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These variants can cause increased actin\u2013myosin crossbridge cycling, resulting in ventricular hypercontractility, but mice lacking Mybpc3 exhibited reduced left ventricular ejection time (LVET) as a sign of systolic dysfunction. In this study, we tested whether LVET is specifically altered in patients carrying MYBPC3 variants by retrospective echocardiographic analysis in two genotype-defined HCM cohorts.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>LVET was measured by echocardiography and adjusted for heart rate [LVET index (LVETI)] in 166 patients. Variant carriers were stratified for the presence (LVH+) or absence of left ventricular hypertrophy with septal thickness of \u226513 mm (LVH\u2212). Multivariate analysis of variance (MANOVA) was used to identify differences in LVETI between variant carriers and controls with LVETI as the dependent variable, adjusted for sex, age, left ventricular ejection fraction (LVEF), interventricular septal diameter in diastole (IVSd), diastolic dysfunction, left ventricular outflow tract (LVOT) gradient at rest and medication history as confounders.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>In a total of 166 patients carrying MYBPC3 or MYH7 pathogenic variants (38 \u00b1 3 years, 45% female), we compared the discovery cohort (40 MYBPC3 and 31 MYH7) and the validation cohort (\u2018Valsartan in Attenuating Disease Evolution in Early Sarcomeric HCM\u2019; 54 MYBPC3 and 41 MYH7) with 44 healthy controls. LVETI was lower in MYBPC3 and higher in MYH7 LVH+ patients than in controls in the discovery, validation and pooled cohorts (pooled: MYBPC3 381 \u00b1 19 ms vs. MYH7 437 \u00b1 38 ms, P &amp;lt; 0.001; MYBPC3 vs. controls 411 \u00b1 15 ms, P &amp;lt; 0.001; and MYH7 vs. controls, P &amp;lt; 0.001). Similar findings were seen in LVH\u2212 (pooled: MYBPC3 380 \u00b1 16 ms vs. MYH7 437 \u00b1 39 ms, P &amp;lt; 0.001; MYBPC3 vs. controls, P &amp;lt; 0.001). While MYH7 variants were all missense as expected, 87% of the MYBPC3 variants were truncating (including nonsense variants, out-of-frame deletion and splice site variants) and 13% were non-truncating (missense and in-frame deletion). LVETI did not differ between the groups and was significantly lower than the control in both.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>The data suggest that variants in MYBPC3 and MYH7 result in distinct biophysical consequences, which can be detected by measuring LVETI in patients. The findings may have implications for potential genotype-specific differences in response to therapies targeting sarcomere function.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1002\/ehf2.15346","type":"journal-article","created":{"date-parts":[[2025,7,4]],"date-time":"2025-07-04T05:11:19Z","timestamp":1751605879000},"page":"3416-3425","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["Lower Left Ventricular Ejection Time in\n                    <i>MYBPC3<\/i>\n                    Variant Carriers with Overt or Subclinical Hypertrophic Cardiomyopathy"],"prefix":"10.1093","volume":"12","author":[{"given":"Isabell","family":"Yan","sequence":"first","affiliation":[{"name":"Department of Cardiology, University Heart and Vascular Center Hamburg, University Medical Center Hamburg-Eppendorf , Hamburg 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,","place":["Germany"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Julia","family":"M\u00fcnch","sequence":"additional","affiliation":[{"name":"Department of Cardiology, University Heart and Vascular Center Hamburg, University Medical Center Hamburg-Eppendorf , Hamburg ,","place":["Germany"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rixa","family":"Woitschach","sequence":"additional","affiliation":[{"name":"Institute of Human Genetics, University Medical Center Hamburg-Eppendorf , Hamburg ,","place":["Germany"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Paulus","family":"Kirchhof","sequence":"additional","affiliation":[{"name":"Department of Cardiology, University Heart and Vascular Center Hamburg, University Medical Center Hamburg-Eppendorf , Hamburg ,","place":["Germany"]},{"name":"German Centre for Cardiovascular Research (DZHK), Partner Site Hamburg\/Kiel\/L\u00fcbeck , Hamburg ,","place":["Germany"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lucie","family":"Carrier","sequence":"additional","affiliation":[{"name":"German Centre for Cardiovascular Research (DZHK), Partner Site Hamburg\/Kiel\/L\u00fcbeck , Hamburg ,","place":["Germany"]},{"name":"Institute of Experimental Pharmacology and Toxicology, University Medical Center Hamburg-Eppendorf , Hamburg ,","place":["Germany"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Carolyn Y.","family":"Ho","sequence":"additional","affiliation":[{"name":"Cardiovascular Division, Brigham and Women's Hospital , Boston, Massachusetts ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Thomas","family":"Eschenhagen","sequence":"additional","affiliation":[{"name":"German Centre for Cardiovascular Research (DZHK), Partner Site Hamburg\/Kiel\/L\u00fcbeck , Hamburg ,","place":["Germany"]},{"name":"Institute of Experimental Pharmacology and Toxicology, 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