Modeling cardiac contractility in pre-clinical catheterization laboratory settings remains an important task to collect results under controlled hemodynamic conditions, while providing an assessment of systolic and diastolic indices. Diligent hemodynamic monitoring with acute-based pressure-volume modeling uncovers early indicators of heart failure (HF). In this article, basic procedural assessments are outlined, while deeper dive into systolic index of contractility, the end systolic elastance is provided with references to older, while comparing it to novel approaches. Transient preload reduction using inferior vena cava occlusion (IVCO) is the current standardized maneuver used in hemodynamic protocols to provide an assessment of contractile responsiveness. In this article an example of standard measures from a single catheterization lab were depicted using tables and figures, giving background to transient preload reduction to assess the values of systolic cardiac contractility. Additionally, novel twists on other possible index(ices) coming from capturing ES point may well present future opportunities to collect systolic cardiac contractility. In this instance, both single beat systolic PPESPVR and IVCO using ES points present unique opportunities in this niche area of research. Final two sections of this article are dedicated to procedural steps and how to standardize execution of IVCO. Final section is reserved for analytical steps of how to visually compare systolic indices post-IVCO in case of linear and quadratic relationship.

Uveal melanoma is a highly aggressive intraocular malignancy with limited therapeutic options for metastatic disease. Existing transgenic uveal melanoma mouse models inadequately recapitulate human disease progression, whereas transplant models lack immune competence for studying the tumor immune microenvironment and therapeutic interventions. To address these limitations, we developed a genetically engineered mouse model incorporating stepwise genetic alterations implicated in human uveal melanoma progression. Spatiotemporally controlled expression of mutant GNAQQ209L from the endogenous locus induced choroidal nevi with limited penetrance. Concomitant BAP1 deletion enhanced nevus formation, whereas further MYC activation led to fully penetrant intraocular tumors with the potential to disseminate. Single-cell RNA sequencing revealed that malignant cells segregated into melanocytic and neural crest–like subpopulations characterized by distinct transcriptional and biosynthetic programs. Trajectory analyses inferred dedifferentiation from the melanocytic toward the neural crest–like state during tumor progression. Comparison with human uveal melanoma revealed commonalities with highly aggressive class 2 uveal melanoma, including gene expression signatures and copy-number gains affecting genes that map to human chromosome 8q beyond the activated MYC allele, suggesting cooperative effects of multiple drivers in this chromosomal region. The tumor microenvironment featured immunosuppressive macrophage populations and exhausted T cells, closely resembling human uveal melanoma. This physiologically relevant, immune-competent model provides a platform for investigating uveal melanoma biology, functionally characterizing candidate driver genes, and developing immune-based therapeutic strategies. Significance: Development of a mouse model resembling the genetic progression and phenotypic plasticity of human uveal melanoma offers an immune-competent preclinical platform for understanding disease immunogenomics and testing immune and targeted treatments.

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Proteinase-activated receptor-2 (PAR2) regulates cardiac pressure and vascular function through context-dependent mechanisms that integrate G protein-coupled receptor signalling. We investigated the baseline cardiovascular phenotype of PAR2-deficient (PAR2^−/−) mice and the acute in vivo effects of the PAR2 agonist trans-cinnamoyl-Leu-Ile-Gly-Arg-Leu-Orn-amide (tcLIGRLO). Left ventricular pressure–volume (PV) analysis revealed that PAR2^−/− mice had elevated systolic and diastolic pressures with reduced end-diastolic volumes and increased ejection fraction while maintaining stroke volume and cardiac output. Thus, PAR2 deficiency produces a pressure-dominant cardiovascular state with increased mechanical work and preserved global function. In WT mice, tcLIGRLO dose-dependently reduced cardiac pressure generation, contractility, relaxation kinetics, and stroke work, whereas these effects were absent in PAR2^−/− mice, indicating PAR2-dependent cardiac regulation. Despite these changes, global cardiac output remained largely preserved despite modest reductions in heart rate. In contrast, tcLIGRLO elicited strain-dependent vascular responses, including altered effective aortic elastance and reduced carotid blood flow in PAR2^−/− mice. Ex vivo experiments showed that tcLIGRLO-induced contraction in PAR2^−/− arteries required Gq-dependent signalling in this experimental context. These findings identify PAR2 as a context-dependent regulator of cardiac pressure and vascular tone, in which PAR2-dependent cardiac effects and PAR2-independent, Gq-mediated vascular responses reflect distinct but interacting signalling mechanisms.

Maternal obesity and high-fat, high-sucrose (HFHS) diets during development increase cardiometabolic risk in offspring, but long-term, sex-specific cardiac effects remain underexplored. This study examined how continuous HFHS exposure impacts cardiac function in male and female mice. Female dams were fed a control standard chow (CON) diet or HFHS diet for 8 weeks before pregnancy, continuing through gestation and lactation. Offspring were maintained on their dam’s diet until 29–32 weeks of age. Body composition and cardiac function were assessed using pressure–volume (P–V) loop analysis. HFHS offspring exhibited increased body weight and fat mass, with males showing greater adiposity. Lean mass was higher in males, but relative lean mass decreased in both sexes by 22 weeks in response to the HFHS diet. Cardiac assessments revealed load-dependent and load-independent impairments. HFHS exposure increased end-diastolic and end-systolic volumes, reduced ejection fraction, and lowered end-systolic elastance, indicating systolic dysfunction in both sexes. Diastolic function showed sex-specific alterations; HFHS exposure in males led to slower myocardial relaxation (less negative dP/dt min), while in females it increased end-diastolic elastance (Eed), suggesting greater ventricular stiffness. Ventricular–arterial coupling (Ees/Ea) was reduced in HFHS-exposed animals of both sexes, with females showing more pronounced impairments. Our results highlight sex-specific cardiac dysfunction in HFHS-exposed offspring, with females more susceptible to myocardial stiffness and coupling deficits. This underscores the need for sex-tailored interventions to mitigate long-term cardiovascular risks from early-life HFHS exposure.