Lifelong high-fat, high-sucrose diet causes sex-specific heart dysfunction in mouse offspring

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 (E<i>ed</i>), suggesting greater ventricular stiffness. Ventricular-arterial coupling (E<i>es</i>/E<i>a</i>) 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.