https://doi.org/10.1007/s00392-024-02526-y
1Universitätsklinikum Düsseldorf Klinik für Kardiologie, Pneumologie und Angiologie Düsseldorf, Deutschland; 2UKBB - Universitäts-Kinderspital beider Basel Kinderkardiologie Basel, Schweiz; 3Universitätsklinikum Düsseldorf Institut für Molekulare Medizin III Düsseldorf, Deutschland
Background:
Type 2 Diabetes mellitus (T2D) Patients show decreased myocardial strain and worse outcome after acute myocardial infarction. This might in part be due to reduced remote myocardial function. The sphingolipid sphingosine-1-phosphate (S1P) can improve cardiac outcome after ischemia and was shown to be reduced in T2D. In this study, we investigated the effect of increased circulating S1P levels on remote myocardial function in mice with diet-induced obesity (DIO). In addition, we focused on myocardial S1P release which was shown to be dependent on pannexin channels. Therefore, we evaluated remote myocardial strain after ischemia in pannexin1 deficient mice.
Methods:
Wildtype mice were treated with high-fat diet (EF Bio-Serv #F1850 mod. 24% sucrose HF 35.85% lard) for 24 weeks. The S1P lyase inhibitor 4-deoxypyridoxine (DOP) was additionally given by drinking water for 12 weeks leading to increased circulating S1P levels. Strain analysis was conducted at the end of diet by including longitudinal, circumferential, and radial strain (MS 400, VEVO 3100, VisualSonicsInc., Toronto, Canada; analysis of peak strain [%], time to peak [ms], strain rate [1/s]). DIO mice were transferred to ischemia/reperfusion induced by transient ligation of the left-anterior descending artery for the duration of 30 minutes. After reperfusion of 24 hours, re-assessment of post-ischemic myocardial strain separated into segments of infarcted area and remote myocardium was conducted. In pannexin-1 deficient mice (Panx1-/-), retrospective analysis of echocardiographic pictures prior and 24h after IR was conducted equally. Worsening of strain and time-to-peak were calculated in percent of baseline in these segments. Ratio paired t-test and unpaired t-test was conducted to compare groups, p<0.05 was considered significant.
Results:
DIO and normal chow diet mice showed equal infarct size. However, worsening of remote myocardial function was aggravated in DIO compared to NCD regarding circumferential and radial strain (in percent of baseline; circumferential - NCD 96.5±20.4% vs. DIO 68.58±15.35%, p=0.0159; radial – NCD 82.23±22.3% vs. DIO 51.62±17.0%, p=0.0113). In the infarcted area, worsening did not differ between groups (in percent of baseline; circumferential – NCD 70.72±23.6% vs. DIO 52.47±13.81%, p=0.1102; radial – NCD 63.96±21.45% vs. DIO 70.93±26.7%, p=0.5906). Worsening of longitudinal strain was equal both in the remote and infarct zone. Long-term DOP treatment led to higher maintenance of remote myocardial radial strain (DIO vs. DIO+DOP 109.2±49.64%, p=0.0279). This was accompanied by higher time-to peak in these segments (in percent of baseline; DIO – 82.9±14.5% vs. DIO+DOP 107.6±21.5%, p=0.0468). Worsening of circumferential and longitudinal strain was equal. In the Panx1-/- mice, worsening of remote function was equal compared to non-deficient littermates.
Conclusion:
In this study, we could demonstrate that global strain is worse under DIO conditions after myocardial infarction. Increased S1P levels by long-term DOP treatment prior to AMI improve remote post-ischemic function. Hence, S1P might be a promising therapeutic target for patients with diabetic conditions. Interestingly, deficiency of Pannexin1 channels did not affect aggravation of myocardial strain. This indicates that endogenous myocardial S1P does not seem to have a relevant impact on remote myocardial function.