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3 Heart failure (HF) poses a significant public health challenge as a primary cause of morbidity and 4 mortality worldwide. Even though HF with preserved ejection fraction (HFpEF, defined as having a left 5 ventricular ejection fraction of 50% or higher) has emerged as the most common form of HF, heart failure 6 with reduced ejection fraction (HFrEF, ejection fraction under 40%)—mainly consequent to coronary 7 artery disease and myocardial infarction (MI)—continues to be a critical clinical issue. Despite a wide 8 array of available drug-based and non-drug treatments, the prognosis for HFrEF patients five years after 9 diagnosis remains poor, highlighting the urgent need for new treatment strategies. 1 HFrEF was seminally 10 defined nearly two decades ago as ‘An engine out of fuel’as the consequence of major changes in cardiac 11 metabolism leading to the reduction of energetic equivalents, ie. reduction in …