Mechanical Unloading Promotes Myocardial Energy Recovery in Human Heart Failure

Abstract

Background Impaired bioenergetics is a prominent feature of the failing heart, but the underlying metabolic perturbations are poorly understood. Methods and Results We compared metabolomic, gene transcript, and protein data from six paired failing human left ventricular (LV) tissue samples obtained during left ventricular assist device (LVAD) insertion (heart failure (HF) samples) and at heart transplant (post-LVAD samples). Non-failing left ventricular (NFLV) wall samples procured from explanted hearts of patients with right HF served as novel comparison samples. Metabolomic analyses uncovered a distinct pattern in HF tissue: 2.6 fold increased pyruvate concentrations coupled with reduced Krebs cycle intermediates and short-chain acylcarnitines, suggesting a global reduction in substrate oxidation. These findings were associated with decreased transcript levels for enzymes that catalyze fatty acid oxidation and pyruvate metabolism and for key transcriptional regulators of mitochondrial metabolism and biogenesis, peroxisome proliferator-activated receptor gamma co-activator1α (PGC1A, 1.3 fold) and estrogen-related receptor α (ERRA, 1.2 fold) and γ (ERRG, 2.2 fold). Thus, parallel decreases in key transcription factors and their target metabolic enzyme genes can explain the decreases in associated metabolic intermediates. Mechanical support with LVAD improved all of these metabolic and transcriptional defects. Conclusions These observations underscore an important pathophysiologic role for severely defective metabolism in HF, while the reversibility of these defects by LVAD suggests metabolic resilience of the human heart.

Cardiac nuclear receptors: architects of mitochondrial structure and function

“…Indeed, Ppargc1a/b-knockout mice have reduced cardiolipin and impaired mitochondrial respiration. Third, a number of studies in animal models and in humans have shown reduced levels of PGC-1α and ERR transcripts and protein levels in heart failure (117)(118)(119)(120)(121). Collectively, these data clearly connect diminished mitochondrial respiration capacity with reduced ERR/PGC-1 signaling and suggest that this may be a final common pathway in heart failure ( Figure 3).…”

“…Indeed, a diminished ratio of PCr to ATP has been shown to be an excellent prognostic indicator of survival in human heart failure (112,113). Gene expression and proteomic profiling, together with ultrastructural studies, indicate that the expression of genes and proteins involved in mitochondrial energy transduction and respiration is downregulated in the late-stage failing heart (114)(115)(116)(117). In addition, several recent studies have revealed changes in the metabolome indicative of alterations (bottlenecks) in fuel oxidation and mitochondrial respiration (87,89,117).…”

“…Gene expression and proteomic profiling, together with ultrastructural studies, indicate that the expression of genes and proteins involved in mitochondrial energy transduction and respiration is downregulated in the late-stage failing heart (114)(115)(116)(117). In addition, several recent studies have revealed changes in the metabolome indicative of alterations (bottlenecks) in fuel oxidation and mitochondrial respiration (87,89,117). These observations have led to a description of the failing heart as energy starved, a condition that can result from any of a myriad of potential metabolic derangements that occur during heart failure, ranging from alterations in fuel oxidation to ATP synthesis and storage.…”

Estrogen-Related Receptor α (ERRα) and ERRγ Are Essential Coordinators of Cardiac Metabolism and Function

“…Altered expression of ERR␣ and ERR␥ as well as mutations of their target genes have been associated with cardiomyopathy, heart failure, and conduction disorders in humans (66)(67)(68). Like many other nuclear receptors, the activities of ERR␣ and ERR␥ can be modulated by available small-molecule ligands (C29, XCT790, GSK5182, GSK4716, etc.)…”

Pet Imaging and its Application in Cardiovascular Diseases

“…Our close collaboration with the Houston Methodist transplant team of cardiologists, cardiothoracic surgeons, and cardiovascular researchers has facilitated prompt isolation and study of failing human heart tissue. These ventricular wall samples are procured from failing hearts with and without support from LV assist devices, 42 and the close proximity of our laboratory to the operating suites allows transfer for studies within minutes after hand-off.…”