Cardiac fibrosis is a major driver of heart failure, a leading cause of morbidity and mortality worldwide. Advances in single-cell transcriptomics have revealed the pivotal role of SPP1+ macrophages in the pathogenesis of cardiac fibrosis, positioning them as critical mediators and promising therapeutic targets. SPP1+ macrophages, characterized by elevated expression of secreted phosphoprotein 1 (SPP1) and often co-expressing Triggering Receptor Expressed on Myeloid Cells 2 (TREM2), localize to fibrotic niches in the heart and other organs. These cells interact with activated fibroblasts and myofibroblasts, driving extracellular matrix remodeling and fibrosis progression. Their differentiation is orchestrated by signals such as CXCL4, GM-CSF, and IL-17A, further emphasizing their regulatory complexity. Therapeutic strategies targeting SPP1+ macrophages have shown encouraging preclinical results. Approaches include silencing Spp1 using antibody–siRNA conjugates and modulating key pathways involved in macrophage differentiation. These interventions have effectively reduced fibrosis and improved cardiac function in animal models. The mechanisms underlying SPP1+ macrophage function in cardiac fibrosis provide a foundation for innovative therapies aimed at mitigating pathological remodeling and improving outcomes in patients with heart failure. This emerging field has significant potential to transform the treatment of fibrotic heart disease.

Cirrhotic patients often suffer from cirrhotic cardiomyopathy (CCM). Previous animal models of CCM were inconsistent concerning the time and mechanism of injury; thus, the temporal dynamics and cardiac vulnerability were studied in more detail. Rats underwent bile duct ligation (BDL) and a second surgery 28 days later. Cardiac function was assessed by conductance catheter and echocardiography. Histology, gene expression, and serum parameters were analyzed. A chronotropic incompetence (P_d31 < 0.001) and impaired contractility at rest and a reduced contractile reserve (P_d31 = 0.03, P_dob-d31 < 0.001) were seen 31 days after BDL with increased creatine (P_d35, P_d42, and P_d56 < 0.05) and transaminases (P_d31 < 0.001). A total of 56 days after BDL, myocardial fibrosis was seen (P_d56 < 0.001) accompanied by macrophage infiltration (CD68: P_group < 0.001) and systemic inflammation (TNFα: P_group < 0.001, white blood cell count: P_group < 0.001). Myocardial expression of peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC1α) was increased after 31 (P_d31 < 0.001) and decreased after 42 (P_d42 < 0.001) and 56 days (P_d56 < 0.001). Caspase-3 expression was increased 31 and 56 days after BDL (P_d31 = 0.005; P_d56 = 0.005). Structural changes in the myocardium were seen after 8 weeks. After the second surgery (second hit), transient myocardial insufficiency with secondary organ dysfunction was seen, characterized by reduced contractility and contractile reserve.

To investigate whether acute liver failure (ALF) leads to secondary acute myocardial injury, 100 ALF patients that were retrospectively identified in a single center based on ICD 10 codes and 8 rats from an experimental study that died early after bile duct ligation (BDL) were examined. Creatine kinase (CK), creatine kinase-MB isoenzyme (CKMB) and cardiac troponin-I (cTnI) were analyzed as markers of myocardial injury. For histological analysis,hematoxylin-eosin(HE),elastic Van Gieson(EVG), CD41 and myeloperoxidase were used to stain rat hearts. Major adverse cardiac events (MACEs) were a critical factor for mortality (p = 0.037) in human ALF. Deceased patients exhibited higher levels of CKMB than survivors (p = 0.023). CKMB was a predictor of mortality in ALF (p = 0.013). Animals that died early after BDL exhibited increased cTnI, CKMB, tumor necrosis factor α (TNFα) and interleukin-6 (IL-6) levels compared to controls (cTnI: p = 0.011, CKMB: p = 0.008, TNFα: p = 0.003, IL-6: p = 0.006). These animals showed perivascular lesions and wavy fibers, microthrombi and neutrophilic infiltration in the heart. MACEs are decisive for mortality in human ALF, and elevated CKMB values indicate that this might be due to structural myocardial damage. Accordingly, CKMB was found to have predictive value for mortality in ALF. The results are substantiated by data from a rat BDL model demonstrating diffuse myocardial injury.

Severity assessment in animals is an ongoing field of research. In particular, the question of objectifiable and meaningful parameters of score-sheets, as well as their best combination, arise. This retrospective analysis investigates the suitability of a score-sheet for assessing severity and seeks to optimise it for predicting survival in 89 male Sprague Dawley rats (Rattus norvegicus), during an experiment evaluating the influence of liver cirrhosis by bile duct ligation (BDL) on vascular healing. The following five parameters were compared for their predictive power: (i) overall score; (ii) relative weight loss; (iii) general condition score; (iv) spontaneous behaviour score; and (v) the observer’s assessment whether pain might be present. Suitable cut-off values of these individual parameters and the combination of multiple parameters were investigated. A total of ten rats (11.2%; 10/89) died or had to be sacrificed at an early stage due to pre-defined humane endpoints. Neither the overall score nor any individual parameter yielded satisfactory results for predicting survival. Using retrospectively calculated cut-off values and combining the overall score with the observer’s assessment of whether the animal required analgesia (dipyrone) for pain relief resulted in an improved prediction of survival on the second post-operative day. This study demonstrates that combining score parameters was more suitable than using single ones and that experienced human judgement of animals can be useful in addition to objective parameters in the assessment of severity. By optimising the score-sheet and better understanding the burden of the model on rats, this study contributes to animal welfare.

Background: Previous studies have shown cardiac abnormalities in acute liver injury, suggesting a potential role in the associated high mortality. Methods: We designed an experimental study exploring the short-term effects of acute cholestasis-induced liver injury on cardiac function and structure in a rodent bile duct ligation (BDL) model to elucidate the potential interplay. Thirty-seven male Sprague-Dawley rats were subjected to BDL surgery (n = 28) or served as sham-operated (n = 9) controls. Transthoracic echocardiography, Doppler evaluation of the left anterior descending coronary artery, and myocardial contrast echocardiography were performed at rest and during adenosine and dobutamine stress 5 days after BDL. Immunohistochemical staining of myocardial tissue samples for hypoxia and inflammation as well as serum analysis were performed. Results: BDL animals exhibited acute liver injury with elevated transaminases, bilirubin, and total circulating bile acids (TBA) 5 days after BDL (TBA control: 0.81 ± 2.54 µmol/L vs. BDL: 127.52 ± 57.03 µmol/L; p < 0.001). Concurrently, cardiac function was significantly impaired, characterized by reduced cardiac output (CO) and global longitudinal strain (GLS) in the echocardiography at rest and under pharmacological stress (CO rest control: 120.6 ± 24.3 mL/min vs. BDL 102.5 ± 16.6 mL/min, p = 0.041; GLS rest control: −24.05 ± 3.8% vs. BDL: −18.5 ± 5.1%, p = 0.01). Myocardial perfusion analysis revealed a reduced myocardial blood flow at rest and a decreased coronary flow velocity reserve (CFVR) under dobutamine stress in the BDL animals (CFVR control: 2.1 ± 0.6 vs. BDL: 1.7 ± 0.5 p = 0.047). Immunofluorescence staining indicated myocardial hypoxia and increased neutrophil infiltration. Conclusions: In summary, acute cholestasis-induced liver injury can lead to impaired cardiac function mediated by coronary microvascular dysfunction, suggesting that major adverse cardiac events may contribute to the mortality of acute liver failure. This may be due to endothelial dysfunction and direct bile acid signaling.