Abstract 17141: Mavacamten Improves Left Ventricular Relaxation and Compliance in Obstructive Hypertrophic Cardiomyopathy Through Direct Myosin Modulation

Circulation ◽  
2018 ◽  
Vol 138 (Suppl_1) ◽  
Author(s):  
Stephen Heitner ◽  
Daniel Jacoby ◽  
Steven Lester ◽  
Anjali T Owens ◽  
Andrew Wang ◽  
...  
Keyword(s):  
Hypertrophic Cardiomyopathy ◽  
Exercise Capacity ◽  
Left Ventricular ◽  
Open Label ◽  
End Diastolic Volume ◽  
Concomitant Reduction ◽  
Obstructive Hypertrophic Cardiomyopathy ◽  
Healthy Dogs ◽  
Cross Bridges ◽  
Doppler Indices

Introduction: Obstructive hypertrophic cardiomyopathy (oHCM) consists of a constellation of LV hypercontractility, LV outflow tract obstruction (LVOTO), and impaired relaxation, often resulting in dyspnea and reduced exercise capacity. In healthy dogs, the novel myosin modulator mavacamten (MAVA), decreased LV hypercontractility and improved compliance. In the PIONEER-HCM clinical study, improvements in post-exercise LVOT gradient, exercise capacity, and symptoms were reported. To examine whether MAVA could also limit residual myosin-actin cross-bridges during diastole, and improve LV compliance, its effects on diastolic indices were evaluated. Methods: In PIONEER-HCM, an open-label, multi-site, prospective study, oHCM subjects received MAVA for 12 weeks at either 10-20 mg/d (n = 11, Cohort A; 10 completed) or at 2-5 mg/d (n = 10, Cohort B). Echo-Doppler indices of LV filling and relaxation were compared at baseline to week 12. The p-values are from Wilcoxon signed rank tests, evaluating the distribution of within-subject 12-wk changes from baseline around a null of zero. Results: MAVA reduced hypercontractility in a dose-dependent fashion, with relief of LVOTO in all subjects achieving plasma MAVA concentration >350 ng/ml (data previously reported). There was also an increase in mitral annular velocity during early diastole (e’ lat ). There was a concomitant reduction in E/e’ lat and increase in LV end-diastolic volume (LVEDV) consistent with improved LV compliance (Table). MAVA improved dyspnea score with a trend towards reduction in NT-proBNP. Conclusions: Administration of MAVA is associated with improvement in measures of myocardial relaxation (e’ lat ) and compliance in parallel with reduction in LVOT gradient. These findings are consistent with preclinical findings reported in healthy dogs and support additional evaluation of MAVA in patients with obstructive or non-obstructive HCM.

228Long-term safety and effectiveness of mavacamten in symptomatic obstructive hypertrophic cardiomyopathy (oHCM) patients (pts): update from PIONEER open-label extension (PIONEER-OLE) study

2019 ◽  
Vol 40 (Supplement_1) ◽  
Author(s):  
A Wang ◽  
S B Heitner ◽  
D Jacoby ◽  
S Lester ◽  
L Fang ◽  
...  
Keyword(s):  
Hypertrophic Cardiomyopathy ◽  
Beta Blockers ◽  
Nyha Class ◽  
Study Drug ◽  
Class Ii ◽  
Left Ventricular ◽  
P Value ◽  
Class Iii ◽  
Open Label ◽  
Obstructive Hypertrophic Cardiomyopathy

Abstract Background In a phase 2 PIONEER-HCM study, pts with symptomatic, obstructive hypertrophic cardiomyopathy (oHCM) showed improvement in left ventricular outflow tract (LVOT) obstruction, exercise capacity, and symptoms after 12 wk of treatment with the novel myosin modulator, mavacamten (Mava). Purpose To examine the long-term safety and effectiveness of Mava in PIONEER-OLE study Methods PIONEER-OLE (NCT03496168) is an ongoing 2-y multicenter study for adults with symptomatic oHCM who completed PIONEER-HCM (NCT02842242). The starting dose of Mava is 5 mg/d with titration at wk 6 to an individualized therapeutic dose (5, 10, or 15 mg). Evaluations are at wk 4, 6, 8, 12 and every 12 wk thereafter to monitor LV ejection fraction (LVEF), LVOT gradient, New York Heart Association (NYHA) class, NT-proBNP, drug concentration, and safety. Results 13 pts (mean age, 57.8 y; 9 male; 12 on beta-blockers) were enrolled. Mean baseline LVOT obstruction and LVEF, and wk 12 changes from baseline, were similar to those in PIONEER-HCM (Table). Mava significantly reduced resting and provoked LVOT gradients and NT-proBNP at wk 12 and 24 compared with baseline (P<0.004). Of 10 pts who reached wk 24, 8 reported improvement in NYHA class (1 improved Class III to II; 7 improved Class II to I), and 2 pts remained Class II. Mava has been well tolerated up to 40 wk; 31 adverse events (AEs; 22 mild, 5 moderate) were reported in 8 pts; 1 pt had 3 severe and 1 serious AE (cholangiocarcinoma); all AEs were unrelated to study drug. Results from PIONEER-OLE Parameter PIONEER-HCMa PIONEER-OLE Baseline Wk 12 Baselineb Wk 12 Change at Wk 12 Wilcoxon Signed Wk 24 Change at Wk 24 Wilcoxon Signed Mean ± SD Mean ± SD Mean ± SD Mean ± SD Mean ± SD Rank Mean ± SD Mean ± SD Rank (n=13) (n=13) (n=13)c (n=12)c (n=12)c P value (n=10)c (n=10)c P value LVOT Rest gradient, mmHg 69.7±53.9 27.8±31.3 67.3±42.8 12.0±5.4 −57.9±43.2 0.0005 10.5±4.8 −66.6±42.4 0.0020 LVOT Valsalva gradient, mmHg 93.7±55.6 36.8±37.5 89.9±30.7 (n=12) 23.6±20.0 −66.4±35.3 (n=11) 0.0020 21.1±11.5 −67.3±33.5 (n=9) 0.0039 LVEF, % 73.0±5.6 64.6±10.5 72.0±4.9 67.6±7.2 −4.4±5.5 0.0269 68.2±6.5 −3.2±3.3 0.0195 NT-proBNP, pg/mL 1601.3±2782 (n=12) 684±980 1836±2886 181±211 −1759±2789 0.0005 170±225 −2128±3104 0.0039 Data extraction date January 24, 2019. aCombined results shown for pts from PIONEER-HCM originally in cohort A (n=5) and cohort B (n=8). bBaseline in PIONEER-OLE occurred 6–18 months after completion of PIONEER-HCM. cNumber of pts with data available for analysis, unless otherwise specified. Conclusion Despite management with current therapies, pts enrolled in PIONEER-OLE with similar levels of obstruction and hypercontractility as in PIONEER-HCM. In this longest observation period, Mava significantly reduced obstruction (LVOT gradient) in pts with oHCM beyond standard HCM therapy, while maintaining normal LVEF and improving symptoms. Acknowledgement/Funding MyoKardia

ASSESSMENT OF SEGMENTAL MYOCARDIAL STRAIN OF THE LEFT VENTRICULAR MYOCARDIUM IN CHILDREN WITH HYPERTROPHIC CARDIOMYOPATHY

2021 ◽  
Vol 100 (5) ◽  
pp. 46-52
Author(s):  
N.Yu. Chernykh ◽  
◽  
А.А. Tarasova ◽  
O.S. Groznova ◽  
I.M. Shigabeev ◽  
...  
Keyword(s):  
Hypertrophic Cardiomyopathy ◽  
Longitudinal Strain ◽  
Contractile Function ◽  
Myocardial Strain ◽  
Left Ventricular ◽  
Normative Values ◽  
Left Ventricular Myocardium ◽  
Open Label ◽  
Timely Initiation ◽  
Compensatory Increase

Assessment of segmental myocardial strain is a promising and relevant direction in the diagnosis of early impairments of left ventricular (LV) contractility in children with hypertrophic cardiomyopathy (HCM). Objective of the study: to assess the indicators of segmental myocardial strain in children with HCM. Materials and methods of research: prospective, open-label, nonrandomized, controlled. 61 patients with asymmetric HCM aged 7 to 17 years (median 9 [7,6; 13,2]) underwent echocardiography according to the standard technique with the determination of segmental longitudinal, radial, circular LV myocardium in 2D speckle tracking mode. 45 (74%) children had a non-obstructive form (NF) of HCM, 16 (26%) children had an obstructive form (OF). Obstruction was detected at the level of the LV outflow tract with a pressure gradient of 30-50 mm Hg. Results: when assessing segmental myocardial strain, a decrease in longitudinal strain was found less than the normative values in the antero-septal, anterior, antero-lateral segments in children with NF HCM with a compensatory increase in strain values in the contralateral segments (inferior septal, inferior lateral and lower ). In similar segments in children with OF, there was a significant decrease in deformity, while in the contralateral segments a less pronounced compensatory increase in deformity was determined, as well as a decrease in the minimum values of strain indicators. Assessment of segmental radial and circular strain, a statistically significant predominance of indicators in all segments, except for anterolateral, in the group with NF compared to the OF HCM was determined. A decrease in strain in the antero-septal, anterior, antero-lateral segments was found, but less pronounced compared to the indicators of longitudinal strain, as well as a compensatory increase in strain in the antero-septal values in the contralateral segments (inferior septal, inferior lateral and inferior). It has been found that the assessment of global strain values widely used in clinical practice might not be optimal enough, since too many segmental strain values are discarded and averaged, which are unevenly distributed, and therefore the assessment of strain in each segment of the myocardium in children with an asymmetric form of HCM acquires important diagnostic value. Conclusion: changes in the indicators of segmental myocardial strain reflect violations of LV contractile function and are most pronounced in OF compared with NF HCM. Their study in children is important for the timely initiation of therapy and improving the prognosis of the disease.

Abstract 4344: Biventricular Pacemaker Therapy Corrects Dyssynchrony in Non-Obstructive Hypertrophic Cardiomyopathy

Circulation ◽  
2008 ◽  
Vol 118 (suppl_18) ◽  
Author(s):  
Ibrar Ahmed ◽  
Khalid Abozguia ◽  
Ganesh Nallur-Shivu ◽  
Thanh T Phan ◽  
Abdul Maher ◽  
...  
Keyword(s):  
Hypertrophic Cardiomyopathy ◽  
Biventricular Pacing ◽  
Cardiac Resynchronisation Therapy ◽  
Tissue Doppler ◽  
Left Ventricular ◽  
Control Group ◽  
Pacemaker Therapy ◽  
Time To Peak ◽  
Obstructive Hypertrophic Cardiomyopathy ◽  
Peak Longitudinal Strain

Background. Previous studies have reported dyssynchrony using Tissue Doppler in patients with hypertrophic cardiomyopathy (HCM). In this study we assessed dyssynchrony using speckle tracking echocardiography (STE) in patients with non-obstructive hypertrophic cardiomyopathy vs a healthy control group and in a subgroup of highly symptomatic patients evaluated the acute effects of biventricular pacing on STE and Tissue Doppler (TDI) derived measures of dyssynchrony. Methods. We studied 48 healthy controls (age 48 ±18yrs, 22 males, LVEF 63 ±5%, QRS 86 ±7ms) and 57 patients with HCM (age 54 ±11yrs, 38 males, LVEF 61 ±7%, QRS 110 ±36ms). A subgroup of 15 symptomatic patients with HCM (Peak VO2<60% predicted) underwent biventricular pacing (age 53 ±12yrs, 12 males, LVEF 61 ±7%, QRS 110 ±32ms). Echocardiography was performed with the pacemaker off (VVi30) and on (DDDR, AV delay 90ms, LV-RV delay 0 – 4ms). Using STE, the standard deviation (SD) in time to peak longitudinal strain (Tϵ-SD), the time to peak longitudinal systolic velocity (Ts) for each of 18 left ventricular segments and the SD of this timing (Ts-SD) was derived. Using TDI dyssynchrony was assessed from the SD of Ts for the basal six segments and the maximum difference in Ts between any two basal segments (Ts-peak[basal]). Results. Using STE, Tϵ-SD (54.99 ±33.61ms vs 24.55 ±21.18ms p<0.001), Ts-SD (71.06 ±32.32ms vs 46.17 ±21.50ms p<0.001) and Ts (155.74 ±23.14ms vs 123.71 ±11.25ms p<0.001) were greater in HCM than in controls. Using STE we demonstrated that biventricular pacing significantly reduced Tϵ-SD and Ts-SD to values similar to those observed in controls (Ts-SD p=0.13). Using TDI we demonstrated that biventricular pacing significantly reduced Ts, Ts-SD, and Ts-peak[basal]. See Table . (All values expressed as mean ±SD) Conclusion. Cardiac resynchronisation therapy significantly reduced dyssynchrony in symptomatic patients with non-obstructive HCM as demonstrated using STE and TDI. Table

scholarly journals Alcohol septal ablation in hypertrophic cardiomyopathy

2018 ◽  
Vol 2018 (3) ◽  
Author(s):  
Juan José Santos Mateo ◽  
Juan R Gimeno
Keyword(s):  
Hypertrophic Cardiomyopathy ◽  
Interventricular Septum ◽  
Ventricular Outflow Tract ◽  
Clinical Results ◽  
Left Ventricular ◽  
Alcohol Septal Ablation ◽  
Obstructive Hypertrophic Cardiomyopathy ◽  
Left Ventricular Outflow ◽  
Surgical Myectomy

Alcohol septal ablation (ASA) has become an alternative to surgical myectomy in obstructive hypertrophic cardiomyopathy since it was first introduced in 1994 by Sigwart. The procedure alleviates symptoms by producing a limited infarction of the upper interventricular septum, resulting in a decrease in left ventricular outflow tract (LVOT) gradient. The technique has been improved over time and the results are comparable with those of myectomy. Initial concerns about long-term outcomes have been largely resolved. In this review, we discuss indications, technical aspects, clinical results and patient selection to ASA.

scholarly journals Assessment of myocardial function in obstructive hypertrophic cardiomyopathy cats with and without response to medical treatment by carvedilol

2019 ◽  
Vol 15 (1) ◽  
Author(s):  
Ryohei Suzuki ◽  
Yohei Mochizuki ◽  
Yunosuke Yuchi ◽  
Yuyo Yasumura ◽  
Takahiro Saito ◽  
...  
Keyword(s):  
Hypertrophic Cardiomyopathy ◽  
Treatment Response ◽  
Myocardial Function ◽  
Left Ventricular Outflow Tract ◽  
Beta Blockers ◽  
Ventricular Outflow Tract ◽  
Left Ventricular ◽  
Outflow Tract ◽  
Obstructive Hypertrophic Cardiomyopathy ◽  
Left Ventricular Outflow

Abstract Background Inconsistency of treatment response in cats with obstructive hypertrophic cardiomyopathy is well recognized. We hypothesized that the difference in response to beta-blockers may be caused by myocardial functional abnormalities. This study was designed to compare myocardial function in cats with obstructive hypertrophic cardiomyopathy with and without response to beta-blockers. Twenty-one, client-owned, hypertrophic cardiomyopathy cats treated with carvedilol were analyzed. After carvedilol treatment, cats with decreased left ventricular outflow tract velocity were categorized as responders (n = 10); those exhibiting no response (no decrease in the left ventricular outflow tract velocity) were categorized as non-responders (n = 11). The cats were examined using layer-specific assessment of the myocardial function (whole, endocardial, and epicardial layers) longitudinally and circumferentially by two-dimensional speckle-tracking echocardiography, before and after carvedilol treatment. Results The non-responder cats had a significantly higher age, end-diastolic left ventricular posterior-wall thickness, peak velocity of left ventricular outflow tract, and dose of carvedilol than the responders (p = 0.04, p < 0.01, p < 0.01, and p < 0.01, respectively). The circumferential strain in the epicardial layer was lower and circumferential endocardial to epicardial strain ratio was higher in non-responders than responders (p < 0.001 and p = 0.006). According to the multivariate analysis, circumferential strain in the epicardial layer was the only independent correlate of treatment response with carvedilol. Conclusions Myocardial function, assessed by two-dimensional speckle-tracking echocardiography, differed in cats with hypertrophic cardiomyopathy with and without response to beta-blockers. The determination of layer-specific myocardial function may facilitate detailed pathophysiologic assessment and treatment response in cats with hypertrophic cardiomyopathy.

Sign in / Sign up

Export Citation Format

Share Document