{
  "abstract": "Introduction Hearts subjected to prolonged high workloads will dilate and fail. We hypothesized that high workload would cause oxidative stress within myocardium which in turn releases mitochondrial damage associated molecular patterns, causing immune activation.Methods Patients undergoing invasive cardiac procedures were stratified into three groups:Control (normal cardiac dimensions and contractility)Left ventricular failure (ejection fraction <40%, elevated BNP)Pressure overload right ventricular failurePatients underwent a cardiac MRI protocol consisting of cine imaging and phosphorous-31 magnetic resonance spectroscopy and an invasive protocol consisting of paired coronary sinus and systemic blood sampling with pressure measurement. Pressure-volume loops were generated by combining MR and pressure data.Results Uncorrected spectral PCr/ATP values in structurally normal hearts (1.21 ± 0.34) and right ventricular failure (1.20 ± 0.43) were consistently higher than left ventricular failure (0.89 ± 0.28).Mechano-energetic uncoupling was demonstrated in failing hearts: (figure 1A) LV pressure-volume area was greater in LV failure (17.7 ± 3 L.mmHg) than controls (15.1 ± 0.32), and RV PVA was greater in RV failure (14.2 ± 8.9 L.mmHg) than controls (2.78 ± 0.12). Total pressure volume area was divided by PCr/ATP ratio to produce a mechano-energetic coupling index, which was higher in LV failure (14.6 ± 3.07 L.mmHg) and RV failure (16.1 ± 3.45) than controls (10.3 ± 3.62).mtDAMPs: Mitochondrial DNA was elevated in coronary sinus samples of failing hearts The difference between coronary sinus and systemic mitochondrial DNA count was low in controls (124 ± 249 copies/µL) and higher in right (710 ± 2165) and left (1548 ± 2931) ventricular failure groups (figure 1B). Coronary levels of mitochondrial DNA were high in patients with the worst cardiac energetics (PCr/ATP <1, mtDNA 1762 ± 2758 copies/µL) but negligible in other patients (PCr/ATP >1, mtDNA -20 ± 205 copies/µL, figure 1B).mtDAMPs: Succinate excretion correlated with uncoupling: Succinate was excreted by the myocardium, while malonate, lactate and fumarate were taken up (figure 2A). Levels of coronary sinus succinate correlated with mechano-energetic coupling index (R2 = 0.409, p = 0.05, figure 2B).Pro-inflammatory cytokines were elevated in failing hearts: (figure 2C) Coronary sinus levels of pro-inflammatory cytokines such as IL-1β were higher in LV failure (0.24 ± 0.2 pg/ml) than controls (0.15 ± 0.06 pg/ml), and correlated with levels of fumarate (R2=0.65, p=0.008). The anti-inflammatory cytokine IL-10 was lower in LV failure (0.3 ± 0.13 pg/ml) than controls (0.51 ± 0.37 pg/ml) and correlated positively with PCr/ATP levels (R2=0.42, p=0.04).Conclusions Combining pressure-volume loops with phosphorous-31 magnetic resonance spectroscopy produces an index of mechano-energetic coupling. There was a correlation between uncoupling and release of mitochondrial damage associated molecular patterns.",
  "authors": [
    {
      "affiliations": [
        "University of Cambridge, Cambridge, United Kingdom"
      ],
      "name": "Will Watson"
    },
    {
      "affiliations": [
        "University of Cambridge, Cambridge, United Kingdom"
      ],
      "name": "Leo Nagy"
    },
    {
      "affiliations": [
        "Royal Papworth Hospital, Cambridge, United Kingdom"
      ],
      "name": "Katherine Bunclark"
    },
    {
      "affiliations": [
        "Royal Papworth Hospital, Cambridge, United Kingdom"
      ],
      "name": "Manoj Goonewardene"
    },
    {
      "affiliations": [
        "Royal Papworth Hospital, Cambridge, United Kingdom"
      ],
      "name": "Paul Bambrough"
    },
    {
      "affiliations": [
        "Royal Papworth Hospital, Cambridge, United Kingdom"
      ],
      "name": "Patrick Heck"
    },
    {
      "affiliations": [
        "Royal Papworth Hospital, Cambridge, United Kingdom"
      ],
      "name": "Simon Fynn"
    },
    {
      "affiliations": [
        "Royal Papworth Hospital, Cambridge, United Kingdom"
      ],
      "name": "Clare Goldsmith"
    },
    {
      "affiliations": [
        "Royal Papworth Hospital, Cambridge, United Kingdom"
      ],
      "name": "Ukpong Antigha"
    },
    {
      "affiliations": [
        "University of Cambridge, Cambridge, United Kingdom"
      ],
      "name": "Stephen Burr"
    },
    {
      "affiliations": [
        "University of Cambridge, Cambridge, United Kingdom"
      ],
      "name": "Jabrane Karkouri"
    },
    {
      "affiliations": [
        "University of Cambridge, Cambridge, United Kingdom"
      ],
      "name": "Christopher Rodgers"
    },
    {
      "affiliations": [
        "University of Cambridge, Cambridge, United Kingdom"
      ],
      "name": "Michael Murphy"
    },
    {
      "affiliations": [
        "Royal Papworth Hospital, Cambridge, United Kingdom"
      ],
      "name": "Stephen Hoole"
    }
  ],
  "title": "209 Mitochondrial stress induced DAMP release in heart failure: a pro-inflammatory mechanism for myocardial injury",
  "uid": "1b4739fc-0ab2-5d89-b00d-d1eccff318f1"
}