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BACKGROUND: Cardiac allograft vasculopathy (CAV) remains the Achilles' heel of long-term survival of HTx patients. Mitochondrial dysfunction has been reported in both arteriosclerotic coronary disease and heart failure. However, myocardial mitochondrial function has not been examined in HTx patients with CAV.METHODS: 43 HTx patients (21 patients with CAV and 22 patients without CAV) ≥12 months after HTx were enrolled. Endomyocardial biopsies were analyzed using high-resolution respirometry for glucose-coupled mitochondrial respiration. Number and area of mitochondria profiles as well as cristae morphology were assessed by transmission electron microscopy. Echocardiography and coronary angiography were used to measure global longitudinal strain (GLS) and grade CAV.RESULTS: Complex I+II-linked respiration was reduced in patients with CAV compared with patients without CAV (82.7 ± 31.9 pmol O2/(s•mg) vs 116 ± 35.9 pmol O2/(s•mg), p = 0.003). Mitochondrial respiratory function measured as oxidative phosphorylation coupling efficiency was positively associated with left ventricular GLS (r = 0.49, p = 0.002) and negatively associated with elevated biomarkers (Troponin T: r=-0.33, p = 0.04 and NT-proBNP: r = -0.41, p = 0.009). Mitochondrial profile number and area did not differ. However, patients with CAV had a larger proportion of mitochondria with abnormal cristae morphology (p < 0.001).CONCLUSIONS: Myocardial mitochondrial respiration is impaired in patients with CAV and is associated with an abnormal cristae morphology. The mitochondrial dysfunction appears to be associated with reduced myocardial contractile function and elevated biomarkers. These results highlight that mitochondrial targeted treatment in patients with CAV should be assessed in future clinical studies.

BACKGROUND: Survival after heart transplantation has increased due to continuously refined and effective care management. Knowledge is sparse on the influence of multimorbidity and social vulnerability on management. We assessed the long-term influence of multimorbidity and socioeconomic factors on cross-sectional health care service utilization in heart transplant recipients.METHODS: First-time heart transplant recipients, from the Transplant Center at Aarhus University Hospital, were followed from transplant until December 31, 2018. We linked individual-level data from the Scandiatransplant Database to Danish national registers. We followed recipients for 15 years using descriptive statistic.RESULTS: We identified 325 recipients; 79% were male and 60% were between 41 and 60 years of age. The median (IQR) number of chronic conditions at baseline was 1.0 (1.0-2.0). The prevalence of recipients with ≥3 chronic conditions in the follow-up period 0 to 1 year was 10% and 65% within 10 to 15 years. The median use of cross-sectional health care services was higher in recipients with ≥3 chronic conditions compared to CONCLUSIONS: The use of cross-sectional health care services was higher in heart transplant recipients with increased incidence of comorbidities during follow-up intervals. A socioeconomic influence was observed in the utilization of services.

BACKGROUND: After heart transplantation (HTx), invasive coronary angiography is gold standard for surveillance of cardiac allograft vasculopathy (CAV). Non-invasive CAV surveillance is desirable.PURPOSE: We examined left ventricular global longitudinal strain (LVGLS) and non-invasive coronary flow velocity reserve (CFVR) related to CAV and prognosis after heart transplantation (HTx).METHODS: Echocardiographic Doppler coronary flow velocity reserve (CFVR) and left ventricular global longitudinal strain (LVGLS) were evaluated in 98 HTx patients. All-cause mortality and major adverse cardiac events (MACE) including hospitalization due to heart failure, cardiovascular death and significant CAV progression, were recorded.RESULTS: Median follow-up was 3.3 (range 1.7-5.4) years. Patients with low CFVR (CONCLUSIONS: In HTx patients with severe CAV, a higher prevalence of low CFVR and worsened LVGLS was observed. Both measurements were strong independent predictors of MACE and all-cause mortality in HTx-patients. Combined CFVR and LVGLS provided incremental prognostic value and showed an excellent ability to rule out significant CAV and may be considered as part of routine CAV surveillance of HTx-patients.

Heart transplantation (HTx) remains the optimal treatment for selected patients with end-stage advanced heart failure. However, survival is limited early by acute rejection and long term by cardiac allograft vasculopathy (CAV). Even though the diagnosis of rejection is based on histology, cardiac imaging provides a pivotal role for early detection and severity assessment of these hazards. The present review focuses on the use and reliability of different invasive and non-invasive imaging modalities to detect and monitor CAV and rejection after HTx. Coronary angiography remains the corner stone in routine CAV surveillance. However, angiograms are invasive and underestimates the CAV severity especially in the early phase. Intravascular ultrasound and optical coherence tomography are invasive methods for intracoronary imaging that detects early CAV lesions not evident by angiograms. Non-invasive imaging can be divided into myocardial perfusion imaging, anatomical/structural imaging and myocardial functional imaging. The different non-invasive imaging modalities all provide clinical and prognostic information and may have a gatekeeper role for invasive monitoring. Acute rejection and CAV are still significant clinical problems after HTx. No imaging modality provides complete information on graft function, coronary anatomy and myocardial perfusion. However, a combination of invasive and non-invasive modalities at different stages following HTx should be considered for optimal personalized surveillance and risk stratification.

Objectives This study aims to identify patients with nonischemic heart failure who are more likely to benefit from implantable cardioverter-defibrillator (ICD) implantation by use of established risk prediction models. Background It has been debated whether an ICD for primary prevention reduces mortality in patients with nonischemic heart failure. Methods The Seattle Heart Failure Model (SHFM) predicts all-cause mortality whereas the Seattle Proportional Risk Model (SPRM) predicts the proportion of sudden cardiac death (SCD) versus nonsudden death, with a higher score indicating a greater proportion of SCD. We report the effect of ICD implantation on all-cause mortality and SCD, according to median SPRM and SHFM scores in all 1,116 patients enrolled in the DANISH (Danish study to Assess the Efficacy of ICDs in Patients with Non-ischemic Systolic Heart Failure on mortality) trial. Results Among patients with an SPRM score above the median (n = 558), ICD implantation reduced all-cause mortality (hazard ratio [HR]: 0.63; 95% confidence interval [CI]: 0.43 to 0.94), whereas patients with lower SPRM scores (n = 558) had no effect (HR: 1.08; 95% CI: 0.78 to 1.49, p for interaction = 0.04). The corresponding numbers for SHFM score above and below the median were HR: 0.84; 95% CI: 0.62 to 1.13 and HR: 0.82; 95% CI: 0.53 to 1.28, respectively (p for interaction = 0.980). In 177 patients with upper SPRM/upper SHFM, ICD implantation reduced all-cause mortality (HR: 0.45; 95% CI: 0.25 to 0.80) when compared to 381 patients with lower SPRM/upper SHFM (HR: 1.09; 95% CI: 0.76 to 1.55) (p for interaction Conclusions Nonischemic heart failure patients with high predicted relative likelihood of SCD, as estimated by higher SPRM score, seemed to benefit from ICD implantation. (DANISH [Danish ICD Study in Patients With Ditaled Cardiomyopathy]; NCT00542945)

Graphical abstract, Highlights • CPFs in relation to the pulmonary valve are very rare. • Physical obstruction of the right coronary ostium by a tumor is a rare finding. • Three-dimensional TEE can demonstrate the pathophysiologic mechanism of a tumor.

Purpose Cardiac allograft vasculopathy (CAV) after heart transplantation (HTx) affects the epicardial arteries and veins and also the coronary microcirculation. In the absence of proximal epicardial artery stenosis, coronary flow velocity reserve (CFVR) reflects the function of the myocardial microcirculation. We aimed to determine the prognostic value of 1) CFVR and 2) a combination of CFVR and left ventricular global longitudinal strain (LVGLS) in HTx patients. Methods CFVR was evaluated using pulsed wave Doppler echocardiography in 98 HTx patients (median 6.9 years from HTx) examined with coronary angiography. Patients were enrolled from 2013 to 2018 and prospectively followed until June 1st 2020. All-cause mortality and major adverse cardiac events (MACE) including heart failure, significant CAV progression, coronary intervention or cardiovascular death, were recorded. Results Median follow-up was 3.2 [interquartile range 1.9-5.1] years. Patients with low CFVR ( -15.5%), we obtained a strong predictive model for MACE (HR 10.5, 95% CI 4.5-24.5, p Conclusion CFVR strongly predicts MACE and all-cause mortality in HTx-patients. A model combining low CFVR and low LVGLS magnitude was a strong model for MACE and all-cause mortality prediction and could be considered as a non-invasive method for routine CAV surveillance.

Purpose To investigate the impact of cerebral reperfusion on cardiac contractile function after normothermic regional perfusion (NRP) after anoxic circulatory death in a porcine model. Methods The animals were anaesthetized and biventricular pressure-volume catheters and a pulmonary artery catheter were inserted percutaneously. Through a midline sternotomy, the heparinised animals were cannulated for extracorporeal circulation. Baseline data were obtained before cessation of mechanical ventilation. Death was determined 5 minutes after mechanical asystole and after additional 3 minutes of warm ischemia NRP was started using a heart-lung machine. The animals were randomized before reperfusion to either clamping (CL) (n=8) or non-clamping (NCL) (n=8) of the aortic arch vessels; the infrarenal aorta was clamped in both groups. The NRP-protocol includes early volume loading of the right ventricle, infusion of dobutamine and norepinephrine and gradual wean over 30 minutes. The animals were observed for 180 minutes after weaning from NRP. Results All animals were successfully weaned from NRP. Both groups demonstrated an acceptable cardiac function after weaning with a mean arterial blood pressure above 75 mmHg and low filling pressures. The NCL group received significantly more norepinephrine (p=0.0484) than the CL group. The left ventricle End-systolic pressure-volume relationship as an index of contractility showed improvement in both groups after wean from NRP compared to baseline (p=0.0009). In the CL group, LV contractility showed a tendency to a better improvement compared to the NCL group (p=0.226) (Fig. 1). The RV showed preserved contractility in both groups. Conclusion LV contractility but not RV contractility improves after circulatory death and weaning from NRP. The improvement of the left ventricular contractility tends to be better when the aortic arch vessels are clamped compared to upper-body perfusion.

Objectives The aims of this study were to characterize cardiac allograft vasculopathy (CAV) phenotypes using optical coherence tomography (OCT) and to evaluate the prognostic significance of OCT-determined CAV severity. Background Intravascular OCT enables in vivo characterization of CAV microstructure after heart transplantation. Methods Sixty-two patients undergoing heart transplantation were enrolled at routine angiography from September 2013 through October 2015 and prospectively followed until censoring on May 27, 2016. Optical coherence tomographic acquisitions aimed for the longest possible pull-backs, including proximal segments of all 3 major vessels. Plaques and bright spots were analyzed by delineating circumferential borders and measuring the angulation of total circumference. Layers were contoured for absolute and relative estimates. Nonfatal CAV progression (NFCP) during follow-up was registered. NFCP included occluded vessels or severe (≥70%) new angiographic coronary stenosis or percutaneous coronary intervention. Results A total of 172 vessels were categorized as follows: no CAV, n = 111; mild to moderate CAV ( Conclusions OCT enables the detection of CAV-associated plaque compositions and allows early detection and differentiation of vessel wall disease not visible on angiography. LFP was the most prevalent plaque component, was strongly associated with NFCP, and may be associated with stepwise CAV progression caused by organizing mural thrombi. (The GRAFT Study: Evaluation of Graft Function, Rejection and Cardiac Allograft Vasculopathy in First Heart Transplant Recipients; NCT02077764)

INTRODUCTION: Mechanical circulatory support may be considered as a therapeutic option in selected patients with refractory cardiac arrest (rCA). Animal studies suggest a potential role for the Impella(®) left ventricular assist device in this setting, but so far no human data have been published.METHODS: Eight patients with rCA were treated with the Impella CP(®) device at our institution from November 2014 to October 2015. The Impella CP(®) was used at the discretion of the treating physicians in patients with rCA and pulseless electrical activity with presumed primary left ventricular failure. These patients were compared to 12 patients with cardiogenic shock also treated with the Impella device during the same period.RESULTS: All cardiac arrests were witnessed with a no-flow time of 0min, six in-hospital and two out-of-hospital. Low-flow time was 50±52min (SD). The Impella device was successfully inserted in all patients with rCA and circulation was re-established. Survival rate to hospital discharge with good neurological outcome was similar among patients with rCA and cardiogenic shock treated with the Impella device (50% vs. 58%). Major vascular complications after Impella insertion occurred more frequently among patients with rCA compared to patients with cardiogenic shock (50% vs. 0%, PCONCLUSION: Mechanical support with the Impella CP(®) device is a feasible and promising treatment option for selected patients with rCA. Further studies are warranted to determine the full potential and optimal patient selection compared to other modalities of mechanical circulatory support.

Purpose To investigate brain activity and intracerebral physiological parameters following no-touch and normothermic regional perfusion (NRP) in donors after circulatory death. Methods The study comprised 16 female pigs of 85 kg. Following anesthesia, five burr holes were placed in the skull targeting the parasagittal cortex bilaterally. To assess cortical brain activity two needles were used to record electroencephalography (EEG) and somatosensory evoked potentials (SSEP). Two probes measuring intracranial pressure and cerebral blood perfusion (CBF), temperature, and oxygen were inserted. Additionally, a microdialysis catheter for metabolic monitoring of lactate, pyruvate, glycerol, and glucose was inserted. The animals were cannulated for the heart-lung machine and baseline measurements were performed before withdrawal from life support. Before NRP, the animals were randomized into two groups: Clamp or non-clamp of the aortic arch vessels. After mechanical asystole, a no-touch period of 8 minutes was observed before the institution of NRP. The animals were weaned from NRP after 30 minutes and subsequently monitored for 3 hours after weaning. Results In the clamp group, flatline EEG and no-SSEPs were recorded after weaning in all pigs. In the non-clamp group, SSEPs were observed after weaning in 6/8 pigs. In all pigs, a peculiar EEG activity of periodic 4-5 Hz complexes, amplitude up to 300 μV, with a repetition interval of one in every 8-60 seconds was recorded. In two pigs, continuous EEG activity was observed alongside the periodic complexes. Additionally, spontaneous respiratory movements were observed in 6/8 pigs in the non-clamp group during a brief pause of ventilation. Preliminary analysis of intracranial measurements of CBF, oxygen, and temperature indicates successful occlusion of the arch vessels in the clamp group and as such cessation of cerebral perfusion. All results await final statistical analysis. Conclusion Some degree of cerebral function returns following circulatory death and resuscitation with NRP and cerebral reperfusion. We observed continuous EEG activity alongside periodic complexes resembling the so-called Nu-complexes thought to originate in the hippocampus. In addition, SSEP response and negative apnea tests suggest that brain stem function returns following NRP with preserved cerebral perfusion.

Purpose Cardiac allograft vasculopathy (CAV) remains the Achilles’ heel of long-term survival of heart transplanted (HTx) patients. CAV affects approximately 50 % of HTx patients 10 years after transplant. We evaluated whether cardiac allograft vasculopathy is associated with mitochondrial dysfunction. Methods A total of 36 HTx patients (18 patients with CAV and 18 patients without CAV) ≥ 12 months after HTx were enrolled. Endomyocardial biopsies were analyzed using high-resolution respirometry for glucose-coupled mitochondrial respiration. Echocardiography and coronary angiography were used to grade CAV according to ISHLT nomenclature. Results Maximally coupled respiration of mitochondrial complex I and II was significantly reduced in patients with CAV compared with patients without CAV (97.2 pmol O2/(s*mg) [65.5; 133.6] vs. 59.1 pmol O2/(s*mg) [53.9; 83.0], p = 0.009) (Fig. 1). Patients with positive donor specific antibodies (MFI > 3000) had a lower maximally coupled respiration compared with patients without (56.5 pmol O2/(s*mg) [53.3; 69.0] vs. 90.6 pmol O2/(s*mg) [59.8; 113.9], p = 0.009). Mitochondrial respiratory function measured as oxidative phosphorylation coupling efficiency was positively associated with both left ventricular function (global longitudinal strain, r2=0.239, p = 0.0045) and right ventricular function (tricuspid annular plane systolic excursion, r2=0.133, p=0.03). Conclusion Mitochondrial respiration is impaired in patients with CAV compared with patients without CAV. Decreased mitochondrial respiratory function is associated with impaired myocardial contractile function.

Purpose The impact of mild (1R) acute cellular rejection (ACR) on the development of cardiac allograft vasculopathy (CAV) after heart transplantation (HTx) remains unclear. We aimed to investigate the association between mild ACR within 1 year of HTx and development of CAV at 3 years post HTx. Methods This is a substudy of the SCHEDULE trial (n=115) in which de novo HTx recipients were randomized to either (i) everolimus or (ii) conventional CNI-based immunosuppression. 76 patients (66%) were eligible for inclusion based on matched intravascular ultrasound (IVUS) examinations at baseline (BL) and 3 years post HTx. Biopsy proven ACR within year 1 was recorded and graded according to ISHLT criteria (1R, 2R, 3R). Development of CAV was assessed by IVUS and coronary angiography at year 3 post HTx. Results Median age was 53 years (45-61) and 71% were male. In 67% of patients ACR was recorded during year 1 (1R in 63%, 2R in 24%, and 3R in 3% of patients, respectively). Patients were grouped by rejection profile: no ACR (33%), only 1R (42%), at least one 2R/3R (25%). At 3 years post HTx 49% of patients had CAV on IVUS (maximal intimal thickness, MIT ≥ 0.5 mm) with no difference in the incidence of IVUS-CAV between groups (p=0.43). Median ∆MITBL-3Y was 0.09 mm (0.05-0.15) with no significant difference among groups (p=0.84) (figure 1). At 3 years post HTx angiographic CAV was present in 26% of patients with no significant between group difference (no ACR: 40%, only 1R: 24%, at least one 2R/3R: 7%; p=0.06). No correlation was found between number of 1R and ∆MITBL-3Y (r=-0.03, p=0.83). Number of 1R did not predict ∆MITBL-3Y in an adjusted linear regression model (p=0.69). No significant interaction with treatment regimen (everolimus/CNI) was found (p=0.84). Conclusion Mild ACR within 1 year of HTx was not associated with development of CAV assessed by IVUS and coronary angiography at year 3 post HTx.

A 52-year old man was admitted with out-of-hospital cardiac arrest, and he was resuscitated after 100 minutes. The initial hemodynamic condition was critical due to cardiogenic shock (left ventricular ejection fraction 10 % and mean arterial pressure 60 mmHg on inotropics). Acute coronary angiography did not reveal any new lesions. Due to persistent hemodynamic instability, mechanical support with Impella LP 5.0 was decided. The surgical procedure guided by fluoroscopy and transesophageal echocardiography was uncomplicated. The hemodynamic improved subsequently and after 17 days of intensive care, and additional 30 days of hospitalization, the patient was ready for discharge. Routine echocardiography prior to discharge revealed severe mitral regurgitation due to perforation of anterior mitral leaflet, a finding not observed in the previous echocardiograms. The patient was discharged to close follow up of the severe mitral regurgitation and future surgical intervention is likely. Therefore, close monitoring of mitral valve is necessary and explanation may be required if valve dysfunction is observed, as repositioning of the Impella system is not possible.

Purpose Cardiac allograft vasculopathy (CAV) is a unique form of accelerated atherosclerosis that is characterized by a diffuse, progressive thickening of the arterial intima of the allograft coronaries. CAV accounts for 30% of deaths occurring beyond the first year after heart transplantation. It is partly caused by immunological factors, partly brought about by established risk factors for atherosclerosis, such as elevated LDL cholesterol levels. Evolocumab is a fully humanized monoclonal antibody that inhibits the enzyme proprotein convertase subtilisin-kexin type 9 (PCSK9), thereby reducing LDL cholesterol levels by as much as 70 %. The EVOLVD trial is designed to test the hypothesis that treatment with evolocumab can ameliorate CAV in heart transplant recipients. Methods The EVOLVD trial is a randomized, controlled double-blind trial designed to test the efficacy and safety of one year's treatment with evolocumab in de novo heart transplant recipients. The trial will be conducted at the Nordic transplantation sites in Norway, Denmark, Sweden, and Finland. We aim to randomize 130 recently transplanted patients in a 1:1 fashion to receive monthly subcutaneous injections of 420 mg evolocumab or matching placebo supplied by the manufacturer. The trial is powered to detect a 0.05 mm between-group difference in the change in the intima thickness as measured by coronary intravascular ultrasound (IVUS). Secondary objectives are to assess the impact of treatment on cholesterol levels, renal function, inflammation, cardiac function as assessed by biomarkers and echocardiography, quality of life, and safety and tolerability. All participants must provide written, informed consent. Exclusion criteria include contraindications to study medication, inability to perform coronary angiography with IVUS, and an estimated glomerular filtration rate Results Applications have been submitted to regulatory authorities. We aim to recruit patients from November 2018 through December 2020, with last patient, last visit in January 2022. Conclusion The EVOLVD trial is a randomized, controlled, double blind study designed to assess the efficacy and safety of the PCSK9 inhibitor evolocumab in de novo heart transplant recipients. We expect results to be available in January 2022.

Purpose Sudden cardiac death (SCD) is a frequent and unexplained complication in relation to heart transplantation (HTx). The mechanism is expectedly multifactorial and Cardiac Allograft Vasculopathy (CAV) is possibly related to SCD. We aimed to investigate the relation between CAV and arrhythmias and silent ischemia in long-term HTx patients. Methods CAV was classified in accordance with the International Society of Heart and Lung Transplantation guideline by coronary angiography and echocardiography . Patients were divided into three CAV groups (CAV 0, 1 and 2+3). Incidence of arrhythmias and silent ischemia were detected by 48-hour electrocardiogram monitoring , and analyzed blinded to CAV status. Results We included 49 HTx patients transplanted a median of 9 years ago [4-14]. We saw a higher incidence of nonsustained ventricular tachycardia (NSVT) in CAV 2+3 patients than in CAV 0 and 1 patients (p=0.01). Also, isolated premature ventricular contractions (PVC) were more frequently observed in this group than in CAV 0 and 1 patients (p=0.01). No difference in incidence of isolated premature atrial contractions (p=0.67) and supraventricular tachycardia (p=0.13) was observed between the CAV groups. Silent ischemia was only observed in CAV 2+3 patients (p=0.04), all patients with silent ischemia (n=3) died within 12 months. The PQ-interval was increased in CAV patients compared with patients without CAV (p=0.01) but no episodes of advanced AV-block were detected. Conclusion Patients with substantial CAV showed a higher incidence of PVCs and NSVT. However, the burden of ventricular rhythm-disturbances was modest and not clearly indicating an increased risk of SCD. In contrast, presence of silent ischemia in patients with severe CAV was associated with high mortality.

In this 12-month multicenter Scandinavian study, 78 maintenance heart transplant (HTx) recipients randomized to everolimus with reduced calcineurin inhibitor (CNI) exposure or continued standard CNI-therapy underwent matched virtual histology (VH) examination to evaluate morphological progression of cardiac allograft vasculopathy (CAV). Parallel measurement of a range of inflammatory markers was also performed. A similar rate of quantitative CAV progression was observed in the everolimus (n = 30) and standard CNI group (n = 48) (plaque index 1.9 ± 3.8% and 1.6 ± 3.9%, respectively; p = 0.65). However, VH analysis revealed a significant increase in calcified (2.4 ± 4.0 vs. 0.3 ± 3.1%; p = 0.02) and necrotic component (6.5 ± 8.5 vs. 1.1 ± 8.6%; p = 0.01) among everolimus patients compared to controls. The increase in necrotic and calcified components was most prominent in everolimus patients with time since HTx >5.1 years and was accompanied by a significant increase in levels of von Willebrand (vWF) factor (p = 0.04) and vascular cell adhesion molecule (VCAM) (p = 0.03). Conversion to everolimus and reduced CNI is associated with a significant increase in calcified and necrotic intimal components and is more prominent in patients with a longer time since HTx. A significant increase in vWF and VCAM accompanied these qualitative changes and the prognostic implication of these findings requires further investigation.

Background A prolonged-release formulation of tacrolimus for once-daily administration (tacrolimus QD) has been developed. This phase II, open-label, multicenter, prospective single-arm study compared the pharmacokinetics (PK) of tacrolimus in stable heart transplant patients before and after conversion from twice-daily tacrolimus (tacrolimus BID) to tacrolimus QD. Methods Heart transplant recipients (≥6 months after transplant), previously maintained on tacrolimus BID–based therapy, received tacrolimus BID from Days 1 to 7 and were converted on a 1:1 (mg/mg) basis to tacrolimus QD. Five 24-hour PK profiles were collected (Days 1, 7, 8, 14, 21). Safety parameters were also evaluated. Results Of 85 patients, 45 (50.6%) completed all 5 evaluable PK profiles. Steady-state tacrolimus area under the curve, 0 to 24 hours (AUC 0–24 ) and minimum concentration (C min ) were comparable for both formulations, with treatment ratio means of 90.5% (90% confidence intervals [CI], 86.4%–94.6%) and 87.4% (95% CI, 82.9%–92.0%), respectively (acceptance interval, 80%–125%). There was good correlation between AUC 0–24 and C min for tacrolimus QD ( r = 0.94) and BID ( r = 0.91). The relationship between these 2 parameters was also similar. Conclusions This study provides evidence for successful conversion from tacrolimus BID to QD on a 1:1 (mg/mg) total daily dose basis. Approximately one-third of patients may require dose adjustments. Both formulations were well tolerated, with stable renal function during the study. Adverse events were reported by approximately one-tenth of patients receiving tacrolimus BID and a quarter of those who received QD.

s S99 the use of antiplatelet therapy with aspirin (ASA) initiated early post transplant influences the future development of CAV. Methods: We conducted a retrospective cohort study in all 1-year survivors that underwent de novo, isolated heart transplantation (1/2004-9/2010). Early ASA use was defined as a minimum of 6 months therapy in the first year post transplant. The primary outcome was 5-year incidence of angiographic CAV (> 50% stenosis in at least 1 vessel, corresponding to at least ISHLT Grade I CAV). The secondary outcomes included time to CAV, CAV free survival, death, and CAV related death. Results: Of 120 eligible patients, the ASA (n= 60) and no ASA (n= 60) groups were evaluated with a similar mean follow up time of 7.0±2.6 years. Overall 5-year CAV incidence was 20.4% (21/103). Among patients who received ASA, 9.8% developed CAV within 5 years post transplant, while 30.8% of patients without ASA developed CAV over the same time period (p= 0.008). After adjusting for other potential CAV risk factors, the odds of developing CAV within 5 years post transplant in the ASA group remained 92% lower than in the no ASA group (p= 0.009, Table 1). Time to CAV development was significantly prolonged among the ASA users who developed CAV (5.6±0.5 vs. 3.2 ±0.6 years; p= 0.006). CAV free survival was significantly better in the ASA group (Cox proportional hazard ratio for ASA use was 0.247, 95% CI 0.079-0.778, p= 0.017) after adjusting for other CAV risk factors (Table 1). Conclusion: This investigation suggests that the early initiation of antiplatelet therapy with ASA influences the 5 year development of CAV after cardiac transplantation by reducing the incidence as well as delaying the occurrence of this complication. Further outcomes-based prospective randomized trials are warranted to delineate and confirm this benefit.

s S133 OT analysis showed in EVE group (42/93 patients) a lower incidence of MACE (0% vs 15±5.3% p= 0.02), similar mortality (9.2±5.2% vs 11.5±5.0%, p= 0.52) and a promising lower estimated incidence of cancers (at 10 yrs 10±5.6% vs. 39.4±16.1%, p= 0.34). ITT and OT analysis showed a similar GFR one and five years after HTx in both groups. Conclusion: This is a single-center post-hoc analysis of long-term outcomes in patients initially randomized in trials with different endpoints. While confirming major problems in maintaining the assigned EVE therapy in the early post-HTx period, we found suggestive evidence of potential long-term benefits of EVE in reducing MACE and cancers. Although these data are only hypothesis generating, they suggest a delayed introduction of EVE to favor tolerability, aiming to take better advantage of its possible long-term benefits.

s S129 Conclusion: Using a portable Freedom driver, TAH-t patients are increasingly mobile, allowing discharge from the hospital with successful bridge to transplantation, while residing in a home environment.

s S41 II. Of the Class II antibodies, 53%, 42.6%, and 4.4% were DR, DQ, and DP respectively. The Class I was predominately against B (54.3%) followed by Cw (28.6%) and A (17.1%). The 1, 2 and 3 year survival after the development of Class I DSA was 91%, 81% and 79% and after Class II DSA was 93%, 80%, and 80%, respectively. Conclusion: At five years, more than a third of CTX patients developed DSA, primarily to Class II. Patients who developed DSA were more than twice as likely to have a PRA > = 20. Once a patient developed DSA their mortality in the subsequent 3 years was approximately 20%. Additional studies are warranted to evaluate long-term survival and graft function.

Purpose Immunosuppressant regimes centered on everolimus have been demonstrated to provide a quantitative reduction in cardiac allograft vasculopathy (CAV) amongst de-novo heart transplant (HTx) recipients. However, the effect of such therapy on CAV assessed by the qualitative method of Virtual Histology (VH) is unknown and was investigated in this prospective randomized-controlled trial. Methods and Materials In this 12-month multicenter Scandinavian study 190 maintenance HTx recipients were randomized to everolimus with reduced calcineurin inhibitor (CNI) exposure or continue standard CNI-therapy. Both groups continued their prior usage of azathioprine (AZA) or mycophenolate mofetil (MMF). 78 patients had evaluable VH examinations at baseline and 12 months and matched analysis was performed to measure change in fibrotic, fibrofatty, calcified and necrotic tissue component. Results When considering all 78 patients, mean age 57.4±10.3 years and mean time post-HTx 5.4±4.1 yrs, a similar rate of quantitative CAV progression was observed in the everolimus (n=30) versus standard CNI therapy group (n=48) (plaque index 1.9±3.9% and 1.6±3.7%, respectively; p=0.65). Virtual Histology analysis revealed a significant increase in calcified (2.4±4.0 versus 0.3±3.1%; p=0.02) and necrotic component (6.4±8.5 versus 1.0±8.6%; p 0.05). Conclusions Conversion to everolimus and reduced CNI does not significantly influence quantitative progression of CAV but is associated with a significant increase in calcified and necrotic tissue component. The prognostic implication of these qualitative changes in HTx recipients is unclear and warrants further investigation.

Purpose Calcineurin inhibitors (CNIs) remain the mainstay of immunosuppression following heart transplantation (HTx) but are associated with significant complications such as nephrotoxicity. We therefore designed a randomized trial to assess whether early introduction of everolimus (Evr) followed by withdrawal of cyclosporine (CsA) would lead to superior renal function and less chronic allograft vasculopathy (CAV) in de novo HTx recipients compared to a standard protocol of CsA-based immunosuppression. Methods and Materials A 12 months’ prospective, multicenter, parallell group, open-labeled study with randomization within 5 days post-HTx to CsA, mycophenolate mofetil (MMF) and corticosteroids (CS) (Group A) or to low dose Evr and reduced dose CsA, MMF and CS, with CsA withdrawal and full-dose Evr after 7-11 weeks (Group B). Results The primary objective was to compare renal function assessed by measured glomerual filtration rate (mGFR) 12 months after HTx. Secondary objectives included differences in progression of CAV assessed by IVUS, renal function evaluated by change of mGFR between weeks 7-11 to month 12, renal function estimated by calculated GFR (cGFR) at each follow-up visit, number of rejections and occurence of treatment failures up to 12 months (graft loss, death, loss to follw-up or discontinuation due to lack of efficacy or toxicity), proteinuria, lipid profile, left ventricular function, safety and tolerability). Altogether 116 patients were recruited and randomized to Group A (n = 59) and Group B (n = 57) with mean (SD) age of 51.5 (12.4) and 51.1 (12.8), respectively, from 1. of December 2009 to 31. of December 2011. The last patient will complete the study in December 2012. Conclusions To be presented at the meeting.

on post transplant survival of patients (pts) bridged to transplant. Methods and Materials: 490 pts were implanted with HeartMate II LVAD in the multicenter BTT clinical trial. 416/490 (85%) had TPG data available for analysis. TPG was calculated as the difference between mean pulmonary arterial pressure and pulmonary capillary wedge. Pts were divided into two groups based on the median TPG value. Results: The median TPG of all pts was 10 mmHg. Pts age (50 13 vs. 51 12), sex, co morbidities, renal and hepatic function, and pre-HTX LVAD support times (239 264 days vs. 262 264 days) did not differ between groups. Overall, there were no differences in LVAD outcomes (Recovery, HTX, or ongoing support) for pts below median TPG ( 10 mmHg) and those above median TPG ( 10 mmHg). However, one year post HTX survival for pts with TPG below the median value ( 10 mmHg) was significantly higher (94%) than for those patients with TPG 10 mmHg (82%) (p 0.006). Analysis based on median PVR of 2.69 or upper quartile PVR of 3.8 did not reveal any differences between LVAD outcome of the groups or their post HTX survival. (91% vs 86% p 0.308, and 90% vs 84% p 0.3 respectively). Conclusions: Elevated TPG prior to LVAD implantation rather than high PVR, is associated with worse 1-year survival in HTX recipients. Elevated TPG appears as an important risk factor for post HTX mortality and therefore should be taken into consideration when contemplating heart transplant versus LVAD destination therapy in patients with advanced CHF.

mus levels (ng/mL) were generally lower for the C-1H v. controls: month 1-6 (8.6 v. 11.4, p 0.00001), month 7-12 (9.9 v.10.9, p 0.0008), month 13-18 (9.8 v. 10.4, p 0.09), month 19-24 (8.8 v. 10.1, p 0.0009) month 25-30 (8.9 v. 10.0, p 0.006), months 31-36 (9.2 v. 9.3, p 0.86). Survival at 3 years was not different between C-1H and controls, 81% v. 77% p 0.35. At 3 years overall freedom from rejection (ISHLT 3A/2R) was superior in the C-1H group: 79% v. 62%, p 0.0005.

Purpose The NOCTET (NOrdic Certican Trial in HEart and lung Transplantation) trial demonstrated that everolimus improves renal function in maintenance thoracic transplant recipients. Nevertheless, switch to everolimus is not recommended for patients with advanced renal failure. We evaluated NOCTET data to assess everolimus introduction amongst thoracic transplant recipients with advanced renal failure. Methods and Materials In this 12-month multicenter Scandinavian study 282 maintenance thoracic transplant recipients were randomized to everolimus with calcineurin inhibitor (CNI) reduction (56% reduction in CNI exposure achieved) or standard CNI therapy. GFR was measured at baseline and 1-year using Cr-EDTA clearance. Results In patients with baseline GFR 60 ml/min the effect was more modest. Time since transplant was a mediating factor as GFR improvement was limited to patients with time since transplant Conclusions Conversion to everolimus and reduced CNI significantly improves renal function amongst maintenance thoracic transplant patients with pre-existing advanced renal failure. This beneficial effect is limited to patients undergoing conversion less than 5 years after transplant indicating a "window of opportunity" that is appropriate for pharmacological intervention with everolimus.

Purpose We recently presented preliminary data on the preventive effects of everolimus (EVE) on biopsy-proven microvasculopathy (MVP) after heart transplantation (HTx). Here we show the final analysis from re-evaluation of the European cohort of the RAD B253 Trial (EVE 3 mg or 1.5 mg vs. azathioprine [AZA] in primary HTx pts). Methods and Materials We studied 135 pts, mean age 56 yrs, and 567 biopsies harvested 1 wk (n=125), 4 wks (n=131), 3 months (n=128), 1 yr (n=101) and 2 yrs (n=82) after HTx. Acute cellular rejection (ACR; ISHLT) and both endothelial disease (endothelial cell layer at least as thick as its cell cores) and MVP (ratio of luminal radius to media thickness Conclusions Everolimus suppresses MVP in biopsy early after HTx and seems to have preventive effects on endothelial disease, also. Its effects beyond the first post-transplant yr deserve further study.