TECHNOLOGY UPDATE TIVUS (Cardiosonic) Klaus Hertting Park-Hospital Leipzig, Germany

I have no real or apparent conflicts of interest to report. Klaus Hertting, MD I have no real or apparent conflicts of interest to report.

Cardiosonic TIVUS™ System and Setup for Renal Denervation 6 Fr TIVUSTM Console – illustration 5 F shaft; 6F tip _ contrast injection during treatment possible 3

Non-Focused High Intensity Ultrasonic Catheter Core Technology: Non-Focused High Intensity Ultrasonic Catheter Non-Focused Ultrasonic Ray Cooling effect by the blood flow T [C0] Depth into artery [mm] Thermal Effect Threshold

Renal Denervation Using TIVUSTM: Localized Targeted Nerve Damage Renal Denervation Symplicity® vs. TIVUSTM: Swine Study, TTC Stain and H&E Histology 10/01/2012 (Leipzig, Germany) Renal Artery Cross-Section Large nerve fibers bundles with fat cover Nerve fibers Aorta Lumen Adventitia Media Intima/ Endothelium

Pre Clinical Results Ultrasonic Transducer High intensity ultrasonic beam TIVUS™ Catheter Safety: no significant kidney function alteration and no significant angiography luminal narrowing Remote effect: No contact with the luminal wall, endothelial sparing Localized effect: Within the ultrasonic ray Thermal Modulation: Controlled effect size by parameters Effective: NE concentration lower by up to 93% compared to independent untreated animals.

TIVUS™ Treatment Protocol 12 o'clock 6 o'clock 3 o'clock 9 o'clock 1-3 treatment sites along the artery. Up to 4 circumferential treatment points per site, 90°rotation. Clear angiographic imaging of treatment head circumferential positioning. Ultrasonic position feedback. Minimal need for contrast injection Next Generation TIVUSTM: single-operation simultaneous circumferential treatment

The TIVUS™ Technology Advantages for Renal Denervation Remote, localized, and controlled thermal modulation of vessel wall tissue components Prevents disruption of the endothelium, elastic lamina, and other surrounding tissues Energy delivery without physical contact with the vessel intima Non-occlusive catheter with no collateral tissue damages Real-time ultrasonic positioning feedback for safety Simply fluoroscopically guided treatment Short excitation: 30 - 40 seconds per treatment point

TIVUS™ I Study The TIVUS™ I First In Man Study; Prospective, multicenter, non-randomized, single-arm, open-label clinical study of the Safety & Performance of the TIVUS™ System Jonas M., LINC 2013

TIVUS™ I Study Jonas M., LINC 2013

TIVUS™ I Study-Case Study Jonas M., LINC 2013 11 | Confidential

TIVUS™ I Study-Baseline *Dipper 21% Jonas M., LINC 2013

TIVUS™ I Study-Baseline Selective Renal Angiography- Baseline R L 6Fr TIVUS™ Catheter, 0.014” OTW, 6Fr Steerable Introducer 30 seconds per treatment point Jonas M., LINC 2013

No Spasm, Normal Renal Arteries No AE, SAE or Complications TIVUS™ I Study-Procedure End of Procedure: No Spasm, Normal Renal Arteries No AE, SAE or Complications R L Jonas M., LINC 2013

TIVUS™ I Study-Post Procedure Jonas M., LINC 2013

TIVUS™ I Study-Preliminary Results No safety concerns No device malfunction or complication No SAE Successfully & effectively delivered ultrasonic treatment Minimal Patient discomfort compared with RF technology Short Duration per treatment point Protection of the luminal artery wall Jonas M., LINC 2013

Cardiosonic TIVUSTM Technology Special Capabilities for Renal Denervation Renal denervation from the aorta (around the ostium) Denervation of renal arteries with early bifurcation Renal denervation through a renal stent Venous access renal artery denervation - possibly for problematic arterial anatomies Probable: renal denervation through soft plaque/stenosis

Renal artery denervation from the aorta (around the ostium) XN A Renal Nerve Thermal Effect Region B XN High Intensity Ultrasound Energy B A Histopathology (H&E) XN: Necrosed Nerves Solid Black line: Thermal damage border TIVUSTM Catheter

Renal Denervation of Renal Artery with Early Bifurcation Cardiosonic TIVUSTM treatment head (ultrasonic transducer) 10mm

Denervation Through a Renal Stent Histopathology: Endoneural degenerated cells some with vacuolated cytoplasm (black border region) with adjacent cells with pyknotic nuclei. H&E. (CVPath Institute) Stent #2

Venus Access Renal Artery Denervation: TIVUSTM in Vena-Cava Positioning Histopathology (H&E) XN: Necrosed Nerves Solid Black line: Thermal damage border Dashed Green Line: Vena cava General: intact endothelium of the vena-cava and renal artery (no thermal damage or other)

Treatment Through a Human Atherosclerotic Plaque (amputation, ex-vivo) Histopathology (H&E) Solid Black line: Thermal damage border General: intact endothelium of the artery and plaque (no thermal damage or other)

Thank you !