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Aims Immunocompromised patients have been excluded from studies of SARS-CoV-2 messenger RNA vaccines. The immune response to vaccines against other infectious agents has been shown to be blunted in such patients. We aimed to analyse the humoral and cellular response to prime-boost vaccination with the BNT162b2 vaccine (Pfizer-BioNTech) in cardiothoracic transplant recipients. Methods and results A total of 50 transplant patients [1–3 years post heart (42), lung (7), or heart–lung (1) transplant, mean age 55 ± 10 years] and a control group of 50 healthy staff members were included. Blood samples were analysed 21 days after the prime and the boosting dose, respectively, to quantify anti-SARS-CoV-2 spike protein (S) immunoglobulin titres (tested by Abbott, Euroimmun and RocheElecsys Immunoassays, each) and the functional inhibitory capacity of neutralizing antibodies (Genscript). To test for a specific T-cell response, heparinized whole blood was stimulated with SARS-CoV-2 specific peptides, covering domains of the viral spike, nucleocapsid and membrane protein, and the interferon-γ release was measured (QuantiFERON Monitor ELISA, Qiagen). The vast majority of transplant patients (90%) showed neither a detectable humoral nor a T-cell response three weeks after the completed two-dose BNT162b2 vaccination; these results are in sharp contrast to the robust immunogenicity seen in the control group: 98% exhibited seroconversion after the prime dose already, with a further significant increase of IgG titres after the booster dose (average > tenfold increase), a more than 90% inhibition capability of neutralizing antibodies as well as evidence of a T-cell responsiveness. Conclusions The findings of poor immune responses to a two-dose BNT162b2 vaccination in cardiothoracic transplant patients have a significant impact for organ transplant recipients specifically and possibly for immunocompromised patients in general. It urges for a review of future vaccine strategies in these patients.

Background We report the results of a prospective study on the immunogenicity of a 3rd dose of BNT162b2 in thoracic organ recipients with no or minimal response following a two-dose BNT162b2 vaccination scheme. Methods A total of 243 transplant recipients received a homologue 3rd dose. Anti-SARS-CoV2-immunoglobulins (IgGs) were monitored immediately before (T1), 4 weeks (T2) as well as 2 and 4 months after the 3rd dose. Neutralizing antibody capacity (NAC) was determined at T2. To reveal predictors for detectable humoral response, patients were divided into a positive response group (n = 129) based on the combined criteria of IgGs and NAC above the defined cut-offs at T2—and a group with negative response (n = 114), with both, IgGs and NAC beyond the cut-offs. Results The 3rd dose induced a positive humoral response in 53% of patients at T2, 47% were still non-responsive. Sero-positivity was significantly stronger in patients who presented with weak, but detectable IgGs already prior to the booster (T1), when compared to those with no detectable response at T1. Multivariable analysis identified age > 55 years, a period since transplantation Conclusions Our data indicate that a lack of immunogenicity is linked to the type and extent of maintenance immunosuppression. The necessity of the cumulative immunosuppressive regimen might individually be questioned and possibly be reduced to enhance the chance of an immune response following an additional booster dose.

Aims Timely referrals for transplantation and left ventricular assist device (LVAD) play a key role in favourable outcomes in patients with advanced heart failure (HF). The purpose of the Catheter Ablation for atrial fibrillation in patientS with end‐sTage heart faiLure and Eligibility for Heart Transplantation (CASTLE‐HTx) trial is to test the hypothesis that atrial fibrillation (AF) ablation has beneficial effects on mortality and morbidity during ‘waiting time’ for heart transplantation (HTx) or to prolong the time span until LVAD implantation. Methods and Results CASTLE‐HTx is a randomized evaluation of ablative treatment of AF in patients with severe left ventricular dysfunction who are candidates and eligible for HTx. The primary endpoint is the composite of all‐cause mortality, worsening of HF requiring a high urgent transplantation, or LVAD implantation. The secondary study endpoints are all‐cause mortality, cardiovascular mortality, cerebrovascular accidents, worsening of HF requiring unplanned hospitalization, AF burden reduction, unplanned hospitalization due to cardiovascular reason, all‐cause hospitalization, quality of life, number of delivered implantable cardioverter defibrillator therapies, time to first implantable cardioverter defibrillator therapy, number of device‐detected ventricular tachycardia/ventricular fibrillation episodes, left ventricular function, exercise tolerance, and percentage of right ventricular pacing. Ventricular myocardial tissue will be obtained from patients who will undergo LVAD implantation or HTx to assess the effect of catheter ablation on human HF myocardium. CASTLE‐HTx will randomize 194 patients over a minimum time period of 2 years. Conclusions CASTLE‐HTx will determine if AF ablation has beneficial effects on mortality in patients with end‐stage HF who are eligible for HTx.

Assessing hemodynamics, especially central venous pressure (CVP), is essential in heart failure (HF). Right heart catheterization (RHC) is the gold-standard, but non-invasive methods are also needed. However, the role of 2-dimensional echocardiography (2DE) remains uncertain, and 3-dimensional echocardiography (3DE) is not always available. This study investigated standardized and breathing-corrected assessment of inferior vena cava (IVC) volume using echocardiography (2DE and 3DE) versus CVP determined invasively using RHC. Sixty consecutive HF patients were included (82% male, age 54 ± 11 years, New York Heart Association class 2.23 ± 0.8, ejection fraction 46 ± 18.4%, brain natriuretic peptide 696.93 ± 773.53 pg/mL). All patients underwent Swan-Ganz RHC followed by 2DE and 3DE, and IVC volume assessment. On 2DE, mean IVC size was 18.3 ± 5.5 mm and 13.8 ± 6 mm in the largest deflection and shortest distention, respectively. Mean CVP from RHC was 9.3 ± 5.3 mmHg. Neither 2DE nor 3DE showed acceptable correlation with invasively measured CVP; IVC volume acquisition showed optimal correlation with RHC CVP (0.64; 95% confidence interval 0.46–0.77), with better correlation when mitral valve early diastole E wave and right ventricular end-diastolic diameter were added. Using a CVP cut-point of 10 mmHg, receiver operating characteristic curve showed true positivity (specificity) of 0.90 and sensitivity of 62% for predicting CVP. A validation study confirmed these findings and verified the high predictive value of IVC volume assessment. Neither 2DE nor 3DE alone can reliably mirror CVP, but IVC volume acquisition using echocardiography allows non-invasive and adequate approximation of CVP. Correlation with invasively measured pressure was strongest when CVP is > 10 mmHg.

Importance: Sodium glucose cotransporter 2 inhibitors reduce morbidity and mortality in patients with heart failure and reduced ejection fraction (HFrEF). Clinicians may find estimates of the projected long-term benefits of sodium glucose cotransporter 2 inhibitors a helpful addition to clinical trial results when communicating the benefits of this class of drug to patients. Objective: To estimate the projected long-term treatment effects of dapagliflozin in patients with HFrEF over the duration of a patient’s lifetime. Design, Setting, and Participants: Exploratory analysis was performed of Dapagliflozin and Prevention of Adverse Outcomes in Heart Failure (DAPA-HF), a phase 3 randomized, placebo-controlled clinical trial conducted at 410 sites in 20 countries. Patients with an ejection fraction less than or equal to 40% in New York Heart Association functional classification II to IV and elevated plasma levels of N-terminal pro B-type natriuretic peptide were enrolled between February 15, 2017, and August 17, 2018, with final follow-up on June 6, 2019. Mean (SD) duration of follow-up was 17.6 (5.2) months. Interventions: Dapagliflozin, 10 mg, once daily vs placebo in addition to standard therapy. Main Outcomes and Measures: The primary composite outcome was time to first hospitalization for heart failure, urgent heart failure visit requiring intravenous therapy, or cardiovascular death. The trial results were extrapolated to estimate the projected long-term treatment effects of dapagliflozin over the duration of a patient’s lifetime for the primary outcome and the secondary outcome of death from any cause. Results: A total of 4744 patients (1109 women [23.4%]; 3635 men [76.6%]) were randomized in DAPA-HF, with a mean (SD) age of 66.3 (10.9) years. The extrapolated mean event-free survival for an individual aged 65 years from a primary composite end point event was 6.2 years for placebo and 8.3 years for dapagliflozin, representing an event-free survival time gain of 2.1 years (95% CI, 0.8-3.3 years; P = .002). When considering death from any cause, mean extrapolated life expectancy for an individual aged 65 years was 9.1 years for placebo and 10.8 years for dapagliflozin, with a gain in survival of 1.7 years (95% CI, 0.1-3.3; P = .03) with dapagliflozin. Similar results were seen when extrapolated across the age range studied. In analyses of subgroups of patients in DAPA-HF, consistent benefits were seen with dapagliflozin on both event-free and overall survival. Conclusions and Relevance: These findings indicate that dapagliflozin provides clinically meaningful gains in extrapolated event-free and overall survival. These findings may be helpful in communicating the benefits of this treatment to patients with HFrEF. Trial registration: ClinicalTrials.gov Identifier: NCT03036124.

Aims Some risk assessment tools have been developed to categorize mortality risk in heart transplant recipients, but it is unclear whether these tools can be used interchangeable in different transplant regions. Methods and results We performed a retrospective single‐centre study in 1049 adult German heart transplant recipients under jurisdiction of Eurotransplant. Univariable and multivariable Cox regression analysis was used to generate a risk scoring system. C‐statistics were used to compare our score with a US score and a French score regarding their ability to discriminate between 1 year survivors and non‐survivors within our study cohort. Of 38 parameters assessed, seven recipient‐specific parameters [age, height, dilated cardiomyopathy (DCM), ischaemic cardiomyopathy (ICM), total bilirubin, extracorporeal membrane oxygenation (ECMO), and biventricular assist device/total artificial heart (BVAD/TAH) implant], one donor‐specific parameter (cold ischaemic time), and one recipient‐independent and donor‐independent other parameter (late transplant era) were statistically significant in predicting 1 year mortality. The initial score was generated by using the regression coefficients from the multivariable analysis as follows: 1.70 * ln age − 4.0 * ln height − 0.9 * diagnosis (= 1 if diagnosis = DCM) − 0.67 * diagnosis (= 1 if diagnosis = ICM) + 0.33 * ln total bilirubin + 1.74 * ln cold ischaemic time + 0.98 * mechanical circulatory support (MCS) implant (= 1 if MCS implant = ECMO) + 0.47 * MCS implant (= 1 of MCS implant = BVAD/TAH) − 0.66 * transplant era (= 1 if transplant era = 2017–2018). The initial score was converted into the Bad Oeynhausen (BO) score as a positive integer variable by means of the following formula: BO score = (initial score + 8) * 3. In patients scoring 2 to

Assessing hemodynamics, especially central venous pressure (CVP), is essential in heart failure (HF). Right heart catheterization (RHC) is the gold-standard, but non-invasive methods are also needed. However, the role of 2-dimensional echocardiography (2DE) remains uncertain, and 3-dimensional echocardiography (3DE) is not always available. This study investigated standardized and breathing-corrected assessment of inferior vena cava (IVC) volume using echocardiography (2DE and 3DE) versus CVP determined invasively using RHC. Sixty consecutive HF patients were included (82% male, age 54 \(\pm\) 11 years, New York Heart Association class 2.23 \(\pm\) 0.8, ejection fraction 46 \(\pm\) 18.4%, brain natriuretic peptide 696.93 \(\pm\) 773.53 pg/mL). All patients underwent Swan-Ganz RHC followed by 2DE and 3DE, and IVC volume assessment. On 2DE, mean IVC size was 18.3 \(\pm\) 5.5 mm and 13.8 \(\pm\) 6 mm in the largest deflection and shortest distention, respectively. Mean CVP from RHC was 9.3 \(\pm\) 5.3 mmHg. Neither 2DE nor 3DE showed acceptable correlation with invasively measured CVP; IVC volume acquisition showed optimal correlation with RHC CVP (0.64; 95% confidence interval 0.46–0.77), with better correlation when mitral valve early diastole E wave and right ventricular end-diastolic diameter were added. Using a CVP cut-point of 10 mmHg, receiver operating characteristic curve showed true positivity (specificity) of 0.90 and sensitivity of 62% for predicting CVP. A validation study confirmed these findings and verified the high predictive value of IVC volume assessment. Neither 2DE nor 3DE alone can reliably mirror CVP, but IVC volume acquisition using echocardiography allows non-invasive and adequate approximation of CVP. Correlation with invasively measured pressure was strongest when CVP is > 10 mmHg.

Diabetes is an independent risk factor for atrial fibrillation (AF). Frequently, it is part of the metabolic syndrome cluster, which includes obesity and hypertension that are independently associated with AF. The risk appears to be higher with longer duration of diabetes and inadequate glycemic control. Patients with diabetes and AF have a substantially increased risk of death and serious cardiovascular complications compared with those in sinus rhythm. Conversely, good metabolic control appears to be associated with maintenance of rhythm after successful therapeutic conversion to sinus rhythm by catheter ablation or electrical cardioconversion of AF. AF puts patients with type 2 diabetes at a high risk of cardiovascular complications and death, which could be successfully addressed by new classes of antidiabetic agents such as incretin analogues or sglt-2 inhibitors. Thus, a diagnostic strategy that addresses the increased risk for AF is urgently recommended, in addition to diabetes monitoring in routine outpatient practice. In order to prevent thromboembolic complications, which frequently determine the prognosis for this patient population, appropriate anticoagulation remains the mainstay of therapy, whereas the prognostic value of reinstalling sinus rhythm awaits further evidence.

Determination of cardiac output (CO) is essential in diagnosis and management of heart failure (HF). The gold standard to obtain CO is invasive assessment via thermodilution (TD). Noninvasive pulse contour analysis (NPCA) is supposed as a new method of CO determination. However, a validation of this method in HF is pending and performed in the present study. Patients with chronic-stable HF and reduced left ventricular ejection fraction (LVEF ≤ 45%; HF-REF) underwent right heart catheterization including TD. NPCA using the CNAP Monitor (V5.2.14, CNSystems Medizintechnik AG) was performed simultaneously. Three standardized TD measurements were compared with simultaneous auto-calibrated NPCA CO measurements. In total, 84 consecutive HF-REF patients were enrolled prospectively in this study. In 4 patients (5%), TD was not successful and for 22 patients (26%, 18 with left ventricular assist device), no NPCA signal could be obtained. For the remaining 58 patients, Bland–Altman analysis revealed a mean bias of + 1.92 L/min (limits of agreement ± 2.28 L/min, percentage error 47.4%) for CO. With decreasing cardiac index, as determined by the gold standard of TD, there was an increasing gap between CO values obtained by TD and NPCA (r = − 0.75, p

Objectives The aim of this study was to assess the outcomes of patients at prohibitive surgical risk undergoing MitraClip therapy (Abbott Vascular, Redwood City, California) for severe mitral regurgitation (MR). Background The safety of percutaneous mitral valve repair has been documented. However, midterm development of mitral valve function, ventricular remodeling, and clinical outcomes in patients not amenable to surgery are unknown. Methods A total of 104 consecutive patients (mean age 74 ± 9 years; 64 men; 49 and 54 with MR 3+ and 4+, respectively; 69 with functional MR; 59 and 45 in New York Heart Association classes III and IV, respectively) were followed for a median of 359 days. Results Device success was achieved in 96 patients (92%). In patients with successful index procedures, MR grade ≤2+ was present at follow-up in 82.5%, left ventricular end-diastolic and -systolic volumes were reduced, and forward stroke volumes were significantly increased. Improvements in New York Heart Association functional class were observed in 80% of patients, with 69% in class I or II; 75% improved in the 6-min walk test; and 74% reported improvements in quality of life. One-year estimates of mortality and rehospitalization were 22% and 31%, respectively. Forward stroke volume at discharge emerged as a predictor of event-free survival. Conclusions MitraClip therapy improves clinical and echocardiographic outcomes at 1 year in about three-quarters of critically ill, elderly patients with moderate to severe MR not amenable to surgery.

Background. Influenza A (H1N1) has emerged as a considerable threat for recipients of organ transplants. Vaccination against the novel influenza A (H1N1) virus has generally been advocated. There is limited experience with AS03-adjuvanted A/H1N1 pandemic influenza vaccines in immunosuppressed patients. Methods. We conducted an observational, nonrandomized single-center study to assess antibody response and vaccine-related adverse effects in 47 heart transplant recipients (44men; age, 56+/-13 years). The AS03-adjuvanted, inactivated split-virion A/California/7/2009 H1N1v pandemic vaccine was administered. Antibody titers were measured using hemagglutination inhibition; immunoglobulin G (IgG) response was assessed using a new pandemic influenza A IgG enzyme-linked immunosorbent assay (ELISA) test kit and compared with hemagglutination-inhibition titers. Adverse effects of vaccination were assessed by a questionnaire. Results. Postvaccination antibody titers of greater than or equal to 1: 40 were found in only 15 patients, corresponding to a seroprotection rate of 32% (95% confidence interval, 19%-47%). Sensitivity, specificity, positive predictive value, and negative predictive value of ELISA testing were 80.0%, 68.8%, 54.5%, and 88.0%, respectively. Age, time posttransplantation, and immunosuppressive regimen did not impact antibody response. Vaccination was well tolerated. Conclusions. Single-dose administration of an AS03-adjuvanted vaccine against the novel influenza A (H1N1) virus did not elicit seroprotective antibody concentrations in a substantial proportion of heart transplant recipients; the new pandemic influenza A IgG ELISA test kit proved to be of limited clinical use.

Aims We sought to assess the feasibility of catheter-based mitral valve repair using the MitraClip system in high-surgical-risk patients with mitral regurgitation (MR) ≥grade 3+. Methods and results MitraClip therapy was performed in 51 consecutive patients [73 ± 10 years; 34 (67%) men] with symptomatic functional [ n = 35 (69%)] or organic MR [ n = 16 (31%)]. Mean logistic EuroSCORE was 29 ± 22%; Society of Thoracic Surgeons score was 15 ± 11. Left ventricular (LV) ejection fraction was 36 ± 17%. In 35 patients (69%), adverse mitral valve morphology and/or severe LV dysfunction were present. MitraClip implantation was successful in 49 patients (96%). Most patients [ n = 34/49 (69%)] were treated with a single clip, whereas 14 patients (29%) received two clips and one patient received three clips. Mean device and fluoroscopy times were 105 ± 65 min and 44 ± 28 min, respectively. Procedure-related reduction in MR severity was one grade in 16 patients (31%), two grades in 24 patients (47%), and three grades in 9 patients (18%). Forty-four of the 49 successfully treated patients (90%) showed clinical improvement at discharge [NYHA functional class ≥III in 48 patients (98%) before and 16 patients (33%) after the procedure ( P < 0.0001)]. There were no procedure-related major adverse events and no in-hospital mortality. Conclusion Mitral valve repair using the MitraClip system was shown to be feasible in patients at high surgical risk primarily determined by an adverse mitral valve morphology and/or severe LV dysfunction.

Vorhofflimmern ist eine haufigste Arrhythmie bei Patienten mit chronischer Herzinsuffizienz, assoziiert mit einer betrachtlichen Morbiditat und Mortalitat.

Treatment of decompensated heart failure often includes administration of levosimendan. Myeloperoxidase (MPO) is released during polymorphonuclear neutrophil (PMN) degranulation and mediates dysregulation of vascular tone in heart failure. We evaluated the effects of levosimendan-treatment on MPO in patients with acute decompensation of chronic heart failure over a one week course. Plasma MPO levels were significantly decreased after levosimendan treatment (from 252.1 ± 31.1 pmol/l at baseline to 215.02 ± 27.96 pmol/l at 6 h, p < 0.05). Ex vivo incubation of whole blood with levosimendan decreased MPO release after PMN-stimulation (8.2 ± 1.4-fold increase at baseline vs. 6.0 ± 1.1-fold increase with levosimendan). MPO levels also significantly correlated with diastolic blood pressure over the time course. In a multivariate linear model, the main contributor to systolic, diastolic and mean blood pressure was level of PMN elastase. MPO contributed only in heparin-treated patients, suggesting a more significant role for endothelial-bound MPO than for circulating MPO or elastase with respect to blood pressure regulation. We here provide the first evidence that levosimendan treatment inhibits MPO release by PMNs in decompensated heart failure patients. This mechanism may regulate endothelial function and vascular tone in heart failure patients.

In this report, transmission of malaria via a liver, a kidney, and possibly a heart allograft from a single donor is described. The donor had immigrated from Cameroon to Germany 18 months before, but had no clinical signs of active malaria infection. The liver transplant recipient and one of the two kidney transplant patients developed febrile illness with the appearance of Plasmodium vivax in blood smears 5 and 6 wk after transplantation, respectively. In the heart transplant recipient, a subclinical malaria infection was suspected based on a rise of malaria antibodies late after transplantation, whereas the recipient of the second kidney allograft had no clinical or laboratory evidence of malaria. Both liver and kidney recipients with active malaria responded to medical treatment. However, the liver transplant patient developed progressive cholestasis and died 5 months after transplantation from liver failure possibly due to side effects of the malaria medication. Other cases of malaria in solid organ recipients are briefly reviewed.