Heterogeneous abnormalities of in-vivo left ventricular calcium influx and function in mouse models of muscular dystrophy cardiomyopathy.

BACKGROUND: Manganese-enhanced cardiovascular magnetic resonance (MECMR) can non-invasively assess myocardial calcium influx, and calcium levels are known to be elevated in muscular dystrophy cardiomyopathy based on cellular studies. METHODS: Left ventricular functional studies and MECMR were performed in mdx mice (model of Duchenne muscular dystrophy, 24 and 40 weeks) and Sgcd -/- mice (limb girdle muscular dystrophy 2 F, 16 and 32 weeks), compared to wild type controls (C57Bl/10, WT). RESULTS: Both models had left ventricular hypertrophy at the later age compared to WT, though the mdx mice had reduced stroke volumes and the Sgcd -/- mice increased heart rate and cardiac index. Especially at the younger ages, MECMR was significantly elevated in both models (both P < 0.05 versus WT). The L-type calcium channel inhibitor diltiazem (5 mg/kg i.p.) significantly reduced MECMR in the mdx mice (P < 0.01), though only with a higher dose (10 mg/kg i.p.) in the Sgcd -/- mice (P < 0.05). As the Sgcd -/- mice had increased heart rates, to determine the role of heart rate in MECMR we studied the hyperpolarization-activated cyclic nucleotide-gated channel inhibitor ZD 7288 which selectively reduces heart rate. This reduced heart rate and MECMR in all mouse groups. However, when looking at the time course of reduction of MECMR in the Sgcd -/- mice at up to 5 minutes of the manganese infusion when heart rates were matched to the WT mice, MECMR was still significantly elevated in the Sgcd -/- mice (P < 0.01) indicating that heart rate alone could not account for all the increased MECMR. CONCLUSIONS: Despite both mouse models exhibiting increased in-vivo calcium influx at an early stage in the development of the cardiomyopathy before left ventricular hypertrophy, there are distinct phenotypical differences between the 2 models in terms of heart rates, hemodynamics and responses to calcium channel inhibitors.

Annual mass budget of Antarctic ice shelves from 1997 to 2021.

Antarctic ice shelves moderate the contribution of the Antarctic Ice Sheet to global sea level rise; however, ice shelf health remains poorly constrained. Here, we present the annual mass budget of all Antarctic ice shelves from 1997 to 2021. Out of 162 ice shelves, 71 lost mass, 29 gained mass, and 62 did not change mass significantly. Of the shelves that lost mass, 68 had statistically significant negative mass trends, 48 lost more than 30% of their initial mass, and basal melting was the dominant contributor to that mass loss at a majority (68%). At many ice shelves, mass losses due to basal melting or iceberg calving were significantly positively correlated with grounding line discharge anomalies; however, the strength and form of this relationship varied substantially between ice shelves. Our results illustrate the utility of partitioning high-resolution ice shelf mass balance observations into its components to quantify the contributors to ice shelf mass change and the response of grounded ice.

Sea level rise from West Antarctic mass loss significantly modified by large snowfall anomalies.

Mass loss from the West Antarctic Ice Sheet is dominated by glaciers draining into the Amundsen Sea Embayment (ASE), yet the impact of anomalous precipitation on the mass balance of the ASE is poorly known. Here we present a 25-year (1996-2021) record of ASE input-output mass balance and evaluate how two periods of anomalous precipitation affected its sea level contribution. Since 1996, the ASE has lost 3331 ± 424 Gt ice, contributing 9.2 ± 1.2 mm to global sea level. Overall, surface mass balance anomalies contributed little (7.7%) to total mass loss; however, two anomalous precipitation events had larger, albeit short-lived, impacts on rates of mass change. During 2009-2013, persistently low snowfall led to an additional 51 ± 4 Gt yr-1 mass loss in those years (contributing positively to the total loss of 195 ± 4 Gt yr-1). Contrastingly, extreme precipitation in the winters of 2019 and 2020 decreased mass loss by 60 ± 16 Gt yr-1 during those years (contributing negatively to the total loss of 107 ± 15 Gt yr-1). These results emphasise the important impact of extreme snowfall variability on the short-term sea level contribution from West Antarctica.

Long-term blocking of calcium channels in mdx mice results in differential effects on heart and skeletal muscle.

The disease mechanisms underlying dystrophin-deficient muscular dystrophy are complex, involving not only muscle membrane fragility, but also dysregulated calcium homeostasis. Specifically, it has been proposed that calcium channels directly initiate a cascade of pathological events by allowing calcium ions to enter the cell. The objective of this study was to investigate the effect of chronically blocking calcium channels with the aminoglycoside antibiotic streptomycin from onset of disease in the mdx mouse model of Duchenne muscular dystrophy (DMD). Treatment in utero onwards delayed onset of dystrophic symptoms in the limb muscle of young mdx mice, but did not prevent degeneration and regeneration events occurring later in the disease course. Long-term treatment had a positive effect on limb muscle pathology, reduced fibrosis, increased sarcolemmal stability, and promoted muscle regeneration in older mice. However, streptomycin treatment did not show positive effects in diaphragm or heart muscle, and heart pathology was worsened. Thus, blocking calcium channels even before disease onset does not prevent dystrophy, making this an unlikely treatment for DMD. These findings highlight the importance of analyzing several time points throughout the life of the treated mice, as well as analyzing many tissues, to get a complete picture of treatment efficacy.

Rapid accelerations of Antarctic Peninsula outlet glaciers driven by surface melt.

Atmospheric warming is increasing surface melting across the Antarctic Peninsula, with unknown impacts upon glacier dynamics at the ice-bed interface. Using high-resolution satellite-derived ice velocity data, optical satellite imagery and regional climate modelling, we show that drainage of surface meltwater to the bed of outlet glaciers on the Antarctic Peninsula occurs and triggers rapid ice flow accelerations (up to 100% greater than the annual mean). This provides a mechanism for this sector of the Antarctic Ice Sheet to respond rapidly to atmospheric warming. We infer that delivery of water to the bed transiently increases basal water pressure, enhancing basal motion, but efficient evacuation subsequently reduces water pressure causing ice deceleration. Currently, melt events are sporadic, so efficient subglacial drainage cannot be maintained, resulting in multiple short-lived (<6 day) ice flow perturbations. Future increases in meltwater could induce a shift to a glacier dynamic regime characterised by seasonal-scale hydrologically-driven ice flow variations.

Cardiogoniometry Compared to Fractional Flow Reserve at Identifying Physiologically Significant Coronary Stenosis: The CARDIOFLOW Study.

Cardiogoniometry (CGM) is method of 3-dimensional electrocardiographic assessment which has been shown to identify patients with angiographically defined, stable coronary artery disease (CAD). However, angiographic evidence of CAD, does not always correlate to physiologically significant disease. The aim of our study was to assess the ability of CGM to detect physiologically significant coronary stenosis defined by fractional flow reserve (FFR). In a tertiary cardiology centre, elective patients with single vessel CAD were enrolled into a prospective double blinded observational study. A baseline CGM recording was performed at rest. A second CGM recording was performed during the FFR procedure, at the time of adenosine induced maximal hyperaemia. A significant CGM result was defined as an automatically calculated ischaemia score < 0 and a significant FFR ratio was defined as < 0.80. Measures of diagnostic performance (including sensitivity and specificity) were calculated for CGM at rest and during maximal hyperaemia. Forty-five patients were included (aged 61.1 ± 11.0; 60.0% male), of which eighteen (40%) were found to have significant CAD when assessed by FFR. At rest, CGM yielded a sensitivity of 33.3% and specificity of 63.0%. At maximal hyperaemia the sensitivity and specificity of CGM was 71.4 and 50.0% respectively. The diagnostic performance of CGM to detect physiologically significant stable CAD is poor at rest. Although, the diagnostic performance of CGM improves substantially during maximal hyperaemia, it does not reach sufficient levels of accuracy to be used routinely in clinical practice.

Cardiosphere-Derived Cells Require Endoglin for Paracrine-Mediated Angiogenesis.

Clinical trials of stem cell therapy to treat ischemic heart disease primarily use heterogeneous stem cell populations. Small benefits occur via paracrine mechanisms that include stimulating angiogenesis, and increased understanding of these mechanisms would help to improve patient outcomes. Cardiosphere-derived-cells (CDCs) are an example of these heterogeneous stem cell populations, cultured from cardiac tissue. CDCs express endoglin, a co-receptor that binds specific transforming growth factor ß (TGFß) family ligands, including bone morphogenetic protein 9 (BMP9). In endothelial cells endoglin regulates angiogenic responses, and we therefore hypothesized that endoglin is required to promote the paracrine pro-angiogenic properties of CDCs. Cre/LoxP technology was used to genetically manipulate endoglin expression in CDCs, and we found that the pro-angiogenic properties of the CDC secretome are endoglin dependent both in vitro and in vivo. Importantly, BMP9 pre-treatment of endoglin-depleted CDCs restores their pro-angiogenic paracrine properties. As BMP9 signaling is normally required to maintain endoglin expression, we propose that media containing BMP9 could be critical for therapeutic CDC preparation.

Using MRI to predict future adverse cardiac remodelling in a male mouse model of myocardial infarction.

BACKGROUND: Mice are frequently used in research to examine outcomes of myocardial infarction (MI) and to investigate therapeutic interventions at an early pre-clinical stage. The MI model is generated by surgically occluding a major coronary artery, but natural variation in murine coronary anatomy can generate variable outcomes that will inevitably affect the accuracy of such investigations. The aim of this study was to use MRI to derive the most sensitive early variable that could be used to predict subsequent adverse cardiac remodelling in a male mouse model of MI. METHODS: Using a longitudinal study design, heart structure and function were evaluated using cardiac MRI at one week following surgical MI to generate the early measurements and again at four weeks, when the scar had matured. The primary variables measured at week one were left ventricular volumes at end systole (LV-ESV) and at end diastole (LV-EDV), infarct size, LV-cardiac mass, and ejection fraction (EF). RESULTS: Univariate and multiple regression analyses showed that LV-ESV at one week following MI could be used to accurately predict various parameters of adverse LV remodelling at four weeks post-MI. However, the highest correlation was between LV-ESV at one week following MI and LV-EDV at four weeks (r = 0.99; p < 0.0001), making LV-ESV at one week a valuable predictor variable of future adverse ventricular remodelling after MI. CONCLUSION: Using MRI to determine LV-ESV at an early stage following MI enables a more robust analysis of potential therapeutic interventions to ameliorate adverse cardiac remodelling.