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This article discusses a study that aimed to prove the feasibility and safety of a minimally invasive aortic valve reimplantation procedure called the David procedure. The study included 122 patients who underwent the procedure between 2000 and 2023. The primary endpoints of the study were peri- and postoperative outcomes and long-term aortic valve performance. The results showed that the procedure can be performed safely, but it should be limited to centers with experience in minimally invasive cardiac surgery. The study also emphasized the importance of precise patient selection and preoperative planning. [Extracted from the article]

This article, published in the journal Thoracic & Cardiovascular Surgeon, compares the outcomes of aortic valve replacement (AVR) using two different surgical approaches: upper ministernotomy (MiniAVR) and conventional AVR via full sternotomy (FS). The study, conducted at the University Hospital Frankfurt, included 918 patients, with 63% undergoing FS and 37% undergoing MiniAVR. The results showed that MiniAVR provided similar short- and long-term outcomes to FS in high-risk elderly patients receiving biological prostheses. The authors suggest that these findings support the use of MiniAVR as a standard procedure for AVR, even in high-risk populations. [Extracted from the article]

This article, titled "Coronary Plaque Quantification Using a New CT Imaging Software¿A Feasibility Study," discusses the potential benefits of using Cinematic Rendering (CR) visualization in detecting nonobstructive coronary plaques. The study included 26 patients who underwent cardiac surgery and had previous cardiac CT scans. The results showed that CR visualization correlated well with intraoperative palpation in quantifying the presence of plaques. The authors suggest that CR has the potential to improve the planning of coronary artery bypass surgery by allowing for easier interpretation of plaque localization. Further research will be conducted to validate these findings. [Extracted from the article]

Background: Various mitral valve (MV) repair techniques are nowadays in use. Non-resection techniques, that rely exclusively on Gore-Tex® neochords and annuloplasty, have been popularized; however, their efficacy in Barlow's disease, characterized by large myxomatous leaflets, is yet unclear., Methods: Consecutive patients undergoing MV repair for Barlow's disease between 2011 and 2019 were selected on the basis of being eligible for resection and non-resection techniques. Study endpoints included overall survival, freedom from MV reintervention and recurrent regurgitation., Results: Of 209 patients meeting the inclusion criteria, 135 (65%) underwent MV repair with and 74 (35%) without resection. There was one early reoperation due to residual regurgitation (resection group). Mean clinical follow-up duration was 6.1 (IQR 3.9-8.5) years. At 6 years after surgery, there was no difference in overall survival or freedom from MV reintervention. Mean echocardiographic follow-up (95% complete) duration was 3.5 (IQR 2.3-5.8) years. At 6 years, there was no difference in freedom from recurrent regurgitation rate (86.1%, 95% CI 78.5-93.7% vs. 83.0%, 95% CI 71.6-94.4%, P = 0.20) between the groups. Inverse probability-of-treatment weighting adjusted analysis demonstrated no significant difference between groups (HR 0.535, 95% CI 0.212-1.349, P = 0.20). Uni- and multivariable Cox proportional regression analysis did not demonstrate an effect of valve repair technique on the occurrence of recurrent regurgitation., Conclusions: At mid-term, the clinical and echocardiographic results of valve repair for Barlow's disease were very good and MV reintervention was rarely needed. At this time point, the results of non-resection techniques were comparable to the "gold standard" resection techniques., Competing Interests: Declaration of competing interest The authors have nothing to disclose., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Background: The management of acute type A aortic dissection (ATAAD) using the Ascyrus Medical Dissection Stent (AMDS) can lead to complications due to the persistence of the false lumen (FL). This case report presents two instances of failed AMDS treatment for ATAAD, highlighting the novel use of a trifurcated hybrid prosthesis for redo aortic arch repair using a minimally invasive frozen elephant trunk (FET) technique., Case Presentation: Case 1: A 57-year-old male, previously treated with AMDS for ATAAD, presented with an enlarging aortic arch and persistent FL two years post-surgery caused by re-entry in the distal aortic arch. Redo surgery using the FET technique with an E-vita OPEN NEO Trifurcated hybrid prosthesis resulted in successful repair and partial FL thrombosis. Case 2: A 51-year-old male with prior AMDS treatment for ATAAD presented with severe aortic valve regurgitation and a maintained FL perfusion due to a residual re-entry in the proximal region of the descending aorta. Redo surgery using the FET technique with the same hybrid prosthesis led to successful repair and good recovery, confirmed by follow-up imaging., Conclusions: The use of the E-vita OPEN NEO Trifurcated hybrid prosthesis in the FET technique offers a promising solution for redo aortic arch repair in cases of failed AMDS treatment for ATAAD. This approach can improve patient outcomes by addressing complications associated with persistent FL and enhancing long-term survival., (© 2024. The Author(s).)

Background and Objectives : The majority of cardiac surgical procedures are performed using cardiopulmonary bypass and cardioplegia-induced cardiac arrest. Cardiac arrest and reperfusion may lead to ischemia-reperfusion injury of the myocardium. The aim of this study was to investigate whether gradual reperfusion with a slow increase in oxygen partial pressure leads to a reduction in reperfusion injury. Materials and Methods : Fifty patients undergoing elective cardiac surgery were included in this prospective randomized study. Patients in the hyperoxemic (control) group received conventional reoxygenation (paO 2 250-300 mmHg). Patients in the normoxemic (study) group received gradual reoxygenation (1st-minute venous blood with paO 2 30-40 mmHg, 2nd-minute arterial blood with paO 2 100-150 mmHg). Periprocedural blood samples were taken serially, and markers of myocardial injury were analyzed. In addition, the influence of gradual reoxygenation on hemodynamics, inflammation, and the overall perioperative course was evaluated. Results : There was a trend toward higher CK levels in the hyperoxemia group without statistical significance; however, CK-MB and troponin T levels did not show any statistical difference between the two groups. Potassium concentrations in the coronary sinus were significantly higher in the hyperoxemia group at 3 and 8 min after opening of the aortic cross-clamp (6.88 ± 0.87 mmol/L vs. 6.30 ± 0.91 mmol/L and 5.87 ± 0.73 mmol/L vs. 5.43 ± 0.42 mmol/L, respectively; p = 0.03 and p = 0.02). All other measurements did not show a statistical difference between the two groups. Conclusions : The use of gradual reperfusion in cardiac surgery with cardiopulmonary bypass and cardiac arrest is safe. However, it does not reduce ischemia-reperfusion injury compared to standard hyperoxemic reperfusion.

Introduction: Although cardiovascular surgery societies in Europe and the USA constantly strive for the exchange of knowledge and best practices in coronary artery bypass grafting (CABG), the available evidence on whether such efforts result in similar patient outcomes is limited. Therefore, in the present analysis, we sought to compare patient profiles and overall survival outcomes for up to 3 years between large European and US patient cohorts who underwent isolated CABG., Methods: Patients from the European DuraGraft Registry ( n  = 2,522) who underwent isolated CABG at 45 sites in eight different European countries between 2016 and 2019 were compared to randomly selected patients from the US STS database who were operated during the same period ( n  = 294,725). Free conduits (venous and arterial grafts) from the DuraGraft Registry patients were intraoperatively stored in DuraGraft, an endothelial damage inhibitor, before anastomosis, whereas grafts from the STS Registry patients in standard-of-care solutions (e.g., saline). Propensity score matching (PSM) models were used to account for differences in patient baseline and surgical characteristics, using a primary PSM with 35 variables (2,400 patients matched) and a secondary PSM with 25 variables (2,522 patients matched, sensitivity analysis). The overall survival for up to 3 years after CABG was assessed as the primary endpoint., Results: The comparison of patient profiles showed significant differences between the European and US cohorts. The European patients had more left main disease, underwent more off-pump CABG, and received more arterial grafts together with more complete arterial grafting procedures. In contrast, the US patients received more distal anastomoses with more saphenous vein grafts (SVGs) that were mainly harvested endoscopically. Such differences, however, were well balanced after PSM for the mortality comparison. Mortality comparison at 30 days, 12 months, and 24 months between the European and US patients was 2.38% vs. 1.96%, 4.32% vs. 4.79%, and 5.38% vs. 6.96%, respectively. At 36 months, the mortality was significantly lower in the European patients than that of their US counterparts (7.37% vs. 9.65%; p -value = 0.016). The estimated hazard ratio (HR) was 1.29 (95% CI 1.05-1.59)., Conclusion: This large-scale transatlantic comparative analysis shows that there are some significant differences in patient profiles between large cohorts of European and US patients. These differences were adjusted by using PSM for the mortality analysis. No significant difference in mortality was detected between groups through 2 years, but survival was significantly better in the European DuraGraft Registry patients at 3 years post-CABG., Competing Interests: EC, MM, JA, SS, Y-HC, and AB are members of the registry advisory committee (RAC). LP is a member of the RAC and is a consultant for Marizyme. ME is the principal investigator of the registry, the chair of the RAC, and a consultant for Marizyme. EF received research grants from Somalution, a Marizyme company. Other authors have nothing to disclose. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (© 2024 Caliskan, Misfeld, Sandner, Böning, Aramendi, Salzberg, Choi, Perrault, Tekin, Cuerpo, Lopez-Menendez, Weltert, Böhm, Krane, González-Santos, Tellez, Holubec, Ferrari, Doros and Emmert.)

Objectives: Both aortic root remodelling and aortic valve (AV) reimplantation have been used for valve-sparing root replacement in patients with aortic root aneurysm with or without aortic regurgitation. There is no clear evidence to support one technique over the another. This study aimed to compare remodelling with basal ring annuloplasty versus reimplantation on a multicentre level with the use of propensity-score matching., Methods: This was a retrospective international multicentre study of patients undergoing remodelling or reimplantation between 2010 and 2021. Twenty-three preoperative covariates (including root dimensions and valve characteristics) were used for propensity-score matching. Perioperative outcomes were analysed along with longer-term freedom from AV reoperation/reintervention and other major valve-related events., Results: Throughout the study period, 297 patients underwent remodelling and 281 had reimplantation. Using propensity-score matching, 112 pairs were selected and further compared. We did not find a statistically significant difference in perioperative outcomes between the matched groups. Patients after remodelling had significantly higher reintervention risk than after reimplantation over the median follow-up of 6 years (P = 0.016). The remodelling technique (P = 0.02), need for decalcification (P = 0.03) and degree of immediate postoperative AV regurgitation (P < 0.001) were defined as independent risk factors for later AV reintervention. After exclusion of patients with worse than mild AV regurgitation immediately after repair, both techniques functioned comparably (P = 0.089)., Conclusions: AV reimplantation was associated with better valve function in longer-term postoperatively than remodelling. If optimal immediate repair outcome was achieved, both techniques provided comparable AV function., (© The Author(s) 2024. Published by Oxford University Press on behalf of the European Association for Cardio-Thoracic Surgery. All rights reserved.)

Background : Infectious endocarditis (IE) remains a critical condition despite all the medical advances in recent decades. Reliable pathogen identification is indispensable for precise therapy. The aim of this study was to evaluate the diagnostic and therapeutic benefit of additional polymerase chain reaction (PCR) in comparison with microbiological culture alone based on intraoperative tissue sampling for patients operated on due to IE. Methods : A total of 224 patients diagnosed with acute or subacute IE were analyzed. Intraoperatively resected infectious tissue was analyzed using both PCR and microbiological culture. Subsequently, the results of the detection of bacteria obtained based on intraoperative measurements from tissue via culture and PCR were compared with preoperative blood culture results. Furthermore, we evaluated the therapeutic impact of the culture and/or PCR results obtained from cardiac tissue. Results : The 224 patients were 63 ± 17 years old, and 64 (29%) were female. In total, 149 (67%) suffered from aortic valve endocarditis, 45 (45%) had mitral valve endocarditis, and 39 (18%) were afflicted with double-valve endocarditis. Prosthetic valve endocarditis was present in 70 (31%) patients. Pathogens were detected in 70% of the cases analyzed via PCR using cardiac valve tissue and in 25% of those analyzed via a culture of cardiac valve tissue; this figure was only 64% for preoperative blood culture. Overall, a pathogen was identified in 197 patients (88%), leading to antibiotic therapy. Targeted antibiotic therapy, based on the PCR results, was carried out in 37 cases and was conducted based on a culture from cardiac valve tissue in three cases. Finally, in 12% of patients, the causative pathogen remained unclear. Conclusions : For patients suffering endocarditis, PCR analysis is indispensable and superior to preoperative blood culture and intraoperative culture in detecting bacteria. Based on PCR testing, antibiotic therapy can be individually adjusted. The high precision of pathogen identification may lead to a significant reduction in IE-associated morbidity and mortality.

Background: Anomalous left coronary artery originating from the pulmonary artery (ALCAPA), is a unique congenital anomaly, comprising only 0.24-0.46% of all congenital cardiac anomalies. Late presentations, ranging from asymptomatic cases to sudden cardiac arrest, are exceptionally rare. This unique case highlights the complexity of managing ALCAPA in adulthood and underscores the necessity of a comprehensive surgical approach addressing both coronary and valvular issues., Presentation: A 34-year-old female patient, who had been diagnosed with ALPACA in her early childhood, suffered sudden cardiac arrest at work, followed by out-of-hospital resuscitation. The patient had been followed-up regularly until adolescence, however, she had refused surgery. In the diagnostic work-up following successful resuscitation severe mitral valve regurgitation was additionally revealed. Subsequently, the patient underwent surgery, involving coronary artery bypass grafting (CABG), using bilateral internal mammary arteries, and mitral valve repair, with an excellent postsurgical result. At 16-month follow-up, the patient was asymptomatic and quality of life had significantly improved., Conclusion: This rare case initially presented as silent myocardial ischemia, resulting in reduced left ventricular function and secondary mitral incompetence. Surgical treatment of ALCAPA in adults poses greater challenges and a higher risk than in children. CABG procedure offers an excellent prognostic therapeutic strategy, since this procedure is a routine in adult cardiac surgery., (© 2024. The Author(s).)

Objectives: The aim of this multicentre study was to demonstrate the safety and clinical performance of E-vita OPEN NEO Stent Graft System (Artivion, Inc.) in the treatment of aneurysm or dissection, both acute and chronic, in the ascending aorta, aortic arch and descending thoracic aorta., Methods: In this observational study of 12 centres performed in Europe and in Asia patients were enrolled between December 2020 and March 2022. All patients underwent frozen elephant trunk using E-vita OPEN NEO Stent Graft System. Primary end point was the rate of all-cause mortality at 30 days and secondary end points included further clinical and safety data are reported up to 3-6 months postoperatively., Results: A total of 100 patients (66.7% male; mean age, 57.7 years) were enrolled at 12 sites. A total of 99 patients underwent surgery using the E-vita OPEN NEO for acute or subacute type A aortic dissection (n = 37), chronic type A aortic dissection (n = 33) or thoracic aortic aneurysm (n = 29), while 1 patient did not undergo surgery. Device technical success at 24 h was achieved in 97.0%. At discharge, new disabling stroke occurred in 4.4%, while new paraplegia and new paraparesis was reported in 2.2% and 2.2%, respectively. Renal failure requiring permanent (>90 days) dialysis or hemofiltration at discharge was observed in 3.3% of patients. Between discharge and the 3-6 months visit, no patients experienced new disabling stroke, new paraplegia or new paraparesis. The 30-day mortality was 5.1% and the estimated 6-month survival rate was 91.6% (standard deviation: 2.9)., Conclusions: Total arch replacement with the E-vita OPEN NEO can be performed with excellent results in both the acute and chronic setting. This indicates that E-vita OPEN NEO can be used safely, including in the setting of acute type A aortic dissection., (© The Author(s) 2024. Published by Oxford University Press on behalf of the European Association for Cardio-Thoracic Surgery.)

Background: Minimally invasive aortic valve replacement (AVR) via upper ministernotomy (MiniAVR) is a standard alternative to full sternotomy access. Minimally invasive cardiac surgery has been proven to provide a number of benefits to patients. The aim of this study was to compare the short- and long-term outcomes after MiniAVR versus conventional AVR via full sternotomy (FS) using a biological prosthesis in an elderly higher-risk population., Methods: Between January 2006 and July 2009, 918 consecutive patients received AVR ± additional procedures with different prostheses at our center. Amongst them, 441 received isolated AVR using a biological prosthesis (median age of 74.5; range: 52-93 years; 50% females) and formed the study population (EuroSCORE II: 3.62 ± 5.5, range: 0.7-42). In total, 137 (31.1%) of the operations were carried out through FS, and 304 (68.9%) were carried out via MiniAVR. Follow-up was complete in 96% of the cases (median of 7.6 years, 6610 patient-years). Propensity score matching (PSM) resulted in two groups of 68 patients with very similar baseline profiles. The primary endpoints were long-term survival, freedom from reoperation, and endocarditis, and the secondary endpoints were early major adverse cardiac and cerebrovascular events (MACCEs)., Results: FS led to shorter cardio-pulmonary bypass and aortic cross-clamp durations: 90 (47-194) vs. 100 (46-246) min ( p = 0.039) and 57 (33-156) vs. 69 (32-118) min ( p = 0.006), respectively. Perioperative stroke occurred in three patients (4.4%; FS) vs. one patient (1.5%; MiniAVR) ( p = 0.506). The 30-day mortality was similar in both groups (2.9%, p = 1.000). Survival at 1, 5, and 10 years was 94.1 ± 3% (FS and MiniAVR), 80.3 ± 5% vs. 75.7 ± 5%, and 45.3 ± 6% vs. 43.8 ± 6%, respectively ( p = 0.767). There were two (2.9%) reoperations in each group and two thrombo-embolic events (2.9%) vs. one (1.5%) thrombo-embolic event in the MiniAVR and FS groups, respectively ( p = 0.596)., Conclusions: In comparison to FS, MiniAVR provided similar short- and long-term outcomes in a higher-risk elderly population receiving biological prostheses. In particular, long-term survival, freedom from reoperation, and the incidence of endocarditis were comparable. These results clearly advocate for the routine use of MiniAVR as a standard procedure for AVR, even in a high-risk population., Competing Interests: The authors declare no conflicts of interest.

Objectives: Several short-term analyses from German Registry for Acute Aortic Dissection Type A (GERAADA) have been published. This study investigated whether short-term risk factors are transferable to the long-term prognosis of patients., Methods: Thirty-three centres with 2686 patients participated in the long-term follow-up. A total of 1164 patients died, 1063 survived and 459 were lost to follow-up during the follow-up timeframe (mean duration: 10.2 years). Long-term mortality of the cohort was compared with an age-stratified, German population., Results: One, 5 and 10 years after initial surgery, the survival of the GERAADA patient cohort was 71.4%, 63.4% and 51%, respectively. Without the early deaths (90-day mortality 25.4%), survival was calculated after 1, 5 and 10 years: 95.6%, 83.5% and 68.3%. Higher age, longer extracorporeal circulation time, shorter perioperative ventilation time and postoperative neurologic deficits were predictive of long-term prognosis. In an age-divided landmark analysis, the mortality of aortic dissection surgery survivors was found to be similar to that of the general German population. If patients are sorted in risk groups according to the GERAADA score, long-term survival differs between the risk groups., Conclusions: If patients have survived an acute postoperative period of 90 days, life expectancy comparable to that of the general German population can be assumed in lower- and medium-risk patients. Whether the GERAADA score can provide valuable insights into the long-term prognosis of patients undergoing surgery for acute aortic dissection type A is still unclear., (© The Author(s) 2024. Published by Oxford University Press on behalf of the European Association for Cardio-Thoracic Surgery. All rights reserved.)

Competing Interests: The authors reported no conflicts of interest. The Journal policy requires editors and reviewers to disclose conflicts of interest and to decline handling manuscripts for which they may have a conflict of interest. The editors and reviewers of this article have no conflicts of interest.

Background: Diagnostic laboratory tests are an integral part of managing hospitalized patients. In particular, patients in the intensive care units (ICUs) can experience a concerning amount of blood loss due to diagnostic testing, which can increase the risk developing iatrogenic anemia. Several interventions exist to curtail avoidable blood loss, for example computerized decision support, smaller phlebotomy tubes, and other blood conservation devices. Nevertheless, use of these interventions is not standardized. Therefore, the objective of our study was to quantify the daily phlebotomy volume taken from patients who had undergone major cardiac or vascular surgery., Methods: We estimated the number of blood analyses and volumes of drawn blood of 400 consecutive patients (≥ 18 yr) undergoing major cardiac or vascular surgery. The amount of blood saved using small-volume tubes and in combination with blood conservation device rather than standard-volume tubes was estimated for serum chemistry (serum), ethylenediaminetetraacetic acid (EDTA) tubes, sodium citrate coagulation (SCC) tubes, and arterial blood gas (ABG) analysis., Results: The mean total blood loss due to phlebotomy drawing using standard-volume tubes during hospitalization was 167.9 mL (95% confidence interval [CI], 158.0 to 177.8), 255.6 mL (95% CI, 226.5 to 284.6), and 695.3 mL (95% CI, 544.1 to 846.4) for patients undergoing cardiac surgery with a hospital length of stay (LOS) of 0-10, 11-20, and ≥ 21 days, respectively. The mean total blood loss due to phlebotomy during hospitalization was 80.5 mL (95% CI, 70.5 to 90.6), 225.0 mL (95% CI, 135.1 to 314.8 mL) and 470.3 mL (95% CI, 333.5 to 607.1) for vascular surgery patients with LOS 0-10, 11-20, and ≥ 21 days, respectively. Patients with at least a two-day stay at the ICU had a mean blood loss of 146.6 mL (95% CI, 134.6 to 158.6 mL) and those with ≥ 11 days incurred a loss of 1,428 mL (95% CI, 1,117.8 to 1,739.2). The use of closed blood collection device and small-volume tubes (serum, EDTA, SCC, and ABG) reduced blood loss by 82.8 mL for patients with an ICU stay of 2 days and up to 824.0 mL for patients with a ICU stay of ≥ 11 days., Conclusion: Diagnostic laboratory tests are associated with significant patient blood loss, but are a modifiable risk factor. The use of small-volume tubes and closed blood collection devices decreases the volume of patient blood drawn for analysis and prevents blood waste., (© 2024. The Author(s).)

Objective:  Spinal cord injury (SCI) with subsequent paraplegia and/or stroke after arch repair with frozen elephant trunk (FET) remain the most devastating complications. In this study, we aim to examine the impact of different cerebral perfusion strategies on the neurological outcome comparing bilateral antegrade cerebral perfusion (bACP) and trilateral antegrade cerebral perfusion (tACP)., Methods:  Between 2009 and 2021, 88 patients underwent total arch replacement using a hybrid prosthesis in FET technique for acute (40.4%) and chronic (59.6%) aortic pathologies. After excluding 14 patients who underwent FET with unilateral ACP the remaining 74 patients were divided into two groups. Propensity score matching was performed based on pre- and perioperative patient characteristics resulting in 22 patients in each group. The primary endpoint was a combination of major cerebral event and SCI. Secondary end point was all-cause mortality., Results:  Major cerebral events occurred in 9% of the patients in bACP versus 13.6% in tACP group ( p  = 0.63). No postoperative SCI was observed in patients with bACP and only one patient suffered SCI with tACP ( p  = 0.31). There was no significant difference in 30-day mortality between the two groups (22.7% in bACP vs. 13.6% in tACP; p  = 0.43)., Conclusion:  In patients undergoing total aortic arch repair using FET technique, both perfusion strategies (bilateral and trilateral ACP) are safe and effective. The rates of neurological complications as well as mortalities are acceptably low in both groups. Further studies with larger patient cohorts are warranted., Competing Interests: None declared., (Thieme. All rights reserved.)

Background: Cardiovascular research heavily relies on mouse (Mus musculus) models to study disease mechanisms and to test novel biomarkers and medications. Yet, applying these results to patients remains a major challenge and often results in noneffective drugs. Therefore, it is an open challenge of translational science to develop models with high similarities and predictive value. This requires a comparison of disease models in mice with diseased tissue derived from humans., Results: To compare the transcriptional signatures at single-cell resolution, we implemented an integration pipeline called OrthoIntegrate, which uniquely assigns orthologs and therewith merges single-cell RNA sequencing (scRNA-seq) RNA of different species. The pipeline has been designed to be as easy to use and is fully integrable in the standard Seurat workflow.We applied OrthoIntegrate on scRNA-seq from cardiac tissue of heart failure patients with reduced ejection fraction (HFrEF) and scRNA-seq from the mice after chronic infarction, which is a commonly used mouse model to mimic HFrEF. We discovered shared and distinct regulatory pathways between human HFrEF patients and the corresponding mouse model. Overall, 54% of genes were commonly regulated, including major changes in cardiomyocyte energy metabolism. However, several regulatory pathways (e.g., angiogenesis) were specifically regulated in humans., Conclusions: The demonstration of unique pathways occurring in humans indicates limitations on the comparability between mice models and human HFrEF and shows that results from the mice model should be validated carefully. OrthoIntegrate is publicly accessible (https://github.com/MarianoRuzJurado/OrthoIntegrate) and can be used to integrate other large datasets to provide a general comparison of models with patient data., (© The Author(s) 2024. Published by Oxford University Press GigaScience.)

Aims: Cardiac fibrosis drives the progression of heart failure in ischaemic and hypertrophic cardiomyopathy. Therefore, the development of specific anti-fibrotic treatment regimens to counteract cardiac fibrosis is of high clinical relevance. Hence, this study examined the presence of persistent fibroblast activation during longstanding human heart disease at a single-cell resolution to identify putative therapeutic targets to counteract pathological cardiac fibrosis in patients., Methods and Results: We used single-nuclei RNA sequencing with human tissues from two samples of one healthy donor, and five hypertrophic and two failing hearts. Unsupervised sub-clustering of 7110 nuclei led to the identification of 7 distinct fibroblast clusters. De-convolution of cardiac fibroblast heterogeneity revealed a distinct population of human cardiac fibroblasts with a molecular signature of persistent fibroblast activation and a transcriptional switch towards a pro-fibrotic extra-cellular matrix composition in patients with established cardiac hypertrophy and heart failure. This sub-cluster was characterized by high expression of POSTN, RUNX1, CILP, and a target gene adipocyte enhancer-binding protein 1 (AEBP1) (all P < 0.001). Strikingly, elevated circulating AEBP1 blood level were also detected in a validation cohort of patients with confirmed cardiac fibrosis and hypertrophic cardiomyopathy by cardiac magnetic resonance imaging (P < 0.01). Since endogenous AEBP1 expression was increased in patients with established cardiac hypertrophy and heart failure, we assessed the functional consequence of siRNA-mediated AEBP1 silencing in human cardiac fibroblasts. Indeed, AEBP1 silencing reduced proliferation, migration, and fibroblast contractile capacity and α-SMA gene expression, which is a hallmark of fibroblast activation (all P < 0.05). Mechanistically, the anti-fibrotic effects of AEBP1 silencing were linked to transforming growth factor-beta pathway modulation., Conclusion: Together, this study identifies persistent fibroblast activation in patients with longstanding heart disease, which might be detected by circulating AEBP1 and therapeutically modulated by its targeted silencing in human cardiac fibroblasts., Competing Interests: Conflict of interest: E.N. has received speaker fees educational grants from Bayer AG., (© The Author(s) 2023. Published by Oxford University Press on behalf of the European Society of Cardiology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)