Myocardial ischemia: From disease to syndrome.
Angina; Chronic coronary syndromes; Coronary artery disease; Ischemic heart disease; Microvascular dysfunction
Although current guidelines on the management of stable coronary artery disease acknowledge that multiple mechanisms may precipitate myocardial ischemia, recommended diagnostic, prognostic and therapeutic algorithms are still focused on obstructive epicardial atherosclerotic lesions, and little progress has been made in identifying management strategies for non-atherosclerotic causes of myocardial ischemia. The purpose of this consensus paper is three-fold: 1) to marshal scientific evidence that obstructive atherosclerosis can co-exist with other mechanisms of ischemic heart disease (IHD); 2) to explore how the awareness of multiple precipitating mechanisms could impact on pre-test probability, provocative test results and treatment strategies; and 3) to stimulate a more comprehensive approach to chronic myocardial ischemic syndromes, consistent with the new understanding of this condition.
Marzilli Mario; Crea Filippo; Morrone Doralisa; Bonow Robert O; Brown David L; Camici Paolo G; Chilian William M; DeMaria Anthony; Guarini Giacinta; Huqi Alda; Merz C Noel Bairey; Pepine Carl; Scali Maria Chiara; Weintraub William S; Boden William E
International journal of cardiology
2020
2020-04-26
Article information provided for research and reference use only. All rights are retained by the journal listed under publisher and/or the creator(s).
journalArticle
<a href="http://doi.org/10.1016/j.ijcard.2020.04.074" target="_blank" rel="noreferrer noopener">10.1016/j.ijcard.2020.04.074</a>
Induction of vascular progenitor cells from endothelial cells stimulates coronary collateral growth.
*Collateral Circulation; *Coronary Circulation; Animal; Animals; Biomarkers/metabolism; Cell Differentiation; Cell Lineage; Cells; Coronary Occlusion/genetics/metabolism/pathology/physiopathology/*surgery; Coronary Vessels/metabolism/pathology/*physiopathology; Cultured; Developmental; Disease Models; Endothelial Cells/metabolism/pathology/*transplantation; Epigenesis; Gene Expression Profiling; Gene Expression Regulation; Genetic; Induced Pluripotent Stem Cells/metabolism/*transplantation; Mice; Muscle; Myocytes; Neovascularization; Physiologic; Rats; Regenerative Medicine/methods; Regional Blood Flow; Reverse Transcriptase Polymerase Chain Reaction; SCID; Smooth; Smooth Muscle/metabolism/pathology/*transplantation; Sprague-Dawley; Teratoma/metabolism/pathology; Time Factors; Transcription Factors/genetics/metabolism; Transduction; Vascular/metabolism/pathology/*physiopathology
RATIONALE: A well-developed coronary collateral circulation improves the morbidity and mortality of patients following an acute coronary occlusion. Although regenerative medicine has great potential in stimulating vascular growth in the heart, to date there have been mixed results, and the ideal cell type for this therapy has not been resolved. OBJECTIVE: To generate induced vascular progenitor cells (iVPCs) from endothelial cells, which can differentiate into vascular smooth muscle cells (VSMCs) or endothelial cells (ECs), and test their capability to stimulate coronary collateral growth. METHODS AND RESULTS: We reprogrammed rat ECs with the transcription factors Oct4, Klf4, Sox2, and c-Myc. A population of reprogrammed cells was derived that expressed pluripotent markers Oct4, SSEA-1, Rex1, and AP and hemangioblast markers CD133, Flk1, and c-kit. These cells were designated iVPCs because they remained committed to vascular lineage and could differentiate into vascular ECs and VSMCs in vitro. The iVPCs demonstrated better in vitro angiogenic potential (tube network on 2-dimensional culture, tube formation in growth factor reduced Matrigel) than native ECs. The risk of teratoma formation in iVPCs is also reduced in comparison with fully reprogrammed induced pluripotent stem cells (iPSCs). When iVPCs were implanted into myocardium, they engrafted into blood vessels and increased coronary collateral flow (microspheres) and improved cardiac function (echocardiography) better than iPSCs, mesenchymal stem cells, native ECs, and sham treatments. CONCLUSIONS: We conclude that iVPCs, generated by partially reprogramming ECs, are an ideal cell type for cell-based therapy designed to stimulate coronary collateral growth.
Yin Liya; Ohanyan Vahagn; Pung Yuh Fen; Delucia Angelo; Bailey Erin; Enrick Molly; Stevanov Kelly; Kolz Christopher L; Guarini Giacinta; Chilian William M
Circulation research
2012
2012-01
Article information provided for research and reference use only. All rights are retained by the journal listed under publisher and/or the creator(s).
<a href="http://doi.org/10.1161/CIRCRESAHA.111.250126" target="_blank" rel="noreferrer noopener">10.1161/CIRCRESAHA.111.250126</a>
Resolution of mitochondrial oxidative stress rescues coronary collateral growth in Zucker obese fatty rats.
Animal; Animals; Antioxidants/*pharmacology; Collateral Circulation/*drug effects/physiology; Coronary Vessels/drug effects/*growth & development; Disease Models; Heart/*drug effects/physiology; Lipid Peroxidation/drug effects/physiology; Lipid Peroxides/metabolism; Male; Metabolic Syndrome/*metabolism/physiopathology; Mitochondria; Mitochondrial Proteins/metabolism; Obesity/*metabolism/physiopathology; Organophosphorus Compounds/pharmacology; Oxidative Stress/*drug effects/physiology; Piperidines/pharmacology; Rats; Reactive Oxygen Species/metabolism; Ubiquinone/pharmacology; Zucker
OBJECTIVE: We have previously found abrogated ischemia-induced coronary collateral growth in Zucker obese fatty (ZOF) rats compared with Zucker lean (ZLN) rats. Because ZOF rats have structural abnormalities in their mitochondria suggesting dysfunction and also show increased production of O(2), we hypothesized that mitochondrial dysfunction caused by oxidative stress impairs coronary collateral growth in ZOF. METHODS AND RESULTS: Increased levels of reactive oxygen species were observed in aortic endothelium and smooth muscle cells in ZOF rats compared with ZLN rats. Reactive oxygen species levels were decreased by the mitochondria-targeted antioxidants MitoQuinone (MQ) and MitoTempol (MT) as assessed by MitoSox Red and dihydroethidine staining. Lipid peroxides (a marker of oxidized lipids) were increased in ZOF by approximately 47% compared with ZLN rats. The elevation in oxidative stress was accompanied by increased antioxidant enzymes, except glutathione peroxidase-1, and by increased uncoupling protein-2 in ZOF versus ZLN rats. In addition, elevated respiration rates were also observed in the obese compared with lean rats. Administration of MQ significantly normalized the metabolic profiles and reduced lipid peroxides in ZOF rats to the same level observed in lean rats. The protective effect of MQ also suppressed the induction of uncoupling protein-2 in the obese rats. Resolution of mitochondrial oxidative stress by MQ or MT restored coronary collateral growth to the same magnitude observed in ZLN rats in response to repetitive ischemia. CONCLUSIONS: We conclude that mitochondrial oxidative stress and dysfunction play a key role in disrupting coronary collateral growth in obesity and the metabolic syndrome, and elimination of the mitochondrial oxidative stress with MQ or MT rescues collateral growth.
Pung Yuh Fen; Rocic Petra; Murphy Michael P; Smith Robin A J; Hafemeister Jennifer; Ohanyan Vahagn; Guarini Giacinta; Yin Liya; Chilian William M
Arteriosclerosis, thrombosis, and vascular biology
2012
2012-02
Article information provided for research and reference use only. All rights are retained by the journal listed under publisher and/or the creator(s).
<a href="http://doi.org/10.1161/ATVBAHA.111.241802" target="_blank" rel="noreferrer noopener">10.1161/ATVBAHA.111.241802</a>
Endothelin-mediated in vivo pressor responses following TRPV1 activation.
*Blood Pressure/drug effects; *Vasoconstriction/drug effects; Adrenergic alpha-Agonists/administration & dosage; Analysis of Variance; Animal; Animals; Azepines/administration & dosage; Biphenyl Compounds/administration & dosage; Capsaicin/administration & dosage; Cells; Cultured; Diabetes Mellitus; Diabetic Angiopathies/genetics/*metabolism/physiopathology; Dipeptides/administration & dosage; Disease Models; Dose-Response Relationship; Drug; Endothelial Cells/metabolism; Endothelin A Receptor Antagonists; Endothelin A/metabolism; Endothelin B Receptor Antagonists; Endothelin B/metabolism; Endothelin-1/*metabolism; Enzyme-Linked Immunosorbent Assay; Femoral Artery/drug effects/*metabolism/physiopathology; Inbred C57BL; Indoles/administration & dosage; Infusions; Intravenous; Knockout; Male; Mice; Phenylephrine/administration & dosage; Receptor; TRPV Cation Channels/agonists/deficiency/genetics/*metabolism; Type 2/genetics/*metabolism/physiopathology; Vasoconstrictor Agents/administration & dosage
Transient receptor potential vanilliod 1 (TRPV1) channels have recently been postulated to play a role in the vascular complications/consequences associated with diabetes despite the fact that the mechanisms through which TRPV1 regulates vascular function are not fully known. Accordingly, our goal was to define the mechanisms by which TRPV1 channels modulate vascular function and contribute to vascular dysfunction in diabetes. We subjected mice lacking TRPV1 [TRPV1((-/-))], db/db, and control C57BLKS/J mice to in vivo infusion of the TRPV1 agonist capsaicin or the alpha-adrenergic agonist phenylephrine (PE) to examine the integrated circulatory actions of TRPV1. Capsaicin (1, 10, 20, and 100 mug/kg) dose dependently increased MAP in control mice (5.7 +/- 1.6, 11.7 +/- 2.1, 25.4 +/- 3.4, and 51.6 +/- 3.9%), which was attenuated in db/db mice (3.4 +/- 2.1, 3.9 +/- 2.1, 7.0 +/- 3.3, and 17.9 +/- 6.2%). TRPV1((-/-)) mice exhibited no changes in MAP in response to capsaicin, suggesting the actions of this agonist are specific to TRPV1 activation. Immunoblot analysis revealed decreased aortic TRPV1 protein expression in db/db compared with control mice. Capsaicin-induced responses were recorded following inhibition of endothelin A and B receptors (ET(A) /ET(B)). Inhibition of ET(A) receptors abolished the capsaicin-mediated increases in MAP. Combined antagonism of ET(A) and ET(B) receptors did not further inhibit the capsaicin response. Cultured endothelial cell exposure to capsaicin increased endothelin production as shown by an endothelin ELISA assay, which was attenuated by inhibition of TRPV1 or endothelin-converting enzyme. TRPV1 channels contribute to the regulation of vascular reactivity and MAP via production of endothelin and subsequent activation of vascular ET(A) receptors. Impairment of TRPV1 channel function may contribute to vascular dysfunction in diabetes.
Ohanyan Vahagn A; Guarini Giacinta; Thodeti Charles K; Talasila Phani K; Raman Priya; Haney Rebecca M; Meszaros J Gary; Damron Derek S; Bratz Ian N
American journal of physiology. Heart and circulatory physiology
2011
2011-09
Article information provided for research and reference use only. All rights are retained by the journal listed under publisher and/or the creator(s).
<a href="http://doi.org/10.1152/ajpheart.00082.2011" target="_blank" rel="noreferrer noopener">10.1152/ajpheart.00082.2011</a>
Disruption of TRPV1-mediated coupling of coronary blood flow to cardiac metabolism in diabetic mice: role of nitric oxide and BK channels.
13-dienoic Acid/pharmacology; 15-Hydroxy-11 alpha; 9 alpha-(epoxymethano)prosta-5; Anilides/pharmacology; Animals; Capsaicin/analogs & derivatives/pharmacology; Cinnamates/pharmacology; Coronary Vessels/drug effects/*metabolism/physiopathology; Diabetes Mellitus; Diabetic Cardiomyopathies/drug therapy/*metabolism; Enzyme Inhibitors/pharmacology; Inbred C57BL; Large-Conductance Calcium-Activated Potassium Channels/antagonists & inhibitors/*metabolism; Male; Mice; Microvessels/drug effects/physiopathology; NG-Nitroarginine Methyl Ester/pharmacology; Nitric Oxide/*metabolism; Peptides/pharmacology; TRPV Cation Channels/agonists/antagonists & inhibitors/biosynthesis/*metabolism; Type 2/drug therapy/*metabolism; Vasoconstrictor Agents/pharmacology; Vasodilation/drug effects
We have previously shown transient receptor potential vanilloid subtype 1 (TRPV1) channel-dependent coronary function is compromised in pigs with metabolic syndrome (MetS). However, the mechanisms through which TRPV1 channels couple coronary blood flow to metabolism are not fully understood. We employed mice lacking TRPV1 [TRPV1((-/-))], db/db diabetic, and control C57BKS/J mice to determine the extent to which TRPV1 channels modulate coronary function and contribute to vascular dysfunction in diabetic cardiomyopathy. Animals were subjected to in vivo infusion of the TRPV1 agonist capsaicin to examine the hemodynamic actions of TRPV1 activation. Capsaicin (1-100 mug.kg(-1).min(-1)) dose dependently increased coronary blood flow in control mice, which was inhibited by the TRPV1 antagonist capsazepine or the nitric oxide synthase (NOS) inhibitor N-nitro-l-arginine methyl ester (L-NAME). In addition, the capsaicin-mediated increase in blood flow was attenuated in db/db mice. TRPV1((-/-)) mice exhibited no changes in coronary blood flow in response to capsaicin. Vasoreactivity studies in isolated pressurized mouse coronary microvessels revealed a capsaicin-dependent relaxation that was inhibited by the TRPV1 inhibitor SB366791 l-NAME and to the large conductance calcium-sensitive potassium channel (BK) inhibitors iberiotoxin and Penetrim A. Similar to in vivo responses, capsaicin-mediated relaxation was impaired in db/db mice compared with controls. Changes in pH (pH 7.4-6.0) relaxed coronary vessels contracted to the thromboxane mimetic U46619 in all three groups of mice; however, pH-mediated relaxation was blunted in vessels obtained from TRPV1((-/-)) and db/db mice compared with controls. Western blot analysis revealed decreased myocardial TRPV1 protein expression in db/db mice compared with controls. Our data reveal TRPV1 channels mediate coupling of myocardial blood flow to cardiac metabolism via a nitric oxide-dependent, BK channel-dependent pathway that is corrupted in diabetes.
Guarini Giacinta; Ohanyan Vahagn A; Kmetz John G; DelloStritto Daniel J; Thoppil Roslin J; Thodeti Charles K; Meszaros J Gary; Damron Derek S; Bratz Ian N
American journal of physiology. Heart and circulatory physiology
2012
2012-07
Article information provided for research and reference use only. All rights are retained by the journal listed under publisher and/or the creator(s).
<a href="http://doi.org/10.1152/ajpheart.00011.2012" target="_blank" rel="noreferrer noopener">10.1152/ajpheart.00011.2012</a>
BCNU-induced gR2 defect mediates S-glutathionylation of Complex I and respiratory uncoupling in myocardium.
Alkylating/*adverse effects/pharmacology; Animals; Antineoplastic Agents; Cardiotoxins/adverse effects/pharmacology; Carmustine/*adverse effects/pharmacology; Cattle; Cell Line; Complex I; Electron Transport Complex I/chemistry/*metabolism; Fatty Acids; Glutathione reductase; Glutathione Reductase/*antagonists & inhibitors/metabolism; Glutathione/*metabolism; Heart Ventricles/drug effects/metabolism/physiopathology; Heart/*drug effects/metabolism; Ion Channels/metabolism; Left/*chemically induced/metabolism/physiopathology; Male; Mice; Mitochondria; Mitochondrial Proteins/metabolism; Nonesterified/metabolism; Oxidative stress; Oxidative Stress/drug effects; Post-Translational/drug effects; Protein Processing; Rats; S-Glutathionylation; Sprague-Dawley; Superoxide Dismutase/genetics/metabolism; Systolic dysfunction; Transgenic; Uncoupling Protein 3; Ventricular Dysfunction
A deficiency of mitochondrial glutathione reductase (or GR2) is capable of adversely affecting the reduction of GSSG and increasing mitochondrial oxidative stress. BCNU [1,3-bis (2-chloroethyl)-1-nitrosourea] is an anticancer agent and known inhibitor of cytosolic GR ex vivo and in vivo. Here we tested the hypothesis that a BCNU-induced GR2 defect contributes to mitochondrial dysfunction and subsequent impairment of heart function. Intraperitoneal administration of BCNU (40 mg/kg) specifically inhibited GR2 activity by 79.8 +/- 2.7% in the mitochondria of rat heart. However, BCNU treatment modestly enhanced the activities of mitochondrial Complex I and other ETC components. The cardiac function of BCNU-treated rats was analyzed by echocardiography, revealing a systolic dysfunction associated with decreased ejection fraction, decreased cardiac output, and an increase in left ventricular internal dimension and left ventricular volume in systole. The respiratory control index of isolated mitochondria from the myocardium was moderately decreased after BCNU treatment, whereas NADH-linked uncoupling of oxygen consumption was significantly enhanced. Extracellular flux analysis to measure the fatty acid oxidation of myocytes indicated a 20% enhancement after BCNU treatment. When the mitochondria were immunoblotted with antibodies against GSH and UCP3, both protein
Kang Patrick T; Chen Chwen-Lih; Ren Pei; Guarini Giacinta; Chen Yeong-Renn
Biochemical pharmacology
2014
2014-06
Article information provided for research and reference use only. All rights are retained by the journal listed under publisher and/or the creator(s).
<a href="http://doi.org/10.1016/j.bcp.2014.03.012" target="_blank" rel="noreferrer noopener">10.1016/j.bcp.2014.03.012</a>
Impaired coronary metabolic dilation in the metabolic syndrome is linked to mitochondrial dysfunction and mitochondrial DNA damage.
Animal; Animals; Coronary circulation; Coronary microcirculation; Coronary Vessels/metabolism/*physiopathology; Diabetes; Disease Models; DNA; DNA Damage/physiology; DNA Fragmentation; Metabolic Syndrome/metabolism/*physiopathology; Mitochondria; Mitochondria/*metabolism; Mitochondrial/*metabolism; Obesity; Oxidative Stress/physiology; Rats; Reactive Oxygen Species/metabolism; Vasodilation/physiology; Zucker
Mitochondrial dysfunction in obesity and diabetes can be caused by excessive production of free radicals, which can damage mitochondrial DNA. Because mitochondrial DNA plays a key role in the production of ATP necessary for cardiac work, we hypothesized that mitochondrial dysfunction, induced by mitochondrial DNA damage, uncouples coronary blood flow from cardiac work. Myocardial blood flow (contrast echocardiography) was measured in Zucker lean (ZLN) and obese fatty (ZOF) rats during increased cardiac metabolism (product of heart rate and arterial pressure, i.v. norepinephrine). In ZLN increased metabolism augmented coronary blood flow, but in ZOF metabolic hyperemia was attenuated. Mitochondrial respiration was impaired and ROS production was greater in ZOF than ZLN. These were associated with mitochondrial DNA (mtDNA) damage in ZOF. To determine if coronary metabolic dilation, the hyperemic response induced by heightened cardiac metabolism, is linked to mitochondrial function we introduced recombinant proteins (intravenously or intraperitoneally) in ZLN and ZOF to fragment or repair mtDNA, respectively. Repair of mtDNA damage restored mitochondrial function and metabolic dilation, and reduced ROS production in ZOF; whereas induction of mtDNA damage in ZLN reduced mitochondrial function, increased ROS production, and attenuated metabolic dilation. Adequate metabolic dilation was also associated with the extracellular release of ADP, ATP, and H2O2 by cardiac myocytes; whereas myocytes from rats with impaired dilation released only H2O2. In conclusion, our results suggest that mitochondrial function plays a seminal role in connecting myocardial blood flow to metabolism, and integrity of mtDNA is central to this process.
Guarini Giacinta; Kiyooka Takahiko; Ohanyan Vahagn; Pung Yuh Fen; Marzilli Mario; Chen Yeong-Renn; Chen Chwen-Lih; Kang Patrick T; Hardwick James P; Kolz Christopher L; Yin Liya; Wilson Glenn L; Shokolenko Inna; Dobson James G Jr; Fenton Richard; Chilian William M
Basic research in cardiology
2016
2016-05
Article information provided for research and reference use only. All rights are retained by the journal listed under publisher and/or the creator(s).
<a href="http://doi.org/10.1007/s00395-016-0547-4" target="_blank" rel="noreferrer noopener">10.1007/s00395-016-0547-4</a>