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13. Aging of the Vasculature

Author

Leucker, Thorsten M., Goldenberg, Joseph, Gerstenblith, Gary, Toth, Peter P., Series Editor, Leucker, Thorsten M., editor, and Gerstenblith, Gary, editor

Published
2023
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14. Mitochondrial Creatine Kinase Attenuates Pathologic Remodeling in Heart Failure

Author

Keceli, Gizem, Gupta, Ashish, Sourdon, Joevin, Gabr, Refaat, Schär, Michael, Dey, Swati, Tocchetti, Carlo G, Stuber, Annina, Agrimi, Jacopo, Zhang, Yi, Leppo, Michelle, Steenbergen, Charles, Lai, Shenghan, Yanek, Lisa R, O’Rourke, Brian, Gerstenblith, Gary, Bottomley, Paul A, Wang, Yibin, Paolocci, Nazareno, and Weiss, Robert G

Subjects
Biomedical and Clinical Sciences, Medical Physiology, Cardiovascular Medicine and Haematology, Nutrition, Cardiovascular, Clinical Research, Heart Disease, 2.1 Biological and endogenous factors, Aetiology, Adenosine Diphosphate, Adenosine Triphosphate, Animals, Creatine Kinase, Creatine Kinase, Mitochondrial Form, Energy Metabolism, Heart Failure, Humans, Hypertrophy, Left Ventricular, Mice, Myocardium, Reactive Oxygen Species, Ventricular Remodeling, antioxidants, creatine, dilatation, heart failure, myofibrils, Cardiorespiratory Medicine and Haematology, Clinical Sciences, Cardiovascular System & Hematology, Cardiovascular medicine and haematology, Clinical sciences
Abstract

BackgroundAbnormalities in cardiac energy metabolism occur in heart failure (HF) and contribute to contractile dysfunction, but their role, if any, in HF-related pathologic remodeling is much less established. CK (creatine kinase), the primary muscle energy reserve reaction which rapidly provides ATP at the myofibrils and regenerates mitochondrial ADP, is down-regulated in experimental and human HF. We tested the hypotheses that pathologic remodeling in human HF is related to impaired cardiac CK energy metabolism and that rescuing CK attenuates maladaptive hypertrophy in experimental HF.MethodsFirst, in 27 HF patients and 14 healthy subjects, we measured cardiac energetics and left ventricular remodeling using noninvasive magnetic resonance 31P spectroscopy and magnetic resonance imaging, respectively. Second, we tested the impact of metabolic rescue with cardiac-specific overexpression of either Ckmyofib (myofibrillar CK) or Ckmito (mitochondrial CK) on HF-related maladaptive hypertrophy in mice.ResultsIn people, pathologic left ventricular hypertrophy and dilatation correlate closely with reduced myocardial ATP levels and rates of ATP synthesis through CK. In mice, transverse aortic constriction-induced left ventricular hypertrophy and dilatation are attenuated by overexpression of CKmito, but not by overexpression of CKmyofib. CKmito overexpression also attenuates hypertrophy after chronic isoproterenol stimulation. CKmito lowers mitochondrial reactive oxygen species, tissue reactive oxygen species levels, and upregulates antioxidants and their promoters. When the CK capacity of CKmito-overexpressing mice is limited by creatine substrate depletion, the protection against pathologic remodeling is lost, suggesting the ADP regenerating capacity of the CKmito reaction rather than CK protein per se is critical in limiting adverse HF remodeling.ConclusionsIn the failing human heart, pathologic hypertrophy and adverse remodeling are closely related to deficits in ATP levels and in the CK energy reserve reaction. CKmito, sitting at the intersection of cardiac energetics and redox balance, plays a crucial role in attenuating pathologic remodeling in HF. Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT00181259.

Published
2022

26. Vericiguat prevents high glucose-mediated impaired vascular smooth muscle cGMP production and vasorelaxation.

Author

Polhemus, David, Almodiel, Diego, Harb, Tarek, Ziogos, Efthymios, Amat-Codina, Nuria, Ranek, Mark, Santhanam, Lakshmi, Gerstenblith, Gary, and Leucker, Thorsten M.

Abstract

Normal endothelial cell dependent vascular smooth muscle cell function is mediated by nitric oxide (NO), which stimulates soluble guanylyl cyclase (sGC) production of the second messenger cyclic guanosine monophosphate (cGMP) leading to increased protein kinase G (PKG) activity and vascular smooth muscle relaxation. NO bioavailability is impaired in high glucose (HG). We tested the hypothesis that the sGC sensitizer vericiguat reverses HG-mediated decreased sGC activity in two experimental models, human aortic vascular smooth muscle cells (HVSMCs) and isolated mouse aortic rings. HVSMCs were exposed to normal glucose (NG) or to HG with or without 1 μm vericiguat for 24 h and cGMP and PKG activity were measured. Murine aortic rings were incubated in NG or HG for 24 h. Following incubation, the aortic rings were placed in an organ chamber bath containing the same NG or HG concentration used during the incubation. Dose-response curves to increasing concentrations of acetylcholine (ACh) and sodium nitroprusside were constructed for four groups: control (NG), NG + vericiguat, HG, and HG + vericiguat. As compared with the results in the NG group, cGMP production and PKG activity were significantly impaired in the HG cells incubated without, but not in those incubated with, vericiguat. In isolated aortic rings, ACh-mediated relaxation was impaired following treatment with HG, but not when a HG group was treated with vericiguat. The findings suggest clinical studies are warranted to investigate the potential of sGC sensitization as a therapeutic intervention to improve vascular NO-cGMP signaling endothelium -dependent function that is impaired in HG settings such as diabetes and the metabolic syndrome. [ABSTRACT FROM AUTHOR]

Published
2025
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31. Sarcopenia and Cardiovascular Diseases

Author

Damluji, Abdulla A., Alfaraidhy, Maha, AlHajri, Noora, Rohant, Namit N., Kumar, Manish, Al Malouf, Christina, Bahrainy, Samira, Ji Kwak, Min, Batchelor, Wayne B., Forman, Daniel E., Rich, Michael W., Kirkpatrick, James, Krishnaswami, Ashok, Alexander, Karen P., Gerstenblith, Gary, Cawthon, Peggy, deFilippi, Christopher R., and Goyal, Parag

Published
2023
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34. Emerging clinical role of proprotein convertase subtilisin/kexin type 9 inhibition—Part one: Pleiotropic pro‐atherosclerotic effects of PCSK9.

Author

Cao Zhang, Alexander M., Ziogos, Efthymios, Harb, Tarek, Gerstenblith, Gary, and Leucker, Thorsten M.

Subjects
LIPOPROTEIN receptors, ATHEROSCLEROTIC plaque, LIPID metabolism, SUBTILISINS, DISEASE management
Abstract

Background: Proprotein convertase subtilisin/kexin type 9 (PCSK9) is primarily recognized for its role in lipid metabolism, but recent evidence suggests that it may have broader implications due to its diverse tissue expression. Objective: This review aims to explore the multifaceted functions of PCSK9, highlighting its pro‐atherosclerotic effects, including its impact on circulating lipoprotein variables, non‐low‐density lipoprotein receptors, and various cell types involved in atherosclerotic plaque development. Conclusions: PCSK9 exhibits diverse roles beyond lipid metabolism, potentially contributing to atherosclerosis through multiple pathways. Understanding these mechanisms could offer new insights into therapeutic strategies targeting PCSK9 for cardiovascular disease management. [ABSTRACT FROM AUTHOR]

Published
2024
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35. Emerging clinical role of proprotein convertase subtilisin/kexin type 9 inhibition–Part two: Current and emerging concepts in the clinical use of PCSK9 inhibition.

Author

Cao Zhang, Alexander M., Ziogos, Efthymios, Harb, Tarek, Gerstenblith, Gary, and Leucker, Thorsten M.

Subjects
ACUTE coronary syndrome, LIPID metabolism, ATHEROSCLEROTIC plaque, RANDOMIZED controlled trials, SUBTILISINS
Abstract

Background: Proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors have emerged as a novel class of drugs with cardioprotective effects through their lipid‐lowering effects. Objective: This review aims to discuss existing and novel strategies of PCSK9 inhibition, providing an overview of established randomized controlled trials and ongoing outcome trials that assess the efficacy and long‐term safety of PCSK9 inhibitors. It also explores the evolving role of PCSK9 beyond lipid metabolism and outlines the pleiotropic actions of PCSK9 inhibition in various disorders and future directions including novel strategies to target PCSK9. Conclusion: PCSK9 inhibition shows promise not only in lipid metabolism but also in other disease processes, including atherosclerotic plaque remodeling, acute coronary syndrome, stroke, inflammation, and immune response. [ABSTRACT FROM AUTHOR]

Published
2024
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36. Intra-individual variability in lipoprotein(a): the value of a repeat measure for reclassifying individuals at intermediate risk.

Author

Harb, Tarek, Ziogos, Efthymios, Blumenthal, Roger S, Gerstenblith, Gary, and Leucker, Thorsten M

Subjects
MEDICAL record databases, DISEASE risk factors, ELECTRONIC health records, CORONARY artery disease, CORONARY disease
Abstract

Aims Lipoprotein(a) [Lp(a)] levels are predominantly genetically determined and repeat measurements are generally considered unlikely to be clinically useful. However, the temporal variation of Lp(a) is not well characterized. Our aim was to determine the intra-individual variability of Lp(a) and whether a repeated measure reclassified Lp(a)-specific cardiovascular risk using the European Atherosclerosis Society (EAS) consensus statement risk categories. Methods and results This retrospective cohort study analysed initial and repeated serum Lp(a) levels measured using the same methodology from 609 individuals in the Nashville Biosciences database, a de-identified electronic medical records database. Baseline and follow-up paired values were significantly different (P < 0.05), with an absolute change of ≥10 mg/dL in 38.1% [95% CI 34.2–42%] and a >25% change in 40.5% [95% CI 36.6–44.3%] of individuals. Although the categories of those whose values were in the EAS low-risk and high-risk categories did not change, 53% of those in the intermediate 'grey-zone' category transitioned to either the low-risk (20%) or high-risk (33%) category. Black individuals exhibited greater variability than White individuals and women exhibited greater variability than men. There was a positive correlation between the baseline Lp(a) levels and the absolute changes in Lp(a), (r = 0.59, P < 0.01). Conclusion Temporal-related changes in Lp(a) variability were present in many individuals. A repeat Lp(a) measure may allow more precise Lp(a)-specific cardiovascular risk prediction for individuals whose initial value is in the EAS-defined intermediate 'grey-zone' category. Lp(a) variability should be included in calculating the expected effect sizes in future clinical research studies targeting Lp(a). [ABSTRACT FROM AUTHOR]

Published
2024
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45. Galectin‐3, Metabolic Risk, and Incident Heart Failure: The ARIC Study

Author

Echouffo‐Tcheugui, Justin B., primary, Zhang, Sui, additional, Florido, Roberta, additional, Pankow, James S., additional, Michos, Erin D., additional, Goldberg, Ronald B., additional, Nambi, Vijay, additional, Gerstenblith, Gary, additional, Post, Wendy S., additional, Blumenthal, Roger S., additional, Ballantyne, Christie M., additional, Coresh, Josef, additional, Selvin, Elizabeth, additional, and Ndumele, Chiadi E., additional

Published
2024
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