Author Correction: Consistent success in life-supporting porcine cardiac xenotransplantation.

In this Letter, Mayuko Kurome and Valeri Zakhartchenko have been added to the author list (affiliated with Institute of Molecular Animal Breeding and Biotechnology, Gene Center, LMU Munich, Munich, Germany). The author list and 'Author contributions' section have been corrected online; see accompanying Amendment.

Consistent success in life-supporting porcine cardiac xenotransplantation.

Heart transplantation is the only cure for patients with terminal cardiac failure, but the supply of allogeneic donor organs falls far short of the clinical need1-3. Xenotransplantation of genetically modified pig hearts has been discussed as a potential alternative4. Genetically multi-modified pig hearts that lack galactose-α1,3-galactose epitopes (α1,3-galactosyltransferase knockout) and express a human membrane cofactor protein (CD46) and human thrombomodulin have survived for up to 945 days after heterotopic abdominal transplantation in baboons5. This model demonstrated long-term acceptance of discordant xenografts with safe immunosuppression but did not predict their life-supporting function. Despite 25 years of extensive research, the maximum survival of a baboon after heart replacement with a porcine xenograft was only 57 days and this was achieved, to our knowledge, only once6. Here we show that α1,3-galactosyltransferase-knockout pig hearts that express human CD46 and thrombomodulin require non-ischaemic preservation with continuous perfusion and control of post-transplantation growth to ensure long-term orthotopic function of the xenograft in baboons, the most stringent preclinical xenotransplantation model. Consistent life-supporting function of xenografted hearts for up to 195 days is a milestone on the way to clinical cardiac xenotransplantation7.

Hypoxia-inducible factor controls immunoregulatory properties of myeloid cells in mouse cardiac allografts - an experimental study.

Hypoxia-inducible factors (HIFs) play a critical role in inflammatory properties of myeloid-derived cells. The effect of HIFs on myeloid-derived cell functions in organ transplantation remains unknown, however. We transplanted hearts into transgenic mice with myeloid cell-targeted deletions of HIF-1α or its negative regulator von Hippel-Lindau (VHL) to investigate the effects of HIF-1α inactivation or HIF pathway activation, respectively, on ischemia-reperfusion injury (IRI) and acute rejection. Deletion of VHL in myeloid cells enhanced mRNA expression of anti-inflammatory genes IDO, Arg-1, and HO-1 in vitro. In vivo, VHL-/- myeloid-derived cells of allograft recipients alleviated IRI and acute rejection, evidenced by reduced cardiomyocyte damage, decreased proinflammatory cytokine mRNA levels, and absence of inflammatory infiltrate at 5 days after transplantation. Ultimately, allograft survival was significantly prolonged. In vitro, VHL-/- myeloid-derived cells dose-dependently inhibited T-cell proliferation. Myeloid cells with HIF-1α-deletion retained proinflammatory qualities in vitro and in vivo. Deletion of VHL in myeloid cells of nonimmunosuppressed cardiac allograft recipients reduced myocardial injury and acute rejection. We suggest that HIF transcription factors induce a regulatory phenotype in myeloid-derived cells, which may be harnessed as a novel therapeutic strategy to regulate immune responses after heart transplantation.

VEGF Pathways in the Lymphatics of Healthy and Diseased Heart.

Cardiac lymphatic system is a rare focus of the modern cardiovascular research. Nevertheless, the growing body of evidence is depicting lymphatic endothelium as an important functional unit in healthy and diseased myocardium. Since the discovery of angiogenic VEGF-A in 1983 and lymphangiogenic VEGF-C in 1997, an increasing amount of knowledge has accumulated on the essential roles of VEGF ligands and receptors in physiological and pathological angiogenesis and lymphangiogenesis. Tissue adaptation to several stimuli such as hypoxia, pathogen invasion, degenerative process and inflammation often involves coordinated changes in both blood and lymphatic vessels. As lymphatic vessels are involved in the initiation and resolution of inflammation and regulation of tissue edema, VEGF family members may have important roles in myocardial lymphatics in healthy and in cardiac disease. We will review the properties of VEGF ligands and receptors concentrating on their lymphatic vessel effects first in normal myocardium and then in cardiac disease.

Gigantic biatrial myxoma in a young female with an atrial septal defect: a case report.

Background: Myxomas are uncommon and benign cardiac neoplasms that can present with various cardiac, systemic, embolic, or without symptoms depending on their location and size. Very few cases of large, truly biatrial, or tumours connected via the cardiac atria have been reported throughout the years. Case summary: We present an unusual case of an apparently healthy 25-year-old French woman, who presented with dyspnoea at Munich's Octoberfest. Echocardiography and computed tomography identified gigantic masses in left and right atrium, which were connected through an atrial septal defect. They were successfully removed by emergent cardiac surgery. Discussion: This case describes an uncommon tumour and highlights the importance of a quick diagnosis and prompt surgery. We describe the management and surgery for atrial myxomas as well as demonstrating pre- and intraoperative pictures.

Metastatic Penile Squamous Cell Carcinoma: Unmasked by an Acute Myocardial Infarction and Terminal Heart Failure.

A young patient, recently treated for squamous cell penile carcinoma, presented with acute myocardial infarction and severe heart failure. Despite repeatedly ruling out metastatic disease on imaging, surgery for a mechanical assist device revealed unexpected squamous cell metastasis in the pericardium. Consequently, palliative care was initiated.

Redo surgical aortic valve replacement for bioprosthetic structural valve deterioration.

OBJECTIVES: To compare isolated primary bioprosthetic surgical aortic valve replacement (SAVR) with isolated redo surgical aortic valve replacement (rSAVR) due to structural valve deterioration (SVD). METHODS: Clinical data of consecutive patients who underwent primary isolated SAVR and isolated rSAVR due to SVD between 1 January 2011 and 31 December 2022, at Leipzig Heart Center were retrospectively compared with regard to the primary outcome of all-cause mortality or stroke during hospitalization. Secondary outcomes of interest included myocardial infarction, re-exploration for bleeding, and permanent pacemaker implantation. RESULTS: A total of 2620 patients, 39.5% females, with a median EuroSCORE II of 1.7 [interquartile range (IQR) 1.1-2.7] were identified, of which rSAVR was performed in 174 patients (6.6%). Patients undergoing primary SAVR were older (69 vs 67 years of age, P = 0.001) and were less likely to have a history of prior stroke (0.9% vs 4.0%, P = 0.003). Although both all-cause death and death or stroke occurred less often following primary SAVR (0.5% vs 5.8%, and 2.2% vs 6.9%, respectively; P < 0.001), prior surgery was not associated with adverse clinical outcome in multivariable analysis. In a matched comparison of 322 patients, rates of death or stroke did not differ between groups (4.8% for both rSAVR and SAVR, P = 1.0). CONCLUSIONS: Although redo surgery for SVD is associated with increased rates of early mortality and stroke by univariate analysis, much of this increased risk can be accounted for by comorbidities. Patients undergoing rSAVR on an elective basis can expect an outcome similar to that of primary SAVR.

Pre-Implant Immune Status is Associated with Infection Risk After Left Ventricular Assist Device Implantation.

Purpose: Infection is the most common complication after left ventricular assist device (LVAD) implantation. The immune status of LVAD patients is relevant for the incidence and severity of infection, but it is unknown if there is a predisposing immune status prior to LVAD implantation that contributes to an increased risk for infection in the post-implant period. We analyzed the pre-LVAD immune status in patients with infection within 3 months after LVAD implantation in comparison to infection-free patients. Patients and Methods: Fifty-four consecutive LVAD patients were included in this study. According to their infectious history in the first 3 months after LVAD implantation, these patients were grouped into an infection (n=23) and an infection-free group (n=31). Pre-LVAD blood samples were obtained for flow cytometric analysis of immunological parameters including B cells, subsets of T, dendritic and natural killer cells. Patient-specific, clinical and laboratory data were recorded. Results: Blood count analysis prior to LVAD implantation showed comparable counts of erythrocytes (p=0.19), platelets (p=0.33) and leukocytes (p=0.50) between patients with infection and infection-free patients in the post-implant period. Patients with infection in the first 3 months after LVAD implantation had lower concentrations of lymphocytes (p=0.02). Forty percent of the patients with infection showed more often pre-LVAD neutrophil-to-lymphocyte ratios (NLR) >7 than patients without infection in the first 3 months after LVAD implantation (14%, p=0.05). Patients with infection already had lower percentages of CD3+ T cells (p=0.03), CD19+ B cells (p<0.01), BDCA2+ pDCs (p=0.03) and BDCA4+ plasmacytoid DCs (pDCs) (p=0.05) prior to LVAD implantation than infection-free patients. Conclusion: Our results demonstrated that patients with infection in the early post-implant period showed lower concentrations of lymphocytes, especially of CD3+ T cells and CD19+ B cells, decreased percentages of BDCA2+ and BDCA4+ pDCs, and had more often NLRs >7 indicating moderate-to-severe inflammation. Thus, we identified specific immunological changes pre-LVAD that could help to identify patients at risk for infection in the early post-implant period.

The European Registry for Patients with Mechanical Circulatory Support (EUROMACS): fourth Paediatric EUROMACS (Paedi-EUROMACS) report.

OBJECTIVES: The use of ventricular assist devices (VADs) in children is increasing. However, absolute numbers in individual centres and countries remain small. Collaborative efforts such as the Paedi-European Registry for Patients with Mechanical Circulatory Support (EUROMACS) are therefore essential for combining international experience with paediatric VADs. Our goal was to present the results from the fourth Paedi-EUROMACS report. METHODS: All paediatric (<19 years) patients from the EUROMACS database supported by a VAD were included. Patients were stratified into a congenital heart disease (CHD) group and a group with a non-congenital aetiology. End points included mortality, a transplant and recovery. Cox proportional hazard models were used to explore associated factors for mortality, cerebrovascular accident and pump thrombosis. RESULTS: A total of 590 primary implants were included. The congenital group was significantly younger (2.5 vs 8.0 years, respectively, P < 0.001) and was more commonly supported by a pulsatile flow device (73.5% vs 59.9%, P < 0.001). Mortality was significantly higher in the congenital group (30.8% vs 20.4%, P = 0.009) than in the non-congenital group. However, in multivariable analyses, CHD was not significantly associated with mortality [hazard ratio (HR) 1.285; confidence interval (CI) 0.8111-2.036, P = 0.740]. Pump thrombosis was the most frequently reported adverse event (377 events in 132 patients; 0.925 events per patient-year) and was significantly associated with body surface area (HR 0.524, CI 0.333-0.823, P = 0.005), CHD (HR 1.641, CI 1.054-2.555, P = 0.028) and pulsatile flow support (HR 2.345, CI 1.406-3.910, P = 0.001) in multivariable analyses. CONCLUSIONS: This fourth Paedi-EUROMACS report highlights the increasing use of paediatric VADs. The patient populations with congenital and non-congenital aetiologies exhibit distinct characteristics and clinical outcomes.

Coronary Sparing Aneurysmectomy.

Repairing left ventricular aneurysms that form after myocardial infarction may be challenging, especially if located close to the important native coronary arteries. Here, we describe a rare case of anterolateral aneurysm of the basal LV wall and a safe, efficient approach for a patch plasty sparing the native left anterior descending.

Bicuspid Morphology and Rapid Deployment Valve Replacement: Is This Still a Contraindication?

When using rapid deployment surgical aortic valve replacement (RD SAVR) in treating bicuspid aortic valve morphology (BAV), several challenges are faced due to annular asymmetry. The Sievers classification has been traditionally used for the description of BAV morphology. In this study, we aimed to conduct a retrospective feasibility analysis of RD SAVR in relation to the Sievers classification. From January 2014 to March 2022, 31 patients with BAV morphology (15 patients with Sievers type 0 BAV and 16 with Sievers type 1 BAV) underwent RD SAVR. Specific surgical techniques were applied depending on the BAV morphology. Comparable clinical outcomes were observed. No paravalvular leaks and no valvular re-interventions occurred in either group. CPB and cross-clamping times, as well as the prosthesis sizes used, were also not significantly different. Postoperative mean gradients were comparable in both groups. No significant distinction was found between the groups in terms of postoperative pacemaker indication, postoperative stroke, or death. Annular symmetry can be adequately restored through precise prosthesis sizing and placement according to an individual's valve morphology regardless of the Sievers classification of BAV by choosing a different landmark for the initial suture. RD SAVR seems to be a safe approach for any bicuspid morphology, with good hemodynamic results and time-saving potential in experienced hands.

Body mass index-dependent immunological profile changes after left ventricular assist device implantation.

Purpose: Infection is a common complication following left ventricular assist device (LVAD) implantation. Patients with obesity are particularly at risk due to their high percentage of adipose tissue and the resulting chronic inflammatory state and resulting immunological changes. This study investigated changes of immunological parameters in relation to body mass index (BMI) during the first year after LVAD implantation. Methods: Blood samples were obtained prior to LVAD implantation and at 3 (1st FU), 6 (2nd FU) and 12 mo (3rd FU) after LVAD implantation. Patients were divided into three groups (normal weight: BMI of 18.5-24.9 kg/m2; n=12; pre-obesity: 25.0-29.9 kg/m2; n=15; obesity: ≥ 30.0 kg/m2; n=17) based on their BMI at the time of LVAD implantation. Flow cytometric analyses for CD4+ and CD8+ T cells, regulatory T cells (Tregs), B cells as well as dendritic cells (DCs) were performed. Results: After LVAD implantation, obese patients (0.51 ± 0.20%) showed a higher proportion of overall DCs than normal-weight (0.28 ± 0.10%) and pre-obese patients (0.32 ± 0.11%, p<0.01) at 3rd FU. The proportion of BDCA3+ myeloid DCs was lower in obese patients (64.3 ± 26.5%) compared to normal-weight patients (82.7 ± 10.0%, pnormal-weight vs. obesity=0.05) at 2nd FU after LVAD implantation. The analysis of BDCA4+ plasmacytoid DCs revealed a reduced proportion in pre-obese (21.1 ± 9.8%, pnormal-weight vs. pre-obesity=0.01) and obese patients (23.7 ± 10.6%, pnormal-weight vs. obesity=0.05) compared to normal-weight patients (33.1 ± 8.2%) in the 1st FU. T cell analysis showed that CD4+ T cells of obese patients (62.4 ± 9.0%) significantly increased in comparison to pre-obese patients (52.7 ± 10.0%, ppre-obesity vs. obesity=0.05) and CD8+ T cells were lower in obese patients (31.8 ± 8.5%) than in normal-weight patients (42.4 ± 14.2%; pnormal-weight vs. obesity=0.04) at the 3rd FU. Furthermore, we observed significantly reduced proportions of Tregs in pre-obese patients compared to normal-weight and obese patients at 2nd FU (p=0.02) and 3rd FU (p=0.01) after LVAD implantation. Conclusion: This study reported changes of the innate and adaptive immune system of pre-obese and obese compared to normal-weight patients one year after LVAD implantation. DCs and their subsets, CD8+ T cells and Tregs were affected immune cell populations that indicate immunological changes which might increase the incidence of postoperative infection.

Interdisciplinary Management of the Emergency Treatment in an Atrioesophageal Fistula.

The atrioesophageal fistula is a fulminant complication of radiofrequency ablation in atrial fibrillation, with a mortality as high as 80%. Surgical approaches have been insufficiently dealt with in literature. Treating a 42-year-old male patient, we developed an interdisciplinary two-step concept: (1) resection of the affected third of the esophagus and closing of the atrial defect using cardiopulmonary bypass and cardioplegic cardiac arrest; and (2) a second surgery to restore gastrointestinal continuity after an adequate term. Our patient has fully recovered.

Evaluation of a rapid deployment prosthesis strategy for the treatment of aortic valve endocarditis.

OBJECTIVES: The aim of this study was to evaluate the surgical outcome of patients suffering from native aortic valve (NVE) or prosthetic aortic valve endocarditis (PVE) treated with the EDWARDS INTUITY Elite rapid-deployment valve prosthesis. METHODS: Between February 2019 and June 2020, 25 patients suffering from NVE (n = 9; 36%) and PVE (n = 16; 64%) of the aortic valve received an INTUITY valve at our institution. Preoperative, operative and follow-up data were collected. RESULTS: In our cohort, the mean EuroSCORE II was 13.4%. Eleven patients (44%) received concomitant aortic root patch plasty. Four patients (16%) received coronary artery bypass graft surgery, 3 patients (12%) received mitral valve repair and 2 patients (8%) underwent replacement of the ascending aorta. The cardiopulmonary bypass and aortic cross-clamp times were 124 ± 56 and 75 ± 39 min, respectively. The mean intensive care unit stay was 5 days. The mean size of the implanted prostheses was 25 ± 2 mm and the mean prosthesis transvalvular gradient 3 months after surgery was 9 ± 4 mmHg. During follow-up, no case of recurrent endocarditis occurred, 1 patient died of multisystem organ failure which had already been present preoperatively. CONCLUSIONS: Surgery for NVE and PVE of the aortic valve may be safely performed using the EDWARDS INTUITY Elite valve system. This procedure could be well implemented in cases with extensive infection, fragile root tissue and root abscesses requiring root reconstruction. In our institution, the rapid-deployment aortic valve replacement strategy has become an important tool in the armamentarium of the surgical endocarditis treatment.

Atrio-aortic erosion caused by Amplatzer Atrial Septal Occluder - a case report.

BACKGROUND: In specialized centers, percutaneous closure using specific occluders is the first-choice treatment in atrial septal defects (ASD). Late complications after this intervention, such as erosion of the aorta or the atria, are rare and have not been sufficiently approached and dealt with in literature. In our clinic we have been faced with the problematic situation of diagnosing and treating such cases. That is why, we have decided to share our experience with other colleagues. CASE PRESENTATION: We present two cases of severe late complications after percutaneous closure of atrial septal defects (ASD). In both cases, the atrial septal occluder (Amplatzer™ Atrial Septal Occluder Device, Abbott, Chicago USA) caused the erosion between the left atrium and the aortic root. The atrio-aortic erosion led to acute cardiac tamponade with upper venous congestion and shock. As the bleeding source remained undetectable for any imaging tools, a diagnostical sternotomy remained the only solution. The cause of the acute bleeding was discovered to be the erosion between the left atrium and the aortic root. The treatment consisted in the removal of the occluder, direct suturing of the perforated areas and the surgical closure of the remaining ASD. The patients fully recovered within the nine to fourteen days' hospital stay. Six months after surgery both patients were well and able to recover their daily routine. CONCLUSIONS: The atrio-aortic erosion after percutaneous closure of atrial septal defects is a surgical emergency. The more so, since it can be complicated by the absence of specific symptoms. A key-element in the diagnosis of this rare pathology remains the medical history of the patient, which the surgeon has to consider thoroughly and launch the diagnostic sternotomy without delay.

Impact of Operative Timing in Infective Endocarditis with Cerebral Embolism-The Risk of Intermediate Deterioration.

Cerebral embolism due to infective endocarditis (IE) is associated with significant morbidity and mortality. The optimal time-interval between symptomatic stroke and cardiac surgery remains unclear. This study aimed to analyze the patients' outcomes and define the potential risk factors with regard to surgical timing for IE patients with preoperative symptomatic cerebral embolism (CE). A total of 119 IE patients with CE were identified and analyzed with regard to operative timing: early (1-7 days), intermediate (8-21 days), and late (>22 days). The preoperative patient data, comorbidities and previous cardiac surgical procedures were analyzed to identify potential predictors and independent risk factors for in-hospital mortality using univariate and multivariate regression analysis. Actuarial survival was estimated by the Kaplan-Meier method. In-hospital mortality for the entire study cohort was 15.1% (n = 18), and in comparison, between groups was found to be highest in the intermediate surgical group (25.7%). Univariate analysis identified preoperative mechanical ventilation dependent respiratory insufficiency (p = 0.006), preoperative renal insufficiency (p = 0.019), age (p = 0.002), large vegetations (p = 0.018) as well as intermediate (p = 0.026), and late (p = 0.041) surgery as predictors of in-hospital mortality. The presence of large vegetations (>8 mm) (p = 0.019) and increased age (p = 0.037)-but not operative timing-were identified as independent risk factors for in-hospital mortality. In the presence of large vegetations (>8 mm), cardiac surgery should be performed early and independently from the entity of cerebral embolic stroke. Postponing surgery to achieve clinical stabilization and better postoperative outcomes of IE patients with CE is reasonable, however, worsening of the disease process with deterioration and resulting heart failure during the first 3 weeks after CE results in a significantly higher in-hospital mortality and inferior long-term survival.

Bilirubin and lactate: easy to determine and valuable to predict outcome in cardiac surgery.

BACKGROUND: Cardiopulmonary bypass during cardiac surgery is associated with metabolic changes after operation and results inter alia in increased levels of lactate and bilirubin. Since prediction of the course after operation has become very important for the management of an ICU and the patients themselves, we evaluated easily assessable markers (lactate and bilirubin), regarding their potential to predict mortality 90 days after surgery and the length of stay in ICU. METHODS: All patients within a period of five years undergoing cardiac surgery were enrolled in the study. Among others peak levels of lactate and bilirubin within 48 hours after operation were recorded. A Cox proportional hazard model as well as a logistic regression model were used to predict mortality or rather length of stay in ICU. RESULTS: Increased levels of bilirubin and lactate were associated with a significantly increase in mortality and length of stay in ICU (in a concentration-related manner). Interestingly, creatinine serum levels before operation showed a similar performance. CONCLUSIONS: Three easily assessable and cheap laboratory parameters (bilirubin, lactate, and creatinine) are useful to predict 90-day mortality and length of stay in ICU. These findings might be helpful to give patients a reliable prediction about short and mid-term-survival and to improve the management of an ICU.

Incidence and Surgical Outcomes of Patients With Native and Prosthetic Aortic Valve Endocarditis.

BACKGROUND: The aim of this study was to retrospectively evaluate the incidence and surgical outcomes of patients with native infective endocarditis (IE) and prosthetic aortic valve endocarditis (PVE) over the past decade at a single institution. METHODS: Between January 2005 and December 2015, 289 patients (mean age, 63.3 ± 14.2 years) suffering from native IE (n = 186) and PVE (n = 103) of the aortic valve underwent surgical procedures. Perioperative data were acquired retrospectively for statistical analysis. RESULTS: During the study period the mean incidence of endocarditis increased from 22.0 ± 4.2 (2005-2009) to 29.8 ± 10.1 (2010-2015) cases per year. In-hospital mortality was significantly increased in PVE (22.3%) versus IE (9.1%) patients (P < .001). In elective cases in-hospital mortality between the 2 groups was comparable (2.2% vs 4.6%; P = .288). Multivariate analysis identified urgent surgery (odds ratio [OR], 6.461; 95% CI, 1.941-21.509; P = .002), mitral regurgitation II (OR, 4.230; 95% CI, 1.249-14.331; P = .021), previous homograft operation (OR, 66.096; 95% CI, 2.369-1844.272; P = .0.14), and left ventricular ejection fraction < 40% (OR, 8.267; 95% CI, 1.931-35.388; P = .004) as independent risk factors for in-hospital mortality, whereas pathogen identification by preoperative blood cultures (OR, .228; 95% CI, 0.063-0.817; P = .023) was found to be independently protective. CONCLUSIONS: Surgery for native IE and PVE of the aortic valve may be performed with satisfactorily results at experienced cardiac surgical centers. In comparison PVE patients suffer from a more than twice as high in-hospital mortality, more postoperative complications, and inferior long-term survival. However preoperative identification of causative pathogens in IE and PVE allows for improved in-hospital survival.

Morphological and quantitative changes of the initial myocardial lymphatics in terminal heart failure.

BACKGROUND: Terminal heart failure is associated with chronic myocardial edema, which in part is compensated by increased myocardial lymph flow. However, little is known about the impact of terminal heart failure on lymphangiogenesis. The purpose of the study was to investigate the morphological and quantitative changes of the initial myocardial lymphatics in terminal heart failure. METHODS: Paraffin-embedded left ventricular endomyocardial biopsies, taken during heart transplantation from 7 heart transplant recipients (failing heart) and 8 heart transplant donors (control), were investigated by immunohistostaining and triple immunofluorescence for lymphatic endothelial markers LYVE-1, PROX-1, and VEGFR-3. The vessel density was calculated and the ratio of open versus collapsed vessels was estimated by analyzing randomly selected marked vessels. RESULTS: The absolute densities of lymph vessels in failing and control myocardium were not significantly different for all investigated markers. The ratio of open LYVE-1 positive lymph vessels in failing heart was significantly higher than in control (64+/-12.5 vs. 44.3+/-9.3, p<0.008). There was no difference for the ratio of open VEGFR-3 vessels between groups (69.0+/-17.5 vs. 70.7+/-17.2). Triple fluorescent immunohistostaining revealed in failing hearts LYVE-1 and PROX-1 positive open vessels, which were VEGFR-3 negative. VEGFR-3 positive, but LYVE-1 and PROX-1 negative vessels could also be seen. CONCLUSIONS: Myocardial initial lymphatics in patients with terminal heart failure undergo significant morphological changes in comparison to normal hearts. The ratio of open LYVE-1 vessels was higher in failing hearts by no difference in absolute densities for all markers. These findings suggest that appositional growth of initial lymphatics, rather than "de novo" genesis from pluripotent stem cells or sprouting from preexisting venous vessels, may be the predominant mechanism of lymphangiogenesis in terminal heart failure.