Textbook outcome: A novel metric in heart transplantation outcomes.

OBJECTIVE: Assessing heart transplant program quality using short-term survival is insufficient. We define and validate the composite metric textbook outcome and examine its association with overall survival. METHODS: We identified all primary, isolated adult heart transplants in the United Network for Organ Sharing/Organ Procurement and Transplantation Network Standard Transplant Analysis and Research files from May 1, 2005, to December 31, 2017. Textbook outcome was defined as length of stay 30 days or less; ejection fraction greater than 50% during 1-year follow-up; functional status 80% to 100% at 1 year; freedom from acute rejection, dialysis, and stroke during the index hospitalization; and freedom from graft failure, dialysis, rejection, retransplantation, and mortality during the first year post-transplant. Univariate and multivariate analyses were performed. Factors independently associated with textbook outcome were used to create a predictive nomogram. Conditional survival at 1 year was measured. RESULTS: A total of 24,620 patients were identified with 11,169 (45.4%, 95% confidence interval, 44.7-46.0) experiencing textbook outcome. Patients with textbook outcome were more likely free from preoperative mechanical support (odds ratio, 3.504, 95% confidence interval, 2.766 to 4.439, P < .001), free from preoperative dialysis (odds ratio, 2.295, 95% confidence interval, 1.868-2.819, P < .001), to be not hospitalized (odds ratio, 1.264, 95% confidence interval, 1.183-1.349, P < .001), to be nondiabetic (odds ratio, 1.187, 95% confidence interval, 1.113-1.266, P < .001), and to be nonsmokers (odds ratio, 1.160, 95% confidence interval,1.097-1.228, P < .001). Patients with textbook outcome have improved long-term survival relative to patients without textbook outcome who survive at least 1 year (hazard ratio for death, 0.547, 95% confidence interval, 0.504-0.593, P < .001). CONCLUSIONS: Textbook outcome is an alternative means of examining heart transplant outcomes and is associated with long-term survival. The use of textbook outcome as an adjunctive metric provides a holistic view of patient and center outcomes.

The Role of Recipient Thyroid Hormone Supplementation in Primary Graft Dysfunction After Heart Transplantation: A Propensity-Adjusted Analysis.

OBJECTIVES: To investigate whether recipient administration of thyroid hormone (liothyronine [T3]) is associated with reduced rates of primary graft dysfunction (PGD) after orthotopic heart transplantation. DESIGN: Retrospective cohort study. SETTING: Single-center, university hospital. PARTICIPANTS: Adult patients undergoing orthotopic heart transplantation. INTERVENTIONS: A total of 609 adult heart transplant recipients were divided into 2 cohorts: patients who did not receive T3 (no T3 group, from 2009 to 2014), and patients who received T3 (T3 group, from 2015 to 2019). Propensity-adjusted logistic regression was performed to assess the association between T3 supplementation and PGD. MEASUREMENTS AND MAIN RESULTS: After applying exclusion criteria and propensity-score analysis, the final cohort included 461 patients. The incidence of PGD was not significantly different between the groups (33.9% no T3 group v 40.8% T3 group; p = 0.32). Mortality at 30 days (3% no T3 group v 2% T3 group; p = 0.53) and 1 year (10% no T3 group v 12% T3 group; p = 0.26) were also not significantly different. When assessing the severity of PGD, there were no differences in the groups' rates of moderate PGD (not requiring mechanical circulatory support other than an intra-aortic balloon pump) or severe PGD (requiring mechanical circulatory support other than an intra-aortic balloon pump). However, segmented time regression analysis revealed that patients in the T3 group were less likely to develop severe PGD. CONCLUSIONS: These findings indicated that recipient single-dose thyroid hormone administration may not protect against the development of PGD, but may attenuate the severity of PGD.

Cardiac xenotransplantation: from concept to clinic.

For many patients with terminal/advanced cardiac failure, heart transplantation is the most effective, durable treatment option, and offers the best prospects for a high quality of life. The number of potentially life-saving donated human organs is far fewer than the population who could benefit from a new heart, resulting in increasing numbers of patients awaiting replacement of their failing heart, high waitlist mortality, and frequent reliance on interim mechanical support for many of those deemed among the best candidates but who are deteriorating as they wait. Currently, mechanical assist devices supporting left ventricular or biventricular heart function are the only alternative to heart transplant that is in clinical use. Unfortunately, the complication rate with mechanical assistance remains high despite advances in device design and patient selection and management, and the quality of life of the patients even with good outcomes is only moderately improved. Cardiac xenotransplantation from genetically multi-modified (GM) organ-source pigs is an emerging new option as demonstrated by the consistent long-term success of heterotopic (non-life-supporting) abdominal and life-supporting orthotopic porcine heart transplantation in baboons, and by a recent 'compassionate use' transplant of the heart from a GM pig with 10 modifications into a terminally ill patient who survived for 2 months. In this review, we discuss pig heart xenotransplantation as a concept, including pathobiological aspects related to immune rejection, coagulation dysregulation, and detrimental overgrowth of the heart, as well as GM strategies in pigs to prevent or minimize these problems. Additional topics discussed include relevant results of heterotopic and orthotopic heart transplantation experiments in the pig-to-baboon model, microbiological and virologic safety concepts, and efficacy requirements for initiating formal clinical trials. An adequate regulatory and ethical framework as well as stringent criteria for the selection of patients will be critical for the safe clinical development of cardiac xenotransplantation, which we expect will be clinically tested during the next few years.

Treatment of Pediatric Patients With COVID Infection After Heart Transplantation.

The COVID-19 pandemic that has been ongoing since the beginning of 2020 has forced health care into a difficult struggle for wellness and the lives of patients. International data and our observations show that the course of the disease in these patients is different than in the general population. Symptoms depend on the immunosuppression and severity of viremia. The period of viral replication is much longer. Our observations include 4 pediatric patients post heart transplant who became infected with the coronavirus. One patient was infected in the hospital during perioperative period. Two others required hospitalization because of the severity of symptoms, and 1 was treated on an outpatient basis. The applied treatment included the reduction of immunosuppression, low-molecular-weight heparin, amantadine or remdesivir, steroids, and supplementation with zinc and vitamins C and D. Based on the antigenic tests performed, we determined the period of active replication to be 3 to 8 weeks from the onset of the first symptoms.

Standards of Psychological Care for Pediatric Patients Awaiting Heart Transplantation and Those Requiring Mechanical Circulatory Support.

Children waiting for a heart transplant who require mechanical circulatory support often experience many months of hospitalization. This has a significant impact on their mental health and their development. Additional risk factors for these disorders are neurologic complications associated with the used treatment. To counteract developmental dysfunctions (despite successful heart transplantation) and possible disability in the sphere of mental health as well as to improve executive functions of children after a neurologic incident, there is a need for comprehensive care provided by a clinical psychologist who is a member of a multidisciplinary medical team taking care of the patient. Based on our own experience, standards of psychological care were developed for pediatric patients awaiting heart transplantation and those requiring mechanical circulatory support.

Ventricular assist device support for children with chemotherapy-induced cardiomyopathy and advanced heart failure: Perspectives gained from a single-center experience.

BACKGROUND: Guidance and data on ventricular assist device (VAD) support for children with chemotherapy-induced cardiomyopathy, particularly within the first 2 years after chemotherapy, are limited. METHODS: We performed a single-center retrospective case series, reviewing medical records of children <18 years of age with chemotherapy-induced cardiomyopathy and advanced heart failure (HF) who received durable VAD support. RESULTS: Six patients met inclusion criteria-5 HeartWare™ HVAD, 1 Berlin Heart EXCOR® . Median age at cancer diagnosis was 6 years (IQR 4.5-10 years). Median dose of anthracycline received was 540 mg/m2 (IQR 450-630 mg/m2 ). All patients developed HF within 1 year after initiation of cancer treatment (median 8 months, IQR 6-11.5 months) and were initiated on durable VAD support at a median of 8 months after completion of cancer treatment (IQR 3.3-43.5 months). Four patients had significant right ventricular dysfunction needing oral pulmonary vasodilator therapy, one patient had a major bleeding complication, and two patients had thromboembolic strokes while on VAD support. Median duration of VAD support was 7.5 months (IQR 3-11.3 months). Two patients underwent VAD explant due to recovery of LV function, one died due to cancer progression, and three underwent heart transplantation. CONCLUSIONS: Durable VAD support should be considered as a therapeutic option for children who have advanced HF due to chemotherapy-induced cardiomyopathy, even within 2 years of completing cancer treatment. A multi-disciplinary approach is essential for appropriate patient selection prior to implant and to ensure comprehensive care throughout the duration of VAD support.

Saireito (TJ-114) Suppressed Donor-Specific Antibody Through Immunomodulatory Effects and Regulatory T Cell Induction in a Murine Heart Transplant Model.

Saireito (Tsumura Japan [TJ]-114) could induce long-term cardiac allograft survival through the generation of CD4+CD25+Foxp3+ cells (regulatory T cells, Tregs). However, little is known regarding the effects of TJ-114 on the suppression of donor-specific antibody (DSA). Therefore, we aimed to further investigate the suppressive properties of TJ-114 and its effects on DSA production in a murine cardiac allograft model. CBA mice underwent transplantation of C57BL/6 hearts and were subsequently administered TJ-114 (2g/kg/d) from the day of transplantation until 7 days afterward. TJ-114-treated recipients demonstrated upregulation of splenic Tregs and suppressed DSA production at postoperative day 10 relative to untreated controls. This effect was sustained at postoperative day 20 even when TJ-114 administration was stopped at day 7. To then investigate the involvement of Tregs in the suppression of DSA production, anti-interleukin-2 receptor alpha antibody (PC-61) was administered to deplete Treg populations in TJ-114-treated CBA recipients on postoperative days 0, 3, 6, and 9 or 20, 23, and 26. At day 10, CBA recipients that received PC-61 with TJ-114 demonstrated suppression of DSA production similar to those receiving only TJ-114. Nonetheless, when mice were treated with PC-61 at days 20, 23, and 26, DSA levels gradually increased to levels comparable to those of untreated mice by day 29, suggesting that Tregs are necessary to sustain the suppression of DSA once the effects of TJ-114 have subsided. Taken together, TJ-114 may be a promising therapeutic strategy to prolong allograft survival through its combined immunosuppressive effects in inducing Tregs and suppressing DSA production.

TET2 Protects Against Vascular Smooth Muscle Cell Apoptosis and Intimal Thickening in Transplant Vasculopathy.

BACKGROUND: Coronary allograft vasculopathy (CAV) is a devastating sequela of heart transplant in which arterial intimal thickening limits coronary blood flow. There are currently no targeted therapies to prevent or reduce this pathology that leads to transplant failure. Vascular smooth muscle cell (VSMC) phenotypic plasticity is critical in CAV neointima formation. TET2 (TET methylcytosine dioxygenase 2) is an important epigenetic regulator of VSMC phenotype, but the role of TET2 in the progression of CAV is unknown. METHODS: We assessed TET2 expression and activity in human CAV and renal transplant samples. We also used the sex-mismatched murine aortic graft model of graft arteriopathy (GA) in wild-type and inducible smooth muscle-specific Tet2 knockout mice; and in vitro studies in murine and human VSMCs using knockdown, overexpression, and transcriptomic approaches to assess the role of TET2 in VSMC responses to IFNγ (interferon γ), a cytokine elaborated by T cells that drives CAV progression. RESULTS: In the present study, we found that TET2 expression and activity are negatively regulated in human CAV and renal transplant samples and in the murine aortic graft model of GA. IFNγ was sufficient to repress TET2 and induce an activated VSMC phenotype in vitro. TET2 depletion mimicked the effects of IFNγ, and TET2 overexpression rescued IFNγ-induced dedifferentiation. VSMC-specific TET2 depletion in aortic grafts, and in the femoral wire restenosis model, resulted in increased VSMC apoptosis and medial thinning. In GA, this apoptosis was tightly correlated with proliferation. In vitro, TET2-deficient VSMCs undergo apoptosis more readily in response to IFNγ and expressed a signature of increased susceptibility to extrinsic apoptotic signaling. Enhancing TET2 enzymatic activity with high-dose ascorbic acid rescued the effect of GA-induced VSMC apoptosis and intimal thickening in a TET2-dependent manner. CONCLUSIONS: TET2 is repressed in CAV and GA, likely mediated by IFNγ. TET2 serves to protect VSMCs from apoptosis in the context of transplant vasculopathy or IFNγ stimulation. Promoting TET2 activity in vivo with systemic ascorbic acid reduces VSMC apoptosis and intimal thickening. These data suggest that promoting TET2 activity in CAV may be an effective strategy for limiting CAV progression.

Bone marrow-derived AXL tyrosine kinase promotes mitogenic crosstalk and cardiac allograft vasculopathy.

Cardiac Allograft Vasculopathy (CAV) is a leading contributor to late transplant rejection. Although implicated, the mechanisms by which bone marrow-derived cells promote CAV remain unclear. Emerging evidence implicates the cell surface receptor tyrosine kinase AXL to be elevated in rejecting human allografts. AXL protein is found on multiple cell types, including bone marrow-derived myeloid cells. The causal role of AXL from this compartment and during transplant is largely unknown. This is important because AXL is a key regulator of myeloid inflammation. Utilizing experimental chimeras deficient in the bone marrow-derived Axl gene, we report that Axl antagonizes cardiac allograft survival and promotes CAV. Flow cytometric and histologic analyses of Axl-deficient transplant recipients revealed reductions in both allograft immune cell accumulation and vascular intimal thickness. Co-culture experiments designed to identify cell-intrinsic functions of Axl uncovered complementary cell-proliferative pathways by which Axl promotes CAV-associated inflammation. Specifically, Axl-deficient myeloid cells were less efficient at increasing the replication of both antigen-specific T cells and vascular smooth muscle cells (VSMCs), the latter a key hallmark of CAV. For the latter, we discovered that Axl-was required to amass the VSMC mitogen Platelet-Derived Growth Factor. Taken together, our studies reveal a new role for myeloid Axl in the progression of CAV and mitogenic crosstalk. Inhibition of AXL-protein, in combination with current standards of care, is a candidate strategy to prolong cardiac allograft survival.

Berberine Prolongs Mouse Heart Allograft Survival by Activating T Cell Apoptosis via the Mitochondrial Pathway.

Berberine, which is a traditional Chinese medicine can inhibit tumorigenesis by inducing tumor cell apoptosis. However, the immunoregulatory of effects berberine on T cells remains poorly understood. Here, we first examined whether berberine can prolong allograft survival by regulating the recruitment and function of T cells. Using a major histocompatibility complex complete mismatch mouse heterotopic cardiac transplantation model, we found that the administration of moderate doses (5 mg/kg) of berberine significantly prolonged heart allograft survival to 19 days and elicited no obvious berberine-related toxicity. Compared to that with normal saline treatment, berberine treatment decreased alloreactive T cells in recipient splenocytes and lymph node cells. It also inhibited the activation, proliferation, and function of alloreactive T cells. Most importantly, berberine treatment protected myocardial cells by decreasing CD4+ and CD8+ T cell infiltration and by inhibiting T cell function in allografts. In vivo and in vitro assays revealed that berberine treatment eliminated alloreactive T lymphocytes via the mitochondrial apoptosis pathway, which was validated by transcriptome sequencing. Taken together, we demonstrated that berberine prolongs allograft survival by inducing apoptosis of alloreactive T cells. Thus, our study provides more evidence supporting the potential use of berberine in translational medicine.

Immuno-Electrophysiological Mechanisms of Functional Electrical Connections Between Recipient and Donor Heart in Patients With Orthotopic Heart Transplantation Presenting With Atrial Arrhythmias.

[Figure: see text].

Heart and Lung Transplantation in the Era of COVID-19: Early Recommendations and Outcomes.

The severe acute respiratory syndrome coronavirus 2 pandemic has dramatically changed medical practices worldwide. These changes have been aimed both to reallocate resources toward fighting the novel coronavirus and to prevent its transmission during nonurgent medical and surgical interventions. Heart and lung transplantation could not be an exception, as most transplant centers have either restricted their activity to only urgent, lifesaving procedures or stopped these surgical procedures for various periods of time depending on the local virus epidemiology. The effect of this infection on the immunosuppressed heart and lung transplant recipient is still questionable; however, there are limited reports suggesting that there is no increased risk of transmission or more severe disease course compared with that shown in the general population. Transplant organizations have disseminated early recommendations as a guidance in a yet evolving situation. Finally, data suggest that lung transplant could potentially serve as an ultimate, lifesaving procedure for COVID-19-related end-stage respiratory failure in carefully selected patients.

The Application of Next-generation Sequencing Tumor Molecular Profiling in the Diagnosis and Management of a Case of Acute Myelogenous Leukemia With MLL-PTD in a Pediatric Heart Transplant Recipient.

A 6-year-old girl with a history of heart transplantation was diagnosed with myelodysplastic syndrome, which progressed to acute myelogenous leukemia. Comprehensive genomic profiling of her tumor discovered an MLL-PTD (partial tandem duplication) and she received chemotherapy and a hematopoietic stem cell transplant (HSCT). She subsequently relapsed and tumor molecular profiling was repeated, revealing 2 new potentially targetable mutations (FLT3 and IDH2). A novel treatment regimen targeting these mutations with sorafenib and azacitidine without using cytotoxic chemotherapy produced remission and she subsequently pursued a second HSCT. She remains disease-free 17 months after HSCT. This case report demonstrates how repeated tumor molecular profiling provided novel actionable information for the diagnosis and management at 2 timepoints.

Hypomagnesemia after heart transplantation or left ventricular assist device implant for end-stage heart failure.

BACKGROUND: Patients with advanced heart failure undergoing heart transplant (HTx) or left ventricular assist device (LVAD) implant are at high risk of magnesium deficiency, that may favor development of diabetes. We aimed to comparatively assess prevalence and correlates of hypomagnesemia during cardiac rehabilitation between 51 HTx and 46 LVAD recipients. METHODS AND RESULTS: We measured serum magnesium and correlated it to clinical and laboratory findings upon admission (T1 ) and at discharge (T2) from cardiac rehabilitation. Among LVAD, magnesium levels increased from admission to discharge. Among HTx, magnesium concentrations were below normal in 33% and 47% at T1 and T2 , respectively, and decreased from admission to discharge. HTx on tacrolimus showed greater decreases in magnesium and increases in glucose levels than those on cyclosporine. Magnesium levels were inversely associated with >15 mg/dL increased glucose concentrations between T2 and T1 (HR 0.373, 95% CI 0.154-0.903, P = .029) after adjustment for pre-existing diabetes, insulin resistance markers, calcineurin inhibitors (cyclosporine/tacrolimus), prednisone doses, and magnesium supplementation. CONCLUSION: Hypomagnesemia is rare in LVAD recipients, but common within 1 month from HTx, worsens during rehabilitation, despite immunosuppression tapering and magnesium supplements, and is independently associated to increasing glucose levels. Studies evaluating whether correcting hypomagnesemia improves outcome are warranted.

Bone Metabolism Impairment in Heart Transplant: Results From a Prospective Cohort Study.

BACKGROUND: Data on the prevention of fractures after heart transplant (HTx) are controversial in the literature. Understanding the effects of HTx on bone may guide appropriate treatments in this high-risk population. METHODS: Seventy adult HTx patients were followed for 12 months. Clinical and laboratory parameters, bone mineral density, microarchitecture, and vertebral fractures were assessed at baseline (after intensive care unit discharge) and at 6 and 12 months. Patients received recommendations regarding calcium intake and vitamin D supplementation after HTx. RESULTS: At baseline, 27% of patients had osteoporosis, associated with the length of hospitalization before HTx (P = 0.001). Bone mineral density decreased in the first 6 months, with partial recovery later. Bone microarchitecture deteriorated, mainly in the trabecular bone in the first 6 months and cortical bone in the subsequent 6 months. At baseline, 92.9% of patients had vitamin D levels <30 ng/mL and 20.0% <10 ng/mL. Patients also had calcium at the lower limit of normal, high alkaline phosphatase, and high bone resorption biomarker. These abnormalities were suggestive of impaired bone mineralization and normalized at 6 months with correction of vitamin D deficiency. The majority of vertebral fractures were identified at baseline (23% of patients). After multivariate analyses, only a lower fat mass persisted as a risk factor for vertebral fractures (odds ratio, 1.23; 95% confidence interval, 1.04-1.47; P = 0.012). CONCLUSIONS: High frequencies of densitometric osteoporosis, vitamin D deficiency, bone markers abnormalities, and vertebral fractures were observed shortly after HTx. Calcium and vitamin D supplementation should be the first step in correcting bone mineralization impairment before specific osteoporosis treatment.

Acute Cellular Rejection and Infection Rates in Alemtuzumab vs Traditional Induction Therapy Agents for Lung and Heart Transplantation: A Systematic Review and Meta-analysis.

BACKGROUND AND OBJECTIVES: Heart and lung transplantation is a high-risk procedure requiring intensive immunosuppressive therapy for preventing organ rejection. Alemtuzumab, a CD52-specific monoclonal antibody, is increasingly used for induction therapy compared with conventional agents. However, there has been no systematic review comparing its efficacy with traditional therapeutic drugs. METHODS: PubMed and EMBASE were searched to October 1, 2017, for articles on alemtuzumab in cardiothoracic transplant surgery. Of the 433 studies retrieved, 8 were included in the final meta-analysis. RESULTS: In lung transplantation, alemtuzumab use was associated with lower odds of acute cellular rejection compared with antithymocyte globulin (odds ratio [OR], 0.21; 95% CI, 0.11-0.40; P < .001), lower acute rejection rates (OR, 0.12; 95% CI, 0.03-0.55; P < .01), and infection rates (OR, 0.69; 95% CI, 0.35-1.36; P = .33) when compared with basiliximab. Multivariate meta-regression analysis found that mean age, male sex, single lung transplant, double lung transplant, cytomegalovirus or Epstein-Barr virus status, idiopathic pulmonary fibrosis, cystic fibrosis, and mean ischemic time did not significantly influence acute rejection outcomes. For heart transplantation, alemtuzumab use was associated with lower acute rejection rates when compared with tacrolimus (OR, 0.44; 95% CI, 0.30-0.66; P < .001). CONCLUSIONS: Alemtuzumab use was associated with lower rejection rates when compared with conventional induction therapy agents (antithymocyte globulin, basiliximab, and tacrolimus) in heart and lung transplantation. However, this was based on observational studies. Randomized controlled trials are needed to verify its clinical use.

Rikkunshito (TJ-43) Improved Reduction of Food Intake in a Murine Cardiac Transplantation Model.

Rikkunshito (TJ-43), an eight-component traditional Japanese herbal medicine, has been used in clinics for gastritis, vomiting, and appetite loss. We investigated the effects of TJ-43 on the amelioration of appetite loss in the surgical-exposed model of murine cardiac allograft transplantation. CBA mice underwent transplantation of a CBA (syngeneic group) or C57BL/6 heart (allogeneic group) and received oral administration of 2 g/kg/d of TJ-43 from the day of transplantation until 7 days afterward. The amount of food intake (FI) and weight change after operation were recorded from 1 to 28 postoperative days. The allogeneic group had less average amounts of FI for 1 week compared with the syngeneic group (FI was 1.90 ± 0.43 g and 2.66 ± 0.46 g, respectively). Average FIs between the syngeneic and allogeneic groups with TJ-43 for 1 week were 2.36 ± 0.44 g and 2.30 ± 0.13 g, respectively, and those with distilled water were 2.66 ± 0.46 g and 1.90 ± 0.43 g, respectively, suggesting that exposure with TJ-43 tended to ameliorate the reduction of FI. Similarly, the effect on the amelioration of average FI in syngeneic and allogeneic groups exposed for 2 weeks was confirmed. However, exposure to with TJ-43 had no effects on FI after 4 weeks. TJ-43 could prevent reduction of average FI induced by the surgical-exposed model of murine cardiac allograft transplantation.

Hyperbaric oxygen therapy for cerebral air gas embolism following orthotopic heart transplant: case report.

Air gas embolism (AGE) is a rare complication of cardiac surgery, with high morbidity and mortality. We present a case of suspected AGE following orthotopic heart transplant. The patient received hyperbaric oxygen therapy with near-complete resolution of symptoms at follow-up. This case exemplifies the difficulty in diagnosis of AGE, the considerations involved in the treatment of a critical care patient in a hyperbaric chamber, and utility in treating a patient for AGE even after a delay in diagnosis.

Weekly oral bisphosphonates over 2 years prevent bone loss in cardiac transplant patients.

BACKGROUND: Heart transplantation (HTX) is an established therapy for end-stage heart disease. The aim of this study was to determine whether application of oral bisphosphonates is effective in preventing osseous complications after HTX. METHODS: Thirty-three cardiac transplant recipients were treated with alendronate 70 mg/wk or risedronate 35 mg/wk in combination with 1000 mg calcium and 800 IU vitamin D. Markers of bone metabolism and dual-energy X-ray absorptiometry (DXA) were determined directly after HTX and 2 years later. Primary endpoints were changes in bone mineral density (BMD), markers of bone metabolism (osteocalcin, crosslaps), serum levels of the cytokines osteoprotegerin (OPG), receptor activator of NF kappa-B ligand (RANKL), and incidence of fractures. RESULTS: Eight patients presented with osteoporosis, and 16 patients with osteopenia by DXA without prevalent fractures. Over 2 years, the BMD improved in 2 patients from osteoporosis to osteopenia, and overall BMD remained stable, and fractures did not occur. In addition, the serum levels of OPG increased (P < .0005), and the RANKL levels (P < .001) as well as the RANKL/OPG-ratio decreased significantly (P < .0005). The serum crosslaps showed no significant changes. The BMD showed a significant association with the increased 25-vitamin D levels only in females (P < .001). CONCLUSIONS: In heart transplanted patients, weekly oral bisphosphonates in combination with calcium and vitamin D supplementation preserved bone mass, prevented uncoupling of bone resorption/formation and fractures. Bone density should be measured and adequately treated, that is, with regular bisphosphonates.