Faster skin wound healing predicts survival after myocardial infarction

Abstract

Skin wound healing and the cardiac healing response to myocardial infarction (MI) both progress through similar pathways involving inflammation, resolution, tissue repair, and scar formation. Due to the similarities, we hypothesized that the healing response to skin wounding would predict future response to MI. Mice were given a 3 mm skin wound using a disposable biopsy punch, and the skin wound was imaged daily until closure. Wound closure was quantified using Image J software. The same set of mice was given MI by permanent coronary artery ligation 28 days later and followed for 7 days. Cardiac physiology (volume, dimension, ejection fraction, fractional shortening, wall thickness) was measured by echocardiography at baseline, and 3 and 7 days post MI. Mice that survived until MI day 7 were grouped as survivors (30 mice, 68%), and animals that died from MI were grouped as non‐survivors (14 mice, 32%). Survivors had faster skin wound healing compared to non‐survivors. Faster skin wound healing predicted MI survival better than commonly used cardiac functional variables (e.g., infarct size, fractional shortening, and end diastolic dimension). We mapped the plasma N‐glycoproteome 3 days after skin wounding and 3 days after MI using mass spectrometry. The glycoproteome profile of MI day 3 plasma revealed alpha‐2‐macroglobulin and ELL‐associated factor 1 as strong predictors of future MI death and progression to heart failure. A second cohort of MI mice validated these findings. In patients, alpha‐2‐macroglobulin was 1.7±0.3‐fold elevated 48h after presentation of MI (p=0.009, 18 controls, 41 MI patients). The glycoproteome profile of plasma collected 3 days post skin wounding identified apolipoprotein D and vitamin D binding protein to mirror skin wound healing. Apolipoprotein D detrimentally regulated both skin and cardiac wound healing in part by promoting inflammation. Plasma levels of vitamin D binding protein and galectin 3 binding after skin wounding also predicted future MI dilation and progression to heart failure. Our results reveal that the skin is a mirror to the heart and common pathways link wound healing across organs.