Permanent Pacemaker Implantation and Long-Term Outcomes of Patients Undergoing Concomitant Mitral and Tricuspid Valve Surgery.

BACKGROUND: Tricuspid valve annuloplasty (TA) during mitral valve repair (MVr) is associated with increased risk of permanent pacemaker (PPM) implantation, but the magnitude of risk and long-term clinical consequences have not been firmly established. OBJECTIVES: This study assesses the incidence rates of PPM implantation after isolated MVr and following MVr with TA as well as the associated long-term clinical consequences of PPM implantation. METHODS: State-mandated hospital discharge databases of New York and California were queried for patients undergoing MVr (isolated or with concomitant TA) between 2004 and 2019. Patients were stratified by whether or not they received a PPM within 90 days of index surgery. After weighting by propensity score, survival, heart failure hospitalizations (HFHs), endocarditis, stroke, and reoperation were compared between patients with or without PPM. RESULTS: A total of 32,736 patients underwent isolated MVr (n = 28,003) or MVr + TA (n = 4,733). Annual MVr + TA volumes increased throughout the study period (P < 0.001, trend), and PPM rates decreased (P < 0.001, trend). The incidence of PPM implantation <90 days after surgery was 7.7% for MVr and 14.0% for MVr + TA. In 90-day conditional landmark-weighted analyses, PPMs were associated with reduced long-term survival among MVr (HR: 1.96; 95% CI: 1.75-2.19; P < 0.001) and MVr + TA recipients (HR: 1.65; 95% CI: 1.28-2.14; P < 0.001). In both surgical groups, PPMs were also associated with an increased risk of HFH (HR: 1.56; 95% CI: 1.27-1.90; P < 0.001) and endocarditis (HR: 1.95; 95% CI: 1.52-2.51; P < 0.001), but not with stroke or reoperation. CONCLUSIONS: Compared to isolated MVr, adding TA to MVr was associated with a higher risk of 90-day PPM implantation. In both surgical groups, PPM implantation was associated with an increase in mortality, HFH, and endocarditis.

Knowledge gaps in heart and lung donation after the circulatory determination of death: Report of a workshop of the National Heart, Lung, and Blood Institute.

In a workshop sponsored by the U.S. National Heart, Lung, and Blood Institute, experts identified current knowledge gaps and research opportunities in the scientific, conceptual, and ethical understanding of organ donation after the circulatory determination of death and its technologies. To minimize organ injury from warm ischemia and produce better recipient outcomes, innovative techniques to perfuse and oxygenate organs postmortem in situ, such as thoracoabdominal normothermic regional perfusion, are being implemented in several medical centers in the US and elsewhere. These technologies have improved organ outcomes but have raised ethical and legal questions. Re-establishing donor circulation postmortem can be viewed as invalidating the condition of permanent cessation of circulation on which the earlier death determination was made and clamping arch vessels to exclude brain circulation can be viewed as inducing brain death. Alternatively, TA-NRP can be viewed as localized in-situ organ perfusion, not whole-body resuscitation, that does not invalidate death determination. Further scientific, conceptual, and ethical studies, such as those identified in this workshop, can inform and help resolve controversies raised by this practice.

Research opportunities and ethical considerations for heart and lung xenotransplantation research: A report from the National Heart, Lung, and Blood Institute workshop.

Xenotransplantation offers the potential to meet the critical need for heart and lung transplantation presently constrained by the current human donor organ supply. Much was learned over the past decades regarding gene editing to prevent the immune activation and inflammation that cause early organ injury, and strategies for maintenance of immunosuppression to promote longer-term xenograft survival. However, many scientific questions remain regarding further requirements for genetic modification of donor organs, appropriate contexts for xenotransplantation research (including nonhuman primates, recently deceased humans, and living human recipients), and risk of xenozoonotic disease transmission. Related ethical questions include the appropriate selection of clinical trial participants, challenges with obtaining informed consent, animal rights and welfare considerations, and cost. Research involving recently deceased humans has also emerged as a potentially novel way to understand how xeno-organs will impact the human body. Clinical xenotransplantation and research involving decedents also raise ethical questions and will require consensus regarding regulatory oversight and protocol review. These considerations and the related opportunities for xenotransplantation research were discussed in a workshop sponsored by the National Heart, Lung, and Blood Institute, and are summarized in this meeting report.

Bioethical implications of organ-on-a-chip on modernizing drug development.

Organ-on-chips are three-dimensional microdevices that emulate the structure, functionality, and behavior of specific tissues or organs using human cells. Combining organoids with microfabricated fluidic channels and microelectronics, these systems offer a promising platform for studying disease mechanisms, drug responses, and tissue performance. By replicating the in vivo microenvironment, these devices can recreate complex cell interactions in controlled conditions and facilitate research in various fields, including drug toxicity and efficacy studies, biochemical analysis, and disease pathogenesis. Integrating human induced pluripotent stem cells further enhances their applicability, thereby enabling patient-specific disease modeling for precision medicine. Although challenges like economy-of-scale, multichip integration, and regulatory compliance exist, advances in this modular technology show promise for lowering drug development costs, improving reproducibility, and reducing the reliance on animal testing. The ethical landscape surrounding organ-on-chip usage presents both benefits and concerns. While these chips offer an alternative to animal testing and potential cost savings, they raise ethical considerations related to community engagement, informed consent, and the need for standardized guidelines. Ensuring public acceptance and involvement in decision-making is vital to address misinformation and mistrust. Furthermore, personalized medicine models using patient-derived cells demand careful consideration of potential ethical dilemmas, such as modeling physiological functions of fetuses or brains and determining the extent of protection for these models. To achieve the full potential of organ-on-a-chip models, collaboration between scientists, ethicists, and regulators is essential to fulfil the promise of transforming drug development, advancing personalized medicine, and contributing to a more ethical and efficient biomedical research landscape.

Pediatric and Congenital Cardiovascular Disease Research Challenges and Opportunities: JACC Review Topic of the Week.

The National Heart, Lung, and Blood Institute convened a workshop in August 2021 to identify opportunities in pediatric and congenital cardiovascular research that would improve outcomes for individuals with congenital heart disease across the lifespan. A subsidiary goal was to provide feedback on and visions for the Pediatric Heart Network. This paper summarizes several key research opportunities identified in the areas of: data quality, access, and sharing; aligning cardiovascular research with patient priorities (eg, neurodevelopmental and psychological impacts); integrating research within clinical care and supporting implementation into practice; leveraging creative study designs; and proactively enriching diversity of investigators, participants, and perspectives throughout the research process.

Pacemaker implantation associated with tricuspid repair in the setting of mitral valve surgery: Insights from a Cardiothoracic Surgical Trials Network randomized trial.

OBJECTIVES: In a recent trial, tricuspid annuloplasty (TA) during mitral valve surgery (MVS) for degenerative mitral regurgitation and moderate or less tricuspid regurgitation (TR) reduced the composite rate of death, reoperation for TR, or TR progression at 2 years. However, this benefit was counterbalanced by an increase in implantation of permanent pacemakers (PPMs). In this study, we analyzed the timing, indications, and risk factors for these implantations. METHODS: We randomized 401 patients (MVS alone = 203; MVS + TA = 198). Potential risk factors for PPMs were assessed using multivariable time-to-event models with death and PPM implantation for heart failure indications as competing risks. RESULTS: A PPM was implanted in 36 patients (9.6; 95% CI, 6.8-13.0) within 2 years of randomization, with 30/187 (16.0%) in the MVS + TA and 6/188 (3.2%) in the MVS groups (rate ratio, 5.08; 95% CI, 2.16-11.94; P < .001). Most (29/36; 80.6%) implantations occurred within 30 days postoperatively. Independent risk factors for PPM implantation within 2 years were TA (hazard ratio [HR], 5.94; 95% CI, 2.27-15.53; P < .001), increasing age (5 years, HR, 1.23; 95% CI, 1.01-1.52; P = .04), and left ventricular ejection fraction (LVEF; HR, 0.96; 95% CI, 0.92-0.99; P = .02). In the subset of TA recipients (n = 197), age (5 years, HR, 1.05; 95% CI, 1.00-1.10; P = .04) and LVEF (HR, 0.95; 95% CI, 0.91-0.99; P = .01) were associated with PPM within 2 years. CONCLUSIONS: Concomitant TA, age, and baseline LVEF were risk factors for PPM implantation in patients who underwent MVS for degenerative mitral regurgitation. Although TA was effective in preventing progression of TR, innovation is needed to identify ways to decrease PPM implantation rates.