The left and right ventricles of the human heart are functionally and developmentally distinct such that genetic or acquired insults can cause dysfunction in one or both ventricles resulting in heart failure. To better understand ventricle-specific molecular changes influencing heart failure development, we first performed unbiased quantitative mass spectrometry on pre-mortem non-diseased human myocardium to compare the metabolome and proteome between the normal left and right ventricles. Constituents of gluconeogenesis, glycolysis, lipogenesis, lipolysis, fatty acid catabolism, the citrate cycle and oxidative phosphorylation were down-regulated in the left ventricle, while glycogenesis, pyruvate and ketone metabolism were up-regulated. Inter-ventricular significance of these metabolic pathways was then found to be diminished within end-stage dilated cardiomyopathy and ischaemic cardiomyopathy, while heart failure-associated pathways were increased in the left ventricle relative to the right within ischaemic cardiomyopathy, such as fluid sheer-stress, increased glutamine-glutamate ratio, and down-regulation of contractile proteins, indicating a left ventricular pathological bias.
Myocardial Posttranscriptional Landscape in Peripartum Cardiomyopathy
Background: Pregnancy imposes significant cardiovascular adaptations, including progressive increases in plasma volume and cardiac output. For most women, this physiological adaptation resolves at the end of pregnancy, but some women develop pathological dilatation and ultimately heart failure late in pregnancy or in the postpartum period, manifesting as peripartum cardiomyopathy (PPCM). Despite the mortality risk of this form of heart failure, the molecular mechanisms underlying PPCM have not been extensively examined in human hearts.
Methods: Protein and metabolite profiles from left ventricular tissue of end-stage PPCM patients (N=6-7) were compared with dilated cardiomyopathy (DCM; N=5-6) and nonfailing donors (N=7-18) using unbiased quantitative mass spectrometry. All samples were derived from the Sydney Heart Bank. Data are available via ProteomeXchange with identifier PXD055986. Differential protein expression and metabolite abundance and Kyoto Encyclopedia of Genes and Genomes pathway analyses were performed.
Results: Proteomic analysis identified 2 proteins, SBSPON (somatomedin B and thrombospondin type 1 domain-containing protein precursor) and TNS3 (tensin 3), that were uniquely downregulated in PPCM. SBSPON, an extracellular matrix protein, and TNS3, involved in actin remodeling and cell signaling, may contribute to impaired tissue remodeling and fibrosis in PPCM. Metabolomic analysis revealed elevated levels of homogentisate and deoxycholate and reduced levels of lactate and alanine in PPCM, indicating disrupted metabolic pathways and glucose utilization. Both PPCM and DCM shared pathways related to inflammation, immune responses, and signal transduction. However, thyroid hormone signaling was notably reduced in PPCM, affecting contractility and calcium handling through altered expression of PLN (phospholamban) and Sarcoendoplasmic Reticulum Calcium ATPase (SERCA). Enhanced endoplasmic reticulum stress and altered endocytosis pathways in PPCM suggested additional mechanisms of energy metabolism disruption.
Conclusions: The present study reveals unique posttranslational molecular features of the PPCM myocardium, which mediates cellular and metabolic remodeling, and holds promise as potential targets for therapeutic intervention.
Aortic and Mitral Valve Endocarditis-Simply Left-Sided Endocarditis or Different Entities Requiring Individual Consideration?-Insights from the CAMPAIGN Database
Background: Aortic valve infective endocarditis (AV-IE) and mitral valve infective endocarditis (MV-IE) are often grouped together as one entity: left-sided endocarditis. However, there are significant differences between the valves in terms of anatomy, physiology, pressure, and calcification tendency. This study aimed to compare AV-IE and MV-IE in terms of patient characteristics, pathogen profiles, postoperative outcomes, and predictors of mortality.
Methods: We retrospectively analyzed data from 3899 patients operated on for isolated AV-IE or MV-IE in six German cardiac surgery centers between 1994 and 2018. Univariable and multivariable analyses were performed to analyze the risk factors for 30 day and 1 year mortality. A Log-rank test was used to test for differences in long-term mortality.
Results: Patients with MV-IE were more likely to be female (41.1% vs. 20.3%.; p < 0.001). Vegetation was detected more frequently in the MV-IE group (66.6% vs. 57.1%; p < 0.001). Accordingly, the rates of cerebral embolic events (25.4% vs. 17.7%; p < 0.001) and stroke (28.2% vs. 19.3%; p < 0.001) were higher in the MV-IE group. Staphylococci had a higher prevalence in the MV-IE group (50.2% vs. 36.4%; p < 0.001). Patients with MV-IE had comparable 30 day mortality (16.7% vs. 14.6%; p = 0.095) but significantly higher 1 year mortality (35.3% vs. 29.0%; p < 0.001) than those with AV-IE. Kaplan-Meier survival analysis showed significantly lower long-term survival in patients with MV-IE (log-rank p < 0.001).
Conclusions: Due to the relevant differences between MV-IE and AV-IE, it might be useful to provide individualized, valve-specific guideline recommendations rather than general recommendations for left-sided IE.
A comparison of fixation and immunofluorescence protocols for successful reproducibility and improved signal in human left ventricle cardiac tissue
Immunohistochemistry (IHC) and immunofluorescence (IF) are crucial techniques for studying cardiac physiology and disease. The accuracy of these techniques is dependent on various aspects of sample preparation and processing. However, standardised protocols for sample preparation of tissues, particularly for fresh-frozen human left ventricle (LV) tissue, have yet to be established and could potentially lead to differences in staining and interpretation. Thus, this study aimed to optimise the reproducibility and quality of IF staining in fresh-frozen human LV tissue by systematically investigating crucial aspects of the sample preparation process. To achieve this, we subjected fresh-frozen human LV tissue to different fixation protocols, primary antibody incubation temperatures, antibody penetration reagents, and fluorescent probes. We found that neutral buffered formalin fixation reduced image artefacts and improved antibody specificity compared to both methanol and acetone fixation. Additionally, incubating primary antibodies at 37°C for 3 h improved fluorescence intensity compared to the commonly practised 4°C overnight incubation. Furthermore, we found that DeepLabel, an antibody penetration reagent, and smaller probes, such as fragmented antibodies and Affimers, improved the visualisation depth of cardiac structures. DeepLabel also improved antibody penetration in CUBIC cleared thick LV tissue fragments. Thus, our data underscores the importance of standardised protocols in IF staining and provides various means of improving staining quality. In addition to contributing to cardiac research by providing methodologies for IF, the findings and processes presented herein also establish a framework by which staining of other tissues may be optimised.
Impact of Complex Anatomy and Patient Risk Profile in Minimally Invasive Mitral Valve Surgery
Background: We aimed to assess the impact of complex mitral valve disease and patient risk profile on operative outcomes in the large cohort of the Mini-Mitral International Registry.
Methods: Patients were assigned to categories of complex degenerative mitral valve regurgitation (DMR; bileaflet or anterior mitral leaflet prolapse/flail) and simple DMR (posterior mitral leaflet prolapse/flail). Subgroup analyses was performed in low-risk (EuroSCORE II <8%) and high-risk (EuroSCORE II >8%) cohorts. A logistic regression model was applied to investigate the impact of valve anatomy and patient risk factors on valve repair rate and operative risk.
Results: The study cohort consisted of 4524 patients with DMR (complex DMR, 1296; simple DMR, 3228). Valve repair rate was 87.3% and 91% in complex DMR and simple DMR, respectively. Predictors of valve replacement were anterior leaflet prolapse/flail, bileaflet flail, female sex, age, and reoperation, whereas Barlow disease was protective. Clinical results were comparable between complex DMR and simple DMR. On subgroup analyses, high-risk patients showed less satisfactory outcomes with respect to both the valve repair and operative mortality rates.
Conclusions: Our findings suggest that complex DMR can be satisfactorily addressed by minimally invasive techniques. However, whereas complex disease was associated with low operative risk, anterior leaflet lesions and bileaflet flail remain negative predictors of successful valve repair. Conversely, valve repair rate was less satisfactory in high-risk patients, regardless of DMR complexity.
Indocyanine Green (ICG): A Versatile Tool in Enhancing Precision in Minimally Invasive Thoracic Surgery
Intraoperative fluorescence imaging using indocyanine green (ICG) is an innovative and safe tool in minimally invasive thoracic surgery. It provides real-time imaging capabilities that can enhance surgical precision. We describe several clinical uses of ICG including intersegmental plane identification, thoracic duct injury localisation, anomalous systemic artery identification in pulmonary sequestration, phrenic nerve identification, and sentinel lymph node mapping. Successful visualisation of ICG was achieved to identify intra-thoracic anatomical structures and boundaries, allowing for safe and precise dissection.
Pearls and Pitfalls of Epicardial Echocardiography for Implantation of Impella CP Devices in Ovine Models
The Impella CP is a percutaneously inserted temporary left ventricular assist device used in clinical practice and in translational research into cardiogenic shock, perioperative cardiac surgery, acute cardiac failure and mechanical circulatory support. Fluoroscopic guidance is usually used for insertion of an Impella, thus limiting insertion to within catheterization laboratories. Transthoracic, transoesophageal and intracardiac echocardiography have been reported to guide Impella CP implantation with identified specific limitations stemming from the surgical, anatomical and equipment factors. We conducted translational prospective descriptive feasibility investigation as a part of two other hemodynamic Impella studies. It showed the successful application of epicardial echocardiographic scanning for implantation of Impella CP devices in ovine models, from which details of the technique and identified pitfalls are described with practical solutions for future investigators and clinicians. Many described findings are relevant to any other echocardiographic techniques when adequate imaging of the Impella and relevant anatomical structures is achievable.
Transatlantic analysis of patient profiles and mid-term survival after isolated coronary artery bypass grafting: a head-to-head comparison between the European DuraGraft Registry and the US STS Registry
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.
Outcomes following heart valve surgery in patients with infective endocarditis and preoperative septic cerebral embolism: insights from the CAMPAIGN study group
Objectives: This study aimed to analyse the impact of preoperative septic cerebral embolism on early and late postoperative outcomes in patients with infective endocarditis undergoing valve surgery.
Methods: Retrospective multicentric study based on the Clinical Multicentric Project for Analysis of Infective Endocarditis in Germany (CAMPAIGN) registry comprising patients with infective endocarditis who underwent valve surgery between 1994 and 2018 at 6 German centres. Patients were divided into 2 groups for statistical comparison according to the presence or absence of preoperative septic cerebral embolism. Propensity score matching was performed for adjusted comparisons of postoperative outcomes. Primary outcomes were 30-day mortality and estimated 5-year survival.
Results: A total of 4917 patients were included in the analysis, 3909 (79.5%) patients without and 1008 (20.5%) patients with preoperative septic cerebral embolism. Patients with preoperative septic cerebral embolism had more baseline comorbidities. Mitral valve endocarditis (44.1% vs 33.0% P < 0.001), large vegetations >10 mm (43.1% vs 30.0%, P < 0.001), and Staphylococcus species infection (42.3% vs 21.3%, P < 0.001) were more frequent in the cerebral embolism group. Among patients with preoperative cerebral embolism, 286 (28.4%) patients had no stroke signs (silent stroke). After matching (1008 matched pairs), there was no statistically significant difference in 30-day mortality (20.1% vs 22.8%; P = 0.14) and 5-year survival (47.8% vs 49.1%; stratified log-rank P = 0.77) in patients with and without preoperative cerebral embolism, respectively.
Conclusions: Preoperative septic cerebral embolism in patients with infective endocarditis requiring valve surgery does not negatively affect early or late mortality; therefore, it should not play a major role in deciding if surgery is to be performed.
Sex-related differences in patients with infective endocarditis requiring cardiac surgery: insights from the CAMPAIGN Study Group
Objectives: Sex-related differences play a role in cardiovascular disease-related outcomes. There is, however, a knowledge gap regarding sex-specific differences in patients with infective endocarditis (IE)-requiring surgical treatment. This study aims to analyse sex-related differences in the clinical presentation, treatment and clinical outcomes of patients with IE-requiring surgical treatment from the multicentric Germany-wide CAMPAIGN registry.
Methods: Patients with IE who underwent cardiac surgery between 1994 and 2018 at six German centres were retrospectively analysed. Outcomes were compared based on patients’ sex. Primary outcomes were 30-day mortality and mid-term survival.
Results: A total of 4917 patients were included in the analysis (1364 female [27.7%] and 3553 male [72.3%]). Female patients presented with more comorbidities and higher surgical risk (EuroScore II 12.0% vs 10.0%, P < 0.001). The early postoperative course of female patients was characterized by longer ventilation times (20.0 h vs 16.0 h; P = 0.004), longer intensive care unit stay (4.0 days vs 3.0 days; P < 0.001), and more frequent new-onset dialysis (265 [20.3%] vs 549 [16.3%]; P = 0.001). The 30-day mortality was 13.8% and 15.5% in female and male patients, respectively (P = 0.06). The estimated mid-term survival was significantly higher amongst male patients (56.1% vs 45.4%; Log-rank P < 0.001). Female sex was an independent predictor of mid-term mortality (HR 1.2 [95% CI 1.0-1.4], P = 0.01).
Conclusions: Male patients more frequently undergo cardiac surgery for IE. However, female patients have a higher surgical risk profile and subsequently an increased early postoperative morbidity, but with similar 30-day mortality compared with male patients. The estimated mid-term survival is lower amongst female patients.
