6 wks LBBB + RA pacing (2ppm) Bi-V pacing (2 ppm) CRT No ablation and pacing Control 14 Anterior 14 Lateral Anterior Control Lateral 5 mv 5 ms 12 1 8 12 1 8 # 6 4 Control (12) 2 (17) CRT (8) 1 2 3 CL (s) 4 6 4 2 1 2 3 4 Control (13) DH F (28) CRT (11) CL (s) CRT Aiba et al. Circulation 119:122-3, 29
Kir2.1 protein (AU) Kv4.3 Protein (AU) KvLQT1 protein (AU) pa/pf pa/pf pa/pf 1 pa/pf 1 pa/pf.1 na Control CRT 1 ms -16-12 -8-4 -2 2 4 mv # 1.8 1.6 1.4 1.2 1.8.6.4.2 Kir2.1 CSQ Control CRT 5-5 -1-15 -2-25 -3-35 Control CRT A L A L A K currents in CRT I K1, I to, I K L Control CRT 5 ms 12 1 8 6 4-6 -4-2 2 4 6 2 1.5 1.5 Kv4.3 CSQ Control -2 A L A L A CRT L mv.6.5.4.3.2.1 IK tail +5-5 Control (n=13) (n=14) CRT (n=12) 4. s Control CRT 2. s -6-4 -2 2 4 6 mv 1.8 1.4 1.6.2 KvLQT1 CSQ Control CRT A L A L A L Aiba et al. Circulation 119:122-3, 29 #
I Na-L (2-22 ms) pa/pf CaMKII p-thr287 A 2 % 2% Inward Na + current (I Na ) 1 ms NF CRT Control CRT CaMKII total 8 x 1 3 7 (AU) 6 5 4 3 2 1 NF CRT 1.8.6.4.2 NF CRT baseline Ranolazine CRT c/w 3 x 1 3 (AU) 25 2 15 1 5 NF CRT NF CRT p <.5 I K1, I K, I to Aiba et al. unpublished
tau (ms) I Ca,L (pc/pf) Normalized expression Normalized expression 2 pa/pf Normalized expression Inward Ca 2+ current (I Ca ) Control 1 ms 1 ms CRT 1 ms Ca V 1.2 (Ca v α1c) 1.4 1.2 1.8.6.4.2 Control CRT 1 1 1 Ca v β1-5 -4-3 -2-1 1 2 3 4 5-1 -2-3 -4-5 (14) -6 (9) 5 4 3 2 1 Control -5-4 -3-2 -1 1 2 3 4 5-1 CRT -2-3 -4-5 -6 (11) (15).1.2.3 Control -5-4 -3-2 -1 1 2 3 4 5-1 -2-3 -4-5 -6 CRT (7) (11) 1.6 1.4 1.2 1.8.6.4.2 Ca v β2.8.7.6.5.4.3.2.1 Control CRT Control CRT Aiba et al. Circulation 119:122-3, 29
F45/495 tau (ms) F45/495 CaT in CRT Control CRT 5 ms.6.5.4.3.2 # 5 4 3 2 #.1 1 Control CRT Control CRT Aiba et al. Circulation 119:122-3, 29
A L L %EAD EADs - CRT 35 3 25 2 15 1 5 # Control CRT APD 2 EAD (-) APD 2 EAD(-) EAD(+) p <.1 APD 9 EAD (+) APD 9 EAD(-) EAD(+) p =.3 2 4 6 8 1 12 14 ms APD 2 APD 2 /APD 9 EAD(-) EAD(+) p <.1 APD 9 1 ms.1.2.3.4.5.6.7 Aiba et al. Circulation 119:122-3, 29
Delta SS (%) Sarcomere length Sarcomere Shortening (%) ECC CRT enhances b-adrenergic response Sarcomere Shortening Baseline ISO 1-7 M 16 Baseline ISO 1-7 M 1.9 1.8 1.7 12 8 4 1.6 1.9 1.8 1 sec DF/F Control Ant Lat Ant Lat Ant Lat Control CRT b1 vs b2 b1: NE 1-7 M + Prazosin 1-6 M b2: ISO 51-7 M + CGP 31-7 M 1.7 1.6 1.9 1.8 6 4 2 1.7 1.6 Chakir et al. Circulation 119:1231-4, 29 CRT CTL CRT GRK-2 :, No D CRT FSK AC stimulation :, No D CRT Gai inhibition: CRT RGS2,3 : CRT
CRT NF CRT regional gene expression NF + CRT 6 5 p<.1 p=.9 p<.1 4 3 2 1 n=6 n=5 n=5 NF CRT Barth et al. Circ Genetics 2:371-8, 29
Mitochondrial protein changes with CRT Agnetti, G. et al. Circ Cardiovasc Genet 21;3:78-87
Integration with mitochondrial bioenergetics (complex I) HF and CRT (complex II) RCR Efficiency of oxidative-phosphorylation complex V Agnetti, G. et al. Circ Cardiovasc Genet 21;3:78-87
Molecular changes in & CRT Summary Active membrane and network properties of the heart are remodeled in K currents, I Na-L, altered Ca 2+ handling Remodeled Cx43 with reduced CV Heart failure is associated with genetically driven regional remodeling of structure and function CRT has the capacity to in part reverse cellular structural, electrical and metabolic remodeling
Acknowledgements Cardiology Fadi Akar Andreas Barth Federica Farinelli Debbie DiSilvestre YanLi Tian Takeshi Aiba Hana Cho Geoff Hesketh Pei Dong Tori Halperin Khalid Chakir Guilio Agnetti Ting Liu University of Utah Frank Sachse Dave Kass Jenny van Eyk Brian O Rourke John Bridge DNA nebula Spitzer Space Telescope