Much of the mortality burden of ischemic heart disease is due to untreatable complications of ischemia-reperfusion (I/R) injury, greatly undermining the translation of cardioprotective interventions. Endothelial damage and dysfunction are centrally involved in many of the clinical consequences of myocardial I/R injury. While a very promising therapeutic defense mechanism against I/R-induced endothelial dysfunction is ischemic preconditioning (IPC), it has not fared well in multi-center phase III clinical trials. Complementary strategies that elicit additive or synergistic benefits against I/R injury are urgently needed. Because lactate has extensive endothelial protective effects, the recruitment of additional protective pathways with lactate that cannot be activated with IPC alone provides an innovative and powerful strategy to greatly enhance cardioprotection in the clinical arena. Little is understood about whether including lactate with IPC as a dual approach can bolster protection in adults with CVD risk in which the endothelial protective effects of IPC are already weakened. The long-term goal of this research is to develop improved combination therapeutic strategies to expedite the clinical application of IPC for cardioprotective purposes. The objective is to better understand how lactate administration can be used to alleviate endothelial I/R injury. In a model of endothelial I/R injury, our central hypothesis is that lactate administration alone will reduce endothelial dysfunction, and when included as a combination strategy with IPC, will improve protection with metabolic syndrome. The rationale for the proposed research is based on the poor translatability of existing cardioprotective strategies to date. The central hypothesis will be tested by pursuing three aims: 1) Determine the degree to which lactate administration attenuates endothelial I/R injury; 2) Determine the superiority of a combined multi-targeted therapeutic strategy against endothelial I/R injury in adults with metabolic syndrome; and 3) Establish mechanistic insight into the endothelial protective effects of lactate. In Aim #1, the investigators will utilize a randomized equivalence trial comparing the effects of lactate administration versus IPC on endothelial function in 32 adults. For Aim #2, a randomized superiority trial in 36 adults with metabolic syndrome will compare the dual effects of IPC combined with lactate versus IPC alone. For Aim #3, a series of biomarker studies by which lactate is likely to modify the therapeutic response to I/R injury are proposed. For Aims #1 and #2, endothelium-dependent vasodilation (primary endpoint) will be compared between trials for equivalence, and superiority, respectively. For Aim #3, the investigators expect lactate will protect against endothelial I/R injury, in part, by reducing circulating microparticles of endothelial activation and vascular inflammation, and increasing total antioxidant capacity, nitric oxide bioavailability, and angiogenic factors. The approach is conceptually innovative because the findings are likely to be the first in vivo evidence supporting the development of a multi-faceted approach that exploits the potential for synergistic cytoprotection involving IPC combined with lactate. This contribution would advance the development of new translatable strategies for cardioprotection.
