Ivan Luptak, MD, PhD

Assistant Professor, Medicine

Ivan Luptak
617.638.8075
650 Albany St Evans Biomed Research Ctr

Biography

The focus of Luptak Lab (https://twitter.com/IvanLuptak) is myocardial energy metabolism. The core of the Lab’s expertise, multinuclear NMR spectroscopy, allows the assessment of contractile function simultaneously with myocardial high energy phosphates (ATP, ADP, phosphocreatine), substrate oxidation rates, and intracellular ion concentrations/movement. Given the enormous ATP requirements of the heart (up to 6kg per day!), the information so obtained is crucial to understanding cardiovascular pathophysiology and identifying novel therapies. The topics of our interest include:

1. Energy substrate preference modulation as a potential cardiovascular therapeutic approach. Cardiac hypertrophy and failure are associated with a poorly understood shift in substrate utilization from fatty acid to glucose. Using phosphorus (31P) and carbon (13C) NMR spectroscopy we showed that improving energetics by modulating glucose utilization can prevent cardiac dysfunction (Circulation 2005;112:2339-2346) and protect against aging-associated increase in susceptibility to ischemic injury (Circulation 2007;116:901–909)

2. Metabolic remodeling due to aberrant activation of AMP kinase characterizes the PRKAG2 cardiac syndrome. An activating mutation in the gamma2 regulatory subunit of AMPK (PRKAG2) leads to familial Wolf-Parkinson–White syndrome and hypertrophic cardiomyopathy (HCM). We showed that activation of the energy sensing protein AMPK in the absence of energetic demands leads to metabolic remodeling, glycogen accumulation and HCM. This work implicates energetic imbalance in the pathobiology of a non-sarcomeric form of HCM (Journal of Clinical Investigation 2007;117:1432-1439).

3. The role of ABCB10 in the recovery of cardiac function after ischemia/reperfusion. Excessive reactive oxygen species (ROS) and mitochondrial dysfunction are central mediators of cardiac dysfunction after ischemia/reperfusion. ABCB10 is an inner mitochondrial membrane transporter with yet unknown function in the heart. We identified ABCB10 as a novel gene that regulates myocardial oxidative stress and thereby determines the ability to tolerate ischemia/reperfusion (Circulation 2011;124:806-813).

4. Myocardial energetic dysfunction in obesity-related diabetes and HCM. We showed reduction in energy and contractile reserve in obesity-related diabetes (JMCC 2018;116:106–114). Importantly, quenching mitochondrial ROS with catalase prevented (Antioxidants & Redox Signaling 2019;31:539–549) and increasing mitochondrial ATP synthesis with butyrate reversed (NMR in Biomedicine 2020;May: e4258) the energetic impairment and corrected myocardial function. Moreover, providing butyrate as a substrate improves energetic balance and diastolic dysfunction in the myosin R403Q model of sarcomeric HCM. (Circulation 2022; Meeting Abstract A10678)

5. Energetic basis for the beneficial effects of SGLT2 inhibition in the heart, independent of diabetes. While it is now apparent that sodium-glucose co-transporter 2 (SGLT2) inhibitors improve heart failure outcomes in patients with or without diabetes, the mechanism is not known. We have shown that SGLT2 inhibition improves mitochondrial function and energetics, and leads to genetic reprogramming that favors increased fatty acid oxidation , independent of diabetes (JAHA 2021;13:e019995), and further, have provided evidence that this effect is mediated by correction of intracellular sodium (Circulation 2020;Meeting Abstract A15315) This on-going work aligns closely with the underlying theme of our research to show that therapeutic targeting of cardiac energetics may be useful in a wide variety of cardiomyopathies.

6. Novel sarcomeric activators may stimulate contractility in a more energetically efficient manner than traditional inotropes. Existing inotropic agents that stimulate contractility improve cardiac function but cause an energetically costly augmentation of calcium cycling and worsen patient survival. We have found that a novel direct troponin activator increases contractility without a deleterious effect on myocardial energetics. (Circulation Heart Failure. 2022 Mar 8; e009195) These findings may provide a basis for clinical drug development of energetically favorable therapies that directly target myocardial contractility.

Our overarching aim is to develop therapeutic approaches for improving outcomes by improving cardiac energy efficiency in patients with heart failure. We are currently studying models of diabetic cardiomyopathy and HCM. Our first R01 application, currently supported by R56 bridge funding, uses SGLT2 inhibition, mitochondrial catalase and direct myosin inhibition to modulate the balance between myocardial contractile function and mitochondrial energy production, and forms the foundation of Luptak Lab future growth.

Other Positions

  • Member, Whitaker Cardiovascular Institute, Boston University

Education

  • Comenius University, MD
  • Comenius University, PhD

Publications

  • Published on 1/1/2022

    Baka T, Repova K, Luptak I, Simko F. Ivabradine in the Management of COVID-19-related Cardiovascular Complications: A Perspective. Curr Pharm Des. 2022; 28(19):1581-1588. PMID: 35345992.

    Read at: PubMed
  • Published on 11/8/2021

    He H, Baka T, Balschi J, Motani AS, Nguyen KK, Liu Q, Slater R, Rock B, Wang C, Hale C, Karamanlidis G, Hartman JJ, Malik FI, Reagan JD, Luptak I. Novel Small-Molecule Troponin Activator Increases Cardiac Contractile Function Without Negative Impact on Energetics. Circ Heart Fail. 2022 03; 15(3):e009195. PMID: 34743528.

    Read at: PubMed
  • Published on 6/25/2021

    Croteau D, Luptak I, Chambers JM, Hobai I, Panagia M, Pimentel DR, Siwik DA, Qin F, Colucci WS. Effects of Sodium-Glucose Linked Transporter 2 Inhibition With Ertugliflozin on Mitochondrial Function, Energetics, and Metabolic Gene Expression in the Presence and Absence of Diabetes Mellitus in Mice. J Am Heart Assoc. 2021 07 06; 10(13):e019995. PMID: 34169737.

    Read at: PubMed
  • Published on 10/20/2020

    Goodman JB, Qin F, Morgan RJ, Chambers JM, Croteau D, Siwik DA, Hobai I, Panagia M, Luptak I, Bachschmid M, Tong X, Pimentel DR, Cohen RA, Colucci WS. Redox-Resistant SERCA [Sarco(endo)plasmic Reticulum Calcium ATPase] Attenuates Oxidant-Stimulated Mitochondrial Calcium and Apoptosis in Cardiac Myocytes and Pressure Overload-Induced Myocardial Failure in Mice. Circulation. 2020 12 22; 142(25):2459-2469. PMID: 33076678.

    Read at: PubMed
  • Published on 9/16/2020

    Burns M, Rizvi SHM, Tsukahara Y, Pimentel DR, Luptak I, Hamburg NM, Matsui R, Bachschmid MM. Role of Glutaredoxin-1 and Glutathionylation in Cardiovascular Diseases. Int J Mol Sci. 2020 Sep 16; 21(18). PMID: 32948023.

    Read at: PubMed
  • Published on 9/9/2020

    Croteau D, Qin F, Chambers JM, Kallick E, Luptak I, Panagia M, Pimentel DR, Siwik DA, Colucci WS. Differential Effects of Sacubitril/Valsartan on Diastolic Function in Mice With Obesity-Related Metabolic Heart Disease. JACC Basic Transl Sci. 2020 Sep; 5(9):916-927. PMID: 33015414.

    Read at: PubMed
  • Published on 7/8/2020

    Panagia M, Yang J, Gale E, Wang H, Luptak I, Chen HH, Patel D, Croteau D, Pimentel DR, Bachschmid MM, Colucci WS, Ran C, Sosnovik DE. A novel tracer for in vivo optical imaging of fatty acid metabolism in the heart and brown adipose tissue. Sci Rep. 2020 07 08; 10(1):11209. PMID: 32641756.

    Read at: PubMed
  • Published on 2/17/2020

    Panagia M, He H, Baka T, Pimentel DR, Croteau D, Bachschmid MM, Balschi JA, Colucci WS, Luptak I. Increasing mitochondrial ATP synthesis with butyrate normalizes ADP and contractile function in metabolic heart disease. NMR Biomed. 2020 05; 33(5):e4258. PMID: 32066202.

    Read at: PubMed
  • Published on 9/19/2019

    Kimura T, Ferran B, Tsukahara Y, Shang Q, Desai S, Fedoce A, Pimentel DR, Luptak I, Adachi T, Ido Y, Matsui R, Bachschmid MM. Production of adeno-associated virus vectors for in vitro and in vivo applications. Sci Rep. 2019 09 19; 9(1):13601. PMID: 31537820.

    Read at: PubMed
  • Published on 7/9/2019

    Luptak I, Morgan R, Baka T, Croteau D, Moverman D, Sarnak H, Kirber M, Bachschmid MM, Colucci WS, Pimentel DR. Genetically targeted fluorescent probes reveal dynamic calcium responses to adrenergic signaling in multiple cardiomyocyte compartments. Int J Biochem Cell Biol. 2019 09; 114:105569. PMID: 31299273.

    Read at: PubMed

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