by Iacopo Olivotto, Jennifer L

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Presentation transcript:

Novel Approach Targeting the Complex Pathophysiology of Hypertrophic Cardiomyopathy by Iacopo Olivotto, Jennifer L. Hellawell, Ramin Farzaneh-Far, Christiana Blair, Raffaele Coppini, Jonathan Myers, Luiz Belardinelli, and Martin S. Maron Circ Heart Fail Volume 9(3):e002764 February 25, 2016 Copyright © American Heart Association, Inc. All rights reserved.

Stages of hypertrophic cardiomyopathy (HCM). Stages of hypertrophic cardiomyopathy (HCM). Thickness of the orange lines reflects prevalence of each stage in HCM cohorts. Prevalence of nonhypertrophic HCM is unknown. LVEF indicates left ventricular ejection fraction. Reprinted from Olivotto et al14 with permission of the publisher. Copyright © 2012, Wolters Kluwer Health. Iacopo Olivotto et al. Circ Heart Fail. 2016;9:e002764 Copyright © American Heart Association, Inc. All rights reserved.

Histopathology of hypertrophic cardiomyopathy (HCM). Histopathology of hypertrophic cardiomyopathy (HCM). A, Gross specimen of a heart from a patient with HCM demonstrating asymmetrical hypertrophy of the left ventricular (LV) wall. B, Histopathology of myocardium from a patient with HCM revealing myocyte disarray. C, Intramural coronary artery with medial thickening and (D) luminal obliteration. Ao indicates aorta; FW, free wall of LV; LA, left atrium; RV, right ventricle; and VS, ventricular septum. Reprinted from Maron19 with permission of the publisher. Copyright ©2009, Springer Publishing. Iacopo Olivotto et al. Circ Heart Fail. 2016;9:e002764 Copyright © American Heart Association, Inc. All rights reserved.

Adverse consequences of enhanced INaL in hypertrophic cardiomyopathy (HCM). Adverse consequences of enhanced INaL in hypertrophic cardiomyopathy (HCM). APD indicates action potential duration; and LVOT, left ventricular outflow tract. Iacopo Olivotto et al. Circ Heart Fail. 2016;9:e002764 Copyright © American Heart Association, Inc. All rights reserved.

INaL-induced abnormalities in hypertrophic cardiomyopathy (HCM) abolished with ranolazine. INaL-induced abnormalities in hypertrophic cardiomyopathy (HCM) abolished with ranolazine. A, Magnitude of INaL in HCM myocytes compared with controls (left). Exposure to ranolazine(10 μmol/L) reduces the magnitude of INaL to control levels (right). B, Action potential duration (APD) at baseline measured at a pacing rate of 1 Hz was 598 ms (±29; n=24) in the HCM myocytes and 351 ms (±28; n=8) in the control myocytes (left). Exposure to ranolazine (10 μmol/L) shortened the APD in HCM myocytes from 659 ms (±46; n=12) to 536 ms (±28; n=12; right). C, Diastolic Na+ (left) and calcium (right) concentrations are significantly increased in HCM myocytes compared with controls. Ranolazine (10 μmol/L) reduced both significantly across a range of pacing frequencies. Reprinted from Coppini et al24 with permission of the publisher. Copyright ©2013, Wolters Kluwer Health. Iacopo Olivotto et al. Circ Heart Fail. 2016;9:e002764 Copyright © American Heart Association, Inc. All rights reserved.

Impact of Late Sodium Current Inhibition on Exercise Capacity in Subjects with Symptomatic Hypertrophic Cardiomyopathy (LIBERTY-HCM) study patient flow diagram. *Safety assessments include physical examination, vital signs, clinical assessments, pregnancy testing, concomitant medication review, and adverse event review. Impact of Late Sodium Current Inhibition on Exercise Capacity in Subjects with Symptomatic Hypertrophic Cardiomyopathy (LIBERTY-HCM) study patient flow diagram. *Safety assessments include physical examination, vital signs, clinical assessments, pregnancy testing, concomitant medication review, and adverse event review. CPET indicates cardiopulmonary exercise testing; ECG, electrocardiogram; ICD, implantable cardioverter-defibrillator; MLHFQ, Minnesota Living with Heart Failure Questionnaire; PK, pharmacokinetic; and ZIO, ZIOPatch. Iacopo Olivotto et al. Circ Heart Fail. 2016;9:e002764 Copyright © American Heart Association, Inc. All rights reserved.

End points of the Impact of Late Sodium Current Inhibition on Exercise Capacity in Subjects with Symptomatic Hypertrophic Cardiomyopathy (LIBERTY-HCM) trial target the pathophysiology of hypertrophic cardiomyopathy. End points of the Impact of Late Sodium Current Inhibition on Exercise Capacity in Subjects with Symptomatic Hypertrophic Cardiomyopathy (LIBERTY-HCM) trial target the pathophysiology of hypertrophic cardiomyopathy. Cardiopulmonary exercise testing (CPET) (VO2) image © COSMED. Echocardiographic images reprinted from Oh et al34 with permission of the publisher, Copyright © 2011, Wolters Kluwer Health, and from Nagueh et al35 with permission of the publisher, Copyright © 2011 Elsevier. MLHFQ image © Getty Images. ZIO Patch image © iRhythm. Iacopo Olivotto et al. Circ Heart Fail. 2016;9:e002764 Copyright © American Heart Association, Inc. All rights reserved.