Cost-Effectiveness of Cardiovascular Magnetic Resonance for Rejection Surveillance After Cardiac Transplantation in the Australian Health Care System.

BACKGROUND: Heart transplantation is an effective treatment for end-stage congestive heart failure, however, achieving the right balance of immunosuppression to maintain graft function while minimising adverse effects is challenging. Serial endomyocardial biopsies (EMBs) are currently the standard for rejection surveillance, despite being invasive. Replacing EMB-based surveillance with cardiac magnetic resonance (CMR)-based surveillance for acute cardiac allograft rejection has shown feasibility. This study aimed to assess the cost-effectiveness of CMR-based surveillance in the first year after heart transplantation. METHOD: A prospective clinical trial was conducted with 40 orthotopic heart transplant (OHT) recipients. Participants were randomly allocated into two surveillance groups: EMB-based, and CMR-based. The trial included economic evaluations, comparing the frequency and cost of surveillance modalities in relation to quality-adjusted life years (QALYs) within the first year post-transplantation. Sensitivity analysis encompassed modelled data from observed EMB and CMR arms, integrating two hypothetical models of expedited CMR-based surveillance. RESULTS: In the CMR cohort, 238 CMR scans and 15 EMBs were conducted, versus (vs) 235 EMBs in the EMB group. CMR surveillance yielded comparable rejection rates (CMR 74 vs EMB 94 events, p=0.10) and did not increase hospitalisation risk (CMR 32 vs EMB 46 events, p=0.031). It significantly reduced the necessity for invasive EMBs by 94%, lowered costs by an average of AUD$32,878.61, and enhanced cumulative QALY by 0.588 compared with EMB. Sensitivity analysis showed that increased surveillance with expedited CMR Models 1 and 2 were more cost-effective than EMB (all p<0.01), with CMR Model 1 achieving the greatest cost savings (AUD$34,091.12±AUD$23,271.86 less) and utility increase (+0.62±1.49 QALYs, p=0.011), signifying an optimal cost-utility ratio. Model 2 showed comparable utility to the base CMR model (p=0.900) while offering the benefit of heightened surveillance frequency during periods of elevated rejection risk. CONCLUSIONS: CMR-based rejection surveillance in orthotopic heart transplant recipients provides a cost-effective alternative to EMB-based surveillance. Furthermore, it reduces the need for invasive procedures, without increased risk of rejection or hospitalisation for patients, and can be incorporated economically for expedited surveillance. These findings have important implications for improving patient care and optimising resource allocation in post-transplant management.

DMD-Associated Dilated Cardiomyopathy: Genotypes, Phenotypes, and Phenocopies.

BACKGROUND: Variants in the DMD gene, that encodes the cytoskeletal protein, dystrophin, cause a severe form of dilated cardiomyopathy (DCM) associated with high rates of heart failure, heart transplantation, and ventricular arrhythmias. Improved early detection of individuals at risk is needed. METHODS: Genetic testing of 40 male probands with a potential X-linked genetic cause of primary DCM was undertaken using multi-gene panel sequencing, multiplex polymerase chain reaction, and array comparative genomic hybridization. Variant location was assessed with respect to dystrophin isoform patterns and exon usage. Telomere length was evaluated as a marker of myocardial dysfunction in left ventricular tissue and blood. RESULTS: Four pathogenic/likely pathogenic DMD variants were found in 5 probands (5/40: 12.5%). Only one rare variant was identified by gene panel testing with 3 additional multi-exon deletion/duplications found following targeted assays for structural variants. All of the pathogenic/likely pathogenic DMD variants involved dystrophin exons that had percent spliced-in scores >90, indicating high levels of constitutive expression in the human adult heart. Fifteen DMD variant-negative probands (15/40: 37.5%) had variants in autosomal genes including TTN, BAG3, LMNA, and RBM20. Myocardial telomere length was reduced in patients with DCM irrespective of genotype. No differences in blood telomere length were observed between genotype-positive family members with/without DCM and controls. CONCLUSIONS: Primary genetic testing using multi-gene panels has a low yield and specific assays for structural variants are required if DMD-associated cardiomyopathy is suspected. Distinguishing X-linked causes of DCM from autosomal genes that show sex differences in clinical presentation is crucial for informed family management.

Tricuspid Regurgitation After Heart Transplantation: The Cause or the Result of Graft Dysfunction?

BACKGROUND: Tricuspid regurgitation (TR) is common following heart transplantation and has been shown to adversely influence patient outcomes. The aim of this study was to identify causes of progression to moderate-severe TR in the first 2 y after transplantation. METHODS: This was a retrospective, single-center study of all patients who underwent heart transplantation over a 6-y period. Transthoracic echocardiogram (TTE) was performed at month 0, between 6 and 12 mo, and 1-2 y postoperatively to determine the presence and severity of TR. RESULTS: A total of 163 patients were included, of whom 142 underwent TTE before first endomyocardial biopsy. At month 0, 127 (78%) patients had nil-mild TR before first biopsy, whereas 36 (22%) had moderate-severe TR. In patients with nil-mild TR, 9 (7%) progressed to moderate-severe TR by 6 mo and 1 underwent tricuspid valve (TV) surgery. Of patients with moderate-severe TR before first biopsy, by 2 y, 3 had undergone TV surgery. The use of postoperative extracorporeal membrane oxygenation (ECMO) in the latter group was significant (78%; P < 0.05) as was rejection profile ( P = 0.02). Patients with late progressive moderate-severe TR had a significantly higher 2-y mortality than those who had moderate-severe TR immediately. CONCLUSIONS: Overall, our study has shown that in the 2 main groups of interest (early moderate-severe TR and progression from nil-mild to moderate-severe TR), TR is more likely to be the result of significant underling graft dysfunction rather than the cause of it.

Rapid triage and transition to telehealth for heart transplant patients in the COVID-19 pandemic setting.

BACKGROUND: In the setting of the COVID-19 pandemic, a rapid uptake of telehealth services was instituted with the aim of reducing the spread of disease to vulnerable patient populations including heart transplant recipients. METHODS: Single-center, cohort study of all heart transplant patients seen by our institution's transplant program during the first 6 weeks of transition from in-person consultation to telehealth (23 March - 5 June 2020). RESULTS: Face-to-face consultation allocation strongly favored patients in the early post-operative period (34 vs. 242 weeks post-transplant; p < 0.001). Telehealth consultation dramatically reduced patient travel and wait times (80 min per visit saved in telehealth patients). No apparent excess re-hospitalization or mortality was seen in telehealth patients. CONCLUSIONS: With appropriate triage, telehealth was feasible in heart transplant recipients, with videoconferencing being the preferred modality. Patients seen face-to-face were those triaged to be higher acuity based on time since transplant and overall clinical status. These patients have the expected higher rates of hospital re-admission, and therefore should continue to be seen in person.

Cardiovascular Magnetic Resonance for Rejection Surveillance After Cardiac Transplantation.

BACKGROUND: Endomyocardial biopsy (EMB) is the gold standard method for surveillance of acute cardiac allograft rejection (ACAR) despite its invasive nature. Cardiovascular magnetic resonance (CMR)-based myocardial tissue characterization allows detection of myocarditis. The feasibility of CMR-based surveillance for ACAR-induced myocarditis in the first year after heart transplantation is currently undescribed. METHODS: CMR-based multiparametric mapping was initially assessed in a prospective cross-sectional fashion to establish agreement between CMR- and EMB-based ACAR and to determine CMR cutoff values between rejection grades. A prospective randomized noninferiority pilot study was then undertaken in adult orthotopic heart transplant recipients who were randomized at 4 weeks after orthotopic heart transplantation to either CMR- or EMB-based rejection surveillance. Clinical end points were assessed at 52 weeks. RESULTS: Four hundred one CMR studies and 354 EMB procedures were performed in 106 participants. Forty heart transplant recipients were randomized. CMR-based multiparametric assessment was highly reproducible and reliable at detecting ACAR (area under the curve, 0.92; sensitivity, 93%; specificity, 92%; negative predictive value, 99%) with greater specificity and negative predictive value than either T1 or T2 parametric CMR mapping alone. High-grade rejection occurred in similar numbers of patients in each randomized group (CMR, n=7; EMB, n=8; P=0.74). Despite similarities in immunosuppression requirements, kidney function, and mortality between groups, the rates of hospitalization (9 of 20 [45%] versus 18 of 20 [90%]; odds ratio, 0.091; P=0.006) and infection (7 of 20 [35%] versus 14 of 20 [70%]; odds ratio, 0.192; P=0,019) were lower in the CMR group. On 15 occasions (6%), patients who were randomized to the CMR arm underwent EMB for clarification or logistic reasons, representing a 94% reduction in the requirement for EMB-based surveillance. CONCLUSIONS: A noninvasive CMR-based surveillance strategy for ACAR in the first year after orthotopic heart transplantation is feasible compared with EMB-based surveillance. REGISTRATION: HREC/13/SVH/66 and HREC/17/SVH/80. AUSTRALIAN NEW ZEALAND CLINICAL TRIALS REGISTRY: ACTRN12618000672257.

Impact of frailty on mortality and morbidity in bridge to transplant recipients of contemporary durable mechanical circulatory support.

BACKGROUND: Frailty is associated with adverse outcomes in advanced heart failure. We studied the impact of frailty on postoperative outcomes in bridge to transplant (BTT) durable mechanical circulatory support (MCS) recipients. METHODS: Patients undergoing left ventricular assist device (LVAD, n = 96) or biventricular support (BiV, n = 11) as BTT underwent frailty assessment. Frailty was defined as ≥ 3 physical domains of the Fried's Frailty Phenotype (FFP) or ≥ 2 physical domains of the FFP plus cognitive impairment on the Montreal Cognitive Assessment (MoCA). RESULTS: No difference in mortality at 360 days was observed in frail (n = 6/38, 15.8%) vs non-frail (n = 4/58, 6.9%) LVAD supported patients, p = 0.19. However, there was a significant excess mortality in frail BiV (n = 4/5) vs non-frail BiV (n = 0/6) supported patients, p = 0.013. In all patients, frail patients compared to non-frail patients experienced longer intensive care unit stay, 12 vs 6 days (p < 0.0001) and hospital length of stay, 48 vs 27 days (p < 0.0001). There was no difference in hemocompatibility and infection related adverse events. The majority (n = 22/29, 75.9%) of frail patients became non-frail following MCS; contrastingly, a minority (n = 3/42, 7.1%) became frail from being non-frail (p = 0.0003). CONCLUSIONS: Abnormal markers of frailty are common in patients undergoing BTT-MCS support and those used herein predict mortality in BiV-supported patients, but not in LVAD patients. These findings may help us better identify patients who will benefit most from BiV-BTT therapy.

Validation of Cognitive Impairment in Combination With Physical Frailty as a Predictor of Mortality in Patients With Advanced Heart Failure Referred for Heart Transplantation.

BACKGROUND: The aim of this study was to validate our previous finding that frailty predicts early mortality in patients with advanced heart failure (AHF) and that including cognition in the frailty assessment enhances the prediction of mortality. METHODS: Patients with AHF referred to our Transplant Unit between November 2015 and April 2020 underwent physical frailty assessment using the modified Fried physical frailty (PF) phenotype as well as cognitive assessment using the Montreal Cognitive Assessment to identify patients who were cognitively frail (CogF). We assessed the predictive value of the 2 frailty measures (PF ≥ 3 of 5 = frail; CogF ≥ 3 of 6 = frail) for pretransplant mortality. RESULTS: Three hundred thirteen patients (233 male and 80 female; age 53 ± 13 y) were assessed. Of these, 224 patients (72%) were nonfrail and 89 (28%) were frail using the PF. The CogF assessment identified an additional 30 patients as frail: 119 (38%). Frail patients had significantly increased mortality as compared to nonfrail patients. Ventricular assist device and heart transplant-censored survival at 12 mo was 92 ± 2 % for nonfrail and 69 ± 5% for frail patients (P < 0.0001) using the CogF instrument. CONCLUSIONS: This study validates our previously published findings that frailty is prevalent in patients with AHF referred for heart transplantation. PF predicts early mortality. The addition of cognitive assessment to the physical assessment of frailty identifies an additional cohort of patients with a similarly poor prognosis.

Everolimus for the Prevention of Calcineurin-Inhibitor-Induced Left Ventricular Hypertrophy After Heart Transplantation (RADTAC Study).

OBJECTIVES: This study aimed to determine the safety and efficacy of combined low-dose everolimus and low-dose tacrolimus compared with standard-dose tacrolimus in attenuating left ventricular hypertrophy (LVH) after orthotopic heart transplantation (OHT). BACKGROUND: Calcineurin inhibitors (CNIs) such as tactrolimus are important in preventing cardiac allograft rejection and reducing mortality after OHT. However CNIs are causatively linked to the development of LVH, and are associated with nephrotoxicity and vasculopathy. CNI-sparing agents such as everolimus have been hypothesized to inhibit adverse effects of CNIs. METHODS: In this prospective, randomized, open-label study, OHT recipients were randomized at 12 weeks after OHT to a combination of low-dose everolimus and tacrolimus (the RADTAC group) or standard-dose tacrolimus (the TAC group), with both groups coadministered mycophenolate and prednisolone. The primary endpoint was LVH indexed as the change in left ventricular mass (ΔLVM) by cardiovascular magnetic resonance (CMR) imaging from 12 to 52 weeks. Secondary endpoints included CMR-based myocardial performance, T1 fibrosis mapping, blood pressure, and renal function. Safety endpoints included episodes of allograft rejection and infection. RESULTS: Forty stable OHT recipients were randomized. Recipients in the RADTAC group had significantly lower tacrolimus levels compared with the TAC group (6.5 ± 3.5 µg/l vs. 8.6 ± 2.8 µg/l; p = 0.02). The mean everolimus level in the RADTAC group was 4.2 ± 1.7 µg/l. A significant reduction in LVM was observed in the RADTAC group compared with an increase in LVM in the TAC group (ΔLVM = -13.0 ± 16.8 g vs. 2.1 ± 8.4 g; p < 0.001). Significant differences were also noted in secondary endpoints measuring function and fibrosis (Δ circumferential strain = -2.9 ± 2.8 vs. 2.1 ± 2.3; p < 0.001; ΔT1 mapping values = -32.7 ± 51.3 ms vs. 26.3 ± 90.4 ms; p = 0.003). No significant differences were observed in blood pressure (Δ mean arterial pressure = 4.2 ± 18.8 mm Hg vs. 2.8 ± 13.8 mm Hg; p = 0.77), renal function (Δ creatinine = 3.1 ± 19.9 µmol/l vs. 9 ± 21.8 µmol/l; p = 0.31), frequency of rejection episodes (p = 0.69), or frequency of infections (p = 0.67) between groups. CONCLUSIONS: The combination of low-dose everolimus and tacrolimus compared with standard-dose tacrolimus safely attenuates LVH in the first year after cardiac transplantation with an observed reduction in CMR-measured fibrosis and an improvement in myocardial strain.

Impact of lung morphology on clinical outcomes with riociguat in patients with pulmonary hypertension and idiopathic interstitial pneumonia: A post hoc subgroup analysis of the RISE-IIP study.

BACKGROUND: Riociguat in Patients with Symptomatic Pulmonary Hypertension associated with Idiopathic Interstitial Pneumonias (RISE-IIP), a randomized, controlled, phase 2b trial of riociguat for pulmonary hypertension associated with idiopathic interstitial pneumonia, was terminated early due to increased mortality in riociguat-treated patients. Baseline characteristics of enrolled patients demonstrated a low diffusing capacity of the lung for carbon monoxide (DLCO) with preserved lung volumes at baseline, suggesting the presence of combined pulmonary fibrosis and emphysema (CPFE) in some patients. This post hoc analysis of RISE-IIP was undertaken to explore lung morphology, assessed by high-resolution computed tomography, and associated clinical outcomes. METHODS: Available baseline/pre-baseline high-resolution computed tomography scans were reviewed centrally by 2 radiologists. The extent of emphysema and fibrosis was retrospectively scored and combined to provide the total CPFE score. RESULTS: Data were available for 65/147 patients (44%), including 15/27 fatal cases (56%). Of these, 41/65 patients (63%) had CPFE. Mortality was higher in patients with CPFE (12/41; 29%) than those without (3/24; 13%). Fourteen patients with CPFE had emphysema > fibrosis (4 died). No relationship was observed between CPFE score, survival status, and treatment assignment. A low DLCO, short 6-min walking distance, and high forced vital capacity:DLCO ratio at baseline also appeared to be risk factors for mortality. CONCLUSIONS: High parenchymal lung disease burden and the presence of more emphysema than fibrosis might have predisposed patients with pulmonary hypertension associated with idiopathic interstitial pneumonia to poor outcomes in RISE-IIP. Future studies of therapy for group 3 pulmonary hypertension should include centrally adjudicated imaging for morphologic phenotyping and disease burden evaluation during screening.

The impact of frailty on mortality after heart transplantation.

BACKGROUND: Frailty is prevalent in the patients with advanced heart failure; however, its impact on clinical outcomes after heart transplantation (HTx) is unclear. The aim of this study was to assess the impact of pre-transplant frailty on mortality and the duration of hospitalization after HTx. METHODS: We retrospectively reviewed the post-transplant outcomes of 140 patients with advanced heart failure who had undergone frailty assessment within the 6-month interval before HTx: 43 of them were frail (F) and 97 were non-frail (NF). RESULTS: Post-transplant survival rates for the NF cohort at 1 and 12 months were 97% (93-100) and 95% (91-99) (95% CI), respectively. In contrast, post-transplant survival rates for the F cohort at the same time points were 86% (76-96) and 74% (60-84) (p < 0.0008 vs NF cohort), respectively. The Cox proportional hazards regression analysis demonstrated that pre-transplant frailty was an independent predictor of post-transplant mortality with a hazard ratio of 3.8 (95% CI: 1.4-10.5). Intensive care unit and hospital length of stay were 2 and 7 days longer in the F cohort (both p < 0.05), respectively, than in the NF cohort. CONCLUSIONS: Frailty within 6 months before HTx is independently associated with increased mortality and prolonged hospitalization after transplantation. Future research should focus on the development of strategies to mitigate the adverse effects of pre-transplant frailty.

Riociguat for idiopathic interstitial pneumonia-associated pulmonary hypertension (RISE-IIP): a randomised, placebo-controlled phase 2b study.

BACKGROUND: Idiopathic interstitial pneumonias are often complicated by pulmonary hypertension, increasing morbidity and mortality. There are no approved treatments for pulmonary hypertension associated with idiopathic interstitial pneumonia (PH-IIP). We aimed to evaluate the efficacy and safety of riociguat in patients with PH-IIP. METHODS: RISE-IIP was a double-blind, randomised, placebo-controlled study done at 65 pulmonary hypertension and interstitial lung disease centres in 19 countries to evaluate the efficacy and safety of riociguat in patients with PH-IIP. Eligible patients were adults (aged 18-80 years) diagnosed with idiopathic interstitial pneumonia (as per American Thoracic Society/European Respiratory Society/Japanese Respiratory Society/Latin American Thoracic Association guidelines), forced vital capacity (FVC) of at least 45%, 6MWD of 150-450 m, WHO functional classes II-IV, precapillary pulmonary hypertension confirmed by right heart catheterisation, systolic blood pressure of at least 95 mm Hg, and no signs or symptoms of hypotension. Patients were randomly allocated (1:1) using an interactive voice and web response system to riociguat (0·5-2·5 mg three times daily) or placebo for 26 weeks (main study), after which they could enter an open-label extension in which all patients received riociguat. The primary endpoint was change in 6-min walking distance (6MWD) in the intention-to-treat population. Prespecified safety variables included adverse events and serious adverse events, laboratory parameters, and adverse events of special interest (haemoptysis and symptomatic hypotension), assessed in the intention-to-treat population. This trial is registered with ClinicalTrials.gov, number NCT02138825. FINDINGS: Between June 4, 2014, and May 5, 2016, we enrolled 229 participants. After the exclusion of 82 participants, 147 were randomly allocated to treatment (73 to riociguat, 74 to placebo). The study was terminated early (median treatment duration 157 days [range 6-203]) at the request of the data monitoring committee owing to increased serious adverse events (main study: 27 [37%] of 73 participants in the riociguat group vs 17 [23%] of 74 in the placebo group) and mortality in patients receiving riociguat, and the absence of efficacy signals in the riociguat group. 11 patients died in the main study (eight in the riociguat group, three in the placebo group), and nine died in the extension phase (one in the riociguat group, eight in the former placebo group; all received riociguat). In the main study, the most common adverse events were peripheral oedema (16 [22%] of 73 in the riociguat group vs seven [9%] of 74 in the placebo group) and diarrhoea (11 [15%] vs seven [9%]). The most common serious adverse events were worsening of interstitial lung disease (main study: six [8%] of 73 in the riociguat group vs five [7%] of 74 in the placebo group) and pneumonia (four [5%] vs one [1%]). Riociguat did not improve 6MWD versus placebo at 26 weeks (least-squares mean difference 21 m; 95% CI -9 to 52). INTERPRETATION: In patients with PH-IIP, riociguat was associated with increased serious adverse events and mortality, and an unfavourable risk-benefit profile. Riociguat should not be used in patients with PH-IIP. FUNDING: Bayer AG and Merck & Co.

A gene-centric strategy for identifying disease-causing rare variants in dilated cardiomyopathy.

PURPOSE: We evaluated strategies for identifying disease-causing variants in genetic testing for dilated cardiomyopathy (DCM). METHODS: Cardiomyopathy gene panel testing was performed in 532 DCM patients and 527 healthy control subjects. Rare variants in 41 genes were stratified using variant-level and gene-level characteristics. RESULTS: A majority of DCM cases and controls carried rare protein-altering cardiomyopathy gene variants. Variant-level characteristics alone had limited discriminative value. Differentiation between groups was substantially improved by addition of gene-level information that incorporated ranking of genes based on literature evidence for disease association. The odds of DCM were increased to nearly 9-fold for truncating variants or high-impact missense variants in the subset of 14 genes that had the strongest biological links to DCM (P <0.0001). For some of these genes, DCM-associated variants appeared to be clustered in key protein functional domains. Multiple rare variants were present in many family probands, however, there was generally only one "driver" pathogenic variant that cosegregated with disease. CONCLUSION: Rare variants in cardiomyopathy genes can be effectively stratified by combining variant-level and gene-level information. Prioritization of genes based on their a priori likelihood of disease causation is a key factor in identifying clinically actionable variants in cardiac genetic testing.

Intensive care, right ventricular support and lung transplantation in patients with pulmonary hypertension.

Intensive care of patients with pulmonary hypertension (PH) and right-sided heart failure includes treatment of factors causing or contributing to heart failure, careful fluid management, and strategies to reduce ventricular afterload and improve cardiac function. Extracorporeal membrane oxygenation (ECMO) should be considered in distinct situations, especially in candidates for lung transplantation (bridge to transplant) or, occasionally, in patients with a reversible cause of right-sided heart failure (bridge to recovery). ECMO should not be used in patients with end-stage disease without a realistic chance for recovery or for transplantation. For patients with refractory disease, lung transplantation remains an important treatment option. Patients should be referred to a transplant centre when they remain in an intermediate- or high-risk category despite receiving optimised pulmonary arterial hypertension therapy. Meticulous peri-operative management including the intra-operative and post-operative use of ECMO effectively prevents graft failure. In experienced centres, the 1-year survival rates after lung transplantation for PH now exceed 90%.

Longitudinal immunosuppression data can minimize misclassification bias in solid organ transplantation cohorts.

BACKGROUND: Most cohort studies investigating the effect of immunosuppression on transplant outcomes use drugs at first hospital discharge. We evaluated the extent of drug exposure misclassification and its impact on outcome prediction. METHODS: We retrospectively collected longitudinal immunosuppression data, at discharge and at 1, 5, 10, and 15 years after transplantation, and outcomes for solid organ transplant recipients 1984-2006 (n = 3133). We compared the risk of death from exposure to individual immunosuppressive drugs (cyclosporine, tacrolimus, azathioprine, and mycophenolate) and dual therapies, as defined by discharge only vs longitudinal immunosuppression data, using adjusted Cox proportional hazards models. RESULTS: During a median follow-up of 5.2 years, immunosuppressive drugs were altered for 947 (30%) recipients and 955 recipients died. Longitudinal receipt of cyclosporine and azathioprine were associated with an increased risk (HR 1.41, 95% CI 1.07-1.89, and HR 1.34, 95% CI 1.00-1.80), and mycophenolate with a reduced risk (HR 0.35, 0.16-0.78), of death. Recipients on mycophenolate and tacrolimus dual therapy had a lower risk of death compared to those on azathioprine and cyclosporine dual therapy (HR 0.30, 0.10-0.93). The increased risk of death associated with the receipt of cyclosporine or azathioprine was not shown in the analyses based on drugs allocated at discharge, and all of the associations between immunosuppressive regimens and death were strengthened in the analyses based on longitudinal immunosuppression data. CONCLUSIONS: Cohort findings based on immunosuppressive drugs allocated at discharge should be interpreted with caution due to potential exposure misclassification. The use of granular, longitudinal data on immunosuppressive regimens could improve prediction.

Comparison of continuous-flow ventricular assist device therapy with intensive medical therapy in fixed pulmonary hypertension secondary to advanced left heart failure.

AIMS: Both ventricular assist device (VAD) and pulmonary vasodilator therapy have been shown in uncontrolled studies to improve pulmonary hypertension secondary to advanced left heart failure (Group 2 PH). This study aimed to compare haemodynamic benefits and survival in patients with fixed Group 2 PH treated with continuous-flow VAD to intensive medical therapy. METHODS AND RESULTS: Ninety-five patients listed for heart transplantation with sequential right heart catheters were studied, 24 patients having fixed Group 2 PH (as defined by cardiac index < 2.8 L/min/m2 , pulmonary capillary wedge pressure > 15 mmHg, and transpulmonary gradient ≥ 15 mmHg or pulmonary vascular resistance > 3.0 WU, unresponsive to vasodilator challenge). Ten patients received VAD therapy, and 14 patients received standard heart failure therapy with or without sildenafil, nitrates, or endothelin receptor antagonists. At repeat right heart catheterization, patients treated with VAD therapy demonstrated significant improvement in both transpulmonary gradient (19 vs. 12 mmHg, P = 0.046) and pulmonary vascular resistance (6.5 vs. 2.9 WU, P = 0.003) compared with baseline, while those treated with medical therapy did not (20.9 vs. 20.3 mmHg and 6.5 vs. 6.4 WU, P = NS for both). Patients who received VAD therapy were significantly more likely to achieve normalized transpulmonary gradient (8/10 vs. 4/14, P = 0.013) and were more likely to be listed for orthotopic heart transplantation (7/10 vs. 4/14, P < 0.05). There were no significant differences between groups in terms of all-cause mortality. CONCLUSIONS: Continuous-flow VAD therapy more effectively reverses fixed Group 2 PH compared with medical therapy alone and may allow a higher rate of listing for orthotopic heart transplantation.

Life-Saving Combined Heart-Kidney Transplantation in a Previous Sequential Heart and Kidney Transplant Recipient.

PURPOSE: Solid organ re-transplantation in the context of allograft failure is a challenging clinical and ethical problem. Ideally, solid organ re-transplantation after initial allograft failure should be performed in all recipients, but this is often not clinically or logistically feasible. METHODS: This report details what we believe is the first combined heart-kidney transplant in a recipient of a previous sequential heart and kidney transplant. RESULTS: Eight years after a combined heart and kidney transplant after initially receiving a sequential heart and kidney transplant, a 31-year-old man is doing extremely well, with no rejection episodes or significant complications after transplantation. SUMMARY: This case confirms that combined heart and kidney transplantation is a viable option for tackling the complex issue of graft failure in recipients of previous cardiac and renal grafts. LEARNING POINTS: Good short- and long-term outcomes following combined heart-kidney transplantation can be achieved in patients with multi-system end-organ dysfunction.Advances in immunosuppressant therapy have enabled multiple transplantation procedures from different donors in a single recipient.We describe the first recipient in the world of combined heart-kidney transplantation on a background of previous sequential heart-kidney transplantation.

Comparison of hemodynamic parameters in treatment-naïve and pre-treated patients with pulmonary arterial hypertension in the randomized phase III PATENT-1 study.

BACKGROUND: Detailed hemodynamic data from the phase III PATENT-1 study of riociguat in patients with pulmonary arterial hypertension (PAH) were investigated. METHODS: Patients with PAH who were treatment naïve or pre-treated with endothelin receptor antagonists or non-intravenous prostanoids were randomly assigned to riociguat up to 2.5 mg 3 times a day or placebo. Hemodynamic parameters were assessed at baseline and week 12. RESULTS: Riociguat significantly decreased pulmonary vascular resistance in treatment-naïve (n = 221; least squares [LS] mean difference -266 dyne∙sec∙cm-5 [95% confidence interval (CI) -357 to -175; p < 0.0001]) and pre-treated (n = 222; LS mean difference -186 dyne∙sec ∙cm-5 [95% CI -252 to -120; p < 0.0001]) patients and significantly increased cardiac index (LS mean difference +0.7 [95% CI 0.5 to 0.8] and +0.5 [95% CI 0.3 to 0.7], respectively [both p < 0.0001]). Mean pulmonary artery pressure (p = 0.0056 and p = 0.0019 for treatment-naïve and pre-treated patients, respectively), mean arterial pressure (both p < 0.0001), and systemic vascular resistance (both p < 0.0001) were significantly reduced, and there was an increase in mixed venous oxygen saturation (p < 0.0001 and p = 0.0004, respectively). Results were similar in patients pre-treated with endothelin receptor antagonists and patients pre-treated with non-intravenous prostanoids. Improvements in 6-minute walking distance correlated very weakly with improvements in pulmonary vascular resistance (r = -0.21 [95% CI -0.30 to -0.11; p < 0.0001]) and cardiac index (r = 0.16 [95% CI 0.06 to 0.25; p < 0.0016]). CONCLUSIONS: Riociguat significantly improved hemodynamic parameters in pre-treated and treatment-naïve patients with PAH.

Iatrogenic immunosuppression and risk of non-Hodgkin lymphoma in solid organ transplantation: A population-based cohort study in Australia.

Iatrogenic immunosuppression is a strong risk factor for non-Hodgkin lymphoma (NHL) but the dose-related association between individual immunosuppressive agents and NHL risk is unknown. We conducted a population-based cohort study of 4131 adult Australian liver, heart and lung transplant recipients (1984-2006). We ascertained NHL incidence by probabilistic record linkage between transplant registries and the Australian Cancer Database, and abstracted risk factor data at transplantation and at regular intervals thereafter from medical records. We estimated adjusted hazard ratios (HR) for early (<1 year after transplantation; n = 29) and late (≥1 year; n = 61) NHL using the Fine and Gray proportional subdistribution hazards model that accounted for death as a competing risk. After adjustment for immunosuppression, the risk of both early and late NHL did not significantly differ by organ type. In final models, higher mean daily doses of azathioprine were associated with increased risk of both early [HR 2·20, 95% confidence interval (CI): 1·21-4·01] and late NHL (HR 1·78, 95% CI: 1·12-2·84). There was no association between any other maintenance immunosuppressive agent and NHL risk. This study provides evidence that differences in immunosuppression may explain variation in NHL incidence by organ type, and high doses of azathioprine may independently predict NHL risk.