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Heart transplantation (HT) recipients may have tachycardia secondary to cardiac denervation. As higher heart rate predicts worse outcomes in cardiovascular disease, we hypothesized that tachycardia and nonuse of β blockers are associated with increased mortality after HT. All patients who underwent HT at our institution from 1987 to 2010 were included. The association of heart rate 3 months after HT and β-blocker use during follow-up to mortality was assessed using Kaplan–Meier and multivariate Cox proportional hazards regression analyses adjusting for clinically relevant baseline variables. From 1987 to 2010, there were 493 HT. After excluding 29 who died within 3 months and 3 with follow-up <3 months, 461 HT recipients (50 ± 2 years; 20% women) were included. Over a follow-up of 12 ± 7 years, selected important univariate predictors of post-HT mortality were older age, male gender, higher body mass index, ischemic cardiomyopathy, longer post-HT intensive care unit stay, and hospitalization and at 3 months, increased mean pulmonary artery pressure, right atrial pressure and pulmonary capillary occlusion pressure, higher heart rate, and nonuse of β blockers during follow-up. In multivariate analysis, older ager, longer hospitalization, higher mean pulmonary artery pressure, higher heart rate at 3 months (hazard ratio 1.02 per beat, 95% confidence interval 1.008 to 1.035, p = 0.02) and nonuse of β blockers (hazard ratio 1.43, 95% confidence interval 1.002 to 2.031, p <0.05) were associated with mortality. In conclusion, in a large single-center cohort of HT recipients, higher heart rate and nonuse of β blockers were independently associated with higher mortality.

Sudden cardiac death (SCD) is the most devastating complication of hypertrophic cardiomyopathy (HCM), but this can be prevented by an implantable cardioverter-defibrillator (ICD). The aim of this study is to evaluate HCM patients with ICDs for primary or secondary prevention of SCD. The study population consisted of all HCM patients with an ICD in 2 tertiary referral clinics. End points during follow-up were total and cardiac mortality, appropriate and inappropriate ICD intervention, and device-related complications. Cox-regression analysis was performed to identify predictors of outcome. ICDs were implanted in 134 patients with HCM (mean age 44 ± 17 years, 34% women, 4.2 ± 4.8 years follow-up). Annualized cardiac mortality rate was 3.4% per year and associated with New York Heart Association class III or IV (HR 5.2 [2.0-14, P = .002]) and cardiac resynchronization therapy (HR 6.3 [2.1-20, P = .02]). Appropriate ICD interventions occurred in 38 patients (6.8%/year) and was associated with implantation for secondary prevention of SCD (HR 4.0 [1.8-9.1], P = .001) and male gender (HR 3.3 [1.2-9.0], P = .02). Inappropriate ICD intervention occurred in 21 patients (3.7%/year) and in 20 patients device related complications were documented (3.6%/year). ICDs successfully abort life-threatening arrhythmias in HCM patients at increased risk of SCD with an annualized intervention rate of 6.8% per year. End-stage heart failure is the main cause of mortality in these patients. The annualized rate of inappropriate ICD intervention was 3.7% per year, whereas device-related complications occurred 3.6% per year.

Background and Objective Tacrolimus is an immunosuppressant commonly administered after solid organ transplantation. It is characterized by a narrow therapeutic window and high variability in exposure, demanding personalized dosing. In recent years, population pharmacokinetic models have been suggested to guide model-informed precision dosing of tacrolimus. We aimed to provide a comprehensive overview of population pharmacokinetic models and model-informed precision dosing software modules of tacrolimus in all solid organ transplant settings, including a simulation-based investigation of the impact of covariates on exposure and target attainment. Methods We performed a systematic literature search to identify population pharmacokinetic models of tacrolimus in solid organ transplant recipients. We integrated selected population pharmacokinetic models into an interactive software tool that allows dosing simulations, Bayesian forecasting, and investigation of the impact of covariates on exposure and target attainment. We conducted a web survey amongst model-informed precision dosing software tool providers and benchmarked publicly available tools in terms of models, target populations, and clinical integration. Results We identified 80 population pharmacokinetic models, including 44 one-compartment and 36 two-compartment models. The most frequently retained covariates on clearance and distribution parameters were cytochrome P450 3A5 polymorphisms and body weight, respectively. Our simulation tool, hosted at https://lpmx.shinyapps.io/tacrolimus/ , allows thorough investigation of the impact of covariates on exposure and target attainment. We identified 15 model-informed precision dosing software tool providers, of which ten offer a tacrolimus solution and nine completed the survey. Conclusions Our work provides a comprehensive overview of the landscape of available tacrolimus population pharmacokinetic models and model-informed precision dosing software modules. Our simulation tool allows an interactive thorough exploration of covariates on exposure and target attainment.

Static cold storage (SCS) remains the gold standard for preserving donor hearts before transplantation but is associated with ischaemia, anaerobic metabolism, and organ injuries, leading to patient morbidity and mortality. We aimed to evaluate whether continuous, hypothermic oxygenated machine perfusion (HOPE) of the donor heart is safe and superior compared with SCS. We performed a multinational, multicentre, randomised, controlled, open-label clinical trial with a superiority design at 15 transplant centres across eight European countries. Adult candidates for heart transplantation were eligible and randomly assigned in a 1:1 ratio. Donor inclusion criteria were age 18–70 years with no previous sternotomy and donation after brain death. In the treatment group, the preservation protocol involved the use of a portable machine perfusion system ensuring HOPE of the resting donor heart. The donor hearts in the control group underwent ischaemic SCS according to standard practices. The primary outcome was time to first event of a composite of either cardiac-related death, moderate or severe primary graft dysfunction (PGD) of the left ventricle, PGD of the right ventricle, acute cellular rejection at least grade 2R, or graft failure (with use of mechanical circulatory support or re-transplantation) within 30 days after transplantation. We included all patients who were randomly assigned, fulfilled inclusion and exclusion criteria, and received a transplant in the primary analysis and all patients who were randomly assigned and received a transplant in the safety analyses. This trial was registered with ClicalTrials.gov (NCT03991923) and is ongoing. A total of 229 patients were enrolled between Nov 25, 2020, and May 19, 2023. The primary analysis population included 204 patients who received a transplant. There were no patients who received a transplant lost to follow-up. All 100 donor hearts preserved with HOPE were transplantable after perfusion. The primary endpoint was registered in 19 (19%) of 101 patients in the HOPE group and 31 (30%) of 103 patients in the SCS group, corresponding to a risk reduction of 44% (hazard ratio 0·56; 95% CI 0·32–0·99; log-rank test p=0·059). PGD was the primary outcome event in 11 (11%) patients in the HOPE group and 29 (28%) in the SCS group (risk ratio 0·39; 95% CI 0·20–0·73). In the HOPE group, 63 (65%) patients had a reported serious adverse event (158 events) versus 87 (70%; 222 events) in the SCS group. Major adverse cardiac transplant events were reported in 18 (18%) and 33 (32%) patients in the HOPE and SCS group (risk ratio 0·56; 95% CI 0·34–0·92). Although there was not a significant difference in the primary endpoint, the 44% risk reduction associated with HOPE was suggested to be a clinically meaningful benefit. Post-transplant complications, measured as major adverse cardiac transplant events, were reduced. Analysis of secondary outcomes suggested that HOPE was beneficial in reducing primary graft dysfunction. HOPE in donor heart preservation addresses the existing challenges associated with graft preservation and the increasing complexity of donors and heart transplantation recipients. Future investigation will help to further elucidate the benefit of HOPE. XVIVO Perfusion.

Aims Information on the prevalence, outcome and factors associated with heart failure in patients with adult congenital heart disease (CHD) (ACHD‐HF) is lacking. We aimed at assessing the prevalence and outcome of ACHD‐HF, the variables associated with ACHD‐HF, and the differences between major anatomical/pathophysiological ACHD subgroups. Methods and results We included 3905 patients (age 35.4 ± 13.2 years) under active follow‐up in our institution (last visit >2010). Outcome of ACHD‐HF cases was compared with sex‐ and age‐matched cases. Univariable and multivariable binary logistic regression with ACHD‐HF diagnosis as a dependent variable was performed. Overall prevalence of ACHD‐HF was 6.4% (mean age 49.5 ± 16.7 years), but was higher in patients with cyanotic CHD (41%), Fontan circulation (30%), and a systemic right ventricle (25%). All‐cause mortality was higher in ACHD‐HF cases when compared with controls (mortality rate ratio 4.67 (2.36–9.27); P = 0.0001). In multivariable logistic regression analysis, age at latest follow‐up [per 10 years; odds ratio (OR) 1.52; 95% confidence interval (CI) 1.31–1.77], infective endocarditis (OR 4.11; 95%CI 1.80–9.38), history of atrial arrhythmia (OR 3.52; 95%CI 2.17–5.74), pacemaker implantation (OR 2.66; 95% CI 1.50–4.72), end‐organ dysfunction (OR 2.41; 95% CI 1.03–5.63), New York Heart Association class (OR 9.28; 95% CI 6.04–14.25), heart rate (per 10 bpm; OR 1.27; 95% CI 1.08–1.50), ventricular dysfunction (OR 3.62; 95% CI 2.54–5.17), and pulmonary hypertension severity (OR 1.66; 95% CI 1.21–2.30) were independently related to the presence of ACHD‐HF. Some variables (age, atrial arrhythmia, pacemaker, New York Heart Association, and ventricular dysfunction) were related to ACHD‐HF in all anatomical/physiological subgroups, whereas others were not. Conclusions ACHD‐HF is prevalent especially in complex CHD and is associated with poor prognosis. Our data provide insight in the factors related to ACHD‐HF including differences between specific anatomical and physiological subgroups.

The role of immunosuppressive therapy on SARS-CoV-2 infection risk and COVID-19 severity remains unclear in unvaccinated solid organ transplant recipients. We included 1957 organ transplant recipients between July 2020 and April 2021 to analyze whether baseline immunosuppressive therapy and other risk factors are associated with SARS-CoV-2 infection and severe COVID-19. In total, 247 (12.6%) had SARS-CoV-2 (defined as positive nasopharyngeal swab and/or positive antibody titer). Of these, 57 (23.1%) had severe COVID-19, defined as oxygen supplementation, intensive care unit admission or death. Multivariable analysis identified diabetes (hazard ratio (HR) 1.39 (95% confidence interval (CI) 1.05–1.83)), chronic lung disease (HR 1.71 (95% CI 1.13–2.60)) and contact with a COVID-19 positive individual (HR 3.61 (95% CI 2.61–4.99) as independent risk factors for SARS-CoV-2 infection. There was no association between immunosuppressive therapy and infection risk. Severe COVID-19 was multivariably associated with hypertension (OR 5.45 (95% CI 1.66–17.84)), chronic kidney disease (OR 3.55 (95% CI 1.75–7.19)), corticosteroid use (OR 2.93 (95% CI 1.03–2.55)) and having a COVID-19 positive housemate (OR 6.77 (95% CI 2.65–17.28)). In conclusion, baseline corticosteroid use, but no other immunosuppressive agent, is independently associated with severe COVID-19 in unvaccinated SOT recipients after correction for hypertension, chronic kidney disease, housemates affected by COVID-19 and transplant type.

ObjectivesAs prognosis in sarcoidosis is determined by cardiac involvement, the objective was to study the added value of cardiovascular magnetic resonance (CMR) in risk stratification.MethodsIn 114 patients (48 ± 12 years/52% male) with biopsy-proven sarcoidosis, we studied the value of clinical and CMR-derived parameters to predict future events, using sustained ventricular tachycardia, ventricular fibrillation, aborted cardiac death, implantable cardioverter-defibrillator (ICD) placement with appropriate shocks, hospitalization for heart failure, and death as composite endpoint. Median follow-up after CMR was 3.1 years (1.1–5.7 years).ResultsThe ejection fraction (EF) was 58.2 ± 9.1% and 54.7 ± 10.8% for left ventricle (LV) and right ventricle (RV), respectively. LV late gadolinium enhancement (LGE) was present in 40 patients (35%) involving 5.1% of the LV mass (IQR, 3.0–12.0%), with concomitant RV involvement in 12 patients (11%). T2-weighting imaging and/or T2 mapping showed active disease in 14 patients. The composite endpoint was reached in 34 patients, with 7 deaths in the LGE-positive group (17.5%), versus two deaths in the LGE-negative group (2.7%) (p = 0.015). At univariate analysis, RVEF (p = 0.009), pulmonary arterial pressure (p = 0.002), and presence of LGE (p < 0.001) and LGE (% of LV) (p < 0.001) were significant. At multivariate analysis, only presence of LGE and LGE (% of LV) was significant (both p = 0.03). At Kaplan-Meier, presence of LGE and an LGE of 3% predicted event-free survival and patient survival. We found no difference in active versus inactive disease with regard to patient survival.ConclusionMyocardial enhancement at LGE-CMR adds independent prognostic value in risk stratification sarcoidosis patients. In contrast, clinical as well as functional cardiac parameters lack discriminative power.Key Points• Sarcoidosis often affects the heart.• Comprehensive CMR, including T2 imaging and LGE enhancement CMR, allows to depict both active and inactive myocardial damage.• Patient prognosis in sarcoidosis is determined by the presence and severity of myocardial involvement at LGE CMR.

In inherited primary arrhythmia syndromes (PAS) and cardiomyopathies (CMP), the yield of genetic testing varies between 20 and 75% in different diseases according to studies performed in the pre next-generation sequencing (NGS) era. It is unknown whether retesting historical negative samples with NGS techniques is worthwhile. Therefore, we assessed the value of NGS-based panel testing in previously genotype negative-phenotype positive probands. We selected 107 patients (47 PAS and 60 CMP) with a clear phenotype who remained genotype negative after genetic analysis of the main genes implicated in their specific phenotype. Targeted sequencing of the coding regions of 71 PAS- and CMP-related genes was performed. Variant interpretation and classification was done according to a cardiology-specific scoring algorithm ('Amsterdam criteria') and the ACMG-AMP criteria. Co-segregation analysis was performed when DNA and clinical data of family members were available. Finally, a genetic diagnosis could be established in 21 patients (20%), 5 PAS (11%) and 16 CMP (27%) patients, respectively. The increased detection rate was due to sequencing of novel genes in 52% of the cases and due to technical failures with the historical analysis in 48%. A total of 118 individuals were informed about their carrier state and either reassured or scheduled for proper follow-up. To conclude, genetic retesting in clinically overt PAS and CMP cases, who were genotype negative with older techniques, resulted in an additional genetic diagnosis in up to 20% of the cases. This clearly supports a policy for genetic retesting with NGS-based panels.

Objectives Symptoms in patients with chronic thromboembolic pulmonary hypertension (CTEPH) predominantly occur during exercise, while haemodynamic assessment is generally performed at rest. We hypothesised that exercise imaging of RV function would better explain exercise limitation and the acute effects of pulmonary vasodilator administration than resting measurements. Methods Fourteen patients with CTEPH and seven healthy control subjects underwent cardiopulmonary testing to determine peak exercise oxygen consumption (VO2peak) and ventilatory equivalent for carbon dioxide (VE/VCO2) at the anaerobic threshold. Subsequently, cardiac MRI was performed at rest and during supine bicycle exercise with simultaneous invasive measurement of mean pulmonary arterial pressure (mPAP) before and after sildenafil. Results During exercise, patients with CTEPH had a greater increase in the ratio of mPAP relative to cardiac output (CO) than controls (6.7 (5.1–8.7) vs 0.94 (0.86–1.8) mm Hg/L/min; p<0.001). Stroke volume index (SVi) and RVEF increased during exercise in controls, but not in patients with CTEPH (interaction p<0.001). Sildenafil decreased the mPAP/CO slope and increased SVi and RVEF in patients with CTEPH (p<0.05) but not in controls. In patients with CTEPH, RVEF reserve correlated moderately with VO2peak (r=0.60; p=0.030) and VE/VCO2 (r=−0.67; p=0.012). By contrast, neither VO2peak nor VE/VCO2 correlated with resting RVEF. Conclusions Exercise measures of RV function explain much of the variance in the exercise capacity of patients with CTEPH while resting measures do not. Sildenafil increases SVi during exercise in patients with CTEPH, but not in healthy subjects.

Abstract Background Transthyretin (ATTR) amyloidosis is more prevalent than initially thought. As much as 13% of patients hospitalized with heart failure with preserved ejection fraction may have ATTR-cardiomyopathy (CM). Conversely, heart transplant patients may manifest left ventricular hypertrophy or diastolic dysfunction, especially late after transplantation. Case summary We present a case of a 82-year-old male heart transplant patient, 31 years following orthotopic heart transplantation. While he was satisfied with his exercise capacity as an octogenarian, several years before, he required pacemaker implantation due to third-degree atrioventricular block, had bilateral carpal tunnel syndrome treated with carpal tunnel release surgery, and experienced idiopathic sudden deafness. Based on increasing left ventricular wall thickness during routine follow-up, a diagnosis of ATTR amyloidosis was suspected. Ultimately, the diagnosis was confirmed non-invasively with a specific scintigraphic exam, while an additional physicochemical stain on an endomyocardial biopsy taken several years before provided pathological proof. We initiated tafamidis, yet stopped this treatment after 1 month because of gastrointestinal intolerance. Ultimately, our patient died 2 years later due to heart failure. Discussion Our case shows the long delay between the onset of ATTR deposition, the presence of clinical signs, and the final diagnosis. Echocardiographic findings suggestive for ATTR-CM include left ventricular hypertrophy and diastolic dysfunction, which are both common in heart transplant patients. Yet, ATTR-CM should be considered in the differential diagnosis, especially late after transplantation, in this closely monitored population.