Late diagnosis of Marfan syndrome is associated with unplanned aortic surgery and cardiovascular death.

BACKGROUND: Marfan syndrome (MFS) guidelines recommend optimal pharmacological therapy (OPT) and replacement of the ascending aorta (RAA) at 5.0cm diameters to prevent acute type A aortic dissection (ATAAD) and death. The effect of early MFS diagnosis and initiation of therapy on outcomes is not known. OBJECTIVE: To evaluate the effect of age at MFS diagnosis and therapy initiation on delayed RAA and death. METHODS: This retrospective observational cohort study with long-term follow-up included consecutive patients with MFS, pathogenic FBN1 variant, and regular visits to a European Reference Network Center. We considered MFS diagnosis at age ≥21 years late, and OPT initiation at age <21 years early. Outcomes were delayed RAA with aneurysm diameter >5.0cm or ATAAD, and death from all causes. We used landmark design starting at age 21 years to determine associations with outcomes. RESULTS: The study group consisted of 288 patients (45.1% male), including 169 patients with late MFS diagnosis (58.7%) and 63 with early OPT (21.9%). During mean follow-up of 25±14.7 years, 78 patients had delayed RAA, with 42 operations for ATAAD and 36 for aneurysms ≥5.0cm. There were 33 deaths, including 11 deaths late after ATAAD. All deaths were cardiovascular. Late diagnosis, but not early OPT, showed univariate association with delayed RAA (P<0.001) and death (P=0.025). Multivariate Cox regression analysis confirmed late diagnosis as predictor of delayed RAA (hazard ratio (HR)=8.01; 95% confidence interval (95%CI) 2.52-25.45; P<0.001) and death (HR=4.68; 95%CI 1.17-18.80; P=0.029). CONCLUSIONS: Late diagnosis of Marfan syndrome is associated with delayed surgery and death.

A Retrospective Analysis of 10-year Experience on Branched and Fenestrated Endovascular Aortic Arch Repair.

OBJECTIVE: This study aimed to present the early and mid-term outcomes of fenestrated/branched thoracic endovascular aortic repair (f/bTEVAR) for aortic arch pathologies. BACKGROUND: f/bTEVAR represents a less invasive treatment option for aortic arch diseases. Previous published series showed decreased early mortality and morbidity compared to open repair. METHODS: A single-center retrospective analysis of consecutive patients, managed with f/bTEVAR (Cook Medical, Bloomington, IN, USA) between 01.09.11and 30.06.22 was conducted. Primary outcomes were technical success, 30-day mortality and stroke. Data during follow-up and factors affecting early mortality and stroke were analyzed. RESULTS: 209 patients were included (38.3% females; mean age 69.8±3.4years; mean aortic diameter 61±4.7 mm); 14.4% were managed urgently. Fenestrations/scallop configuration was used in 39.7%, branched devices in 55.5% and branch/scallop combination in 4.8%. Landing to zone 0 was performed in 65.5% and in zone 1 in 32.1%. Non-native aortas were used for landing in 39.2%. Technical success was 97.1% and 30-day mortality 9.5%. Strokes were identified in 10%; 5.7% major. Non-native proximal aortic landing zone was an independent protective factor for stroke (P=0.002). Post-operative stroke (P<0.001) and pericardial effusion (P<0.001) were independently related to 30-day mortality. The mean follow-up was 21±8 months. The estimated survival and freedom from reintervention rates were 79.5% (standard error; SE3.1%) and 47.1% (SE 4.3%) at 24months, respectively. CONCLUSIONS: f/bTEVAR presented high technical success and acceptable 30-day mortality. Non-native proximal landing zone was related to lower stroke rate. Half of patients needed a reintervention within the 24-month follow-up.

Heart Rate Reduction and Outcomes in Heart Failure Outpatients.

Aim. Pharmacologic reduction in heart rate with beta-blockers (BB) or ivabradine is associated with improved survival in heart failure (HF) with sinus rhythm. We analyzed the association of different heart rate-reducing drug treatments on outcomes in HF outpatients. Methods. Consecutive patients with HF in sinus rhythm referred to a specialized tertiary service were prospectively enrolled from August 2015 until March 2018. Clinical characteristics were assessed at baseline. We performed Cox regression analyses to examine the effect of the resting heart rate and different heart rate-reducing drug regimens on all-cause mortality and a composite endpoint of "all-cause mortality or heart transplantation" over a mean follow-up of 3.1 years. Results. Of the 278 patients included, 213 (76.6%) were male, the median age was 57.0 years (IQR 49.0-66.1), and 185 (73.7%) had an ejection fraction <40%. Most patients received BB in submaximal [n = 118] or maximum dose [n = 136]. Patients on BB in maximum dose plus ivabradine [n = 24] were younger (53.0 vs. 58.0 years) and had a lower EF (25 vs. 31%). Higher resting heart rate was associated with an increased risk of death or transplantation (HR 1.03 [1.01, 1.06], p = 0.0072), even after adjusting for age and sex. There were no differences between the groups concerning all-cause mortality or the composite endpoint. Conclusion. Our prospective study confirms the association between low heart rate and survival in HF patients receiving various heart rate-reducing medications. We could not identify a specific effect of either regimen.

Supervised exercise training in patients with advanced heart failure and left ventricular assist device: A multicentre randomized controlled trial (Ex-VAD trial).

AIMS: Small studies and observations suggested that exercise training may improve peak oxygen consumption (peakVO2 ) in patients with advanced heart failure and left ventricular assist device (LVAD). We investigated whether in this patient group a supervised exercise training can improve exercise capacity. METHODS AND RESULTS: In this multicentre, prospective, randomized, controlled trial, patients with stable heart failure and LVAD were randomly assigned (2:1) to 12 weeks of supervised exercise training or usual care, with 12 weeks of follow-up. The primary endpoint was the change in peakVO2 after 12 weeks (51 patients provided a power of 90% with an expected group difference in peakVO2 of 3 ml/kg/min). Secondary endpoints included changes in submaximal exercise capacity and quality of life. Among 64 patients enrolled (97% male, mean age 56 years), 54 were included in the analysis. Mean difference in the change of peakVO2 after 12 weeks was 0.826 ml/min/kg (95% confidence interval [CI] -0.37, 2.03; p = 0.183). There was a positive effect of exercise training on 6-min walk distance with a mean increase in the intervention group by 43.4 m (95% CI 16.9, 69.9; p = 0.0024), and on the Kansas City Cardiomyopathy Questionnaire physical domain score (mean 14.3, 95% CI 3.7, 24.9; p = 0.0124), both after 12 weeks. The overall adherence was high (71%), and there were no differences in adverse events between groups. CONCLUSION: In patients with advanced heart failure and LVAD, 12 weeks of exercise training did not improve peakVO2 but demonstrated positive effects on submaximal exercise capacity and physical quality of life.

Physical and Mental Recovery after Aortic Valve Surgery in Non-Elderly Patients: Native Valve-Preserving Surgery vs. Prosthetic Valve Replacement.

Background: Exercise capacity and patient-reported outcomes are increasingly considered crucial following aortic valve (AV) surgery in non-elderly adults. We aimed to prospectively evaluate the effect of native valve preservation compared with prosthetic valve replacement. Methods: From October 2017 to August 2020, 100 consecutive non-elderly patients undergoing surgery for severe AV disease were included. Exercise capacity and patient-reported outcomes were evaluated upon admission, and 3 months and 1 year postoperatively. Results: In total, 72 patients underwent native valve-preserving procedures (AV repair or Ross procedure, NV group), and 28 patients, prosthetic valve replacement (PV group). Native valve preservation was associated with an increased risk of reoperation (weighted hazard ratio: 10.57 (95% CI: 1.24-90.01), p = 0.031). The estimated average treatment effect on six-minute walking distance in NV patients at 1 year was positive, but not significant (35.64 m; 95% CI: -17.03-88.30, adj. p = 0.554). The postoperative physical and mental quality of life was comparable in both groups. Peak oxygen consumption and work rate were better at all assessment time points in NV patients. Marked longitudinal improvements in walking distance (NV, +47 m (adj. p < 0.001); PV, +25 m (adj. p = 0.004)) and physical (NV, +7 points (adj. p = 0.023); PV, +10 points (adj. p = 0.005)) and mental quality of life (NV, +7 points (adj. p < 0.001); PV, +5 points (adj. p = 0.058)) from the preoperative period to the 1-year follow-up were observed. At 1 year, there was a tendency of more NV patients reaching reference values of walking distance. Conclusions: Despite the increased risk of reoperation, physical and mental performance markedly improved after native valve-preserving surgery and was comparable to that after prosthetic aortic valve replacement.

SARS-CoV-2 Vaccination-Induced Immunogenicity in Heart Transplant Recipients.

Among heart transplant (HT) recipients, a reduced immunological response to SARS-CoV-2 vaccination has been reported. We aimed to assess the humoral and T-cell response to SARS-CoV-2 vaccination in HT recipients to understand determinants of immunogenicity. HT recipients were prospectively enrolled from January 2021 until March 2022. Anti-SARS-CoV-2-Spike IgG levels were quantified after two and three doses of a SARS-CoV-2 vaccine (BNT162b2, mRNA1273, or AZD1222). Spike-specific T-cell responses were assessed using flow cytometry. Ninety-one patients were included in the study (69% male, median age 55 years, median time from HT to first vaccination 6.1 years). Seroconversion rates were 34% after two and 63% after three doses. Older patient age (p = 0.003) and shorter time since HT (p = 0.001) were associated with lower antibody concentrations after three vaccinations. There were no associations between vaccine types or immunosuppressive regimens and humoral response, except for prednisolone, which was predictive of a reduced response after two (p = 0.001), but not after three doses (p = 0.434). A T-cell response was observed in 50% after two and in 74% after three doses. Despite three vaccine doses, a large proportion of HT recipients exhibits a reduced immune response. Additional strategies are desirable to improve vaccine immunogenicity in this vulnerable group of patients.

Sleep apnea predicts cardiovascular death in patients with Marfan syndrome: a cohort study.

Background: Surgical replacement of the aortic root is the only intervention that can prevent aortic dissection and cardiovascular death in Marfan syndrome (MFS). However, in some individuals, MFS also causes sleep apnea. If sleep apnea predicts cardiovascular death, a new target for predictive, preventive, and personalized medicine (PPPM) may emerge for those individuals with MFS who have sleep apnea. Methods: This is an investigator-initiated study with long-term follow-up data of 105 individuals with MFS. All individuals were screened for sleep apnea regardless of symptoms. Cardiovascular death served as a primary endpoint, and aortic events as a secondary outcome. Results: Sleep apnea with an apnea-hypopnea index (AHI) > 5/h was observed in 21.0% (22/105) with mild sleep apnea in 13% (14/105) and moderate to severe sleep apnea in 7.6% (8/105). After a median follow-up of 7.76 years (interquartile range: 6.84, 8.41), 10% (10/105) had died, with cardiovascular cause of death in 80% (8/10). After adjusting for age and body mass index (BMI), the AHI score emerged as an independent risk factor for cardiovascular death (hazard ratio 1.712, 95% confidence interval [1.061-2.761], p = 0.0276). The secondary outcome of aortic events occurred in 33% (35/105). There was no effect of the AHI score on aortic events after adjusting for age and BMI (hazard ratio 0.965, 95% confidence interval [0.617-1.509]), possibly due to a high number of patients with prior aortic surgery. Interpretation: Sleep apnea is emerging as an independent predictor of cardiovascular death in MFS. It seems mandatory to screen all individuals with MFS for sleep apnea and to include these individuals, with both MFS and sleep apnea, in further studies to evaluate the impact of preventive measures with regard to cardiovascular death. Supplementary Information: The online version contains supplementary material available at 10.1007/s13167-022-00291-4.

Concomitant cardiovascular malformations in isolated bicuspid aortic valve disease: a retrospective cross-sectional study and meta-analysis.

Background: Congenital bicuspid aortic valve affects up to 2% of the general population. It occurs in complex congenital heart defects or in syndromes such as Turner, Marfan, or Loeys-Dietz. However, the majority of bicuspid aortic valves are considered to manifest as isolated malformations. Methods: We aimed to assess retrospectively associated cardiovascular malformations in 200 individuals with bicuspid aortic valve considered to occur as an isolated manifestation. All individuals underwent transthoracic echocardiography, 164 thoracoabdominal tomographic imaging, and 84 coronary artery imaging. In addition, we also performed a meta-analysis of data from the literature to assess the occurrence of associate malformations. Results: In our retrospective cross-sectional study collective, the mean age was 45±15 years, 154 (77%) individuals were male. Anatomy of bicuspid aortic valve according to Schaefer was type 1 in 142 (71%), type 2 in 35 (18%), type 3 in 2 (1%), unicuspid in 6 (3%), and unclassified in 15 (8%) individuals. Coarctation of the aorta had 4.2% of individuals, 3.6% had coronary anomalies. No individual had a patent ductus arteriosus, 0.5% had atrial and ventricular septal defect each, 1.5% mitral valve prolapse. No individual had a tricuspid valve prolapse. Our meta-analysis identified in cohorts with isolated bicuspid aortic valve 11.8% (95% CI: 7.7-16.0%) individuals with aortic coarctation, 3.7% (95% CI: 1.2-6.1%) with coronary anomalies, 3.3% (95% CI: 0.0-6.7%) with patent ductus arteriosus, 5.9% (95% CI: 1.3-10.5%) with ventricular septal defect and 1.6% (95% CI: 1.1-2.1%) with mitral valve prolapse. Conclusions: Individuals with isolated bicuspid aortic valve may exhibit a variety of associated cardiovascular malformations and therefore screening for associated malformations may be warranted.

Gender differences in characteristics and outcomes in heart failure patients referred for end-stage treatment.

AIMS: Despite signals from clinical trials and mechanistic studies implying different resilience to heart failure (HF) depending on gender, the impact of gender on presentation and outcomes in patients with HF remains unclear. This study assessed the impact of gender on clinical presentation and outcomes in patients with HF referred to a specialised tertiary HF service. METHODS AND RESULTS: Consecutive patients with HF referred to a specialised tertiary HF service offering advanced therapy options including left ventricular assist devices (LVAD) and heart transplantation were prospectively enrolled from August 2015 until March 2018. We assessed clinical characteristics at baseline and performed survival analyses and age-adjusted Cox regression analyses in men vs. women for all-cause death and a combined disease-related endpoint comprising death, heart transplantation, and LVAD implantation. Analyses were performed for the overall study population and for patients with HF with reduced ejection fraction (HFrEF). Of 356 patients included, 283 (79.5%) were male. The median age was 58 years (interquartile range 50-67). Two hundred and fifty-one (74.5%) patients had HFrEF. HF aetiology, ejection fraction, functional status measures, and most of the cardiac and non-cardiac comorbidities did not differ between men and women. In a median follow-up of 3.2 years, 50 patients died (45 men, 5 women), 15 patients underwent LVAD implantation, and 8 patients heart transplantation. While all-cause death was not significantly different between both genders in the overall population [16.9 vs. 6.0%, P = 0.065, hazard ratio (HR) 2.29 (95% confidence interval 0.91-5.78), P = 0.078], in the HFrEF subgroup, a significant difference between men and women was observed [20.7% vs. 3.9%, P = 0.017, HR 3.67 (95% confidence interval 1.13-11.91), P = 0.031]. The combined endpoint was more often reached in men than in women in both the overall population [21.6% vs. 9.0%, P = 0.053, HR 2.51 (1.08-5.82), P = 0.032] and the HFrEF subgroup [27.1% vs. 7.7%, P = 0.015, HR 3.58 (1.29-9.94), P = 0.014]. CONCLUSIONS: Patients referred to a specialised tertiary HF service showed a similar clinical profile without relevant gender differences. In the mid-term follow-up, more male than female patients died or underwent heart transplantation and LVAD implantation. These findings call for independent validation and for further research into gender-specific drivers of HF progression.

Hepatitis E virus persists in the ejaculate of chronically infected men.

BACKGROUND & AIMS: Hepatitis E virus (HEV) infections are prevalent worldwide. Various viruses have been detected in the ejaculate and can outlast the duration of viremia, indicating replication beyond the blood-testis barrier. HEV replication in diverse organs, however, is still widely misunderstood. We aimed to determine the occurrence, features and morphology of HEV in the ejaculate. METHODS: The presence of HEV in testis was assessed in 12 experimentally HEV-genotype 3-infected pigs. We further tested ejaculate, urine, stool and blood from 3 chronically HEV genotype 3-infected patients and 6 immunocompetent patients with acute HEV infection by HEV-PCR. Morphology and genomic characterization of HEV particles from various human compartments were determined by HEV-PCR, density gradient measurement, immune-electron microscopy and genomic sequencing. RESULTS: In 2 of the 3 chronically HEV-infected patients, we observed HEV-RNA (genotype 3c) in seminal plasma and semen with viral loads >2 logs higher than in the serum. Genomic sequencing showed significant differences between viral strains in the ejaculate compared to stool. Under ribavirin-treatment, HEV shedding in the ejaculate continued for >9 months following the end of viremia. Density gradient measurement and immune-electron microscopy characterized (enveloped) HEV particles in the ejaculate as intact. CONCLUSIONS: The male reproductive system was shown to be a niche of HEV persistence in chronic HEV infection. Surprisingly, sequence analysis revealed distinct genetic HEV variants in the stool and serum, originating from the liver, compared to variants in the ejaculate originating from the male reproductive system. Enveloped HEV particles in the ejaculate did not morphologically differ from serum-derived HEV particles. LAY SUMMARY: Enveloped hepatitis E virus particles could be identified by PCR and electron microscopy in the ejaculate of immunosuppressed chronically infected patients, but not in immunocompetent experimentally infected pigs or in patients with acute self-limiting hepatitis E.

Assessing palliative care need in left ventricular assist device patients and heart transplant recipients.

OBJECTIVES: Palliative care (PC) has gained rising attention in a holistic treatment approach to chronic heart failure (HF). It is unclear whether there is a need for PC in left ventricular assist device (LVAD) patients or heart transplant recipients. METHODS: In a cross-sectional explorative pilot study, outpatients after heart transplantation (HTx, n = 69) or LVAD implantation (n = 21) underwent screening for palliative care (PC) need and evaluation of symptom burden and psychological distress using tools that emanated from palliative cancer care. RESULTS: The 'Palliative Care Screening Tool for Heart Failure Patients' revealed scores of 4.3 ± 2.2 in HTx and 6.0 ± 2.1 in LVAD patients (max. 12 points, P = 0.003), indicating the need for PC (≥5 points) in 32% of HTx and 67% of LVAD patients. Symptom burden, as assessed by MIDOS ('Minimal Documentation System for Palliative Care') scores was substantial in both groups (4.9 ± 4.7 in HTx vs 6.6 ± 5.3 in LVAD, max. 30 points, P = 0.181). 'Fatigue', 'weakness' and 'pain' were the most frequent symptoms. Using the 'Distress-Thermometer', 'clinically relevant' distress was detected in 57% of HTx and 47% of LVAD patients (P = 0.445). In the PHQ-4 ('4-Item Patient Health Questionnaire'), 45% of LVAD patients, compared to only 10% of HTx patients, reported mild symptoms of anxiety and depression. CONCLUSIONS: Findings reveal substantial need for PC in LVAD patients and, to a lesser extent, in heart transplant recipients, suggesting that multi-disciplinary PC should be introduced into routine aftercare.

Left Ventricular Assist Device Implantation and Concomitant Dor Procedure: a Single Center Experience.

OBJECTIVE: Left ventricular assist device (LVAD) implantation with concomitant Dor plasty is only reported anecdotally. We herein aimed to describe our experience with LVAD and concomitant Dor procedures and describe long-term outcomes of this special subset of heart failure patients. METHODS: Between January/2010 and December/2018, 144 patients received LVAD therapy at our institution. Of those, five patients (80% male, 60.4±7.2 years) presented with an apical aneurysm and received concomitant Dor plasty. Apical aneurysms presented diameter between 75 and 98 mm, with one impending rupture. RESULTS: Procedural success was achieved in all patients. No unplanned right ventricular assist device implantation occurred. Furthermore, no acute 30-day mortality was seen. In follow-up, one patient was lost due to intentional disconnection of the driveline. One patient underwent heart transplantation on postoperative day 630. The remaining three patients are still on device with sufficient flow; pump thromboses were successfully managed by lysis therapy in one patient. CONCLUSION: LVAD implantation with concomitant Dor procedure is feasible, safe, and occasionally performed in patients with ischemic cardiomyopathy. Major advantages are prevention of thromboembolism and facilitation of LVAD placement by improving pump stability and warranting midventricular, coaxial alignment of the inflow cannula. In long-term follow-up, no adverse event associated with Dor plasty was observed.

Left ventricular assist device implantation and concomitant dor procedure: a single center experience

Abstract Objective: Left ventricular assist device (LVAD) implantation with concomitant Dor plasty is only reported anecdotally. We herein aimed to describe our experience with LVAD and concomitant Dor procedures and describe long-term outcomes of this special subset of heart failure patients. Methods: Between January/2010 and December/2018, 144 patients received LVAD therapy at our institution. Of those, five patients (80% male, 60.4±7.2 years) presented with an apical aneurysm and received concomitant Dor plasty. Apical aneurysms presented diameter between 75 and 98 mm, with one impending rupture. Results: Procedural success was achieved in all patients. No unplanned right ventricular assist device implantation occurred. Furthermore, no acute 30-day mortality was seen. In follow-up, one patient was lost due to intentional disconnection of the driveline. One patient underwent heart transplantation on postoperative day 630. The remaining three patients are still on device with sufficient flow; pump thromboses were successfully managed by lysis therapy in one patient. Conclusion: LVAD implantation with concomitant Dor procedure is feasible, safe, and occasionally performed in patients with ischemic cardiomyopathy. Major advantages are prevention of thromboembolism and facilitation of LVAD placement by improving pump stability and warranting midventricular, coaxial alignment of the inflow cannula. In long-term follow-up, no adverse event associated with Dor plasty was observed.

Marfan Syndrome Versus Bicuspid Aortic Valve Disease: Comparative Analysis of Obstetric Outcome and Pregnancy-Associated Immediate and Long-Term Aortic Complications.

Pregnancy poses a threat to women with aortopathy. Conclusive data on the obstetric and aortic outcome in this risk collective, especially when it comes to aortic complications in the long term, are still missing. This study offers a comparative analysis of pregnancy-associated outcome in 113 consecutive women with Marfan syndrome or bicuspid aortic valve disease, including 46 ever-pregnant and 37 never-pregnant women with Marfan syndrome, and 23 ever-pregnant and 7 never-pregnant females with bicuspid aortic valve disease. The overall obstetric outcome was comparable between ever-pregnant women with Marfan syndrome and with bicuspid aortic valve disease (p = 0.112). Pregnancy-associated aortic dissection occurred in two women with Marfan syndrome (3%) during a total of 62 completed pregnancies, whereas no single case of aortic event occurred in women with bicuspid aortic valve disease during a total of 36 completed pregnancies (p = 0.530). In the long-term follow-up, aortic dissection occurred in 21% of ever-pregnant women with Marfan syndrome, but in none of the women with bicuspid aortic valve disease (p = 0.022). Proximal aortic surgery was performed with similar frequency in ever-pregnant women with Marfan syndrome and with bicuspid aortic valve disease in the long term (p = 0.252). However, ever-pregnant women with Marfan syndrome were younger when surgery was performed (44 ± 9 vs. 59 ± 7 years; p = 0.041). In Marfan syndrome, long-term growth of the aorta was comparable between ever-pregnant and never-pregnant women. Pregnancy thus exhibited an increased immediate aortic risk only in women with Marfan syndrome, but not in women with bicuspid aortic valve disease. Previous pregnancy did not relate to an increased long-term risk of adverse aortic events in women with Marfan syndrome or with bicuspid aortic valve disease.

Sex differences in preformed panel-reactive antibody levels and outcomes in patients undergoing heart transplantation.

BACKGROUND: Sex differences in panel-reactive antibody (PRA) levels in heart transplant recipients and their association with transplant-related outcomes are mostly unknown. METHODS: In 20 181 (24.7% women) first-time heart transplant recipients included from July 2004 to March 2015 in the prospective Organ Procurement and Transplantation Network (OPTN), we studied sex differences in most recent (mr) and peak (p)PRA and outcomes (graft failure, rejection, cardiac allograft vasculopathy [CAV], retransplantation, and mortality). Median follow-up (all-cause mortality) was 6 years. Analyses are based on OPTN data (March 6, 2017). RESULTS: MrPRA levels were associated with all-cause mortality (hazard ratio, 95% confidence interval: class I 1.03, 1.01-1.04, P < 0.001) and acute rejection (class II 1.08, 1.03-1.14, P = 0.0044). PPRA levels were associated with all-cause mortality (class I 1.02, 1.00-1.04, P = 0.015) and CAV (class II 1.03, 1.01-1.06, P = 0.020). Sex interactions were seen for the association of pPRA and graft failure with a higher risk in women, and for pPRA and CAV with a higher risk in men. CONCLUSIONS: PRA were associated with different transplant-related outcomes in both sexes. However, women with elevated pPRA were shown to be at higher risk for graft failure, whereas higher levels of pPRA were more hazardous for men in developing CAV.

Next-generation sequencing of 32 genes associated with hereditary aortopathies and related disorders of connective tissue in a cohort of 199 patients.

PURPOSE: Heritable factors play an important etiologic role in connective tissue disorders (CTD) with vascular involvement, and a genetic diagnosis is getting increasingly important for gene-tailored, personalized patient management. METHODS: We analyzed 32 disease-associated genes by using targeted next-generation sequencing and exome sequencing in a clinically relevant cohort of 199 individuals. We classified and refined sequence variants according to their likelihood for pathogenicity. RESULTS: We identified 1 pathogenic variant (PV; in FBN1 or SMAD3) in 15 patients (7.5%) and ≥1 likely pathogenic variant (LPV; in COL3A1, FBN1, FBN2, LOX, MYH11, SMAD3, TGFBR1, or TGFBR2) in 19 individuals (9.6%), together resulting in 17.1% diagnostic yield. Thirteen PV/LPV were novel. Of PV/LPV-negative patients 47 (23.6%) showed ≥1 variant of uncertain significance (VUS). Twenty-five patients had concomitant variants. In-depth evaluation of reported/calculated variant classes resulted in reclassification of 19.8% of variants. CONCLUSION: Variant classification and refinement are essential for shaping mutational spectra of disease genes, thereby improving clinical sensitivity. Obligate stringent multigene analysis is a powerful tool for identifying genetic causes of clinically related CTDs. Nonetheless, the relatively high rate of PV/LPV/VUS-negative patients underscores the existence of yet unknown disease loci and/or oligogenic/polygenic inheritance.

HEV-positive blood donations represent a relevant infection risk for immunosuppressed recipients.

BACKGROUND & AIMS: Routine HEV testing of blood products has recently been implemented in Great Britain and the Netherlands. The relevance of transfusion-transmitted HEV infections is still controversially discussed in Europe. METHODS: All blood donations at the University Medical Center Hamburg-Eppendorf were prospectively tested for HEV RNA by pooled PCR from October 2016 to May 2017. Reactive samples were individually retested. Additionally, stored samples from previous donations of positive donors were tested to determine the duration of HEV viraemia. HEV RNA-positive donors and a control cohort were asked to answer a questionnaire. RESULTS: Twenty-three out of 18,737 HEV RNA-positive donors were identified (0.12%). Only two of the positive donors (8.7%) presented with elevated aminotransferases at time of donation (alanine aminotransferase: 192 and 101 U/L). The retrospective analysis of all positive donors revealed that four asymptomatic donors had been HEV viraemic for up to three months with the longest duration of HEV viraemia exceeding four months. Despite the HEV-testing efforts, 14 HEV RNA-positive blood products were transfused into 12 immunocompromised and two immunocompetent patients. One recipient of these products developed fatal acute-on-chronic liver failure complicated by Pseudomonas septicemia. The questionnaire revealed that HEV RNA-positive donors significantly more often consumed raw pork meat (12 out of 18; 67%) than controls (89 out of 256; 35%; p = 0.01). In two donors, undercooked pork liver dishes were identified as the source of infection. HEV genotyping was possible in 7 out of 23 of HEV viraemic donors and six out of seven isolates belonged to HEV Genotype 3, Group 2. CONCLUSIONS: Prolonged HEV viraemia can be detected at a relatively high rate in Northern German blood donors, leading to transfusion-transmitted HEV infections in several patients with the risk of severe and fatal complications. Eating raw pork tartare represented a relevant risk for the acquisition of HEV infection. LAY SUMMARY: The relevance of transfusion-transmitted hepatitis E virus infections has been discussed controversially. Herein, we present the first report on routine hepatitis E virus screening of blood donations at a tertiary care centre in Germany. Hepatitis E viraemia was found at a relatively high rate of 0.12% among blood donors, which represents a relevant transfusion-related risk for vulnerable patient populations.

Gender differences and outcomes in left ventricular assist device support: The European Registry for Patients with Mechanical Circulatory Support.

BACKGROUND: Despite the increasing use of ventricular assist devices (VADs), gender differences in indications, hemodynamics, and outcome are not well understood. We examined gender differences and gender-specific predictors for perioperative outcome in patients on ventricular support. METHODS: Multicenter data of 966 patients (median age 55 years, 151 women) from the European Registry for Patients with Mechanical Circulatory Support (EUROMACS) were analyzed. Median follow-up was 1.26 years. RESULTS: At the time of VAD implantation, women were more often in an unstable condition (Interagency Registry for Mechanically Assisted Circulatory Support [INTERMACS] profile 1 and 2) (51.7% vs 41.6% in men), experiencing significantly more often major bleeding (p = 0.0012), arrhythmias (p = 0.022), and right ventricular (RV) failure (p < 0.001) with need for additional RV support. The survival of women on isolated LVAD support was significantly worse (1-year survival 75.5% vs 83.2% in men). Age-adjusted Cox regression analyses showed significant associations with mortality for preoperative inotropic therapy, percutaneous mechanical support, INTERMACS profile 1 and 2, RV dysfunction, major bleeding, cerebral bleeding, ischemic stroke, and RV failure. In women, pump thrombosis was more strongly related with mortality compared to men, while the direction of the association of renal dysfunction with mortality was different for women and men (p-value interaction 0.028 and 0.023, respectively). CONCLUSIONS: Women and men differ in perioperative hemodynamics, adverse events, and mortality after VAD implantation. A gender-dependent association of pump thrombosis with mortality was seen. The impact on treatment practice needs to be shown.

The transition of pediatric Marfan patients to adult care: a challenge and its risks.

BACKGROUND: Care for patients with Marfan syndrome (MFS) has improved substantially in recent decades. Increasing clinical knowledge and genetic analysis allow early diagnosis of the disease in childhood. Because of the earlier initiation to preventive and medical treatment, patients' life expectancy has risen. To ensure optimal care, pediatric patients require a safe follow-up regime, multidisciplinary care, and a safe transition to adult care. METHODS: We collected a sample of 149 pediatric Marfan patients, of whom 34 patients had already been transferred to adult care or who were currently transitioning. First, we evaluated clinical aspects of patients that manifest in childhood and are present in the transition process. Second, we analyzed the transition process itself. RESULTS: We found age-dependent manifestation of organ pathologies. Dilatation of the sinus of Valsalva showed a particularly high prevalence during the transition process and 62% of patients required medical treatment. Mean onset of aortic root dilatation was 9.9±5.8 years. Concerning systemic manifestation in MFS skin striae, wrist and thumb sign, and reduced elbow extension occurred significantly more often in patients who were transitioning than in younger children with MFS. All other clinical Marfan features showed an increased prevalence in patients who were transitioning compared with younger patients. In our cohort, transition was successful in 20 patients (58.9%), 12 patients (35.3%) are still in the transition process and 2 patients (5.9%) were lost to follow up. CONCLUSIONS: Marfan patients in the transition process are already under a chronic disease condition with a high onset of especially cardiovascular pathologies. Although early medical treatment in childhood is effective, the pathologies of the connective tissue require lifelong attention and influence life in many ways. The big challenge during transition is the double change of responsibility from the parents and pediatric doctor to the patient and adult doctor. Consequently, patients in transition process require special attention and close contact with the doctor and the family. A reevaluation by the supervising pediatric Marfan specialist of the successful transition to adult care is indispensable before the pediatric care of Marfan patients is completed.

Effective treatment with a new protocol using tissue-type plasminogen activator thrombolysis for pump thrombosis with the HVAD device.

BACKGROUND:: Pump thrombosis is a major complication of the continuous flow left ventricular assist device. Pump exchange is seen as the therapeutic gold standard. In this study, we report on our experience with using tissue-type plasminogen activator thrombolysis for therapy of pump thrombosis. METHODS:: We report on our experience with treatment of continuous flow left ventricular assist device pump thrombosis with the HVAD using tissue-type plasminogen activator thrombolysis in nine patients with 16 thrombotic events. In all events we used a uniform treatment protocol. RESULTS:: All patients presented with a sufficient anticoagulation and had symptoms of heart failure. However, all patients were haemodynamically stable. Six of nine patients presented with a mean arterial pressure above 85 mm Hg and every patient presented with an infection. In all events we achieved short-term success with resolution of the pump thrombosis within a median time of nine hours. Three of nine patients developed recurrent pump thrombosis after >60 days. Besides one case of nonfatal intracranial haemorrhage and one case of minor bleeding, there were no adverse events. CONCLUSION:: Our data indicates that using a uniform treatment protocol that builds on usage of tissue-type plasminogen activator thrombolysis might be an effective tool for treatment of continuous flow left ventricular assist device pump thrombosis in haemodynamically stable patients. Additionally, our data indicates that infection may be a potential trigger for pump thrombosis.