Rheumatic Heart Disease in the Developing World.

Despite recent public policy initiatives, rheumatic heart disease (RHD) remains a major source of morbidity worldwide. Rheumatic heart disease occurs as a sequela of Streptococcus pyogenes (group A streptococcal [GAS]) infection in patients with genetic susceptibility. Strategies for prevention of RHD or progression of RHD include prevention of GAS infection with community initiatives, effective treatment of GAS infection, and secondary prophylaxis with intramuscular penicillin. The cardiac surgical community has attempted to improve the availability of surgery in RHD-endemic areas with some success, and operative techniques and outcomes of valve repair continue to improve, potentially offering patients a safer, more durable operation. Innovation offers hope for a more scalable solution with improved biomaterials and transcatheter delivery technology; however, cost remains a barrier.

Anatomic considerations after commando double valve reconstruction: insights for future valve-in-valve therapies.

OBJECTIVES: The Commando technique for reconstruction of the aortomitral intervalvular fibrous body is effective to facilitate double valve surgery in cases of endocarditis or infiltrative calcification. The length of patch utilized in reconstruction of the intervalvular fibrous body has an important relationship to the geometry of the mitral valve (MV) and aortic valve (AV) and may impact on potential future valve-in-valve (VIV) therapy. Here we report anatomic measurements after Commando reconstruction in a small group of patients and analyse the impact of reconstruction techniques on transcatheter VIV therapies. METHODS: Seven patients from January 2018 to April 2022 who underwent double valve surgery with the Commando technique with postoperative computed tomography (CT) scans were identified. Computed tomographic reconstruction of the AV and MV was performed using 3mensio software and virtual transcatheter valve replacement was performed. Two of these patients who had preoperative imaging was analysed to assess the change in aortomitral geometry resulting from reconstruction. RESULTS: Measurements for each patient post-reconstruction are given in the table. Aortomitral length was grossly inversely proportional to aortomitral angle (AMA). AMA and aortomitral curtain (AMC) length were significantly altered post-Commando in 2 analysed patients with pre- and postoperative computed tomography scan. Transcatheter AV and MV replacements were feasible in all patients post-Commando. The AMA was larger and more favorable for mitral VIV in patients in which the AMC was short. CONCLUSIONS: AMC length, as determined by location of AV annular sutures, may be an important consideration in surgical decision-making for VIV after the Commando procedure.

Decreased serotonin transporter activity in the mitral valve contributes to progression of degenerative mitral regurgitation.

Degenerative mitral valve (MV) regurgitation (MR) is a highly prevalent heart disease that requires surgery in severe cases. Here, we show that a decrease in the activity of the serotonin transporter (SERT) accelerates MV remodeling and progression to MR. Through studies of a population of patients with MR, we show that selective serotonin reuptake inhibitor (SSRI) use and SERT promoter polymorphism 5-HTTLPR LL genotype were associated with MV surgery at younger age. Functional characterization of 122 human MV samples, in conjunction with in vivo studies in SERT-/- mice and wild-type mice treated with the SSRI fluoxetine, showed that diminished SERT activity in MV interstitial cells (MVICs) contributed to the pathophysiology of MR through enhanced serotonin receptor (HTR) signaling. SERT activity was decreased in LL MVICs partially because of diminished membrane localization of SERT. In mice, fluoxetine treatment or SERT knockdown resulted in thickened MV leaflets. Similarly, silencing of SERT in normal human MVICs led to up-regulation of transforming growth factor ß1 (TGFß1) and collagen (COL1A1) in the presence of serotonin. In addition, treatment of MVICs with fluoxetine not only directly inhibited SERT activity but also decreased SERT expression and increased HTR2B expression. Fluoxetine treatment and LL genotype were also associated with increased COL1A1 expression in the presence of serotonin in MVICs, and these effects were attenuated by HTR2B inhibition. These results suggest that assessment of both 5-HTTLPR genotype and SERT-inhibiting treatments may be useful tools to risk-stratify patients with MV disease to estimate the likelihood of rapid disease progression.

Outcomes of treatment for deep left ventricular assist device infection.

OBJECTIVE: Among left ventricular assist device patients, the most commonly infected component is the drive line, which can be managed with antibiotics and local debridement. Infection of intrathoracic device components is less common but more difficult to manage. Herein we describe the incidence of deep device infection (DDI) at our center as well as management and outcomes. METHODS: We retrospectively reviewed 658 patients who underwent implantable left ventricular assist device insertion with HeartMate 2 (Abbott) or HeartMate 3 (Abbott) devices between January 2004 and June 2021. DDI was defined according to radiographic and clinical criteria. Cumulative incidence was calculated using a Fine-Gray subdistribution model; survival analysis was performed using the method of Kaplan and Meier. RESULTS: There were 32 (4.8%) DDIs during this study period. Drive line infection and re-exploration for bleeding were associated with development of DDI. Cumulative incidence of DDI increased over time, affecting 11% (7%-18%) at 5 years. The dominant microbes involved in DDI were Pseudomonas aeruginosa (19%) and methicillin-resistant Staphylococcus aureus (13%). Nineteen patients (59%) with device infection underwent device exchange, 6 (19%) underwent initial transplant, and 7 (22%) were treated solely with debridement and antibiotics. Of those who underwent device exchange, 12 (63%) developed reinfection of their new device and 6 underwent subsequent heart transplant. Patients who underwent transplantation for management of device infection had improved 5-year survival (80% vs 11%; P = .01) but 3 patients (25%) developed deep sternal wound infection after transplant. CONCLUSIONS: DDI is a rare but challenging complication in this destination era. Heart transplantation is the preferred management strategy for eligible patients but infectious complication is common.

Bridge to Sapien: Mechanical Circulatory Support as a Bridge to Transcatheter Mitral Intervention.

Venoarterial membrane oxygenation can be used as a rescue therapy for patients in refractory cardiogenic shock. Whereas there is experience with a bridge-to-transplant and bridge-to-ventricular assist device in the heart failure population, there are no reports of its use as a bridge to definitive valvular intervention. Here, we present a case of venoarterial extracorporeal membrane oxygenation as a bridge to transcatheter mitral valve-in-valve with a Sapien aortic prosthesis (Edwards Life Sciences).

Xenogeneic cross-circulation for extracorporeal recovery of injured human lungs.

Patients awaiting lung transplantation face high wait-list mortality, as injury precludes the use of most donor lungs. Although ex vivo lung perfusion (EVLP) is able to recover marginal quality donor lungs, extension of normothermic support beyond 6 h has been challenging. Here we demonstrate that acutely injured human lungs declined for transplantation, including a lung that failed to recover on EVLP, can be recovered by cross-circulation of whole blood between explanted human lungs and a Yorkshire swine. This xenogeneic platform provided explanted human lungs a supportive, physiologic milieu and systemic regulation that resulted in functional and histological recovery after 24 h of normothermic support. Our findings suggest that cross-circulation can serve as a complementary approach to clinical EVLP to recover injured donor lungs that could not otherwise be utilized for transplantation, as well as a translational research platform for immunomodulation and advanced organ bioengineering.

Human Intestinal Allografts Contain Functional Hematopoietic Stem and Progenitor Cells that Are Maintained by a Circulating Pool.

Human intestinal transplantation often results in long-term mixed chimerism of donor and recipient blood in transplant patients. We followed the phenotypes of chimeric peripheral blood cells in 21 patients receiving intestinal allografts over 5 years. Donor lymphocyte phenotypes suggested a contribution of hematopoietic stem and progenitor cells (HSPCs) from the graft. Surprisingly, we detected donor-derived HSPCs in intestinal mucosa, Peyer's patches, mesenteric lymph nodes, and liver. Human gut HSPCs are phenotypically similar to bone marrow HSPCs and have multilineage differentiation potential in vitro and in vivo. Analysis of circulating post-transplant donor T cells suggests that they undergo selection in recipient lymphoid organs to acquire immune tolerance. Our longitudinal study of human HSPCs carried in intestinal allografts demonstrates their turnover kinetics and gradual replacement of donor-derived HSPCs from a circulating pool. Thus, we have demonstrated the existence of functioning HSPCs in human intestines with implications for promoting tolerance in transplant recipients.

Early expansion of donor-specific Tregs in tolerant kidney transplant recipients.

Allograft tolerance, in which a graft is accepted without long-term immunosuppression, could overcome numerous obstacles in transplantation. Human allograft tolerance has been intentionally induced across HLA barriers via combined kidney and bone marrow transplantation (CKBMT) with a regimen that induces only transient chimerism. Tregs are enriched early after CKBMT. While deletional tolerance contributes to long-term tolerance, the role of Tregs remains unclear. We have optimized a method for identifying the donor-specific Treg repertoire and used it to interrogate the fate of donor-specific Tregs after CKBMT. We expanded Tregs with several different protocols. Using functional analyses and T cell receptor sequencing, we found that expanding sorted Tregs with activated donor B cells identified the broadest Treg repertoire with the greatest potency and donor specificity of suppression. This method outperformed both alloantigen stimulation with CTLA4Ig and sequencing of CFSElo cells from the primary mixed lymphocyte reaction. In 3 tolerant and 1 nontolerant CKBMT recipients, we sequenced donor-specific Tregs before transplant and tracked them after transplant. Preexisting donor-specific Tregs were expanded at 6 months after CKBMT in tolerant patients and were reduced in the nontolerant patient. These results suggest that early expansion of donor-specific Tregs is involved in tolerance induction following CKBMT.

Medial Epicondyle Morphology in Elite Overhead Athletes: A Closer Look Using 3-Dimensional Computer Simulation.

BACKGROUND: Prior studies have attempted to determine morphological characteristics of the medial epicondyle in overhead athletes, but no study has reported on precise quantitative differences between elite overhead athletes and control patients. HYPOTHESIS: The medial epicondyle in overhead athletes is larger in volume than those of control patients. STUDY DESIGN: Cross-sectional study; Level of evidence, 3. METHODS: Computer simulation modeling from advanced (computed tomography/magnetic resonance imaging) imaging of the elbow of 37 patients (22 elite overhead athletes, 15 control patients) was performed to provide detailed assessment of the morphological characteristics of the medial epicondyle. Several quantitative metrics regarding the medial epicondyle were measured and compared across both cohorts, including that of epicondyle width (medial-lateral), height (superior-inferior), thickness (anterior-posterior), volume, percentage cortical volume, and morphology of the inferior slope of the epicondyle. RESULTS: The medial epicondyle in overhead athletes was significantly larger than that found in nonathlete controls (4976 vs 3682 mm(3); P = .001). There was no significance between the 2 cohorts in medial-lateral width (16.8 vs 16.6 mm; P = .68), but there was a difference in anterior-posterior thickness (16.96 vs 14.40 mm; P = .001) and superior-inferior height (39.55 vs 35.86 mm; P = .09) in athletes versus controls. The epicondyle volume was 97.9% cortical bone in athletes compared with 82.3% in control patients (P < .001). There were no differences in the morphology of the inferior epicondyle slope between the 2 groups. CONCLUSION: The medial epicondyle in overhead athletes is larger in volume and anterior-posterior thickness than those of control patients. Additionally, the medial epicondyle is comprised nearly entirely of cortical bone in overhead athletes. CLINICAL RELEVANCE: These quantitative findings support the theory of adaptive remodeling in skeletally immature overhead athletes.