Gupte A.A.,Methodist Diabetes and Metabolism Institute |
Minze L.J.,Methodist Diabetes and Metabolism Institute |
Reyes M.,Methodist Diabetes and Metabolism Institute |
Ren Y.,Methodist Diabetes and Metabolism Institute |
And 11 more authors.
Endocrinology | Year: 2013
In obesity, reduced cardiac glucose uptake and mitochondrial abnormalities are putative causes of cardiac dysfunction. However, high-fat diet (HFD) does not consistently induce cardiac insulin resistance and mitochondrial damage, and recent studies suggest HFD may be cardioprotective. To determine cardiac responses to HFD, we investigated cardiac function, glucose uptake, and mitochondrial respiration in young (3-month-old) and middle-aged (MA) (12-month-old) male Ldlrβ/β mice fed chow or 3 months HFD to induce obesity, systemic insulin resistance, and hyperinsulinemia. In MA Ldlr -1 mice, HFD induced accelerated atherosclerosis and nonalcoholic steatohepatitis, commoncomplications of human obesity. Surprisingly, HFD-fed mice demonstrated increased cardiac glucose uptake, whichwasmost prominent inMAmice, in the absence of cardiac contractile dysfunction or hypertrophy. Moreover, hearts of HFD-fed mice had enhanced mitochondrial oxidation of palmitoyl carnitine, glutamate, and succinate and greater basal insulin signaling compared with those of chow-fed mice, suggesting cardiac insulin sensitivity was maintained, despite systemic insulin resistance. Streptozotocin-induced ablation of insulin production markedly reduced cardiac glucose uptake and mitochondrial dysfunction in HFD-fed, but not in chow-fed, mice. Insulin injection reversed these effects, suggesting that insulin may protect cardiac mitochondria during HFD. These results have implications for cardiac metabolism and preservation of mitochondrial function in obesity. © 2013 by The Endocrine Society.
Gupte A.A.,Methodist Diabetes and Metabolism Institute |
Gupte A.A.,New York Medical College |
Hamilton D.J.,Methodist Diabetes and Metabolism Institute |
Hamilton D.J.,Houston Methodist Hospital |
And 29 more authors.
Circulation: Cardiovascular Genetics | Year: 2014
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 6 paired samples of failing human left ventricular tissue obtained during left ventricular assist device insertion (heart failure samples) and at heart transplant (post-left ventricular assist device samples). Nonfailing left ventricular wall samples procured from explanted hearts of patients with right heart failure served as novel comparison samples. Metabolomic analyses uncovered a distinct pattern in heart failure 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 ? coactivator 1a (PGC1A, 1.3-fold) and estrogen-related receptor a (ERRA, 1.2-fold) and ? (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 left ventricular assist device improved all of these metabolic and transcriptional defects. Conclusions-These observations underscore an important pathophysiologic role for severely defective metabolism in heart failure, while the reversibility of these defects by left ventricular assist device suggests metabolic resilience of the human heart. © 2014 American Heart Association, Inc.
Gupte A.A.,Cornell College |
Cordero-Reyes A.M.,Methodist DeBakey Heart and Vascular Institute |
Youker K.A.,Methodist DeBakey Heart and Vascular Institute |
Matsunami R.K.,Houston Methodist Research Institute |
And 10 more authors.
Journal of Cardiac Failure | Year: 2016
Objectives Right ventricular failure is the primary reason for mortality in pulmonary hypertension (PH), but little is understood about the energetics of the failing right myocardium. Our aim was to examine mitochondrial function and proteomic signatures in paired remodeled right (RM-RV) and non-remodeled left (NRM-LV) ventricular tissue samples procured during heart-lung transplantation. Methods and Results Contractile dysfunction in RM-RV and preserved contractile function in NRM-LV were determined clinically and by echocardiography. Mitochondria were isolated from fresh paired RV and LV wall specimens of explanted hearts. Respiratory states in response to 4 substrates and an uncoupler were analyzed. Proteomic analysis on the mitochondrial isolates was performed with the use of liquid chromatography-mass spectrometry. The RM-RV mitochondria exhibited higher succinate state 4 levels with lower respiratory control ratio (RCR) compared with state 4 levels for pyruvate-malate (PM) and glutamate-malate (GM). RM-RV mitochondria also exhibited lower state 3 for palmitoyl-carnitine (PC) and state 4 for all complex I substrates compared with NRM-LV. The mean RCR were greater in RM-RVs than in NRM-LVs for PM and GM, which is consistent with tight coupling (low state 4 rates, higher RCRs); however, low RM-RV state 3 rates suggest concurrent substrate-dependent impairment in respiratory capacity. Mitochondrial proteomics revealed greater levels of mitochondrial ADP-ATP translocase and proteins of ATP synthesis, mitochondrial pyruvate and short branched chain acyl-CoA metabolism in RM-RV. Conclusions The mitochondrial respiration and proteomics in RM-RV are different from NRM-LV. These results have important implications in expanding our understanding of RV metabolism and future management of RV failure. © 2016 Elsevier Inc. All rights reserved.
Walton B.L.,Texas Heart Institute |
Leja M.,Methodist DeBakey Heart and Vascular Institute |
Vickers K.C.,Baylor College of Medicine |
Estevez-Fernandez M.,University of Texas M. D. Anderson Cancer Center |
And 5 more authors.
Vascular Medicine | Year: 2010
Liposomes have been used as imaging and therapeutic agents in various tissues but only infrequently in the cardiovascular system. We prepared a liposome to target atheromas in a Watanabe heritable hyperlipidemic (WHHL) rabbit model. Liposomes labeled with rhodamine and nanogold were injected intra-arterially into the descending thoracic aortas of WHHL rabbits. The arterial segments of interest were perfusion-fixed and evaluated with immunohistochemistry, light microscopy, and electron microscopy. Deconvolution microscopy showed that rhodamine label was concentrated in the plaque shoulder regions of advanced-stage atheromas; however, rhodamine label was not found in adjacent, non-atherosclerotic aorta. Transmission electron microscopy revealed liposome remnants and the highest concentration of nanogold label in lipid-laden areas of atheromas. Liposomes were concentrated in areas of lipoprotein-associated phospholipase A2 expression. We conclude that modified liposomes can be delivered to the shoulder regions of advanced atheromas in WHHL rabbits and may be useful therapeutically for targeting metabolically active plaque.
Cohen M.G.,University of Miami |
Ghatak A.,University of Miami |
Kleiman N.S.,Methodist DeBakey Heart and Vascular Institute |
Naidu S.S.,Winthrop University |
And 8 more authors.
Catheterization and Cardiovascular Interventions | Year: 2014
Objective To study rotational atherectomy (RA) outcomes in patients undergoing high-risk PCI randomized to receive hemodynamic support using either IABP or Impella 2.5 in the PROTECT II trial. Background RA of heavily calcified lesions is often necessary for complex PCI but can be associated with slow-flow, hypotension, and higher risk of periprocedural MI. Methods We compared baseline, angiographic, procedural characteristics, and outcomes of patients treated with and without RA. We examined also RA technique and outcomes. Results RA was used in 52 of 448 patients (32 with Impella vs 20 with IABP, P-=-0.08). RA patients were older (72 vs. 67 yo, P-=-0.0009), more likely to have prior CABG (48 vs. 32%, P-=-0.017), higher STS (8.1 vs. 5.7, P-=-0.012) and higher SYNTAX scores (37 vs. 29, P-<-0.0001). At 90 days, RA use was associated with higher incidence of MI but no mortality difference. RA was used more aggressively with Impella resulting in higher rate of periprocedural MI (P-<-0.01), with no difference in mortality between groups (P-=-0.78). Repeat revascularization occurred less frequently with Impella (P-<-0.001). There were no differences in 90-day major adverse events between IABP and Impella in patients undergoing RA (P-=-0.29). In patients not treated with RA, fewer MAEs were observed with Impella compared with IABP (P-=-0.03). Conclusions Patients who were treated with RA had more comorbidities, and more complex and extensive coronary artery disease. In patients with Impella, more aggressive RA use resulted in fewer revascularization events but higher incidence of periprocedural MI. © 2013 Wiley Periodicals, Inc.