Heart failure gene therapy: the path to clinical practice

Gene therapy, aimed at the correction of key pathologies being out of reach for conventional drugs, bears the potential to alter the treatment of cardiovascular diseases radically and thereby of heart failure. Heart failure gene therapy refers to a therapeutic system of targeted drug delivery to the heart that uses formulations of DNA and RNA, whose products determine the therapeutic classification through their biological actions. Among resident cardiac cells, cardiomyocytes have been the therapeutic target of numerous attempts to regenerate systolic and diastolic performance, to reverse remodeling and restore electric stability and metabolism. Although the concept to intervene directly within the genetic and molecular foundation of cardiac cells is simple and elegant, the path to clinical reality has been arduous because of the challenge on delivery technologies and vectors, expression regulation, and complex mechanisms of action of therapeutic gene products. Nonetheless, since the first demonstration of in vivo gene transfer into myocardium, there have been a series of advancements that have driven the evolution of heart failure gene therapy from an experimental tool to the threshold of becoming a viable clinical option. The objective of this review is to discuss the current state of the art in the field and point out inevitable innovations on which the future evolution of heart failure gene therapy into an effective and safe clinical treatment relies.

Stiffness, Strength, and Failure Modes of Implant-Supported Monolithic Lithium Disilicate Crowns: Influence of Titanium and Zirconia Abutments

PURPOSE The objective of this study was to evaluate stiffness, strength, and failure modes of monolithic crowns produced using computer-aided design/computer-assisted manufacture, which are connected to diverse titanium and zirconia abutments on an implant system with tapered, internal connections. MATERIALS AND METHODS Twenty monolithic lithium disilicate (LS2) crowns were constructed and loaded on bone level-type implants in a universal testing machine under quasistatic conditions according to DIN ISO 14801. Comparative analysis included a 2 × 2 format: prefabricated titanium abutments using proprietary bonding bases (group A) vs nonproprietary bonding bases (group B), and customized zirconia abutments using proprietary Straumann CARES (group C) vs nonproprietary Astra Atlantis (group D) material. Stiffness and strength were assessed and calculated statistically with the Wilcoxon rank sum test. Cross-sections of each tested group were inspected microscopically. RESULTS Loaded LS2 crowns, implants, and abutment screws in all tested specimens (groups A, B, C, and D) did not show any visible fractures. For an analysis of titanium abutments (groups A and B), stiffness and strength showed equally high stability. In contrast, proprietary and nonproprietary customized zirconia abutments exhibited statistically significant differences with a mean strength of 366 N (Astra) and 541 N (CARES) (P < .05); as well as a mean stiffness of 884 N/mm (Astra) and 1,751 N/mm (CARES) (P < .05), respectively. Microscopic cross-sections revealed cracks in all zirconia abutments (groups C and D) below the implant shoulder. CONCLUSION Depending on the abutment design, prefabricated titanium abutment and proprietary customized zirconia implant-abutment connections in conjunction with monolithic LS2 crowns had the best results in this laboratory investigation.

Influence of Abutment Design on Stiffness, Strength, and Failure of Implant-Supported Monolithic Resin Nano Ceramic (RNC) Crowns

BACKGROUND Recent technical development allows the digital manufacturing of monolithic reconstructions with high-performance materials. For implant-supported crowns, the fixation requires an abutment design onto which the reconstruction can be bonded. PURPOSE The aim of this laboratory investigation was to analyze stiffness, strength, and failure modes of implant-supported, computer-assisted design and computer-aided manufacturing (CAD/CAM)-generated resin nano ceramic (RNC) crowns bonded to three different titanium abutments. MATERIALS AND METHODS Eighteen monolithic RNC crowns were produced and loaded in a universal testing machine under quasi-static condition according to DIN ISO 14801. With regard to the type of titanium abutment, three groups were defined: (1) prefabricated cementable standard; (2) CAD/CAM-constructed individualized; and (3) novel prefabricated bonding base. Stiffness and strength were measured and analyzed statistically with Wilcoxon rank sum test. Sections of the specimens were examined microscopically. RESULTS Stiffness demonstrated high stability for all specimens loaded in the physiological loading range with means and standard deviations of 1,579 ± 120 N/mm (group A), 1,733 ± 89 N/mm (group B), and 1,704 ± 162 N/mm (group C). Mean strength of the novel prefabricated bonding base (group C) was 17% lower than of the two other groups. Plastic deformations were detectable for all implant-abutment crown connections. CONCLUSIONS Monolithic implant crowns made of RNC seem to represent a feasible and stable prosthetic construction under laboratory testing conditions with strength higher than the average occlusal force, independent of the different abutment designs used in this investigation.