Acute effects of a mavacamten-like myosin-inhibitor (MYK-581 in a feline model of obstructed hypertrophic cardiomyopathy: evidence of improved ventricular filling (beyond obstruction reprieve)
Abstract Introduction Hypertrophic cardiomyopathy (HCM) is a progressive disease characterized by cardiac remodeling, hyperdynamic contraction, and impaired ventricular filling that can lead to dynamic left-ventricular outflow-track (LVOT) obstruction and exertional intolerance. Direct myosin-inhibi...
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description | Abstract
Introduction
Hypertrophic cardiomyopathy (HCM) is a progressive disease characterized by cardiac remodeling, hyperdynamic contraction, and impaired ventricular filling that can lead to dynamic left-ventricular outflow-track (LVOT) obstruction and exertional intolerance. Direct myosin-inhibition with mavacamten can normalize contractility and improve exercise capacity in patients with oHCM, providing sustained symptomatic relief. However, mavacamten can also improve ventricular filling by limiting residual cross-bridges during diastole, and therefore, may offer cardiac benefits beyond obstruction reprieve. This study leveraged a feline model of oHCM, cats with the A31P MYBPC3 variant, to study the acute in vivo effects of MYK-581, a mavacamten surrogate, on cardiac hemodynamics and filling.
Methods
A31P-homozygous cats with HCM (A31P, n=10) and wild-type healthy controls (CTRL, n=9) were anesthetized and instrumented for invasive pressure-volume (PV) measurements as well as trans-thoracic echocardiographic recording. A subset of cats were assigned to receive either vehicle (VEH, n=7) or MYK-581 (MYK, n=8) with a short IV infusion. Cardiac hemodynamics, function, and geometry were assessed at steady state before and during dobutamine challenges (2.5 μg/kg/min IV).
Results
A31P cats had thicker ventricular walls (6.4±0.1 vs. 5.2±0.2 mm, P |
doi_str_mv | 10.1093/ehjci/ehaa946.3713 |
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Introduction
Hypertrophic cardiomyopathy (HCM) is a progressive disease characterized by cardiac remodeling, hyperdynamic contraction, and impaired ventricular filling that can lead to dynamic left-ventricular outflow-track (LVOT) obstruction and exertional intolerance. Direct myosin-inhibition with mavacamten can normalize contractility and improve exercise capacity in patients with oHCM, providing sustained symptomatic relief. However, mavacamten can also improve ventricular filling by limiting residual cross-bridges during diastole, and therefore, may offer cardiac benefits beyond obstruction reprieve. This study leveraged a feline model of oHCM, cats with the A31P MYBPC3 variant, to study the acute in vivo effects of MYK-581, a mavacamten surrogate, on cardiac hemodynamics and filling.
Methods
A31P-homozygous cats with HCM (A31P, n=10) and wild-type healthy controls (CTRL, n=9) were anesthetized and instrumented for invasive pressure-volume (PV) measurements as well as trans-thoracic echocardiographic recording. A subset of cats were assigned to receive either vehicle (VEH, n=7) or MYK-581 (MYK, n=8) with a short IV infusion. Cardiac hemodynamics, function, and geometry were assessed at steady state before and during dobutamine challenges (2.5 μg/kg/min IV).
Results
A31P cats had thicker ventricular walls (6.4±0.1 vs. 5.2±0.2 mm, P<0.05) and hyperdynamic contraction (FS: 61±4 vs. 50±3%, P<0.05) relative to controls and presented with dynamic LVOT obstruction in 54% of cases. HCM cats had elevated end-diastolic pressures (17±1.4 vs. 9±1.0 mmHg, P<0.05), with prolonged time constants of relaxation (60±4.1 vs. 36±2.4 ms, P<0.05) and elevated end-diastolic stiffness (Eed: 0.44±0.06 vs. 0.25±0.01 mmHg/mL). Acute treatment with MYK-581 alleviated LVOT obstruction (0% vs. 38%), normalized contractility (FS: −7±2%), and increased systolic/diastolic chamber dimensions (e.g., LVIDd: +13±4%) (all P<0.05), while reducing EDP (15±2 to 13±2 mmHg, P<0.05), suggesting acute improvement in ventricular distensibility. Indeed, MYK-581 treatment reduced end-diastolic stiffness (Eed: 0.48±0.11 vs. 0.36±0. 10 mmHg/mL, P<0.05) and normalized trans-mitral motion patterns during filling.
Conclusions
Bred cats, homozygous for the A31P MYBPC3 variant, presented a cardiac phenotype that models multiple characteristics of the human oHCM phenotype including dynamic LVOT obstruction. Acute treatment with the mavacamten surrogate, MYK-581, not only alleviated hypercontractility and LVOT obstruction, but improved ventricular filling and end-diastolic pressures. Taken together, these pre-clinical observations show potential salutary effects beyond obstruction relief in patients with HCM.
Funding Acknowledgement
Type of funding source: Private company. Main funding source(s): MyoKardia]]></description><identifier>ISSN: 0195-668X</identifier><identifier>EISSN: 1522-9645</identifier><identifier>DOI: 10.1093/ehjci/ehaa946.3713</identifier><language>eng</language><publisher>Oxford University Press</publisher><ispartof>European heart journal, 2020-11, Vol.41 (Supplement_2)</ispartof><rights>Published on behalf of the European Society of Cardiology. All rights reserved. © The Author(s) 2020. For permissions, please email: journals.permissions@oup.com. 2020</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c1743-9af1134ffb123a60d800d121165244033f23a578adb4c2231730241c3c799d313</citedby></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>314,776,780,27901,27902</link.rule.ids></links><search><creatorcontrib>Ferguson, B.S</creatorcontrib><creatorcontrib>Stern, J.A</creatorcontrib><creatorcontrib>Oldach, M.S</creatorcontrib><creatorcontrib>Ueda, Y</creatorcontrib><creatorcontrib>Ontiveros, E.S</creatorcontrib><creatorcontrib>Napierski, N.C</creatorcontrib><creatorcontrib>Del Rio, C.L</creatorcontrib><creatorcontrib>Harris, S.P</creatorcontrib><title>Acute effects of a mavacamten-like myosin-inhibitor (MYK-581 in a feline model of obstructed hypertrophic cardiomyopathy: evidence of improved ventricular filling (beyond obstruction reprieve)</title><title>European heart journal</title><description><![CDATA[Abstract
Introduction
Hypertrophic cardiomyopathy (HCM) is a progressive disease characterized by cardiac remodeling, hyperdynamic contraction, and impaired ventricular filling that can lead to dynamic left-ventricular outflow-track (LVOT) obstruction and exertional intolerance. Direct myosin-inhibition with mavacamten can normalize contractility and improve exercise capacity in patients with oHCM, providing sustained symptomatic relief. However, mavacamten can also improve ventricular filling by limiting residual cross-bridges during diastole, and therefore, may offer cardiac benefits beyond obstruction reprieve. This study leveraged a feline model of oHCM, cats with the A31P MYBPC3 variant, to study the acute in vivo effects of MYK-581, a mavacamten surrogate, on cardiac hemodynamics and filling.
Methods
A31P-homozygous cats with HCM (A31P, n=10) and wild-type healthy controls (CTRL, n=9) were anesthetized and instrumented for invasive pressure-volume (PV) measurements as well as trans-thoracic echocardiographic recording. A subset of cats were assigned to receive either vehicle (VEH, n=7) or MYK-581 (MYK, n=8) with a short IV infusion. Cardiac hemodynamics, function, and geometry were assessed at steady state before and during dobutamine challenges (2.5 μg/kg/min IV).
Results
A31P cats had thicker ventricular walls (6.4±0.1 vs. 5.2±0.2 mm, P<0.05) and hyperdynamic contraction (FS: 61±4 vs. 50±3%, P<0.05) relative to controls and presented with dynamic LVOT obstruction in 54% of cases. HCM cats had elevated end-diastolic pressures (17±1.4 vs. 9±1.0 mmHg, P<0.05), with prolonged time constants of relaxation (60±4.1 vs. 36±2.4 ms, P<0.05) and elevated end-diastolic stiffness (Eed: 0.44±0.06 vs. 0.25±0.01 mmHg/mL). Acute treatment with MYK-581 alleviated LVOT obstruction (0% vs. 38%), normalized contractility (FS: −7±2%), and increased systolic/diastolic chamber dimensions (e.g., LVIDd: +13±4%) (all P<0.05), while reducing EDP (15±2 to 13±2 mmHg, P<0.05), suggesting acute improvement in ventricular distensibility. Indeed, MYK-581 treatment reduced end-diastolic stiffness (Eed: 0.48±0.11 vs. 0.36±0. 10 mmHg/mL, P<0.05) and normalized trans-mitral motion patterns during filling.
Conclusions
Bred cats, homozygous for the A31P MYBPC3 variant, presented a cardiac phenotype that models multiple characteristics of the human oHCM phenotype including dynamic LVOT obstruction. Acute treatment with the mavacamten surrogate, MYK-581, not only alleviated hypercontractility and LVOT obstruction, but improved ventricular filling and end-diastolic pressures. Taken together, these pre-clinical observations show potential salutary effects beyond obstruction relief in patients with HCM.
Funding Acknowledgement
Type of funding source: Private company. Main funding source(s): MyoKardia]]></description><issn>0195-668X</issn><issn>1522-9645</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2020</creationdate><recordtype>article</recordtype><recordid>eNqNkc1O3TAQRq2qlXpLeYGuvISFqcfOb3cIUagKYgMSrCLHHjemiR05vpHydn00fAvqupsZafR9RyMdQr4APwPeyq84PGuXp1JtUZ3JGuQ7soNSCNZWRfme7Di0Jauq5vEj-bQsz5zzpoJqR_6c631CitaiTgsNlio6qVVpNSX0bHS_kU5bWJxnzg-udylEenL79JOVDVDnc9zi6HxOBYPjARD6JcW9TmjosM0YUwzz4DTVKhoXMmxWadi-UVydQa_x0HHTHMOaGyv6FJ3ejypS68ZM_kVPetyCN__ALngacY4OVzz9TD5YNS54_LaPyMP3y_uLa3Zzd_Xj4vyGaagLyVplAWRhbQ9CqoqbhnMDAqAqRVFwKW0-l3WjTF9oISTUkosCtNR12xoJ8oiIV66OYVki2i4_MKm4dcC7g4Pur4PuzUF3cJBL7LUU9vP_5F8A1OaPTw</recordid><startdate>20201101</startdate><enddate>20201101</enddate><creator>Ferguson, B.S</creator><creator>Stern, J.A</creator><creator>Oldach, M.S</creator><creator>Ueda, Y</creator><creator>Ontiveros, E.S</creator><creator>Napierski, N.C</creator><creator>Del Rio, C.L</creator><creator>Harris, S.P</creator><general>Oxford University Press</general><scope>AAYXX</scope><scope>CITATION</scope></search><sort><creationdate>20201101</creationdate><title>Acute effects of a mavacamten-like myosin-inhibitor (MYK-581 in a feline model of obstructed hypertrophic cardiomyopathy: evidence of improved ventricular filling (beyond obstruction reprieve)</title><author>Ferguson, B.S ; Stern, J.A ; Oldach, M.S ; Ueda, Y ; Ontiveros, E.S ; Napierski, N.C ; Del Rio, C.L ; Harris, S.P</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c1743-9af1134ffb123a60d800d121165244033f23a578adb4c2231730241c3c799d313</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2020</creationdate><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Ferguson, B.S</creatorcontrib><creatorcontrib>Stern, J.A</creatorcontrib><creatorcontrib>Oldach, M.S</creatorcontrib><creatorcontrib>Ueda, Y</creatorcontrib><creatorcontrib>Ontiveros, E.S</creatorcontrib><creatorcontrib>Napierski, N.C</creatorcontrib><creatorcontrib>Del Rio, C.L</creatorcontrib><creatorcontrib>Harris, S.P</creatorcontrib><collection>CrossRef</collection><jtitle>European heart journal</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Ferguson, B.S</au><au>Stern, J.A</au><au>Oldach, M.S</au><au>Ueda, Y</au><au>Ontiveros, E.S</au><au>Napierski, N.C</au><au>Del Rio, C.L</au><au>Harris, S.P</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Acute effects of a mavacamten-like myosin-inhibitor (MYK-581 in a feline model of obstructed hypertrophic cardiomyopathy: evidence of improved ventricular filling (beyond obstruction reprieve)</atitle><jtitle>European heart journal</jtitle><date>2020-11-01</date><risdate>2020</risdate><volume>41</volume><issue>Supplement_2</issue><issn>0195-668X</issn><eissn>1522-9645</eissn><abstract><![CDATA[Abstract
Introduction
Hypertrophic cardiomyopathy (HCM) is a progressive disease characterized by cardiac remodeling, hyperdynamic contraction, and impaired ventricular filling that can lead to dynamic left-ventricular outflow-track (LVOT) obstruction and exertional intolerance. Direct myosin-inhibition with mavacamten can normalize contractility and improve exercise capacity in patients with oHCM, providing sustained symptomatic relief. However, mavacamten can also improve ventricular filling by limiting residual cross-bridges during diastole, and therefore, may offer cardiac benefits beyond obstruction reprieve. This study leveraged a feline model of oHCM, cats with the A31P MYBPC3 variant, to study the acute in vivo effects of MYK-581, a mavacamten surrogate, on cardiac hemodynamics and filling.
Methods
A31P-homozygous cats with HCM (A31P, n=10) and wild-type healthy controls (CTRL, n=9) were anesthetized and instrumented for invasive pressure-volume (PV) measurements as well as trans-thoracic echocardiographic recording. A subset of cats were assigned to receive either vehicle (VEH, n=7) or MYK-581 (MYK, n=8) with a short IV infusion. Cardiac hemodynamics, function, and geometry were assessed at steady state before and during dobutamine challenges (2.5 μg/kg/min IV).
Results
A31P cats had thicker ventricular walls (6.4±0.1 vs. 5.2±0.2 mm, P<0.05) and hyperdynamic contraction (FS: 61±4 vs. 50±3%, P<0.05) relative to controls and presented with dynamic LVOT obstruction in 54% of cases. HCM cats had elevated end-diastolic pressures (17±1.4 vs. 9±1.0 mmHg, P<0.05), with prolonged time constants of relaxation (60±4.1 vs. 36±2.4 ms, P<0.05) and elevated end-diastolic stiffness (Eed: 0.44±0.06 vs. 0.25±0.01 mmHg/mL). Acute treatment with MYK-581 alleviated LVOT obstruction (0% vs. 38%), normalized contractility (FS: −7±2%), and increased systolic/diastolic chamber dimensions (e.g., LVIDd: +13±4%) (all P<0.05), while reducing EDP (15±2 to 13±2 mmHg, P<0.05), suggesting acute improvement in ventricular distensibility. Indeed, MYK-581 treatment reduced end-diastolic stiffness (Eed: 0.48±0.11 vs. 0.36±0. 10 mmHg/mL, P<0.05) and normalized trans-mitral motion patterns during filling.
Conclusions
Bred cats, homozygous for the A31P MYBPC3 variant, presented a cardiac phenotype that models multiple characteristics of the human oHCM phenotype including dynamic LVOT obstruction. Acute treatment with the mavacamten surrogate, MYK-581, not only alleviated hypercontractility and LVOT obstruction, but improved ventricular filling and end-diastolic pressures. Taken together, these pre-clinical observations show potential salutary effects beyond obstruction relief in patients with HCM.
Funding Acknowledgement
Type of funding source: Private company. Main funding source(s): MyoKardia]]></abstract><pub>Oxford University Press</pub><doi>10.1093/ehjci/ehaa946.3713</doi><oa>free_for_read</oa></addata></record> |
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title | Acute effects of a mavacamten-like myosin-inhibitor (MYK-581 in a feline model of obstructed hypertrophic cardiomyopathy: evidence of improved ventricular filling (beyond obstruction reprieve) |
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