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Inhibition of myeloperoxidase to treat left ventricular dysfunction in non‐ischaemic cardiomyopathy
Aims Non‐ischaemic cardiomyopathy (NICMP), an incurable disease terminating in systolic heart failure (heart failure with reduced ejection fraction [HFrEF]), causes immune activation, however anti‐inflammatory treatment strategies so far have failed to alter the course of this disease. Myeloperoxida...
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| Published in: | European journal of heart failure 2024-10, Vol.26 (10), p.2269-2281 |
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| container_title | European journal of heart failure |
| container_volume | 26 |
| creator | Geissen, Simon Braumann, Simon Adler, Joana Nettersheim, Felix Sebastian Mehrkens, Dennis Hof, Alexander Guthoff, Henning Stein, Philipp Witkowski, Sven Gerdes, Norbert Tellkamp, Frederik Krüger, Marcus Isermann, Lea Trifunovic, Aleksandra Bunck, Alexander C. Mollenhauer, Martin Winkels, Holger Adam, Matti Klinke, Anna Buch, Gregor Cate, Vincent Hellmich, Martin Kelm, Malte Rudolph, Volker Wild, Philipp S. Rosenkranz, Stephan Baldus, Stephan |
| description | Aims
Non‐ischaemic cardiomyopathy (NICMP), an incurable disease terminating in systolic heart failure (heart failure with reduced ejection fraction [HFrEF]), causes immune activation, however anti‐inflammatory treatment strategies so far have failed to alter the course of this disease. Myeloperoxidase (MPO), the principal enzyme in neutrophils, has cytotoxic, pro‐fibrotic and nitric oxide oxidizing effects. Whether MPO inhibition ameliorates the phenotype in NICMP remains elusive.
Methods and results
Prognostic information from MPO was derived from proteomic data of a large human cardiovascular health cohort (n = 3289). In a murine model of NICMP, we studied the mechanisms of MPO in this disease. In a case series, the MPO inhibitor was also evaluated in NICMP patients. Individuals with increased MPO revealed higher long‐term mortality and worsening of heart failure, with impaired prognosis when MPO increased during follow‐up. MPO infusion attenuated left ventricular ejection fraction (LVEF) in mice with NICMP, whereas genetic ablation or inhibition of MPO decreased systemic vascular resistance (SVR, 9.4 ± 0.7 mmHg*min/ml in NICMP vs. 6.7 ± 0.8 mmHg*min/ml in NICMP/Mpo−/−mice, n = 8, p = 0.006, data expressed as mean ± standard error of the mean) and improved left ventricular function (LVEF 30.3 ± 2.2% in NICMP vs. 40.7 ± 1.1% in NICMP/Mpo−/− mice, n = 16, p |
| doi_str_mv | 10.1002/ejhf.3435 |
| format | article |
| fullrecord | <record><control><sourceid>proquest_cross</sourceid><recordid>TN_cdi_proquest_miscellaneous_3099804144</recordid><sourceformat>XML</sourceformat><sourcesystem>PC</sourcesystem><sourcerecordid>3099804144</sourcerecordid><originalsourceid>FETCH-LOGICAL-c2505-ba67af154a14b5f3e07a3636d1a2c4bb9a3cd9b03e8b75882ef0c41b237e31e43</originalsourceid><addsrcrecordid>eNp1kLtOwzAUQC0EgvIY-AHkEYYUv9I4I0ItD1VigTmynWvVVRIXOwGy8Ql8I19CQoGN6d7h3KOrg9ApJVNKCLuE9cpOueDpDppQmeUJkULsDjuXMsmlYAfoMMY1ITQb8H10wHNGGWP5BMFds3Latc432Ftc91D5DQT_5koVAbcetwFUiyuwLX6Bpg3OdJUKuOyj7Rrzfega3Pjm8_3DRbNSUDuDjQql83XvN6pd9cdoz6oqwsnPPEJPi_nj9W2yfLi5u75aJoalJE20mmXK0lQoKnRqOZBM8RmflVQxI7TOFTdlrgkHqbNUSgaWGEE14xlwCoIfofOtdxP8cwexLerhJagq1YDvYsFJnksiqBjRiy1qgo8xgC02wdUq9AUlxVi1GKsWY9WBPfvRdrqG8o_8zTgAl1vg1VXQ_28q5ve3i2_lFzaohPo</addsrcrecordid><sourcetype>Aggregation Database</sourcetype><iscdi>true</iscdi><recordtype>article</recordtype><pqid>3099804144</pqid></control><display><type>article</type><title>Inhibition of myeloperoxidase to treat left ventricular dysfunction in non‐ischaemic cardiomyopathy</title><source>Wiley</source><creator>Geissen, Simon ; Braumann, Simon ; Adler, Joana ; Nettersheim, Felix Sebastian ; Mehrkens, Dennis ; Hof, Alexander ; Guthoff, Henning ; Stein, Philipp ; Witkowski, Sven ; Gerdes, Norbert ; Tellkamp, Frederik ; Krüger, Marcus ; Isermann, Lea ; Trifunovic, Aleksandra ; Bunck, Alexander C. ; Mollenhauer, Martin ; Winkels, Holger ; Adam, Matti ; Klinke, Anna ; Buch, Gregor ; Cate, Vincent ; Hellmich, Martin ; Kelm, Malte ; Rudolph, Volker ; Wild, Philipp S. ; Rosenkranz, Stephan ; Baldus, Stephan</creator><creatorcontrib>Geissen, Simon ; Braumann, Simon ; Adler, Joana ; Nettersheim, Felix Sebastian ; Mehrkens, Dennis ; Hof, Alexander ; Guthoff, Henning ; Stein, Philipp ; Witkowski, Sven ; Gerdes, Norbert ; Tellkamp, Frederik ; Krüger, Marcus ; Isermann, Lea ; Trifunovic, Aleksandra ; Bunck, Alexander C. ; Mollenhauer, Martin ; Winkels, Holger ; Adam, Matti ; Klinke, Anna ; Buch, Gregor ; Cate, Vincent ; Hellmich, Martin ; Kelm, Malte ; Rudolph, Volker ; Wild, Philipp S. ; Rosenkranz, Stephan ; Baldus, Stephan</creatorcontrib><description>Aims
Non‐ischaemic cardiomyopathy (NICMP), an incurable disease terminating in systolic heart failure (heart failure with reduced ejection fraction [HFrEF]), causes immune activation, however anti‐inflammatory treatment strategies so far have failed to alter the course of this disease. Myeloperoxidase (MPO), the principal enzyme in neutrophils, has cytotoxic, pro‐fibrotic and nitric oxide oxidizing effects. Whether MPO inhibition ameliorates the phenotype in NICMP remains elusive.
Methods and results
Prognostic information from MPO was derived from proteomic data of a large human cardiovascular health cohort (n = 3289). In a murine model of NICMP, we studied the mechanisms of MPO in this disease. In a case series, the MPO inhibitor was also evaluated in NICMP patients. Individuals with increased MPO revealed higher long‐term mortality and worsening of heart failure, with impaired prognosis when MPO increased during follow‐up. MPO infusion attenuated left ventricular ejection fraction (LVEF) in mice with NICMP, whereas genetic ablation or inhibition of MPO decreased systemic vascular resistance (SVR, 9.4 ± 0.7 mmHg*min/ml in NICMP vs. 6.7 ± 0.8 mmHg*min/ml in NICMP/Mpo−/−mice, n = 8, p = 0.006, data expressed as mean ± standard error of the mean) and improved left ventricular function (LVEF 30.3 ± 2.2% in NICMP vs. 40.7 ± 1.1% in NICMP/Mpo−/− mice, n = 16, p < 0.0001). Four patients diagnosed with NICMP and treated with an MPO inhibitor over 12 weeks showed increase in LVEF, decline in natriuretic peptides and improved 6‐min walking distance. MPO inhibitor‐related changes in the proteome of NICMP patients predicted reduced mortality when related to the changes in the proteome of the above referenced cardiovascular health cohort.
Conclusions
Myeloperoxidase predicts long‐term outcome in HFrEF and its inhibition elicits systemic anti‐inflammatory and vasodilating effects which translate into improved left ventricular function. MPO inhibition deserves further evaluation as a novel, complementary treatment strategy for HFrEF.
Myeloperoxidase (MPO) inhibition for the treatment of left ventricular dysfunction in non‐ischaemic cardiomyopathy (NICMP). Ang II, angiotensin II; G‐CSF, granulocyte colony‐stimulating factor; HFrEF, heart failure with reduced ejection fraction; LVESVi, left ventricular end‐systolic volume index; Mlp, muscle LIM protein; NT‐proBNP, N‐terminal pro‐B‐type natriuretic peptide; PMN, polymorphonuclear neutrophil.</description><identifier>ISSN: 1388-9842</identifier><identifier>ISSN: 1879-0844</identifier><identifier>EISSN: 1879-0844</identifier><identifier>DOI: 10.1002/ejhf.3435</identifier><identifier>PMID: 39212229</identifier><language>eng</language><publisher>Oxford, UK: John Wiley & Sons, Ltd</publisher><subject>Aged ; Animals ; Cardiomyopathies - drug therapy ; Cardiomyopathies - etiology ; Cardiomyopathies - physiopathology ; Disease Models, Animal ; Endothelial dysfunction ; Female ; Heart failure ; HFrEF ; Humans ; Male ; Mice ; Middle Aged ; Myeloperoxidase ; Non‐ischaemic cardiomyopathy ; Peroxidase - metabolism ; Prognosis ; Stroke Volume - physiology ; Ventricular Dysfunction, Left - drug therapy ; Ventricular Dysfunction, Left - etiology ; Ventricular Dysfunction, Left - physiopathology ; Ventricular Function, Left - drug effects ; Ventricular Function, Left - physiology</subject><ispartof>European journal of heart failure, 2024-10, Vol.26 (10), p.2269-2281</ispartof><rights>2024 The Author(s). published by John Wiley & Sons Ltd on behalf of European Society of Cardiology.</rights><rights>2024 The Author(s). European Journal of Heart Failure published by John Wiley & Sons Ltd on behalf of European Society of Cardiology.</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><cites>FETCH-LOGICAL-c2505-ba67af154a14b5f3e07a3636d1a2c4bb9a3cd9b03e8b75882ef0c41b237e31e43</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>314,777,781,27905,27906</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/39212229$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Geissen, Simon</creatorcontrib><creatorcontrib>Braumann, Simon</creatorcontrib><creatorcontrib>Adler, Joana</creatorcontrib><creatorcontrib>Nettersheim, Felix Sebastian</creatorcontrib><creatorcontrib>Mehrkens, Dennis</creatorcontrib><creatorcontrib>Hof, Alexander</creatorcontrib><creatorcontrib>Guthoff, Henning</creatorcontrib><creatorcontrib>Stein, Philipp</creatorcontrib><creatorcontrib>Witkowski, Sven</creatorcontrib><creatorcontrib>Gerdes, Norbert</creatorcontrib><creatorcontrib>Tellkamp, Frederik</creatorcontrib><creatorcontrib>Krüger, Marcus</creatorcontrib><creatorcontrib>Isermann, Lea</creatorcontrib><creatorcontrib>Trifunovic, Aleksandra</creatorcontrib><creatorcontrib>Bunck, Alexander C.</creatorcontrib><creatorcontrib>Mollenhauer, Martin</creatorcontrib><creatorcontrib>Winkels, Holger</creatorcontrib><creatorcontrib>Adam, Matti</creatorcontrib><creatorcontrib>Klinke, Anna</creatorcontrib><creatorcontrib>Buch, Gregor</creatorcontrib><creatorcontrib>Cate, Vincent</creatorcontrib><creatorcontrib>Hellmich, Martin</creatorcontrib><creatorcontrib>Kelm, Malte</creatorcontrib><creatorcontrib>Rudolph, Volker</creatorcontrib><creatorcontrib>Wild, Philipp S.</creatorcontrib><creatorcontrib>Rosenkranz, Stephan</creatorcontrib><creatorcontrib>Baldus, Stephan</creatorcontrib><title>Inhibition of myeloperoxidase to treat left ventricular dysfunction in non‐ischaemic cardiomyopathy</title><title>European journal of heart failure</title><addtitle>Eur J Heart Fail</addtitle><description>Aims
Non‐ischaemic cardiomyopathy (NICMP), an incurable disease terminating in systolic heart failure (heart failure with reduced ejection fraction [HFrEF]), causes immune activation, however anti‐inflammatory treatment strategies so far have failed to alter the course of this disease. Myeloperoxidase (MPO), the principal enzyme in neutrophils, has cytotoxic, pro‐fibrotic and nitric oxide oxidizing effects. Whether MPO inhibition ameliorates the phenotype in NICMP remains elusive.
Methods and results
Prognostic information from MPO was derived from proteomic data of a large human cardiovascular health cohort (n = 3289). In a murine model of NICMP, we studied the mechanisms of MPO in this disease. In a case series, the MPO inhibitor was also evaluated in NICMP patients. Individuals with increased MPO revealed higher long‐term mortality and worsening of heart failure, with impaired prognosis when MPO increased during follow‐up. MPO infusion attenuated left ventricular ejection fraction (LVEF) in mice with NICMP, whereas genetic ablation or inhibition of MPO decreased systemic vascular resistance (SVR, 9.4 ± 0.7 mmHg*min/ml in NICMP vs. 6.7 ± 0.8 mmHg*min/ml in NICMP/Mpo−/−mice, n = 8, p = 0.006, data expressed as mean ± standard error of the mean) and improved left ventricular function (LVEF 30.3 ± 2.2% in NICMP vs. 40.7 ± 1.1% in NICMP/Mpo−/− mice, n = 16, p < 0.0001). Four patients diagnosed with NICMP and treated with an MPO inhibitor over 12 weeks showed increase in LVEF, decline in natriuretic peptides and improved 6‐min walking distance. MPO inhibitor‐related changes in the proteome of NICMP patients predicted reduced mortality when related to the changes in the proteome of the above referenced cardiovascular health cohort.
Conclusions
Myeloperoxidase predicts long‐term outcome in HFrEF and its inhibition elicits systemic anti‐inflammatory and vasodilating effects which translate into improved left ventricular function. MPO inhibition deserves further evaluation as a novel, complementary treatment strategy for HFrEF.
Myeloperoxidase (MPO) inhibition for the treatment of left ventricular dysfunction in non‐ischaemic cardiomyopathy (NICMP). Ang II, angiotensin II; G‐CSF, granulocyte colony‐stimulating factor; HFrEF, heart failure with reduced ejection fraction; LVESVi, left ventricular end‐systolic volume index; Mlp, muscle LIM protein; NT‐proBNP, N‐terminal pro‐B‐type natriuretic peptide; PMN, polymorphonuclear neutrophil.</description><subject>Aged</subject><subject>Animals</subject><subject>Cardiomyopathies - drug therapy</subject><subject>Cardiomyopathies - etiology</subject><subject>Cardiomyopathies - physiopathology</subject><subject>Disease Models, Animal</subject><subject>Endothelial dysfunction</subject><subject>Female</subject><subject>Heart failure</subject><subject>HFrEF</subject><subject>Humans</subject><subject>Male</subject><subject>Mice</subject><subject>Middle Aged</subject><subject>Myeloperoxidase</subject><subject>Non‐ischaemic cardiomyopathy</subject><subject>Peroxidase - metabolism</subject><subject>Prognosis</subject><subject>Stroke Volume - physiology</subject><subject>Ventricular Dysfunction, Left - drug therapy</subject><subject>Ventricular Dysfunction, Left - etiology</subject><subject>Ventricular Dysfunction, Left - physiopathology</subject><subject>Ventricular Function, Left - drug effects</subject><subject>Ventricular Function, Left - physiology</subject><issn>1388-9842</issn><issn>1879-0844</issn><issn>1879-0844</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2024</creationdate><recordtype>article</recordtype><sourceid>24P</sourceid><recordid>eNp1kLtOwzAUQC0EgvIY-AHkEYYUv9I4I0ItD1VigTmynWvVVRIXOwGy8Ql8I19CQoGN6d7h3KOrg9ApJVNKCLuE9cpOueDpDppQmeUJkULsDjuXMsmlYAfoMMY1ITQb8H10wHNGGWP5BMFds3Latc432Ftc91D5DQT_5koVAbcetwFUiyuwLX6Bpg3OdJUKuOyj7Rrzfega3Pjm8_3DRbNSUDuDjQql83XvN6pd9cdoz6oqwsnPPEJPi_nj9W2yfLi5u75aJoalJE20mmXK0lQoKnRqOZBM8RmflVQxI7TOFTdlrgkHqbNUSgaWGEE14xlwCoIfofOtdxP8cwexLerhJagq1YDvYsFJnksiqBjRiy1qgo8xgC02wdUq9AUlxVi1GKsWY9WBPfvRdrqG8o_8zTgAl1vg1VXQ_28q5ve3i2_lFzaohPo</recordid><startdate>202410</startdate><enddate>202410</enddate><creator>Geissen, Simon</creator><creator>Braumann, Simon</creator><creator>Adler, Joana</creator><creator>Nettersheim, Felix Sebastian</creator><creator>Mehrkens, Dennis</creator><creator>Hof, Alexander</creator><creator>Guthoff, Henning</creator><creator>Stein, Philipp</creator><creator>Witkowski, Sven</creator><creator>Gerdes, Norbert</creator><creator>Tellkamp, Frederik</creator><creator>Krüger, Marcus</creator><creator>Isermann, Lea</creator><creator>Trifunovic, Aleksandra</creator><creator>Bunck, Alexander C.</creator><creator>Mollenhauer, Martin</creator><creator>Winkels, Holger</creator><creator>Adam, Matti</creator><creator>Klinke, Anna</creator><creator>Buch, Gregor</creator><creator>Cate, Vincent</creator><creator>Hellmich, Martin</creator><creator>Kelm, Malte</creator><creator>Rudolph, Volker</creator><creator>Wild, Philipp S.</creator><creator>Rosenkranz, Stephan</creator><creator>Baldus, Stephan</creator><general>John Wiley & Sons, Ltd</general><scope>24P</scope><scope>WIN</scope><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7X8</scope></search><sort><creationdate>202410</creationdate><title>Inhibition of myeloperoxidase to treat left ventricular dysfunction in non‐ischaemic cardiomyopathy</title><author>Geissen, Simon ; Braumann, Simon ; Adler, Joana ; Nettersheim, Felix Sebastian ; Mehrkens, Dennis ; Hof, Alexander ; Guthoff, Henning ; Stein, Philipp ; Witkowski, Sven ; Gerdes, Norbert ; Tellkamp, Frederik ; Krüger, Marcus ; Isermann, Lea ; Trifunovic, Aleksandra ; Bunck, Alexander C. ; Mollenhauer, Martin ; Winkels, Holger ; Adam, Matti ; Klinke, Anna ; Buch, Gregor ; Cate, Vincent ; Hellmich, Martin ; Kelm, Malte ; Rudolph, Volker ; Wild, Philipp S. ; Rosenkranz, Stephan ; Baldus, Stephan</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c2505-ba67af154a14b5f3e07a3636d1a2c4bb9a3cd9b03e8b75882ef0c41b237e31e43</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2024</creationdate><topic>Aged</topic><topic>Animals</topic><topic>Cardiomyopathies - drug therapy</topic><topic>Cardiomyopathies - etiology</topic><topic>Cardiomyopathies - physiopathology</topic><topic>Disease Models, Animal</topic><topic>Endothelial dysfunction</topic><topic>Female</topic><topic>Heart failure</topic><topic>HFrEF</topic><topic>Humans</topic><topic>Male</topic><topic>Mice</topic><topic>Middle Aged</topic><topic>Myeloperoxidase</topic><topic>Non‐ischaemic cardiomyopathy</topic><topic>Peroxidase - metabolism</topic><topic>Prognosis</topic><topic>Stroke Volume - physiology</topic><topic>Ventricular Dysfunction, Left - drug therapy</topic><topic>Ventricular Dysfunction, Left - etiology</topic><topic>Ventricular Dysfunction, Left - physiopathology</topic><topic>Ventricular Function, Left - drug effects</topic><topic>Ventricular Function, Left - physiology</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Geissen, Simon</creatorcontrib><creatorcontrib>Braumann, Simon</creatorcontrib><creatorcontrib>Adler, Joana</creatorcontrib><creatorcontrib>Nettersheim, Felix Sebastian</creatorcontrib><creatorcontrib>Mehrkens, Dennis</creatorcontrib><creatorcontrib>Hof, Alexander</creatorcontrib><creatorcontrib>Guthoff, Henning</creatorcontrib><creatorcontrib>Stein, Philipp</creatorcontrib><creatorcontrib>Witkowski, Sven</creatorcontrib><creatorcontrib>Gerdes, Norbert</creatorcontrib><creatorcontrib>Tellkamp, Frederik</creatorcontrib><creatorcontrib>Krüger, Marcus</creatorcontrib><creatorcontrib>Isermann, Lea</creatorcontrib><creatorcontrib>Trifunovic, Aleksandra</creatorcontrib><creatorcontrib>Bunck, Alexander C.</creatorcontrib><creatorcontrib>Mollenhauer, Martin</creatorcontrib><creatorcontrib>Winkels, Holger</creatorcontrib><creatorcontrib>Adam, Matti</creatorcontrib><creatorcontrib>Klinke, Anna</creatorcontrib><creatorcontrib>Buch, Gregor</creatorcontrib><creatorcontrib>Cate, Vincent</creatorcontrib><creatorcontrib>Hellmich, Martin</creatorcontrib><creatorcontrib>Kelm, Malte</creatorcontrib><creatorcontrib>Rudolph, Volker</creatorcontrib><creatorcontrib>Wild, Philipp S.</creatorcontrib><creatorcontrib>Rosenkranz, Stephan</creatorcontrib><creatorcontrib>Baldus, Stephan</creatorcontrib><collection>Wiley-Blackwell Titles (Open access)</collection><collection>Wiley Online Library Free Content</collection><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>MEDLINE - Academic</collection><jtitle>European journal of heart failure</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Geissen, Simon</au><au>Braumann, Simon</au><au>Adler, Joana</au><au>Nettersheim, Felix Sebastian</au><au>Mehrkens, Dennis</au><au>Hof, Alexander</au><au>Guthoff, Henning</au><au>Stein, Philipp</au><au>Witkowski, Sven</au><au>Gerdes, Norbert</au><au>Tellkamp, Frederik</au><au>Krüger, Marcus</au><au>Isermann, Lea</au><au>Trifunovic, Aleksandra</au><au>Bunck, Alexander C.</au><au>Mollenhauer, Martin</au><au>Winkels, Holger</au><au>Adam, Matti</au><au>Klinke, Anna</au><au>Buch, Gregor</au><au>Cate, Vincent</au><au>Hellmich, Martin</au><au>Kelm, Malte</au><au>Rudolph, Volker</au><au>Wild, Philipp S.</au><au>Rosenkranz, Stephan</au><au>Baldus, Stephan</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Inhibition of myeloperoxidase to treat left ventricular dysfunction in non‐ischaemic cardiomyopathy</atitle><jtitle>European journal of heart failure</jtitle><addtitle>Eur J Heart Fail</addtitle><date>2024-10</date><risdate>2024</risdate><volume>26</volume><issue>10</issue><spage>2269</spage><epage>2281</epage><pages>2269-2281</pages><issn>1388-9842</issn><issn>1879-0844</issn><eissn>1879-0844</eissn><abstract>Aims
Non‐ischaemic cardiomyopathy (NICMP), an incurable disease terminating in systolic heart failure (heart failure with reduced ejection fraction [HFrEF]), causes immune activation, however anti‐inflammatory treatment strategies so far have failed to alter the course of this disease. Myeloperoxidase (MPO), the principal enzyme in neutrophils, has cytotoxic, pro‐fibrotic and nitric oxide oxidizing effects. Whether MPO inhibition ameliorates the phenotype in NICMP remains elusive.
Methods and results
Prognostic information from MPO was derived from proteomic data of a large human cardiovascular health cohort (n = 3289). In a murine model of NICMP, we studied the mechanisms of MPO in this disease. In a case series, the MPO inhibitor was also evaluated in NICMP patients. Individuals with increased MPO revealed higher long‐term mortality and worsening of heart failure, with impaired prognosis when MPO increased during follow‐up. MPO infusion attenuated left ventricular ejection fraction (LVEF) in mice with NICMP, whereas genetic ablation or inhibition of MPO decreased systemic vascular resistance (SVR, 9.4 ± 0.7 mmHg*min/ml in NICMP vs. 6.7 ± 0.8 mmHg*min/ml in NICMP/Mpo−/−mice, n = 8, p = 0.006, data expressed as mean ± standard error of the mean) and improved left ventricular function (LVEF 30.3 ± 2.2% in NICMP vs. 40.7 ± 1.1% in NICMP/Mpo−/− mice, n = 16, p < 0.0001). Four patients diagnosed with NICMP and treated with an MPO inhibitor over 12 weeks showed increase in LVEF, decline in natriuretic peptides and improved 6‐min walking distance. MPO inhibitor‐related changes in the proteome of NICMP patients predicted reduced mortality when related to the changes in the proteome of the above referenced cardiovascular health cohort.
Conclusions
Myeloperoxidase predicts long‐term outcome in HFrEF and its inhibition elicits systemic anti‐inflammatory and vasodilating effects which translate into improved left ventricular function. MPO inhibition deserves further evaluation as a novel, complementary treatment strategy for HFrEF.
Myeloperoxidase (MPO) inhibition for the treatment of left ventricular dysfunction in non‐ischaemic cardiomyopathy (NICMP). Ang II, angiotensin II; G‐CSF, granulocyte colony‐stimulating factor; HFrEF, heart failure with reduced ejection fraction; LVESVi, left ventricular end‐systolic volume index; Mlp, muscle LIM protein; NT‐proBNP, N‐terminal pro‐B‐type natriuretic peptide; PMN, polymorphonuclear neutrophil.</abstract><cop>Oxford, UK</cop><pub>John Wiley & Sons, Ltd</pub><pmid>39212229</pmid><doi>10.1002/ejhf.3435</doi><tpages>13</tpages><oa>free_for_read</oa></addata></record> |
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| ispartof | European journal of heart failure, 2024-10, Vol.26 (10), p.2269-2281 |
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| subjects | Aged Animals Cardiomyopathies - drug therapy Cardiomyopathies - etiology Cardiomyopathies - physiopathology Disease Models, Animal Endothelial dysfunction Female Heart failure HFrEF Humans Male Mice Middle Aged Myeloperoxidase Non‐ischaemic cardiomyopathy Peroxidase - metabolism Prognosis Stroke Volume - physiology Ventricular Dysfunction, Left - drug therapy Ventricular Dysfunction, Left - etiology Ventricular Dysfunction, Left - physiopathology Ventricular Function, Left - drug effects Ventricular Function, Left - physiology |
| title | Inhibition of myeloperoxidase to treat left ventricular dysfunction in non‐ischaemic cardiomyopathy |
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