Left ventricular ejection fraction, or LVEF, is the percentage of blood the left ventricle pumps out with each contraction, and it remains the workhorse metric of cardiac function worldwide. In the transplant arena, most research attention has focused on the donor heart’s LVEF at the time of procurement. Curiously, that early measurement has proven surprisingly uninformative: donor hearts with impaired function at procurement often recover fully, a phenomenon attributed in part to the catecholamine surge that follows donor brain death, which can temporarily stun the ventricle. When ischemic time is kept under four hours, recipients of such hearts generally fare well. What has been far less clear is whether the LVEF recorded a year after transplantation, once the dust of surgery has settled, carries any prognostic weight.

To answer that question, researchers led by Ahad Firoz of the University of California, Davis Medical Center, together with colleagues at UC Davis and the Lewis Katz School of Medicine at Temple University, analyzed adult first-time isolated orthotopic heart transplant recipients transplanted between January 2010 and September 2022 who survived to their one-year follow-up. Recipients with missing LVEF data at that visit were excluded, leaving a final cohort of 23,629 patients. The investigators deliberately chose the one-year mark because ventricular dysfunction related to procurement injury and acute postoperative graft changes is expected to have resolved by then, making any residual dysfunction a meaningful signal rather than a transient artifact. Follow-up data collected between 0.75 and 1.25 years after transplant were used, and patients were tracked until October 2023.

The cohort was stratified into four clinically grounded categories: preserved LVEF of 50 percent or above, which served as the reference group and comprised 96.4 percent of recipients; mildly reduced LVEF of 40 to 49 percent; moderately reduced LVEF of 30 to 39 percent; and severely reduced LVEF below 30 percent. Mean LVEF values in these groups were 61.1, 44.3, 34.3, and 21.6 percent respectively. The statistical architecture of the study was deliberately conservative. Four sequential models adjusted for an expanding set of covariables, culminating in a fully adjusted model that accounted for recipient demographics, functional status, comorbidities such as diabetes and hepatitis C, rejection episodes, hospitalizations, dialysis requirement, and an extensive panel of donor characteristics including donor LVEF at procurement, ischemic time, donor-recipient predicted heart mass ratio, and HLA-DR and CMV mismatch.

The headline result was a graded, dose-response relationship between one-year LVEF and mortality. Across 1,802 deaths recorded during follow-up, three-year survival from the baseline exam fell from 91.0 percent in the preserved group to 84.7 percent with mildly reduced, 74.3 percent with moderately reduced, and 68.5 percent with severely reduced function. In the fully adjusted Cox regression models, mildly reduced LVEF carried a 28 percent higher hazard of all-cause mortality (hazard ratio 1.28, p = 0.011), moderately reduced LVEF a 90 percent higher hazard (HR 1.90, p < 0.001), and severely reduced LVEF more than double the hazard (HR 2.06, p = 0.002). Cardiovascular mortality followed an even steeper gradient, with hazard ratios of 1.98, 3.17, and 4.54 across the three reduced categories, meaning patients with severely reduced function faced a 354 percent greater risk of dying from cardiovascular causes than those with preserved function.

Beyond survival, the study broke new methodological ground by applying a competing-risk framework to cardiac allograft vasculopathy, the progressive, atherosclerosis-like narrowing of the transplanted heart’s coronary arteries that is among the most feared late complications of transplantation. Using cumulative incidence functions, Gray’s test, and Fine-Gray subdistribution hazard models, with death treated as a competing event, the team found that the median time to CAV after the first annual visit shrank progressively as LVEF declined, from 2.9 years in the preserved group to just 1.2 years in the severely reduced group. After full adjustment, the subdistribution hazard ratios for CAV were 1.28, 1.57, and 1.65 for the mildly, moderately, and severely reduced groups respectively. This is the first report in the literature to assess CAV outcomes across LVEF groups using a competing-risk model, an approach that guards against overestimating risk when many patients die before vasculopathy can develop.

The web of associated morbidity extended well beyond the arteries. Recipients with reduced one-year LVEF experienced higher rates of hospitalization during follow-up, more frequent acute allograft rejection requiring treatment, and greater incidence of both early postoperative kidney injury necessitating dialysis and chronic kidney failure requiring dialysis. New-onset diabetes after transplantation was also more common, affecting 9.7 percent of recipients with reduced LVEF compared with 6.7 percent of those with preserved function. At the two-year follow-up, the differences persisted or widened: only 37.8 percent of patients who had severely reduced LVEF at one year retained preserved function at two years, compared with 97.4 percent of the preserved group, and re-transplantation rates climbed from 1.0 percent in the preserved group to 8.2 percent in the severely reduced group.

The authors propose a plausible biological narrative linking these findings, while cautioning that causality cannot be established from retrospective registry data. Maladaptive processes that predispose the allograft to dysfunction may begin early after surgery, triggering a cascade: reduced cardiac output diminishes renal perfusion, fostering a cardiorenal-like syndrome and dysregulation of the renin-angiotensin-aldosterone system; rejection episodes prompt escalating doses of nephrotoxic immunosuppressants, further injuring the kidneys and promoting new-onset diabetes; and chronic or recurrent rejection, particularly the poorly understood antibody-mediated form, drives the progression from acute graft dysfunction to vasculopathy. Each of these complications, in turn, is independently associated with mortality, which may partly explain the striking survival gradient observed. Consistent with this, functional status at one year and rejection within the first year were the strongest predictors of reduced LVEF in the study’s regression analyses.

The study has limitations inherent to its design. As a retrospective registry analysis, it cannot establish temporal sequence, and the granularity of OPTN data is constrained: the circumstances under which the one-year echocardiogram was obtained, whether routine screening or diagnostic work-up, are unknown, raising the theoretical possibility of ascertainment bias, which the authors mitigated by anchoring measurements to a strict window around the annual visit. Information on CAV severity was also unavailable beyond its presence. Nevertheless, the sheer scale and diversity of the cohort, spanning multiple centers across the United States in the modern era of transplantation, lend the findings considerable generalizability, and the study is by far the largest investigation to date of one-year LVEF after heart transplantation.

The clinical message is straightforward and potentially practice-changing. A single echocardiographic number obtained at the one-year visit, a test many centers already perform, appears to identify a high-risk minority of recipients who warrant intensified surveillance: screening for vasculopathy, close monitoring of renal function and glucose metabolism, vigilance for rejection, and timely escalation of therapy. Because advanced CAV has limited treatment options and re-transplantation carries substantial risk, early identification of patients on that trajectory could mean the difference between intervention while the graft is still salvageable and crisis management after irreversible decline. For the roughly one in twenty-five transplant recipients whose graft function has not normalized by the first anniversary, that routine ultrasound image may now be recognized as far more than a formality; it may be a forecast.

Subject of Research: Prognostic value of one-year left ventricular ejection fraction after heart transplantation

Article Title: Prognostic implications of one-year left ventricular systolic function after heart transplantation

Article References: Firoz, A., Ebong, I., Cadeiras, M., Zhao, H., & Jimenez, S. (2026). Prognostic implications of one-year left ventricular systolic function after heart transplantation. Clinical Research in Cardiology. https://doi.org/10.1007/s00392-026-03022-1

Image Credits: AI Generated

DOI: 10.1007/s00392-026-03022-1

Keywords: heart transplantation, left ventricular ejection fraction, cardiac allograft vasculopathy, graft rejection, mortality, OPTN registry, echocardiography, renal failure, prognosis, survival, immunosuppression, cardiology

Current practice is largely adapted from solid-organ transplantation, even though the immunology of composite grafts can be markedly different. Treatment is commonly organized around the three signals required for T-cell activation. First, a recipient T-cell receptor recognizes donor major histocompatibility complex molecules displayed by antigen-presenting cells. Second, costimulatory interactions, including CD80/86 with CD28, provide the additional confirmation needed for full activation. Third, cytokines such as interleukin-2 drive proliferation through intracellular pathways that include mammalian target of rapamycin. Induction therapy is given around the operation to blunt the initial immune response, maintenance therapy continues indefinitely, and additional drugs are used when rejection appears. In skin-rich grafts, many centers favor rabbit antithymocyte globulin, or rATG, a polyclonal antibody preparation that rapidly depletes T cells and also affects B cells, natural killer cells and other immune populations. The approach can reduce early rejection risk, but it may cause severe leukopenia, thrombocytopenia, cytokine release syndrome and opportunistic infections. Less intensive agents such as basiliximab block the interleukin-2 receptor without depleting lymphocytes, but may provide insufficient early suppression for highly immunogenic skin.

Long-term treatment commonly relies on a three-drug combination of tacrolimus, mycophenolate mofetil and corticosteroids. Tacrolimus inhibits calcineurin, preventing activation of nuclear factor of activated T cells and reducing the transcriptional program needed for T-cell responses. It is generally preferred over cyclosporine in VCA protocols, but prolonged exposure can damage the kidneys and contribute to other metabolic complications. Mycophenolate mofetil inhibits purine synthesis, restricting the proliferation of both T and B lymphocytes, while corticosteroids broadly dampen inflammation and immune activation. Sirolimus and everolimus, which inhibit the mTOR pathway, may be used when calcineurin inhibitor toxicity becomes a concern, although evidence for their use in VCA remains limited. The review emphasizes that reducing therapy is difficult: recipients often experience multiple rejection episodes, and grafts are already maintained at substantial drug intensity. When acute rejection occurs, skin lesions, swelling and redness may provide visible warnings. High-dose intravenous methylprednisolone is usually the first treatment, sometimes supplemented by topical tacrolimus or corticosteroids because the skin component is directly accessible. More resistant episodes may prompt rATG or alemtuzumab, but lymphocyte depletion alone has not reliably prevented rejection.

The burden of this strategy is especially consequential because most hand and face transplants improve quality of life rather than directly preventing death. Lifelong systemic suppression can increase susceptibility to cytomegalovirus, herpes simplex reactivation, fungal infections, pneumonia and Clostridioides difficile colitis. Cytomegalovirus remains a particular concern in donor-positive, recipient-negative mismatches and can occur despite antiviral prophylaxis. Treatment may require combinations of antiviral drugs and immune globulin. Long-term exposure also contributes to hyperglycemia, abnormal lipid levels, low magnesium, renal tubular problems, bone effects and fracture risk. The review notes that studies have reported metabolic dysregulation or malignancy in at least 65 percent of facial transplant recipients. Reduced immune surveillance can facilitate skin cancers and post-transplant lymphoproliferative disorders, while some immunosuppressants may promote tumor-associated pathways or interfere with DNA repair. This creates a difficult cycle: recurrent rejection requires stronger suppression, yet infection, metabolic disease or cancer may force clinicians to reduce treatment, potentially triggering further immune injury. Conventional therapy can control many acute episodes, but it has not provided a dependable way to prevent chronic rejection, the leading cause of late graft failure.

Chronic rejection illustrates why a more precise approach is needed. In VCA, it may appear as premature graft aging, mottled changes in skin color, thickened or prominent suture lines, telangiectasia, dryness of mucosal surfaces, tissue atrophy, fibrosis, loss of hair or other skin structures, nail changes and small-vessel thrombosis. Standard punch biopsies of skin can detect important changes, but they may miss injury in deeper tissues and arteries. In one rejected full-face graft, immunoproteomic analysis identified donor-origin CD8-positive T cells persisting inside the graft and infiltrating deep arteries near degenerating endothelium that had been repopulated by recipient-derived cells. The findings suggest a form of vascular injury that may not be captured by surveillance methods developed for solid organs. Face transplantation can also involve lymph nodes that reject independently of the visible skin. For this reason, the review supports surveillance that combines clinical inspection with scheduled skin and mucosal biopsies, consistent pathology scoring and, ultimately, molecular monitoring. The direct accessibility of VCA grafts is an advantage: clinicians can inspect tissue and sample it with minimally invasive procedures, while sentinel donor-derived flaps and tools such as ultrasound biomicroscopy may help assess rejection or vascular disease without repeatedly disturbing the primary graft.

Different VCA types also create different immunologic problems. Hand grafts contain vascularized bone marrow, which could provide donor blood-forming cells capable of producing mixed chimerism and potentially supporting tolerance, although donor marrow infusion has produced inconsistent clinical results. Hand recipients can experience acute rejection in as many as 85 percent of patients in reported series, and infections may become complex when treatment is intensified. Face grafts combine skin and mucosa with structures such as salivary glands, bone and lymphoid tissue, making rejection assessment more complicated; mucosal biopsies may show higher-grade rejection than skin and can contain infiltrating B cells and plasma cells. Uterine transplantation is different because the graft is temporary, contains no skin and must support a semi-allogeneic pregnancy. Rejection can often be detected through cervical biopsy, but immunosuppressive choices must also account for fetal safety, including replacement of mycophenolate mofetil with azathioprine before embryo transfer. Abdominal wall grafts are highly immunogenic because of their skin content, yet the skin can sometimes act as a visible sentinel for intestinal rejection. Laryngeal transplantation remains extremely rare, with fewer than 20 procedures reported and only four described as successful in the review. Its mucosal, airway and endocrine components make both treatment and surveillance difficult.

The most clinically advanced alternative discussed is costimulation blockade with belatacept, a CTLA4-Ig fusion protein that interrupts CD80/86-CD28 signaling. By targeting a specific activation step, belatacept may avoid the kidney toxicity and some metabolic and neurologic effects associated with calcineurin inhibitors. A reported hand transplant recipient received belatacept with mycophenolate mofetil and prednisone in a calcineurin-inhibitor-free regimen and maintained adequate rejection control for 18 months. However, progressive necrotizing rejection requiring amputation has also occurred during belatacept therapy, indicating that blocking costimulation alone may not be enough against skin-rich grafts. Cellular therapies offer another route. Regulatory T cells, or Tregs, naturally restrain immune activation and may be expanded or engineered to recognize donor antigens. Chimeric antigen receptor Tregs directed against donor HLA-A2 are being investigated, but their clinical use faces obstacles including limited survival after infusion, instability in inflammatory environments and the time needed to produce a patient-specific cell product. Most evidence remains preclinical or comes from isolated clinical reports rather than controlled VCA trials.

Researchers are also attempting to concentrate treatment at the graft instead of exposing the entire body. In a rat hindlimb model, a tacrolimus-eluting disk placed inside the graft supported survival for more than 200 days while maintaining low systemic drug levels; the benefit disappeared after removal of draining lymph nodes, suggesting that regional immune pathways were important. Other microparticles releasing transforming growth factor beta 1, interleukin-2 and rapamycin have prolonged graft survival in rats while enriching Tregs in draining lymph nodes and producing donor-specific tolerance. Biomaterial scaffolds and hydrogels carrying immune-regulating signals are being tested for similar purposes. Ex vivo machine perfusion could provide another platform by allowing a donor graft to be treated before implantation. Normothermic perfusion of porcine forelimbs removed approximately 49 billion donor leukocytes over six hours, potentially reducing the antigen-presenting cells that initiate early rejection. The same interval could be used to deliver drugs, gene therapy vectors or cellular products directly through the graft’s vasculature. Gene-editing tools such as CRISPR-Cas9 may eventually modify donor immune or antigen-presenting cells before transplantation, although safety and durability remain unresolved. Di-chimeric cells, made by fusing donor and recipient cell types, have extended graft survival in rodent studies without the marrow-ablating conditioning required by conventional chimerism protocols.

The review presents these approaches as promising directions, not established treatments. A major requirement for progress is standardization across the small number of centers performing VCA. Protocols, biopsy practices and outcome definitions vary, making it difficult to compare results or identify the safest drug combinations. International registries and improved diagnostic criteria for mucosal, vascular and chronic rejection could provide a common framework. Noninvasive markers, including donor-derived cell-free DNA, gene-expression profiles and blood-based inflammatory signatures, may eventually help clinicians detect injury earlier and adjust treatment according to rejection phenotype. Yet animal results have repeatedly failed to translate directly to humans, reflecting differences in immune memory, immune complexity and the particular difficulty of controlling skin allografts. Larger animal studies, multicenter collaboration and adaptive clinical trial designs will therefore be necessary. The long-term objective is not simply to suppress immunity more powerfully, but to make immune control selective: regional when possible, donor-specific when feasible and guided by the tissues under attack. If that shift succeeds, VCA may become less constrained by infection, organ toxicity, malignancy and chronic graft loss, bringing the risks of these transformative procedures closer to their quality-of-life benefits.

Subject of Research: Immune modulation and rejection prevention in vascularized composite transplantation

Article Title: Immunosuppressive modulation after vascularized composite allotransplantation: current practice and future directions

Article References: Brito, E. M., Gaston, J. O., & Hashem, A. M. (2026). Immunosuppressive modulation after vascularized composite allotransplantation: current practice and future directions. BMC Plastic and Reconstructive Surgery, 2(1), Article 24. https://doi.org/10.1186/s44452-026-00035-7

Image Credits: AI Generated

DOI: 10.1186/s44452-026-00035-7

Keywords: vascularized composite allotransplantation, transplant immunology, immunosuppression, graft rejection, tolerance induction, regulatory T cells, costimulation blockade, ex vivo perfusion, Immunosuppressive, modulation, vascularized, composite