Difference in functional constituents of myocardial passive compliance renders BalbC/J mice sensitive to pulmonary edema compared to C57BL6/J mice

Abstract

Study objective: We have found different survival rates in response to a 4-day angiotensin II (AngII) and high salt diet - treatment in two mouse strains, BalbC/J and C57BL6/J. The mortality is increased in BalbC/J mice alongside increased lung weight but the reason is unknown. Hypothesis: We hypothesize the increased mortality is due to differences in myocardial compliance. Methodology: Male mice were treated with AngII by osmotic mini-pump infusion and fed a high salt-diet (3%) for 4 days. At the end of the treatment the lungs were weighed. Left ventricle (LV) passive compliance was assessed by Langendorff, and collagen and non-collagen functional fractions using demembranated trabecular strips. A commercial assay was used to determine total collagen of the myocardium. All procedures were approved by the local ethics committee. Comparisons were carried out using unpaired t-test. All intervals reflect standard error of the mean. Data: Lung weights of animals before treatment were similar in BalbC/J (148 ± 8.8 mg (n=5)) and C57BL6/J (155 ± 12 mg (n=5)) mice (p>0.05). After treatment they were higher in BalbC/J (255 ± 24 mg (n=7)) than C57BL6/J (166 ± 5.1 mg (n=6)) (p<0.01). LV passive strain was higher in BalbC/J (62.4 ± 11.9 mN/mm2 (n=9)) than C57BL6/J (28.2 ± 2.3 mN/mm2 (n=7)) (p<0.05), at 36 μl LV inflation past 5 mmHg end-diastolic pressure. In demembranated trabeculae, passive stiffness was higher in BalbC/J (38.7 ± 5.5 mN/mm2 (n=6)) than C57BL6/J (22.5 ± 2.0 mN/mm2 (n=6)) (p<0.05) at baseline, as measured by passive tension at 15 % stretch from sarcomere length 2.0 μm. This was derived from the non-collagen fraction which was higher in BalbC (23.4 ± 2.8 mN/mm2 (n=6)) than C57BL6/J (12.4 ± 1.3 mN/mm2 (n=6)) (p<0.01), unlike the collagen fraction that was the same (BalbC/J 15.3 ± 3.8 mN/mm2 (n=6), C57BL6/J 10.1 ± 1.5 mN/mm2 (n=6) (p>0.05)). There was no difference in myocardial collagen content (BalbC/J 0.20 ± 0.01 μg/μl (n=7), C57BL6/J 0.18 ± 0.01 μg/μl (n=9) (p>0.05)). Summary of results: Gross organ evaluation by Langendorff indicates higher myocardial stiffness in BalbC/J than C57BL6/. This renders the heart susceptible to backward failure. This is supported by findings in demembranated tissue bundles. The origin of this appears to lie in the non-collagen fraction of passive stiffness, as indicated by functional and biochemical assays. Conclusion: An acute lung weight increase indicates pulmonary edema. The most common reason for this is backwards failure of the LV. Our investigations into myocardial function suggest that BalbC/J mice has a propensity for this due to lower compliance secondary to increased non-collagen fraction, compared to C57BL6/J. This is likely caused by titin-derived stiffness. Therapies to modulate titin-derived stiffness may be useful to avoid backward failure. These findings also represent important knowledge for the research community modeling human heart disease on the backbone of two common mouse strains. The study was funded with grants from the Swedish Society of Medical Research and Åke Wiberg Foundation to HI, Swedish Heart-Lung Foundation to MH, and from Uppsala University Hospital to HI and MH. 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.