Feasibility and safety of a novel technology for pacing without leads.

BACKGROUND: Pacemaker lead complications and failures remain clinical problems. New devices incorporating three leads are associated with even greater limitations. OBJECTIVES: The purpose of this study was to investigate the feasibility and safety of a technology enabling cardiac pacing without leads in an acute porcine model. METHODS: The system is composed of an ultrasound transmitter delivering energy from the chest wall to a receiver-electrode in contact with the myocardium that then converts the ultrasound energy to electrical energy sufficient to pace. In five feasibility studies, the receiver-electrodes were attached to the tip of a catheter to facilitate intracardiac positioning at pacing sites. In six safety studies (five treatment and one sham), ultrasound energy was transmitted to both chest walls, and histopathologic examinations were performed to evaluate bioeffects due to ultrasound energy transmission. RESULTS: In five feasibility studies, direct and ultrasound-mediated electrical pacing was demonstrated at 30 sites in the right atrium, right ventricle, and left ventricle, at direct electrical pacing outputs of 1.4 +/- 0.6 V and ultrasound-mediated electrical pacing outputs of 1.8 +/- 0.9 V. The mechanical index was 0.6 +/- 0.4 at the receiver site during ultrasound-mediated pacing at a depth of 11.2 +/- 2.4 cm from the chest wall. Using two receiver-electrode catheters, biventricular pacing was demonstrated in all studies. In five safety study treatment animals at a similar depth, the peak mechanical index was 2.3, and the thermal index was 0.4. Microscopic evaluation revealed no evidence of mechanical or thermal bioeffects. CONCLUSION: The feasibility and safety of this novel technology for pacing without leads has been demonstrated acutely in animals.

Ultrasound-enhanced transgene expression in vascular cells is not dependent upon cavitation-induced free radicals.

Although acoustic cavitation is clearly important in ultrasound (US)-enhanced gene delivery (UEGD), the relative importance of mechanical and sonochemical (free radical) bioeffects remains unclear, as does the mechanism of gene delivery at the cellular level. Porcine vascular smooth muscle cells (VSMC) were transfected with luciferase or green fluorescent protein (GFP) plasmid +/- pulsed 956 kHz US (2.0 mechanical index (MI), 128 W cm(-2) spatial peak pulse average intensity, ISPPA) for 60 s, in the presence or absence of 20 mM cysteamine or N-acetyl-L-cysteine. Both compounds effectively scavenged free radical production following US, leaving unaffected the 50- to 100-fold enhancements in luciferase expression seen in US-treated VSMC. US exposure enhanced plasmid uptake (25 +/- 4.6 vs. 3 +/- 1.9 cells/field, n=4, p<0.05), most likely directly into the cytoplasm, and increased both the total number (>sevenfold) and average fluorescence intensity (>sixfold) of GFP-transfected cells. UEGD is not dependent upon cavitation-induced free radical generation and has potential for use with a wide range of therapeutic transgenes.

Transcutaneous ultrasound augments naked DNA transfection of skeletal muscle.

This study was designed to test the hypothesis that transcutaneous ultrasound (US) exposure may augment the transfection efficiency and biological outcome associated with nonviral DNA gene transfer. Hindlimb muscles of New Zealand White rabbits were transfected with the reporter plasmid pCMV-beta, with or without US exposure. Optimization studies employed US exposure at various frequencies, mechanical indices, duty cycles, durations of exposure, and exposure time points. Based on these results, we explored the effect of US exposure on nonviral gene transfer of vascular endothelial growth factor (VEGF, phVEGF165) to promote neovascularization of ischemic hindlimbs. Ultrasound at 1 MHz, 100 W/cm(2), 6% duty cycle, and 5 minutes exposure time, applied immediately following DNA injection, was found to be the most effective among the settings tested, increasing beta-galactosidase expression approximately 20 fold. Compared with US exposure alone, or phVEGF165 only, phVEGF165 + US exposure yielded a statistically significant improvement in revascularization, as determined by calf blood pressure ratio, angiographic score, intravascular Doppler blood flow, and capillary/myocyte ratio. These data demonstrate that ultrasound, when applied directly after intramuscular gene transfer, significantly increases transfection efficiency in vivo. The biological significance of this finding was confirmed by augmented limb perfusion in response to US exposure and naked VEGF DNA.