Cvrx, Inc. · NASDAQ:CVRX
Cvrx — Technical Presentation (May 2013)
24 slides from Cvrx's technical presentation, May 2013
Slide 1: Baroreflex Activation Therapy: Heart Failure Pre-Clinical
Baroreflex Activation Therapy Heart Failure Pre-Clinical Hani N. Sabbah, Ph.D., FACC, FCCP, FAHA Professor of Medicine Wayne State University & Director of Cardiovascular Research Henry Ford Health System 1
Slide 2: Autonomic imbalance in chronic heart failure
Impaired Increased AR HR Signaling CHF Sympathetic Overdrive & Parasympathetic Withdrawal NO Dys- Regulation & Pro- Inflammation Arrhythmic 2
Slide 3: BAT restores autonomic balance
Improved HR AR Reduction Signaling BAT Restores Autonomic Balance Reduce Sympathetic Drive Increase Parasympathetic Drive Modulate NOS Anti- Anti-inflammatory Arrhythmic 3
Slide 4: BAT in Dogs With Chronic Heart Failure
BAT in Dogs With Chronic Heart Failure Objective • Assessment of efficacy of chronic BAT in dogs with heart failure using the Rheos System (CVRx, Inc.) Methods • Heart failure produced by multiple intracoronary microembolizations • The study includes 14 dogs: active group (n=8), sham-operated contro
Slide 5: Electrical Baroreflex Stimulation in Dogs with Coronary Microembolization-Induced Heart Failure
Electrical Baroreflex Stimulation in Dogs with Coronary Microembolization-Induced Heart Failure 1. Bilateral Baroreflex Stimulation 2. Stimulation Protocol: Frequency = 50-100 Hz Pulse wave = 0.5 – 1.0 msec Duty cycle 9 min ON 1 min OFF Sabbah et al, Circulation Heart Failure, 2011 5
Slide 6: Change in Mean Aortic BP and Average Ambulatory HR
∆ Mean Aortic BP and Avg. Ambulatory HR 30 ∆ Systolic BP (mmHg) 20 Control (n = 6) ∆ Heart Rate 10 -2 -27 BAT (n = 8) Or 0 13 7 -10 -20 -30 -40 Mean Aortic Average Pressure Ambulatory Heart Rate Sabbah et al, Circulation Heart Failure, 2011 6
Slide 7: Change in LV Systolic Indexes Treatment Effect
∆ LV Systolic Indexes Treatment Effect 10 8 6 Control (n = 6) 4 2 BAT (n = 8) -2.5 -2.8 -1.2 0 5.5 0.6 6.7 4.0 3.1 -2 -4 -6 EDV ESV EF SV (ml) (ml) % (ml) All p-values <0.05 Sabbah et al, Circulation Heart Failure, 2011 7
Slide 8: Change in LV Diastolic Indexes Treatment Effect
∆ LV Diastolic Indexes Treatment Effect 25 20 15 10 Control (n = 6) 5 BAT (n = 8) -4.0 -5.7 -11 0 2.0 10.6 11.2 -5 -10 -15 -20 -25 LVEDP DT EDWS All p-values <0.05 (mmHg) (msec) (g/cm2) 8 Sabbah et al, Circulation Heart Failure, 2011
Slide 9: LV Histomorphometry
LV Histomorphometry NL VFRF (%) VFIF (%) 25 16 P=0.006 20 12 P=0.023 15 8 10 4 5 0 0 CON BAT CON BAT LV Histomorphometry CHF CD (cap/mm2) MCSA (mm ) 2 2500 800 P=0.006 p<0.05 2250 p<0.05 700 p<0.05 2000 P=0.023 p<0.05 1750 600 1500 500 1250 1000 400 CON BAT CON BAT 9 Sabbah et al, Circulation Heart
Slide 10: BAT in Dogs With Chronic Heart Failure: Effects on Ventricular Arrhythmias
BAT in Dogs With Chronic Heart Failure: Effects on Ventricular Arrhythmias Objective Assess the effects of chronic therapy with BAT on the induction of VT or VF in dogs with coronary microembolization-induced HF (EF~20%). Methods • Study conducted in 14 dogs: active group (n = 7), sham-operated cont
Slide 11: BAT in Dogs With Chronic Heart Failure: EP Stimulation Protocol
BAT in Dogs With Chronic Heart Failure: EP Stimulaltion Protocol Programmed ventricular stimulation was performed from the right ventricular apex and included delivery of up to 4 extra- stimuli at progressively shorter coupling intervals (in steps of 10 msec). Extrastimuli delivered following 8 vent
Slide 12: Percent of Dogs Induced into VT or VF
Control BAT-Treated Percent of Dogs Induced into VT or VF 120 100 Control (n = 7) 80 BAT (n = 7) 60 43 29 40 20 0 PRE 3M 6M 6W Post Wang...Sabbah et al, Circulation 2008 12
Slide 13: Effects of BAT on Arrhythmia Resistance in Experimental Heart Failure
Effects of BAT on Arrhythmia Resistance in Experimental Heart Failure ISO + Incremental Pacing ISO + Burst Pacing Control (n=7) ISO + S1 200 Arrhythmia Resistance Index BAT-Treated (n=7) ISO + S1 250 ISO + S1 300 ISO + S1 400 S1 200 S1 250 S1 300 S1 400 S1 500 S1 600 PRE 3-Month 6-Month 6-Month + 6
Slide 14: Effects of BAT in Experimental Heart Failure Produced by Rapid Pacing
Effects of BAT in Experimental Heart Failure Produced by Rapid Pacing Survival 100% 80% 60% 2X Control BAT N=7 N=8 40% Avg: 31 Avg: 68 20% 0% 0 20 40 60 80 100 Survival Days Zucker et al, Hypertension 2007 14
Slide 15: Effects of BAT in Heart Failure: Plasma Neurohormones and Pressures
Effects of BAT in Experimental Heart Failure Produced by Rapid Pacing Plasma Neurohormones Pressures Zucker et al, Hypertension 2007 15
Slide 16: Adrenergic Pathway
Adrenergic Pathway In heart failure (HF), cardiac β-adrenergic receptor (β-AR) signaling is impaired leading to desensitization of the myocardium to catecholamines. This is associated with reduced gene expression for β1-AR and adenyl cyclase and increased expression of β-adrenergic receptor kinase.
Slide 17: Beta-Adrenergic Receptor Signal Transduction Pathway
Beta-Adrenergic Receptor Signal Transduction Pathway mRNA Beta-1 AR (du) mRNA Beta-2 AR (du) 0.8 0.4 0.6 0.3 0.4 0.2 P<0.05 0.2 0.1 NL HF BAT NL HF BAT (n=6) (n=6) (n=8) mRNA BARK-1 (du) mRNA AC-6 (du) 1.6 0.8 P<0.05 1.2 0.6 0.8 0.4 P<0.05 0.4 0.2 0.0 0.0 NL HF BAT NL HF BAT 17 Sabbah et al, Circula
Slide 18: Nitric Oxide Synthases
Nitric Oxide Synthases eNOS: (Reduced in CHF). Enhances relaxation; regulates contractility; regulates cell growth and apoptosis. iNOS: (Increased in CHF). Overexpression leads to apoptosis, increased fibrosis, hypertrophy, heart block, sudden cardiac death. nNOS: (Increased in CHF). Can modulate ca
Slide 19: Nitric Oxide Pathway
Nitric Oxide Pathway mRNA nNOS (du) mRNA iNOS (du) 2.0 1.0 P<0.05 P<0.05 1.6 0.8 1.2 0.6 0.8 0.4 0.4 0.2 0.0 0.0 NL HF BAT NL HF BAT (n=6) (n=6) (n=8) mRNA eNOS (du) LV Nitrate+Nitrite (pmol/g) 0.8 70 0.7 60 0.6 50 0.5 P<0.05 P<0.05 40 0.4 0.3 30 0.2 20 NL HF BAT NL HF BAT 19 Sabbah et al, Circulati
Slide 20: Inflammation
Inflammation Plasma Neopterin (ng/ml) 6 Baseline Pre-Treatement p<0.05 vs. Base Post-Treatement 5 4 p<0.05 vs. PRE p<0.05 vs. Base 3 2 p<0.05 vs. PRE 1 0 Control BAT-Treated 20
Slide 21: Inflammation, Nitric Oxide and Mitochondrial Biogenesis and Respiration
Inflammation, Nitric Oxide and Mitochondrial Biogenesis and Respiration Inflammation Leads to NO produced from iNOS which inhibits activity of cytochrome c oxidase (complex-IV) by competing with binding sites for O2 21
Slide 22: Summary & Conclusions
SUMMARY & CONCLUSIONS Long-term BAT improves LV systolic and diastolic function in dogs with chronic advanced HF and partially reverses LV remodeling. BAT normalizes mRNA expression of key components of the β-AR signal transduction pathway. Reversal of this maladaptive gene expression is likely to r
Slide 23: Summary & Conclusions
SUMMARY & CONCLUSIONS In addition to improving LV function, long-term immunotherapy with BAT markedly increases the threshold for lethal ventricular arrhythmias in dogs with chronic HF, prolongs survival in dogs with pacing- induced HF and restores heart rate variability in patients with drug-resist
Slide 24: Summary & Conclusions
SUMMARY & CONCLUSIONS These benefits of BAT, when viewed in concert, support the continued exploration of this therapeutic modality for the treatment of patients with chronic HF and increased risk of sudden cardiac death. 24