This scoping review and retrospective medical record review is focused on potential sex differences in cardiovascular diseases in patients with Down syndrome. We limited our review to peer-reviewed, primary articles in the English language, in the PubMed and Web of Science databases from 1965-2021. Four categorical domains were identified and searched using additional keywords: 1) congenital heart disease, 2) baseline physiology and risk factors, 3) heart disease and hypertension, and 4) stroke and cerebrovascular disease. Articles were included if they reported male and female distinct data, participants with Down syndrome, and one of our keywords. The retrospective medical record review was completed using 75 participating health care organizations to identify the incidence of congenital and cardiovascular diseases and to quantify cardiovascular risk factors, in male and female patients. Female patients with Down syndrome are at higher risk of hypertension, ischemic heart disease, and cerebrovascular disease. The risk of congenital heart disease is higher in males with Down Syndrome, at all ages included in our analyses. Some of the male:female sex differences in cardiovascular disease risk in the general patient population are not present, or reversed in the Down syndrome population. This information should be considered for future investigations and ongoing patient care.

Chamber exposures are commonly used to evaluate the physiological and pathophysiological consequences of intermittent hypoxia in animal models. Researchers in this field use both commercial and custom-built chambers in their experiments. The purpose of this Cores of Reproducibility in Physiology paper is to demonstrate potential sources of variability in these systems that researchers should consider. Evaluating the relationship between arterial oxygen saturation and inspired oxygen concentration, we found that there are important sex-dependent differences in the commonly used C57BL6/J mouse model. The time delay of the oxygen sensor that provides feedback to the system during the ramp-down and ramp-up phases was different, limiting the number of cycles per hour that can be conducted and the overall stability of the oxygen concentration. The time to reach the hypoxic and normoxic hold stages, and the overall oxygen concentration, were impacted by the cycle number. These variables were further impacted by whether there are animals present in the chamber, highlighting the importance of verifying the cycling frequency with animals in the chamber. At ≤14 cycles per hour, instability in the chamber oxygen concentration did not impact arterial oxygen saturation but may be important at higher cycle numbers. Taken together, these data demonstrate the important sources of variability that justify reporting and verifying the target oxygen concentration, cycling frequency, and arterial oxygen concentration, particularly when comparing different animal models and chamber configurations.

Chronic intermittent hypoxia, CIH, is a feature of sleep apnea widely used in research to mechanistically examine the physiological effects of sleep apnea. These mechanistic studies commonly utilize mice as the study model. In room air, mice experience periodic apneas and arterial oxygen desaturations. Activation of the carotid body could stabilize breathing and decrease these events. Therefore, we hypothesized that C57BL/6J mice experience fewer hypoxic events with decreasing FIO2.We placed 6 C57BL/6J mice (3 male, 3 female) in an Emka® unrestrained barometric plethysmograph and measured pulse oximetry using the STARR LifeSciences MouseOx® Plus system. The mice were exposed to different levels of FIO2 for 10 minutes each: 0.21, 0.15, 0.12, 0.09, 0.30 ± 0.01. We defined a hypoxic event as 3% deviation from the average oxygen saturation at each FIO2. Mice did not show fewer hypoxic events when exposed to increasing levels of hypoxia. In fact, mice experienced more hypoxic events at 0.15 than 0.21 and 0.30 FIO2 (P<0.05). Mice also experienced more hypoxic events at 0.12 than at 0.30 FIO2. Additionally, we found that hypoxic event nadir SpO2 was significantly lower at all FIO2 levels when compared to 0.21 FIO2. Hypoxic events at all FIO2 levels had significantly lower average SpO2 compared to 0.21 FIO2. No change was observed for average SpO2 for hypoxic events at 0.30 FIO2 relative to 0.21 FIO2. Contrary to our hypothesis, intermittent hypoxic events are not stabilized by exposure to a hypoxic environment. Future work will evaluate this in other mouse strains. 1R56HL152365 This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Over the last couple of decades, the median survival of individuals with Down syndrome (Ds) increased from 30 to 60 years. The Ts65Dn mouse model recapitulates most of the cognitive and neural phenotypes described in Ds individuals and its use continues to expand into other fields. The Ds population is at risk for cardiovascular comorbidities. We hypothesized that contractility in Ts65Dn mice will be lower compared to controls, and differences between strains will become exacerbated with age. The aim of this study was to comprehensively access the cardiac function in the Ts65Dn model across the lifespan. Ts65Dn and C57BL/6J mice (n = 3-5) were tested at 3, 6, and 12 months of age. Left ventricular function was assessed in closed-chest mice using a microtip pressure-volume catheter (PVR-1030, Millar) which was introduced via the right carotid artery and coupled to a digital converter (ADInstruments). By transiently compressing the inferior abdominal vena cava, different preloads were induced, accessing hemodynamic assessment of the left ventricle. Finally, the heart was excised, trimmed, & weighed to assess the Fulton index. The end-diastolic pressure-volume relationship (ESPVR) increased at 12 months in Ts65Dn mice compared to controls. Comparison of the maximal velocity of pressure rise (+ dP/dt) did not differ between ages and genotypes. The maximal velocity of pressure fall (− dP/dt), however, was significantly lower in 12 months Ts65Dn compared to the 6-month group. Cardiac output (Q̇) decreased with aging in Ts65Dn mice compared to controls, therefore decreasing stroke volume (SV) and stroke work (SW). The index of arterial elastance (Ea) increased with aging in Ts65Dn mice compared to the control. Together, Ts65Dn mice have decreased systolic performance accompanied by increased contractility of the heart and increased aortic elastance, and these parameters are revealed as mice age. NIH R21HD099573 This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Children with Down syndrome have a high risk of leukemia and are at a higher risk for delayed early onset heart failure after treatment. Cardiac toxicity is more severe in female patients. Traditional risk factors for cardiovascular diseases in the general population may not be predictive of chemotherapy-induced heart failure in the Down Syndrome population. We used the Ts65Dn Down syndrome mouse model to investigate the impact of the chemotherapy agent daunorubicin on survival and arterial stiffness, a predictor of heart failure risk. We hypothesized that arterial stiffness will be increased in Ts65Dn mice treated with daunorubicin. Four-month-old Ts65Dn (n=12) and control wild-type Ts65Dn (WT Ts65Dn, n=8) mice were treated with low (2mg/kg), high (4mg/kg) dose of daunorubicin, or saline. Mice were injected twice over two weeks. Following treatment, we measured pulse wave velocity (PWV) weekly for 8 weeks using the Indus mouse Doppler flow velocity system. There was a significant decrease in PWV in mice treated with high-dose daunorubicin (p<0.001). Additionally, high-dose daunorubicin treatment resulted in a decreased survival in Ts65Dn mice (p<0.01). Overall, high-dose daunorubicin reduced PWV and survival in Ts65Dn and WT Ts65Dn mice. Daunorubicin has a dose-dependent impact on PWV in Ts65Dn and WT Ts65Dn mice. High-dose daunorubicin decreased aortic stiffness and increased mortality in Ts65Dn and WT Ts65Dn mice. This is the first demonstration that daunorubicin, the well known cardiotoxic agent, significantly impacts the conducting vasculature in Down syndrome as well. NIH R21 HD099573 This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.