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Solid organ transplant recipients (SOTRs) are on lifelong immunosuppression, which may interfere with adaptive immunity to COVID-19. The data on dynamics and duration of antibody response in SOTRs are limited. This longitudinal study examined the longevity of both anti-spike (S)- and anti-nucleocapsid (N)-specific IgG antibodies after COVID-19 in SOTRs compared to matched immunocompetent persons. SOTRs (n = 65) were matched with controls (n = 65) for COVID-19 disease severity, age, and sex in order of priority. Serum-IgG antibodies against N and S antigens of SARS-CoV-2 were analyzed. At 1 and 9 months after COVID-19, anti-S-IgG detectability decreased from 91% to 82% in SOTRs versus 100% to 95% in controls, whereas the anti-N-IgG decreased from 63% to 29% in SOTRs versus 89% to 46% in controls. A matched paired analysis showed SOTRs having significantly lower levels of anti-N-IgG at all time points (1 month p = .007, 3 months p .001, 6 months p = .019, and 9 months p = .021) but not anti-S-IgG at any time points. A mixed-model analysis confirmed these findings except for anti-S-IgG at 1 month (p = .005) and identified severity score as the most important predictor of antibody response. SOTRs mount comparable S-specific, but not N-specific, antibody responses to SARS-CoV-2 infection compared to immunocompetent controls.

Solid organ transplant (SOT) recipients run a high risk for adverse outcomes from COVID-19, with reported mortality around 19%. We retrospectively reviewed all known Swedish SOT recipients with RT-PCR confirmed COVID-19 between March 1 and November 20, 2020 and analyzed patient characteristics, management, and outcome. We identified 230 patients with a median age of 54.0 years (13.2), who were predominantly male (64%). Most patients were hospitalized (64%), but 36% remained outpatients. Age >50 and male sex were among predictors of transition from outpatient to inpatient status. National early warning Score 2 (NEWS2) at presentation was higher in non-survivors. Thirty-day all-cause mortality was 9.6% (15.0% for inpatients), increased with age and BMI, and was higher in men. Renal function decreased during COVID-19 but recovered in most patients. SARS-CoV-2 antibodies were identified in 78% of patients at 1-2 months post-infection. Nucleocapsid-specific antibodies decreased to 38% after 6-7 months, while spike-specific antibody responses were more durable. Seroprevalence in 559 asymptomatic patients was 1.4%. Many patients can be managed on an outpatient basis aided by risk stratification with age, sex, and NEWS2 score. Factors associated with adverse outcomes include older age, male sex, greater BMI, and a higher NEWS2 score.

Background Parvovirus B19 (PVB19) has emerged as one of the viruses possibly inducing chronic myocarditis and subsequent idiopathic dilated cardiomyopathy (IDCM). The aim of this work was to investigate the presence and long-term consequences of PVB19-DNA within myocardial biopsies from patients with IDCM and to compare the findings with those from donor hearts (control group). Methods and Results Forty hospitalized IDCM patients (age 47 ± 12 y) with mean left ventricular ejection fraction 27 ± 12% were included. The presence of PVB19-DNA in myocardial biopsies and of IgG and IgM antibodies in patient sera was analyzed. The control group consisted of 20 donor hearts. The follow-up time was 112 ± 57 months. PVB19-DNA was found in myocardial biopsies of both patients (73%) and control samples (55%; P = .25).Three deaths and 8 heart transplantations occurred in the IDCM group, and 6 deaths in the control group (ie, the recipients of the control hearts). No difference in transplantation-free survival between the PVB19-DNA positive/negative IDCM patients or transplant recipients was found. Conclusions PVB19-DNA is a common finding in both patients with IDCM and in healthy donor hearts, not affecting prognosis. These findings support the view that PVB19 is an innocent bystander, frequently found in myocardium with low DNA copies, and not a plausible cause of IDCM.

Notwithstanding the ongoing coronavirus disease-2019 (Covid-19) pandemic, information on its clinical presentation and prognosis in recipients of a kidney transplant remain scanty. The aim of this registry-based observational study was to explore characteristics and clinical outcomes of recipients of kidney transplants included in the French nationwide Registry of Solid Organ Transplant Recipients with Covid-19. Covid-19 was diagnosed in symptomatic patients who had a positive PCR assay for SARS-CoV-2 or having typical lung lesions on imaging. Clinical and laboratory characteristics, management of immunosuppression, treatment for Covid-19, and clinical outcomes (hospitalization, admission to intensive care unit, mechanical ventilation, or death) were recorded. Risk factors for severe disease or death were determined. Of the 279 patients, 243 were admitted to hospital and 36 were managed at home. The median age of hospitalized patients was 61.6 years; most had comorbidities (hypertension, 90.1%; overweight, 63.8%; diabetes, 41.3%; cardiovascular disease, 36.2%). Fever, cough, dyspnea, and diarrhea were the most common symptoms on admission. Laboratory findings revealed mild inflammation frequently accompanied by lymphopenia. Immunosuppressive drugs were generally withdrawn (calcineurin inhibitors: 28.7%; antimetabolites: 70.8%). Treatment was mainly based on hydroxychloroquine (24.7%), antiviral drugs (7.8%), and tocilizumab (5.3%). Severe Covid-19 occurred in 106 patients (46%). Forty-three hospitalized patients died (30-day mortality 22.8%). Multivariable analysis identified overweight, fever, and dyspnea as independent risk factors for severe disease, whereas age over 60 years, cardiovascular disease, and dyspnea were independently associated with mortality. Thus, Covid-19 in recipients of kidney transplants portends a high mortality rate. Proper management of immunosuppression and tailored treatment of this population remain challenging.

Purpose The development of acute kidney injury (AKI) and renal dysfunction is a common complication after heart transplantation (HTx) that is associated with increased morbidity and mortality. When used for treatment of AKI, infusion of atrial natriuretic peptide (ANP) has been shown to increase renal blood flow and glomerular filtration rate (GFR) after complicated cardiac surgery and in cyclosporine-induced AKI after HTx. Furthermore, it was shown that ANP reduced the probability of dialysis in cardiac surgery-associated AKI. The aim of this investigation was to evaluate whether ANP infusion could prevent or mitigate acute renal dysfunction after HTx. Methods After approval of Ethical Review Board and the Swedish Medical Products Agency, 72 adult patients undergoing HTx were included after informed consent. The patients were randomized to receive either ANP or placebo (saline) by a web-based computerized random-number generator. The anesthesia/intensive staff and physicians were blinded to the allocated treatment throughout the entire study. After induction of anesthesia, a continuous intravenous infusion of either ANP (HANP1000®, Daichii Sankyo Propharma, Japan) at a dose of 50 ng/kg/min or the equivalent volume of placebo (saline) was started. The administration of the study drugs continued for five postop days, or until the patient died or treatment with dialysis was started. Inclusion has been completed. Endpoints The primary end-point was measured mGFR at day five. mGFR was assessed by the infusion clearance of 52Cr-EDTA. The difference in mGFR between groups was estimated using intention-to-treat and per-protocol analyses. To detect a 30% higher mGFR in the ANP group, 31 patients per group would be required, assuming a 80% power and a two-sided error of 0.05. To compensate for drop-outs and for the use of nonparametric tests, we included 35 randomised patients per group. Secondary end-points were: the incidence of postoperative AKI (KDIGO criteria), daily postoperative serum creatinine, need for dialysis, intra- and postoperative diuresis, the use of diuretics, length of ICU and hospital stay, ICU mortality and 30-days mortality, length of mechanical ventilation, incidence of hypotension and arrhythmias and inotropic score.

Purpose High-intensity interval training (HIT) is an effective method to increase exercise capacity in de novo heart transplant recipients, as shown in the recently published HITTS study (High-intensity Interval Training in de novo Heart Transplant recipients in Scandinavia). We were interested to scrutinize the potential effect of HIT in different age categories. The main effects of HIT in one young and one older medically stable de novo heart transplant recipients are reported. Methods The HITTS study is a randomized controlled study comparing HIT versus moderate intensity continuous training (MICT) in de novo heart transplant recipients (mean 11 weeks after heart transplantation). Eighty-one participants were randomized (1:1) to 9 months of HIT or MICT. The primary endpoint was the change in VO2peak. Secondary endpoints included: Heart rate response, muscle strength and self-reported physical function measured by the Short-Form-36. One of the youngest and one of the oldest participants with the highest changes in VO2peak in the HIT intervention group were selected for this case report. Results The youngest male ( 55 years old) increased his VO2peak with 12.6 mL/kg/min (from 15.6 to 28.3 mL/kg/min). Muscle strength, heart rate response, O2 pulse and self-reported physical function also increased substantially (Table). The young heart transplant recipient completed 51 exercise sessions whereas the older heart transplant recipient completed 72 sessions. Conclusion Both the young and the older de novo heart transplant recipient increased their VO2peak with at least 4 METS (> 12 mL/kg/min) after a 9-month long HIT intervention. The results show that both young and older individuals can derive substantial benefit from HIT soon after heart transplantation.

Purpose Medical treatment for cardiac amyloidosis (CA) is evolving rapidly. Heart transplantation can be a valid option when followed by transplantation of bone marrow or liver, dependent on the type and origin of the amyloid protein. Thus, accurate typing of amyloidosis has implications for treatment, prognosis, and genetic counseling. Although non-invasive diagnostic techniques can type CA, endomyocardial biopsy (EMB) may be needed in the case of equivocal imaging findings or discordant data. We aimed to define the role of mass spectrometry (MS) for diagnosis and subtyping of CA. Methods Nineteen previously diagnosed CA cases, who underwent EMB at Sahlgrenska University Hospital (SU), Gothenburg, between the beginning 1990s and 2016, were selected. MS analysis, modified from was conducted on duplicate samples from myocardial tissue for each case included.1 Clinical features and diagnoses were used as gold standard and compared to the MS findings. Results Clinical diagnosis and the MS analysis agreed in 14 cases (73.7 %); in 3/19 (15.8 %) diagnosis was unclear or discordant (Fig.1). MS analysis revealed that transthyretin (TTR) amyloidosis was the most abundant amyloid protein in the samples examined (9/19; 47.3 %), whereas the AA subtype only occurred in 1 case (5.2 %). The AL κ type amyloidosis occurred in 3 cases (15.8 %), and AL λ type in six cases (31.6 %). These results strongly correlated with the clinical features in all patients. Clinical diagnosis could not be retrieved from the medical records in 2 cases (10.4 %). Additional 20 patients with clinical CA are presently under study. Conclusion MS analysis of a small amount of endomyocardial tissue can be used to subtype CA with a high diagnostic validity. The method differentiated between TTR, SAA and Ig light chain amyloidosis. AL κ and AL λ identities correlated to those found in serum and urine electrophoreses. MS can therefore be of use to subtype CA for cases in which clinical findings are inconclusive. 1) Brambilla F et al. Blood. 2012 Feb 23;119(8):1844-7

Objectives Not all patients in need of durable mechanical circulatory support are suitable for a continuous-flow left ventricular assist device. We describe patient populations who were treated with the paracorporeal EXCOR, including children with small body sizes, adolescents with complex congenital heart diseases, and adults with biventricular failure. Methods Information on clinical data, echocardiography, invasive hemodynamic measurements, and surgical procedures were collected retrospectively. Differences between various groups were compared. Results Between 2008 and 2018, a total of 50 patients (21 children and 29 adults) received an EXCOR as bridge to heart transplantation or myocardial recovery. The majority of patients had heart failure compatible with Interagency Registry for Mechanically Assisted Circulatory Support profile 1. At year 5, the overall survival probability for children was 90%, and for adults 75% (P = .3). After we pooled data from children and adults, the survival probability between patients supported by a biventricular assist device was similar to those treated with a left ventricular assist device/ right ventricular assist device (94% vs 75%, respectively, P = .2). Patients with dilated cardiomyopathy had a trend toward better survival than those with other heart failure etiologies (92% vs 70%, P = .05) and a greater survival free from stroke (92% vs 64%, P = .01). Pump house exchange was performed in nine patients due to chamber thrombosis (n = 7) and partial membrane rupture (n = 2). There were 14 cases of stroke in eleven patients. Conclusions Despite severe illness, patient survival on EXCOR was high, and the long-term overall survival probability following heart transplantation and recovery was advantageous. Treatment safety was satisfactory, although still hampered by thromboembolism, mechanical problems, and infections.

Purpose Heart transplantation (HTx) has become the standard treatment for patients with end-stage heart disease. The aim of this study was to report our incidence and long-term outcome of malignancies after HTx. Methods The study is a single centre retrospective study of 664 patients, who underwent HTx at our centre between, 1985-2017. Data were retrieved from the Cancer Registry and the Birth and Death registry, both of which are obligatory national registries managed by the National Board of Health and Welfare. Results In total, 231 malignancies were diagnosed in 138 patients (19.6%). The median follow-up time was 6.9 years (IQR 2.4-13.1). No patient was lost to follow-up. The overall risk of cancer following organ transplantation was 6.1-fold and 2.9-fold when excluding nonmelanoma skin cancer. The three most common malignancies were; nonmelanoma skin cancer, non-Hodgins lymphoma and lung cancer. There was no significant difference (p Conclusion Nineteen percent of patients had experienced a malignancy after almost 7 years of median follow-up after HTx. We have shown an overall risk of cancer to be over 6-fold higher than among the general population, and almost 3-fold higher when non-melanoma skin cancer was excluded, after heart transplantation.

Purpose There is an increasing interest in the use of donor-derived cfDNA (dd-cfDNA) in transplantation for non-invasive diagnosis of allograft injury. We hereby describe a non-commercial routine procedure for dd-cfDNA detection and quantification using digital droplet PCR and target-specific preamplification of a SNP-panel of 35 SNP-assays. The method is based on the difference in genotype between recipients and donors. After establishing our protocol, it has been used in a prospective study following recipients for 12 months after heart transplantation (HTx), and we here briefly describe our protocol. Methods A total of 728 samples from 67 HTx patients have been retrieved and analyzed. The recipients were genotyped preoperatively with respect to the SNP-panel. Upon transplantation, the donor genotype was interrogated with respect to the homozygous alleles found in the recipient. After HTx, blood samples were collected in cell free DNA collection tubes and delivered within the same day to the hospital laboratory. Plasma was separated by centrifugation at 2000g and 16000g, respectively. Isolated plasma was stored at -80C or used immediately for cfDNA extraction. Quality controls were performed by the 4200 Tape Station. The same primers were used for preamplification and downstream PCR. Non-template controls were included in all preamplification steps. The amount of dd-cfDNA was calculated as a fraction of the total cfDNA. Results The variation of extracted cfDNA yield was 10-130 ng/ml plasma. The 50-800 bp sized cfDNA constitutes 90% of the extracted samples, indicating a low background. An average of 2-5 informative SNPS assays for each transplant recipient were used for dd-cfDNA quantification with a detection rate down to 0.01% dd-cfDNA. Elevation of dd-cfDNA was seen not only in conjunction with cellular rejection but also during infection and in episodes of heart failure Conclusion Samples from HTx recipients demonstrated low levels of dd-cfDNA in consecutive samples during optimal treatment in non-eventful cases. Elevation of dd-cfDNA was seen not only during rejection but also in other conditions. This non-invasive method is relatively cheap, enables large sample yields by preamplification, has a fast turn-around time (48 hours) and is thus useful for clinical monitoring of HTx patients. However, it needs to be carefully related to clinical events.

There is no consensus on how, when, and at what intensity exercise should be performed and organized after heart transplantation (HTx). Most rehabilitation programs are conducted in HTx centers, which might be impractical and costly. We have recently shown that high-intensity interval training (HIT) is safe, well tolerated, and efficacious in maintenance HTx recipients, but there are no studies among de novo patients, and whether HIT is feasible and superior to moderate training in HTx recipients is unclear. A total of 120 clinically stable HTx recipients older than 18 years will be recruited from 3 Scandinavian HTx centers. Participants are randomized to HIT or moderate training, shortly after surgery. All exercises are supervised in the patients' local communities. Testing at baseline and follow-up includes the following: VO2peak (primary end point), muscle strength, body composition, quality of life, myocardial performance, endothelial function, biomarkers, and progression of cardiac allograft vasculopathy. A subgroup (n = 90) will also be tested at 3-year follow-up to assess long-term effects of exercise. So far, the HIT intervention is well tolerated, without any serious adverse events. We aim to test whether decentralized HIT is feasible, safe, and superior to moderate training, and whether it will lead to significant improvement in exercise capacity and less long-term complications.

Purpose To investigate the survival of heart transplant (HTx) recipients during different time periods in Sweden. We hypothesized that the survival for HTx recipients has improved following advancements in the management of these patients. Methods Data was obtained through the database of the organ exchange organization Scandiatransplant. All patients who underwent HTx in Sweden between Jan 1988 and Dec 2017 were included. Patients were divided into five cohorts of six-year periods each. Results A total of 1137 HTx recipients were included. Main causes of transplantation were dilated cardiomyopathy (44 %) and ischemic heart disease (18 %). Retransplantation constituted a small portion of the overall total (2 %). The cohorts were similar in terms of age and gender, while later cohorts had higher BMI, lower GFR and longer ischemia time (Tab. 1). The later cohorts received organs from older donors (Tab. 1). The amount of heart transplantations performed in Sweden has increased with time (Tab. 1). Log-rank test comparing the survival curves was able to show improved survival during later eras (Fig. 1). Conclusion Survival among HTx recipients has significantly improved in Sweden over time, despite less favorable recipients and donor characteristics. This was related to both reduced postoperative mortality and also improved long-time survival.

Purpose To investigate outcome of patients with giant cell myocarditis (GCM) or cardiac sarcoidosis (CS) who undergo heart transplantation (HTx) or implantation of mechanical circulatory support (MCS). Methods Data from all patients who received HTx or MCS due to GCM or CS at Sahlgrenska University Hospital (SU), Gothenburg between 1990s and 2018 was reviewed. The long-term survival was compared to 130 controls that were treated with HTx due to all other heart diseases, 5 for each patient with inflammatory cardiomyopathy (ICM), matched by age, sex and HTx duration. Results A total of 26 patients underwent HTx or received MCS because of GCM or CS at SU during the study period. Fifteen of them (58%) suffered from GCM and 11 from CS. Diagnosis was made by endomyocardial biopsy in 10/15 (67%) patients with GCM and 4/11 (36%) patients with CS and the remaining at the time of the pathological investigation of the heart explant. Altogether 8/15 (53%) of GCM patients and 2/11 (18%) required implantation of durable MCS, but 2 patients with GCM died before HTx. During follow-up disease recurrence in the graft was identified in 2/13 (15%) patients with GCM as well as in 2/11 (18%) CS patients. Treatment-requiring cardiac allograft rejection was observed in 6/13 (46%) GCM patients and in 1/11 (9%) CS patients. The mean survival time was numerically higher for patients with ICM (20.2 years, 95 % CI=12.2-28.2) than for the control group (16.9 years, 95 % CI=14.5-19.4), but the difference was not statistically significant (log-rank test (p=0.75) Breslow-test (p=0.68)). Conclusion Patients with GCM or CS with advanced heart failure who are treated with HTx or MCS have similar long-term survival as HTx recipients treated due to all other heart diseases.

Purpose Donor-derived cell-free DNA (dd-cfDNA) as a highly sensitive marker of rejection after heart transplantation (HTx) has gained emerging interest. Recent studies are based on sequencing techniques and use fractional abundance (dd-cfDNA as a fraction of total cfDNA) as their outcome. Here we present patient examples of the BIODRAFT-study (NCT03477383) based on PCR-techniques. Methods Blood samples are taken prospectively in parallel with endomyocardial biopsies (EMB) during the first year after HTx. dd-cfDNA is analyzed using targeted preamplification of 35 single nucleotide polymorphisms followed by digital droplet-PCR. Outcome is fractional abundance as well as total number of DNA copies, both from the donor and the recipient. Results 71 patients (57 adults, 14 children) are so far included and more than 500 blood samples analyzed. In otherwise stable patients, both fractional abundance and total DNA copies seem to follow biopsy patterns with respect to rejection. However, we could also identify different scenarios in which the distribution of cfDNA seems more complicated than hitherto described: Patients with primary graft failure, clinically silent CMV-infection or mild right heart failure show elevated levels of dd-cfDNA, thus complicating the interpretation of results. Some patients present with markedly elevated levels of their own cfDNA without obvious clinical reasons. Conclusion Besides the well-known concept of fractional abundance, our approach gives results that allow following absolute DNA copy numbers of both donor and recipient. This widens the horizon of cfDNA as a marker of graft injury after HTx, and gives an outlook to clinical scenarios with possible false positive (mimicking rejection) and, even worse, false negative results: high levels of recipient-cfDNA could mask ongoing rejection if only fractional abundance can be reported. The biology of cell-free DNA is complex and seems not yet fully understood.

Purpose A main goal after heart transplantation (HTx) is to achieve good health related quality of life (HRQoL). Exercise training after heart transplantation (HTx) is recommended and high-intensity interval training (HIT) seem to be more effective than moderate continuous training (MICT). Studies on the effect of HIT vs. MICT on HRQoL is scarce, and no studies among de novo HTx recipients exist. Methods Eighty-one de novo HTx recipients were included and were randomized 1:1 to either HIT or MICT. HRQoL was assessed by the Short Form-36 (SF-36v2), the Hospital Anxiety and Depression Scale (HADS) at baseline (mean 11 weeks after surgery) and at 1-yr follow- up, additionally, participants reported their overall health on a numeric visual analouge scale after the intervention period. SF-36 scores were calculated using norm based values with a standardized mean of 50±10. All patients underwent a clinical examination and physical tests. Results At 1-yr follow-up 78 patients were retested. Both groups had significant improvements on the physical function components of HRQoL the first year after HTx, while mental health, anxiety and depression scores remain unchanged. There were no serious adverse events related to exercise in either of the groups during the intervention period. Mean ± SD age for the total population was 49±13 years, 73% were men. There was no significant difference between HIT and MICT in seven of the eight SF-36 subscales, in physical component summary score (PCS) or mental component summary score (MCS). However, there was a statistical significant positive change in the role emotional (RE) subscale mean score in the HIT group compared to the MICT group (Table 1). Conclusion From baseline to 1-yr follow-up HIT vs. MICT resulted in similar mean changes in HRQoL, except from on the SF-36 RE subscale. Both groups had significant improvements in PF, RP and PCS,suggesting that exercise training improves some areas of the multidimensional concept of HRQoL.

Danon disease is caused by mutations in the lysosome-associated membrane protein-2 gene, LAMP2, located on the X chromosome. Female carriers with LAMP2 mutations most often present with late onset cardiomyopathy and slow disease progress; however, there are unusual cases that emerge early and show a more severe disease course. We investigated the explanted heart and skeletal muscle biopsies in two girls, aged ten and thirteen years, who underwent cardiac transplantation because of hypertrophic cardiomyopathy secondary to LAMP2 mutations and a 41-year old female with late-onset familial LAMP2 cardiomyopathy with more typical clinical phenotype. The two girls in contrast had clinical features that mimicked severe primary hypertrophic cardiomyopathy caused by mutations in genes encoding sarcomeric proteins. Immunohistochemistry in cardiac muscles showed a remarkable pattern with lack of LAMP2 protein in large regions including thousands of cardiomyocytes that also showed myocyte hypertrophy, lysosomal enlargement and disarray. In other equally large regions there were preserved LAMP2 expression and nearly normal histology. The skeletal muscle biopsy revealed no pathological changes. An uneven distribution of LAMP2 protein may cause deleterious effects depending on which regions of the myocardium are lacking LAMP2 protein in spite of an overall moderate reduction of LAMP2 protein. This may be a more common mechanism behind early aggressive disease in females than an overall skewed X-chromosome inactivation in the tissue.

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 Physical capacity, as assessed by peak oxygen consumption (VO2peak ) or self-reported physical function (PF) from Short Form-36 (SF-36), is a strong predictor of long-term survival in heart transplant (HTx) recipients. VO 2peak and SF36-PF are highly correlated in maintenance HTx, but their association has previously not been examined in de novo HTx recipients. Methods Seventy-eight patients who completed the HITTS study (High-intensity Interval Training in de novo heart Transplant recipients in Scandinavia) were included in the analyses. Patients were tested at baseline (mean 11 weeks after surgery) and at 12 months follow-up, with self-reported PF (SF-36v2), cardiopulmonary exercise test with measurement of VO 2peak, and lower limb isokinetic muscle strength. Pearson´s correlation was used to compare the association between PF and VO2peak (L/min) and PF and muscular strength; early (mean 11 weeks after HTx) and later (1 year after HTx). Results Mean ± SD age was 49 ± 13 years, 73% were men. Both at 11 weeks and after 1 year, there were statistically significant positive correlations indication moderate association between PF and VO2peak (r=0.482 vs. 0.401) (Fig 1), PF and muscular exercise capacity (r= 0.494 vs. 0.388), and PF and maximal muscular strength (r = 0.443 vs. 0.414). Conclusion De novo HTx patients´ self-reported PF is associated with both VO2peak and muscular strength, also found 1 year after HTx. While measuring VO2peak is the preferred method of examining physical capacity and prognosis, self-reported PF is an easy, less resource-demanding assessment that could be considered as a clinical substitute.

Purpose Coronary artery vasculopathy (CAV) leads to increased morbidity and mortality in heart transplant (HTx) recipients. We have previously shown that high-intensity interval training (HIT) in maintenance recipients significantly reduced CAV progression, as compared to a control group. Our hypothesis was that HIT compared to moderate intensity, continuous training (MICT) in de novo HTx recipients would show similar results. Methods 67 HTx recipients (mean ± SD age 49 ± 13, 72 (% men) were randomized to either nine months of HIT or MICT at mean 11 weeks (range 7 - 16) post HTx. The effect of training on CAV progression was assessed by matched intravascular ultrasound (IVUS) examinations at baseline and 12 months, and analyses were performed to measure change in Maximal Intimal Thickness (MIT), Percent Atheroma Volume (PAV) and Total Atheroma Volume (TAV). Results Age and sex were similar between the groups. Peak oxygen consumption (VO2peak L/min) improved with 12.5 ± 10.3 % in the HIT group vs. 8.7 ± 9.3 % in the MICT group (p=0.022). IVUS analysis revealed a relatively small increase in all the three main IVUS parameters in both groups: The mean ± SD increase in MIT was 0.08 ± 0.12mm in the HIT group vs. 0.06 ± 0.10 mm in the MICT group. The increase in PAV was 4.3 ± 5.6 % in the HIT group vs. 3.2 ± 3.9 % in the MICT group, and TAV increased with 20.0 ± 51.5 mm3in the HIT group vs. 25.7 ± 44.8mm3 in the MICT group, but there were no significant differences between the groups (see Table 1). Furthermore, there were no significant correlations between VO2peak and MIT, PAV or TAV in either of the groups. Conclusion The increase in VO2 peak was significantly greater in HIT patients as compared to the MICT group. However, there was no significant difference in progression of CAV between the two treatment groups. We await the results from the 3-year follow-up to evaluate potential long-term effects.

Without a heart transplant, 20% of patients with end-stage heartfailure will die within 6 months. If the patient receives a new heart,however, the estimated median survival time exceeds 10 years [1].Unfortunately, because of the paucity of donors who meet the criteriafortransplantation[2,3],heartsareavailableforonlyasmallpercentageof recipients with refractory heart failure who are eligible for hearttransplantation. Current guidelines stipulate that donor hearts shouldnot have wall motion abnormalities and that ejection fraction shouldbe over 40% [4].Takotsubo syndrome is an acute condition with characteristicreversible regional wall motion abnormalities and decreased ejectionfraction. Takotsubo frequently affects patients with severe somaticdisease [5] and is common in patients with cerebral lesions, includingsubarachnoid hemorrhage [5]. The current guidelines do not mentionwhether patients with brain death and takotsubo could be consideredas organ donors.The process of brain death elicits significant somatic stress and acatecholamine surge [6] Increasing evidence suggests that takotsubosyndrome is caused by direct catecholamine toxicity in predisposedpatients and is therefore probably common in patients with braindeath. Here we present a case in which a heart was successfullytransplanted from a donor with wall motion abnormalities due totakotsubo syndrome.

Background Several treatment options are available for pulmonary vascular disease, and more patients are considered for right heart catheterization. The aims of this study were to evaluate the diagnostic ability of echocardiography to detect pulmonary hypertension and increased pulmonary vascular resistance (PVR). Methods This retrospective study comprised 118 patients investigated within 48 hours of right heart catheterization. Echocardiography was used to assess pulmonary artery systolic pressure and pulmonary artery mean pressure, filling pressures, cardiac output, and PVR. To diagnose increased PVR, three echocardiographic variables related to pressure reflection in the pulmonary circulation were used. Separate cutoff values aimed at ruling in (high positive likelihood ratio [PLR]) and ruling out (low negative likelihood ratio) pulmonary hypertension (pulmonary artery mean pressure >25 mm Hg) and increased PVR (>3 Wood units) were determined from a derivation group ( n = 59, receiver operating characteristic curve analysis) and evaluated in a test group ( n = 59). Results The linear relations between hemodynamic variables assessed with simultaneous echocardiography and right heart catheterization were moderate to strong ( R = 0.55 to 0.95), and there were no significant differences, but the limits of agreement were wide. With Doppler pulmonary artery systolic pressure >39 mm Hg, the PLR for pulmonary artery mean pressure >25 mm Hg was 4.7, and with Doppler pulmonary artery systolic pressure ≤29 mm Hg, the negative likelihood ratio was 0.12. The PLR for pressure reflection variables with ruling-in cutoff values ranged from 4.3 to 6.4. With all three variables positive, the PLR was 9.9. The negative likelihood ratio with ruling-out cutoff values ranged from 0.22 to 0.08. Conclusions Echocardiography that includes assessment of pressure reflection in the pulmonary circulation can rule in and rule out pulmonary hypertension and increased PVR.

Objective Right ventricular failure in patients treated using left ventricular assist devices is associated with poor outcomes. We assessed the strategy of preplanned biventricular assist device implantation in patients with a high risk for right ventricular failure. Methods Between 2010 and 2014, we assigned 20 patients to preplanned biventricular assist device and 21 patients to left ventricular assist device as a bridge to heart transplantation on the basis of the estimated risk of postimplant right ventricular failure. Preimplant characteristics and postimplant outcomes were compared between the 2 groups. Results Patients with a biventricular assist device were younger, more often female, and more frequently had nonischemic heart disease than left ventricular assist device recipients. At preoperative assessment, biventricular assist device recipients had poorer Interagency Registry for Mechanically Assisted Circulatory Support profiles, a lower cardiac index, and more compromised right ventricular function. Survival on device to heart transplantation/weaning/destination for biventricular assist device and left ventricular assist device recipients was 90% versus 86% (not significant), with shorter heart transplantation waiting times for biventricular assist device recipients (median days, 154 vs 302, P Conclusions Planned in advance, the biventricular assist device seems to be a feasible option as bridge to heart transplantation for patients with a high risk of postimplant right ventricular failure. The outcomes for these patients were similar to those observed for contemporary left ventricular assist device recipients, despite those receiving biventricular assist devices being more severely ill.

To investigate the effects of obesity and weight loss on cardiovascular autonomic function, we examined 28 obese patients referred for weight-reducing gastroplasty, 24 obese patients who received dietary recommendations, and 28 lean subjects. Body weight, blood pressure, and 24-hour urinary norepinephrine excretion were measured, and time and frequency domain indexes of heart rate variability (HRV) were obtained from 24-hour Holter recordings. A measure of long-term HRV, the SD of all normal RR intervals (SDANN), was used as an index of sympathetic activity and the high-frequency (HF) component of the frequency domain, reflecting short-term HRV, as an estimate of vagal activity. All 3 study groups were investigated at baseline, and the 2 obese groups were reexamined at 1-year follow-up. Obese patients had higher blood pressure, higher urinary norepinephrine excretion, and attenuated SDANN and HF values than lean subjects (p

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. Arora ,1 K. Karason,2 H. Eisjaer,3 H. Botker,3 F. Gustafsson,4 K. Saunamaki,5 G. Radegran,6 E. Gude,1 L. Aaberge,1 T. Ueland,7 P. Aukrust,7 D. Solbu,8 L. Gullestad.1 1Cardiology, Oslo University Hospital, Rikshospitalet, Oslo, Norway; 2Cardiology, Sahlgrenska University Hospital, Gothenburg, Sweden; 3Cardiology, Skeiby University Hospital, Aarhus, Denmark; 4Cardiology, Rigshospitalet, Copenhagen, Djibouti; 5Cardiology, Rigshospitalet, Copenhagen, Denmark; 6Cardiology, Lund Hospital, Lund, Sweden; 7Research Institute for Internal Medicine, Oslo University Hospital, Rikshospitalet, Oslo, Norway; 8Novartis Norge, Oslo, Norway.

Danon disease is caused by mutations in the lysosome-associated membrane protein-2 gene, LAMP2, which is located on the X chromosome. Female carriers may occasionally present already in childhood with cardiomyopathy and a very severe disease course. It has been proposed that this is a result of unfavorable skewing of X-chromosome inactivation. We have investigated two young girls aged ten and thirteen years who underwent cardiac transplantation because of cardiomyopathy due to de novo heterozygous LAMP2 mutations. We also investigated one adult female with a more typical clinical phenotype. We found no evidence of skewed X-chromosome inactivation in the two young girls. In accordance with this finding skeletal muscle biopsy revealed no pathological changes. Expression of LAMP2 mRNA in cardiac muscle in the youngest patient revealed equal expression of both alleles also supporting the concept that there was no skewed X-chromosome inactivation. Immunohistochemistry in cardiac muscles of all three patients showed an unexpected and remarkable pattern with lack of LAMP2 protein large regions that also showed myocyte hypertrophy, disarray and lysosomal enlargement. In other large regions there was preserved LAMP2 expression and nearly normal histology. Our results demonstrate that skewed X-chromosome inactivation may not be a common cause of the severe cardiac phenotype seen in occasional female carriers of pathogenic LAMP2 mutations. Instead an uneven distribution of LAMP2 protein may cause deleterious effects depending on which regions of the myocardium that are lacking LAMP2 protein in spite of an overall moderate reduction of LAMP2 protein.

et de 20/20 patients pour la douleur thoracique. Chez les 4 patients sans disparition complete de la symptomatologie, la mediane de pression du SIO etait de 18 cmH20 avec transit et endoscopie normaux. Deux patients presentaient des signes cliniques et pH-metriques de reflux. Les resultats sont restes stables sur la periode de suivi. La conclusion des auteurs est que la myotomie etendue avec fundoplicature anterieure est un traitement efficace de la MSDO severe. Les resultats fonctionnels sont ici excellents, notamment, en termes de dysphagie et de douleurs thoraciques.

tained significant rejection (SSR) was defined as ISHLT 2A on two successive biopsies. Students T-test was used to compare rates of rejection between populations. A p-value of 0.05 was defined as significant. Results: 189 patients were followed between 1999 and 2006. The mean age at transplant was 48 years, and 80% were male. 98% of patients had MMF as part of their anti-rejection regimen, and 71% of these patients had their medication dose reduced at some point. The most common reasons for dose reduction of MMF were leucopenia (46%), GI intolerance (33%), and infections (23%). The prevalence of sustained significant rejection (SSR) in the GI intolerant group versus those patients who had no MMF dose reductions was 66% vs 35% (p .002). The SSR rate for patients with MMF dose reductions due to leukopenia or infection was not significantly different compared to those patients who never had a dose reduction (Leukopenia: 35% v 36%, p 1.0; Infection: 35% v 43%, p 0.5). The rate of SSR was significantly higher in patients with MMF dose reductions due to GI intolerance versus those with dose reductions for non-GI reasons (67% vs 35%, p 0.003). Conclusions: MMF dose reduction due to GI intolerance was associated with a significantly increased rate of sustained rejection compared to patients maintained on target doses or who had dose reduction for non-GI reasons. MMF dose reductions for GI intolerance require careful follow-up due to this increased risk of rejection.