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Comprehensive quantification of fuel use by the failing and nonfailing human heart.

ABSTRACT: The heart consumes circulating nutrients to fuel lifelong contraction, but a comprehensive mapping of human cardiac fuel use is lacking. We used metabolomics on blood from artery, coronary sinus, and femoral vein in 110 patients with or without heart failure to quantify the uptake and release of 277 metabolites, including all major nutrients, by the human heart and leg. The heart primarily consumed fatty acids and, unexpectedly, little glucose; secreted glutamine and other nitrogen-rich amino acids, indicating active protein breakdown, at a rate ~10 times that of the leg; and released intermediates of the tricarboxylic acid cycle, balancing anaplerosis from amino acid breakdown. Both heart and leg consumed ketones, glutamate, and acetate in direct proportionality to circulating levels, indicating that availability is a key driver for consumption of these substrates. The failing heart consumed more ketones and lactate and had higher rates of proteolysis. These data provide a comprehensive and quantitative picture of human cardiac fuel use.

SUBMITTER: Murashige D

PROVIDER: S-EPMC7871704 | biostudies-literature | 2020 Oct

REPOSITORIES: biostudies-literature

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Comprehensive quantification of fuel use by the failing and nonfailing human heart.

Murashige Danielle D Jang Cholsoon C Neinast Michael M Edwards Jonathan J JJ Cowan Alexis A Hyman Matthew C MC Rabinowitz Joshua D JD Frankel David S DS Arany Zolt Z

Science (New York, N.Y.) 20201001 6514

The heart consumes circulating nutrients to fuel lifelong contraction, but a comprehensive mapping of human cardiac fuel use is lacking. We used metabolomics on blood from artery, coronary sinus, and femoral vein in 110 patients with or without heart failure to quantify the uptake and release of 277 metabolites, including all major nutrients, by the human heart and leg. The heart primarily consumed fatty acids and, unexpectedly, little glucose; secreted glutamine and other nitrogen-rich amino ac ...[more]

PMID: 33060364

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Project description:BackgroundUp to 50% of the adult human sinoatrial node (SAN) is composed of dense connective tissue. Cardiac diseases including heart failure (HF) may increase fibrosis within the SAN pacemaker complex, leading to impaired automaticity and conduction of electric activity to the atria. Unlike the role of cardiac fibroblasts in pathologic fibrotic remodeling and tissue repair, nothing is known about fibroblasts that maintain the inherently fibrotic SAN environment.MethodsIntact SAN pacemaker complex was dissected from cardioplegically arrested explanted nonfailing hearts (non-HF; n=22; 48.7±3.1 years of age) and human failing hearts (n=16; 54.9±2.6 years of age). Connective tissue content was quantified from Masson trichrome-stained head-center and center-tail SAN sections. Expression of extracellular matrix proteins, including collagens 1 and 3A1, CILP1 (cartilage intermediate layer protein 1), and POSTN (periostin), and fibroblast and myofibroblast numbers were quantified by in situ and in vitro immunolabeling. Fibroblasts from the central intramural SAN pacemaker compartment (≈10×5×2 mm3) and right atria were isolated, cultured, passaged once, and treated ± transforming growth factor β1 and subjected to comprehensive high-throughput next-generation sequencing of whole transcriptome, microRNA, and proteomic analyses.ResultsIntranodal fibrotic content was significantly higher in SAN pacemaker complex from HF versus non-HF hearts (57.7±2.6% versus 44.0±1.2%; P<0.0001). Proliferating phosphorylated histone 3+/vimentin+/CD31- (cluster of differentiation 31) fibroblasts were higher in HF SAN. Vimentin+/α-smooth muscle actin+/CD31- myofibroblasts along with increased interstitial POSTN expression were found only in HF SAN. RNA sequencing and proteomic analyses identified unique differences in mRNA, long noncoding RNA, microRNA, and proteomic profiles between non-HF and HF SAN and right atria fibroblasts and transforming growth factor β1-induced myofibroblasts. Specifically, proteins and signaling pathways associated with extracellular matrix flexibility, stiffness, focal adhesion, and metabolism were altered in HF SAN fibroblasts compared with non-HF SAN.ConclusionsThis study revealed increased SAN-specific fibrosis with presence of myofibroblasts, CILP1, and POSTN-positive interstitial fibrosis only in HF versus non-HF human hearts. Comprehensive proteotranscriptomic profiles of SAN fibroblasts identified upregulation of genes and proteins promoting stiffer SAN extracellular matrix in HF hearts. Fibroblast-specific profiles generated by our proteotranscriptomic analyses of the human SAN provide a comprehensive framework for future studies to investigate the role of SAN-specific fibrosis in cardiac rhythm regulation and arrhythmias.

Project description:BackgroundCarbonic anhydrase enzymes (CA) catalyze the reversible hydration of carbon dioxide to bicarbonate in mammalian cells. Trans-membrane transport of CA-produced bicarbonate contributes significantly to cellular pH regulation. A body of evidence implicates pH-regulatory processes in the hypertrophic growth pathway characteristic of hearts as they fail. In particular, Na+/H+ exchange (NHE) activation is pro-hypertrophic and CA activity activates NHE. Recently Cardrase (6-ethoxyzolamide), a CA inhibitor, was found to prevent and revert agonist-stimulated cardiac hypertrophy (CH) in cultured cardiomyocytes. Our goal thus was to determine whether hypertrophied human hearts have altered expression of CA isoforms.MethodsWe measured CA expression in hypertrophied human hearts to begin to examine the role of carbonic anhydrase in progression of human heart failure. Ventricular biopsies were obtained from patients undergoing cardiac surgery (CS, n = 14), or heart transplantation (HT, n = 13). CS patients presented mild/moderate concentric left ventricular hypertrophy and normal right ventricles, with preserved ventricular function; ejection fractions were ~60%. Conversely, HT patients with failing hearts presented CH or ventricular dilation accompanied by ventricular dysfunction and EF values of 20%. Non-hypertrophic, non-dilated ventricular samples served as controls.ResultsExpression of atrial and brain natriuretic peptide (ANP and BNP) were markers of CH. Hypertrophic ventricles presented increased expression of CAII, CAIV, ANP, and BNP, mRNA levels, which increased in failing hearts, measured by quantitative real-time PCR. CAII, CAIV, and ANP protein expression also increased approximately two-fold in hypertrophic/dilated ventricles.ConclusionsThese results, combined with in vitro data that CA inhibition prevents and reverts CH, suggest that increased carbonic anhydrase expression is a prognostic molecular marker of cardiac hypertrophy.

Dataset Information

Comprehensive quantification of fuel use by the failing and nonfailing human heart.

Publications

Comprehensive quantification of fuel use by the failing and nonfailing human heart.

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