
==== Front
Circ Cardiovasc Imaging
Circ Cardiovasc Imaging
HCI
Circulation. Cardiovascular Imaging
1941-9651
1942-0080
Lippincott Williams & Wilkins Hagerstown, MD

39221824
CIRCCVIM-2024-017185
00002
10.1161/CIRCIMAGING.124.017185
3
10090
10124
Original Articles
Serial Changes in Ventricular Strain in Symptomatic Obstructive Hypertrophic Cardiomyopathy Treated With Mavacamten: Insights From the VALOR-HCM Trial
https://orcid.org/0000-0003-0010-9797
Desai Milind Y. MD, MBA 123
https://orcid.org/0009-0004-8534-6760
Okushi Yuichiro MD 12okushiy@ccf.org

https://orcid.org/0009-0008-8619-3400
Gaballa Andrew MD 12a.wang@duke.edu

Wang Qiuqing MPH a.wang@duke.edu
3
https://orcid.org/0000-0003-1671-4262
Geske Jeffrey B. MD geske.jeffrey@mayo.edu
4
https://orcid.org/0000-0002-9669-8495
Owens Anjali T. MD 5
https://orcid.org/0000-0003-4473-6725
Saberi Sara MD, MS saberis@med.umich.edu
6
https://orcid.org/0000-0001-8729-0933
Wang Andrew MD a.wang@duke.edu
7
https://orcid.org/0000-0002-0794-3306
Cremer Paul C. MD, MS paul.cremer@northwestern.edu
3
https://orcid.org/0000-0003-4972-7780
Sherrid Mark MD 8
https://orcid.org/0000-0001-6458-5421
Lakdawala Neal K. MD nlakdawala@bwh.harvard.edu
9
https://orcid.org/0000-0001-7242-0774
Tower-Rader Albree MD atower-rader@mgh.harvard.edu
9
Fermin David MD david.fermin@corewellhealth.org
10
https://orcid.org/0000-0003-4073-5143
Naidu Srihari S. MD Srihari.Naidu@wmchealth.org
11
Lampl Kathy L. MD Kathy.Lampl@bms.com
12
https://orcid.org/0000-0003-1912-1710
Sehnert Amy J. MD Amy.Sehnert@bms.com
12
https://orcid.org/0000-0002-7231-6464
Nissen Steven E. MD nissens@ccf.org
13
https://orcid.org/0000-0001-5692-2299
Popovic Zoran B. MD, PhD 123
on behalf of the VALOR-HCM Investigators*
1 Hypertrophic Cardiomyopathy Center (M.Y.D., Y.O., A.G., Z.B.P.), Heart Vascular and Thoracic Institute, Cleveland Clinic, OH.
2 Department of Cardiovascular Medicine (M.Y.D., Y.O., A.G., S.E.N., Z.B.P.), Heart Vascular and Thoracic Institute, Cleveland Clinic, OH.
3 Cleveland Clinic Coordinating Center for Clinical Research (M.Y.D., Q.W., P.C.C., S.E.N., Z.B.P.), Heart Vascular and Thoracic Institute, Cleveland Clinic, OH.
4 Department of Cardiovascular Diseases, Mayo Clinic, Rochester, MN (J.B.G.).
5 Division of Cardiology, University of Pennsylvania, Philadelphia (A.T.O.).
6 Department of Internal Medicine, University of Michigan, Ann Arbor (S.S.).
7 Department of Cardiology, Duke University, Durham, NC (A.W.).
8 Department of Cardiology, New York University, NY (M.S.).
9 Division of Cardiology, Mass General Brigham, Boston, MA (N.K.L., A.T.-R.).
10 Department of Cardiology, Corewell Health, Grand Rapids, MI (D.F.).
11 Department of Cardiology, Westchester Medical Center, Valhalla, NY (S.S.N.).
12 Bristol Myers Squibb, Princeton, NJ (K.L.L., A.J.S.).
Desai M. Cleveland Clinic

Masri A. Oregon Health & Science University

Zenker M. Saint Thomas West Hospital

Stendahl J. Yale University School of Medicine

Wheeler M. Stanford University Medical Center

Bach R. Washington University School of Medicine

Orford J. Intermountain Medical Center

Rader F. Cedars-Sinai Medical Center

Bajona P. Allegheny General Hospital

Desai M. Cleveland Clinic Florida-Weston

Correspondence to: Milind Y. Desai, MD, MBA, Heart, Vascular and Thoracic Institute, Cleveland Clinic, 9500 Euclid Ave, Desk J1-5, Cleveland, OH 44195. Email desaim2@ccf.org
02 9 2024
9 2024
17 9 e017185e017185
6 6 2024
31 7 2024
© 2024 The Authors.
2024
https://creativecommons.org/licenses/by-nc-nd/4.0/ Circulation: Cardiovascular Imaging is published on behalf of the American Heart Association, Inc., by Wolters Kluwer Health, Inc. This is an open access article under the terms of the Creative Commons Attribution Non-Commercial-NoDerivs License, which permits use, distribution, and reproduction in any medium, provided that the original work is properly cited, the use is noncommercial, and no modifications or adaptations are made.

BACKGROUND:

In severely symptomatic patients with obstructive hypertrophic cardiomyopathy, VALOR-HCM (A Study to Evaluate Mavacamten in Adults With Symptomatic Obstructive Hypertrophic Cardiomyopathy Who Are Eligible for Septal Reduction Therapy) demonstrated that mavacamten reduces the need for septal reduction therapy with sustained improvement in left ventricular (LV) outflow tract gradients and symptoms. Global longitudinal strain (GLS), a measure of regional myocardial function, is a more sensitive marker of systolic function. In VALOR-HCM, we assessed serial changes in LV and right ventricular (RV) strain.

METHODS:

VALOR-HCM included 112 patients with symptomatic obstructive hypertrophic cardiomyopathy (mean, 60 years; 51% male; LV ejection fraction, 68%). Patients assigned to mavacamten at baseline continued the drug for 56 weeks (n=56) and those assigned to placebo (n=52) transitioned to mavacamten from weeks 16 to 56 (40-week exposure). LV-GLS and RV-GLS assessment was performed using a vendor-neutral software. Non-foreshortened apical (4-, 3-, and 2-chamber) views were used to obtain peak LV-GLS. RV focused 4-chamber view was used to calculate RV 4-chamber and free wall strain. A more negative strain value is favorable.

RESULTS:

At baseline, the mean LV-GLS, RV 4-chamber, and free wall strain values were −14.7%, −22.2%, and −16.8%, respectively (all worse than reported normal means). In the total study sample, LV-GLS significantly improved from baseline to week 56 (P=0.02). Twelve patients had transient reduction in LV ejection fraction (<50%) requiring temporary drug interruption (including 3 permanent discontinuations). The LV-GLS in this subgroup was worse at baseline versus total study population (−11.4%), with no significant worsening from baseline through week 56 (P=0.64). Both free wall and 4-chamber RV-GLS remained unchanged from baseline to week 56 (P=0.62 and P=0.56, respectively).

CONCLUSIONS:

In VALOR-HCM, treatment with mavacamten improved LV-GLS from baseline through week 56 (with no significant worsening of LV-GLS in patients with a reduction in LV ejection fraction ≤50%), suggesting a favorable long-term impact on regional LV systolic function. Additionally, there was no detrimental impact on RV systolic function.

REGISTRATION:

URL: https://www.clinicaltrials.gov; Unique identifier: NCT04349072.

cardiomyopathy, hypertrophic obstructive
global longitudinal strain
Mavacamten
Bristol Myers SquibbNot ApplicableOPEN-ACCESSTRUE
SDCT
==== Body
pmcCLINICAL PERSPECTIVE

In the VALOR-HCM trial (A Study to Evaluate Mavacamten in Adults With Symptomatic Obstructive Hypertrophic Cardiomyopathy Who Are Eligible for Septal Reduction Therapy), despite hypercontractile left ventricular (LV) ejection fraction and preserved right ventricular systolic function at baseline, average baseline LV global longitudinal strain and right ventricular strain were worse than normal. Treatment with mavacamten resulted in a sustained improvement in LV global longitudinal strain from baseline through week 56, suggesting a favorable long-term impact on regional LV systolic function. Additionally, there was no significant detrimental impact on right ventricular volumes and systolic function on serial global longitudinal strain assessment. Whether improvement in LV global longitudinal strain by mavacamten has longer-term prognostic implications needs to be determined.

Hypertrophic cardiomyopathy (HCM) frequently results in dyspnea and reduced exercise capacity due to a combination of dynamic left ventricular outflow tract (LVOT) obstruction, mitral regurgitation, diastolic dysfunction, and hypercontractility. As a result, patients with obstructive HCM have an increased risk of heart failure, atrial fibrillation, and sudden arrhythmia-related cardiac death.1–3 Prior observational studies have demonstrated that surgical septal myectomy, by relieving LVOT obstruction, significantly improves symptoms, improves quality of life, and provides excellent long-term survival.4–10 Additionally, small observational studies have suggested that important temporal changes in cardiac structure and function, measured by sensitive markers of regional function like left ventricular (LV) global longitudinal strain (GLS), occur following surgical myectomy.11–15 Indeed, in a broader HCM population, prior observational reports have suggested that impairment of LV-GLS is a significant prognostic factor of future clinical events such as sudden cardiac death, heart failure, and ventricular arrhythmia.16–19

In previous studies of patients with symptomatic obstructive HCM, mavacamten, a selective allosteric and reversible cardiac myosin inhibitor, improved LVOT gradients, quality of life, symptom burden, physical functioning, and reduced eligibility for septal reduction therapy (SRT).20–25 Mavacamten also resulted in favorable cardiac remodeling, including improvement in LV diastolic function, and biomarkers (NT-proBNP [N-terminal pro-B-type natriuretic peptide] and troponin T).20–26 It is now approved for clinical use in patients with symptomatic obstructive HCM in multiple countries around the world and included in the current American and European guidelines.2,3 However, the impact of mavacamten on sensitive measures of LV and right ventricular (RV) systolic function like GLS is not known. Additionally, it is unknown whether LV-GLS can be utilized to potentially predict which patients may develop overt LV systolic dysfunction with mavacamten treatment. In this report from the VALOR-HCM trial (A Study to Evaluate Mavacamten in Adults With Symptomatic Obstructive Hypertrophic Cardiomyopathy Who Are Eligible for Septal Reduction Therapy), we sought to assess serial changes in LV-GLS and RV-GLS measures through 56 weeks of dose-blinded treatment in patients initially randomized to mavacamten (day 1 to week 56) and patients initially randomized to placebo (day 1 to week 16) who then received mavacamten for the next 40 weeks (weeks 16–56).

METHODS

The authors will not make the data, methods used in the analysis, and materials used to conduct the research available to any researcher for purposes of reproducing the results or replicating the procedure.

This was a multicenter, randomized, double-blind, placebo-controlled, phase 3 trial conducted at 19 sites in the United States.27 The trial was funded by Bristol Myers Squibb (Princeton, NJ) and coordinated by Cleveland Clinic Coordinating Center for Clinical Research (C5Research) and Medpace, a contract research organization (Cincinnati, OH). Details of the academic oversight, study protocol, and statistical analysis plan have been published previously.27 The protocol was approved by institutional review boards at participating centers, and all patients provided written informed consent. The first author wrote the manuscript and made final revisions based on comments from other coauthors, including the sponsor. All authors contributed to and approved the manuscript and assume responsibility for the accuracy of the data analyses.

The details of inclusion and exclusion criteria have been published previously.27 In brief, the trial enrolled patients on maximally tolerated medical therapy, referred for and considering SRT, based on 2011 American College of Cardiology/American Heart Association guidelines.28

Data Sharing Policy

The Bristol Myers Squibb policy on data sharing may be found at https://www.bms.com/researchers-and-partners/independent-research/data-sharing-request-process.html.

Study Procedures

Patients were initially randomized 1:1 to oral mavacamten 5 mg/d or placebo, stratified by SRT type (myectomy or alcohol ablation) and New York Heart Association class. Details of dose titration protocol, participant treatment allocation, and follow-up have been reported previously.22–24 In brief, during the double-blind and active-controlled periods, echocardiography was performed every 4 weeks and used to titrate drug dosage based on LV ejection fraction (LVEF) and LVOT gradient, as measured by the core laboratory at the Cleveland Clinic, according to published guidelines.29 After week 16, patients initially randomized to placebo received mavacamten 5 mg daily, and dose-blinded titration was similarly performed. Patients initially randomized to mavacamten continued the same dose as week 16 with monthly echocardiographic assessments to week 32. Placebo patients started 5 mg at week 16 and underwent dose titration at weeks 20, 24, and 28. After week 28, dose adjustment was allowed for persistently elevated LVOT gradients, with monitoring visits conducted every 12 weeks after week 32. If the LVEF fell below 50% during treatment, mavacamten was temporarily interrupted with follow-up in 2 to 4 weeks. If LVEF was ≥50% at that time, mavacamten was restarted at 1 lower dose level. If the LVEF decreased to ≤30%, mavacamten was permanently discontinued.22–24,27 Until week 32, the patients and study staff remained blinded to the original treatment assignment, mavacamten dose, and blinded core laboratory LVEF and LVOT gradients were used for drug titration. After 32 weeks, the patients and study staff remained blinded to the original treatment assignment, but any further dose titrations were based on site-read LVEF measurements and LVOT gradients.

In addition to LVOT gradients, interventricular septal thickness, and LVEF, both LV and RV end-systolic and end-diastolic volumes (indexed to body surface area) were measured, along with septal E/e′, maximal tricuspid regurgitant velocity, and tricuspid annular plane systolic excursion, according to the current guidelines.29,30 In addition, blinded LV-GLS and RV-GLS assessment was performed offline using a vendor-neutral TOMTEC postprocessing software (TOMTEC-ARENA TTA2; Philips Healthcare) and according to the recommendations of the European Association of Cardiovascular Imaging and American Society of Echocardiography task force for deformation imaging (Figure 1).31 After allowing the TOMTEC software to automatically trace region of interest, manual correction was performed if necessary. Non-foreshortened apical (4-, 3-, and 2-chamber) views were used to obtain peak value of LV-GLS. For RV-GLS, RV focused 4-chamber view was used to calculate RV 4-chamber and free wall strain. A more negative strain value is favorable. The zero reference was set at end diastole (ie, R-R gating) for strain analysis.31

Figure 1. Echocardiographic images of a study patient. Representative images of 2-dimensional echocardiogram demonstrating the measurement of (A) left ventricular (LV) global longitudinal strain (GLS) and (B) right ventricular (RV) free wall and 4-chamber strain.

Statistical Analysis

The analyses include all patients initially randomized to mavacamten and placebo patients who crossed over to mavacamten at week 16. Categorical variables are reported as numbers and percentages. At baseline, continuous variables are presented as mean±SD. Data analysis included all patients who had baseline and follow-up comprehensive LV and RV function analyses. Correlation between various clinical and echocardiographic parameters was tested using Pearson correlation coefficient. Changes from baseline in various echocardiographic parameters are presented in the plots of mean values and corresponding 95% CIs. Comparison of mean changes between treatment groups was analyzed using a Student t test and changes from baseline within the treatment group were evaluated with a paired t test. The primary outcome was the change from baseline to week 56.

A responder analysis was performed, to enable clinical interpretability of strain changes at an individual patient level. This included the proportion of patients who experienced different levels of meaningful improvement in the Kansas City Cardiomyopathy Questionnaire 23-item Clinical Summary Score (KCCQ-23 CSS) from baseline to week 56. In addition, LV-GLS and RV-GLS characteristics of patients with a baseline history of atrial fibrillation and those with mavacamten dose interruption due to LVEF drop <50% were also studied. To assess the association of potential variables with LVEF reduction <50%, logistic regression analysis was performed. All analyses were independently performed by the Cleveland Clinic Coordinating Center for Clinical Research (Q.W.). All analyses were performed using SAS, version 9.4 (SAS Institute, Inc, Cary, NC).

RESULTS

Study Population

The study consisted of 112 patients with highly symptomatic obstructive HCM, referred for SRT at baseline and subsequently followed up to week 56, as described previously.22 At baseline, the mean age was 60±12 years, 51% were men, with 93% patients ≥New York Heart Association class III. The mean resting, Valsalva, and postexercise LVOT gradients were 49±31, 76±30, and 84±36 mm Hg, respectively, on maximally tolerated medical therapy, including 36 (32%) on combination therapy (including disopyramide). Mean LVEF, LV septal wall thickness, LV-GLS, and RV free wall strain and RV 4-chamber strain values were 68±3%, 2.0±0.3 cm, −14.7±4.1%, −22.2±6.8%, and −16.8±5.4%, respectively. The details of baseline characteristics, separated into 2 groups, are shown in Table 1.

Table 1. Baseline Characteristics of the Trial

Serial Changes in Strain Parameters During Follow-Up

Table 2 provides the mean differences between treatment groups for the change from baseline to 56 weeks for various LV and RV parameters. Due to poor tracking, strain data could not be obtained in 5 patients at week 16, 10 patients at week 32, and 10 patients at week 56. While LVEF values were statistically lower from baseline to week 56, the mean values were within normal range. Similarly, the mean indexed LV end-systolic volume values were also significantly increased from baseline to week 56 but still within normal range. In addition to LV mass regression,24 there was also a reduction in interventricular septal wall thickness with mavacamten therapy from baseline to week 56. Despite that, LV-GLS significantly improved in the total population (as well as the 2 subgroups) from baseline to week 56 (Table 2; Figure 2). However, despite the improvement, baseline LV-GLS values were worse than what is reported in normal individuals31 and remained worse than reported normal values at week 56 in the study population. Data on serial changes in segmental LV strain are shown in Table S1. The largest improvement in strain was observed in the basal anteroseptum, at the site of maximum LV hypertrophy.

Table 2. Serial Changes in LV and RV Volumetric and Strain Parameters in the Study Sample

Figure 2. Serial changes in various left ventricular (LV) parameters from baseline to week 56. A, LV ejection fraction (LVEF) in the total study population. B, Septal E/e in the total study population. C, LV global longitudinal strain (GLS) in the total study population. D, LV-GLS in the study population with preserved LVEF throughout the study.

In the subgroup of 12 patients who required mavacamten interruption,24 the mean baseline LV-GLS was lower than the overall study population (−12.3±2.5% versus −14.7±4%; P<0.01), with no significant improvement (or worsening) during follow-up: −11.4±3.2% at week 16, −12.1±2.7% at week 32, and −11.6±2.5% at week 56 (P=0.64). In the remaining 100 patients who did not need mavacamten therapy interrupted during the trial, there was a significant improvement in LV-GLS, as shown in Table 2. At baseline, there were no significant differences between these 12 patients requiring mavacamten interruption and the remainder of the study sample as follows: age (62±14 versus 60±12 years; P=0.63), male sex (67% versus 49%; P=0.25), body mass index (31±6 versus 30±5; P=0.54), New York Heart Association class III (100% versus 92%; P=0.60), KCCQ-23 CSS (66±16 versus 69±18; P=0.72), background HCM therapy (92% versus 95%; P=0.70), resting LVOT gradient (62±25 versus 47±31 mm Hg; P=0.10), post-Valsalva LVOT gradient (80±24 versus 77±31 mm Hg; P=0.76), LV mass index (126±39 versus 119±30 g/m2; P=0.79), and interventricular septal wall thickness (1.9±0.2 versus 2.0±0.3; P=0.79). However, history of atrial fibrillation was higher in 12 patients requiring mavacamten interruption versus the remainder of the study sample (42% versus 14%; P=0.03). On exploratory logistic regression analysis, a history of atrial fibrillation (χ2=4.6; P=0.03) and an increased baseline LV end-diastolic volume (>56 mL/m2; χ2=4.8; P=0.03) were associated, while a baseline LV-GLS worse than −14.6% was only weakly associated (χ2=1.8; P=0.1), with likelihood of developing LVEF <50%. The final optimal logistic model (R2=0.30; C statistic, 0.84) was chosen to maximize the combined sensitivity and specificity. However, in the overall study sample, there were no significant differences in changes in LV-GLS and RV-GLS strain parameters, based on the presence of baseline history of atrial fibrillation (n=19), as shown in Table 3.

Table 3. Data on Various Ventricular Strain Parameters, Separated on the Basis of History of Atrial Fibrillation vs Not

All the RV parameters, including indexed volumes, maximal tricuspid regurgitant velocity, and tricuspid annular plane systolic excursion, remained within normal range, despite statistical differences from baseline to week 56. On the other hand, while RV free wall and 4-chamber GLS did not significantly worsen from baseline to week 56, the values remained worse than the reported normal values (Table 2; Figure 3).

Figure 3. Serial changes in various right ventricular (RV) parameters from baseline to week 56. A, Tricuspid annular plane systolic excursion (TAPSE). B, RV free wall global longitudinal strain (GLS). C, RV 4-chamber in the total study population.

Correlations between baseline LV-GLS and changes in LV-GLS from baseline to week 56 are shown in Tables S2 and S3, respectively. Changes in LV-GLS and RV-GLS values in the entire study sample, separated based on improvements in KCCQ-23 CSS of <5, 5 to 10, and >10 points are shown in Table S4. There were no significant differences in change of LV or RV strain values from baseline to week 56 in various KCCQ-23 CSS improvement categories.

DISCUSSION

The current report from the VALOR-HCM trial describes the results of a detailed analysis of serial changes in LV and RV function, including strain assessments, in patients with severely symptomatic obstructive HCM following exposure to mavacamten. At baseline, despite hyperdynamic LVEF, LV/RV volumes, and tricuspid annular plane systolic excursion within normal limits, LV-GLS and RV-GLS values were abnormal, much worse than what has been reported in normal adults, likely representing the advanced and sicker phenotype of obstructive HCM.31 The observed abnormal baseline LV-GLS was similar to prior data in patients with symptomatic obstructive HCM.17 In the overall study, LV-GLS demonstrated a significant and sustained improvement from baseline to week 56, with normalization in LVEF from a hyperdynamic state. In the original mavacamten group, the maximum improvement in LV-GLS was observed in the first 32 weeks with a sustained improvement at week 56. On the other hand, in the placebo to mavacamten group, there was no significant improvement in LV-GLS during the first 32 weeks with a significant improvement noticed between weeks 32 and 56 (during the time of mavacamten treatment). This suggests that it may take ≥16 weeks of mavacamten exposure for LV-GLS changes to be evident. On segmental LV strain analysis, the largest changes were observed in the basal anteroseptum, at the site of maximal LV hypertrophy. Interestingly, baseline LV-GLS had significant correlations with biomarkers but not with KCCQ-23 CSS. On the other hand, change in LV-GLS from baseline to week 56 occurred independent of changes in biomarkers or KCCQ-23 CSS, suggesting multifactorial reasons for observed improvement in patients treated with mavacamten.

One of the biggest challenges with cardiac myosin inhibitor therapy is identification of potential patients who may respond unfavorably and develop overt LV systolic dysfunction. In the current study, within the subgroup of 12 patients who required interruption of mavacamten therapy at any time during the study, the mean LV-GLS was significantly lower at baseline compared with the rest of the study population and did not improve (or worsen) during the study. However, the relevant baseline characteristics of this subgroup were similar to the overall study sample, except for a higher history of atrial fibrillation at baseline. It is important to note that there were no significant differences in baseline strain parameters or their changes to week 56 in patients with or without atrial fibrillation. In an exploratory analysis, we demonstrate that a history of atrial fibrillation and an increased baseline indexed LV end-diastolic volume (>56 mL/m2) were significantly associated, while a baseline LV-GLS worse than −14.6% was weakly associated with a higher likelihood of developing an LVEF <50%. Whether a low baseline LV-GLS helps identify a subset of patients who may not respond favorably to cardiac myosin inhibitor therapy despite preserved LVEF remains to be conclusively ascertained. Also, it was reassuring to observe that RV volumes, tricuspid velocity, and tricuspid annular plane systolic excursion remained within normal limits throughout the study, despite exposure to cardiac myosin inhibitor therapy. Additionally, both RV strain values, despite being abnormal at baseline,31 did not further worsen at week 56. Also, neither baseline RV strain values nor change in RV strain values from baseline to week 56 correlated with biomarkers or KCCQ-23 CSS.

The current findings should also be put in perspective of surgical myectomy, which is also highly effective in relieving symptoms in patients with obstructive HCM. In previous smaller retrospective reports, authors have reported no improvement or even worsening of LV mechanical dysfunction after surgical myectomy, despite an improvement in various other parameters (eg, left atrial strain and exercise capacity).11–13 A small study has also reported that potential worsening of myocardial fibrosis, measured on cardiac magnetic resonance, might be responsible for worsening/nonimprovement of LV-GLS following surgical myectomy.13 Another study reported that LV-GLS might be significantly reduced in patients with obstructive HCM and an abnormal preoperative LV-GLS was associated with increased mortality.15 However, the lack of improvement in LV-GLS following surgical myectomy might be a result of a mechanically created left bundle branch block, which might not have the same impact on overall LVEF.

In HCM, prior observational data have suggested that LV-GLS is associated with histopathologic changes, in vitro myocardial performance, myocardial fibrosis, and abnormalities in LV-GLS are better reflective of the degree and distribution of hypertrophy as opposed to the genotype.32–35 In addition, identification of an abnormal LV-GLS at baseline may provide long-term incremental prognostic value in patients with HCM by identifying a phenotype that has a higher risk for cardiac events (eg, massively hypertrophied LV or a higher fibrosis burden).15–19 In patients with obstructive HCM, LV function is influenced by LVOT obstruction, subendocardial ischemia, diastolic dysfunction, and progressive myocardial fibrosis. Hence, it makes intuitive sense that hemodynamic load caused by LVOT obstruction, which is significantly improved following the use of mavacamten,22–24,36 is likely important in improving LV-GLS. In addition, mavacamten has also been shown to improve LV mass index and LV wall thickness,20,23,24,26 all of which likely help improve LV-GLS. However, despite encouraging disease-modifying trends toward improvement in LV-GLS (without noticeable worsening of RV function), the strain values did not normalize at week 56, which begets the following questions: (1) are we initiating disease-modifying treatment too late? (2) Should we continue therapy for a longer duration for these values to normalize? (3) Could both phenomena play a role? and (4) What would these changes look like in nonobstructive HCM? The current study is one of the first prospective studies to demonstrate early and sustained improvement in LV-GLS in patients with obstructive HCM treated with mavacamten. However, whether modulation of LV-GLS using medical therapy would translate into improved longer-term outcomes remains to be proven.

Limitations

The sample size of the study population was relatively small with only a 56-week follow-up. Future studies with larger, diverse cohorts (including nonobstructive HCM) and much longer longitudinal follow-up data are needed to confirm these findings, investigate the prognostic implications of ventricular strain, and explore the impact of treatment strategies on strain parameters, focusing on understanding pathophysiological mechanisms and optimizing patient management strategies. Whether improvement in LV-GLS by disease-modifying therapies has longer-term prognostic implications remains to be conclusively determined. The current study included predominantly White patients with obstructive HCM treated at high-volume HCM centers with established good outcomes for SRT procedures. The data may not be generalizable to other variants, including nonobstructive HCM.

Conclusions

In the VALOR-HCM trial, despite hypercontractile LVEF and preserved RV systolic function at baseline, average baseline LV-GLS and RV strain values were worse than normal reference values. Treatment with mavacamten resulted in a serial and sustained improvement in LV-GLS from baseline through week 56, suggesting a favorable long-term impact on regional LV systolic function. Additionally, there was no significant detrimental impact on RV volumes and systolic function on serial GLS assessment. Whether a baseline LV-GLS below a certain threshold helps identify a subset of patients who may not respond favorably to cardiac myosin inhibitor therapy despite preserved LVEF remains to be conclusively ascertained. Finally, whether improvement in LV-GLS by disease-modifying therapy like mavacamten has longer-term prognostic implications needs to be determined.

ARTICLE INFORMATION

Acknowledgments

Cleveland Clinic Coordinating Center for Clinical Research (C5Research) Imaging Core Lab: Paul Cremer, MD, Wael A. Jaber, MD, Serge C. Harb, MD, Ashley Beltran, RDCS, Allen Borowski, RDCS, Jeanne Drinko, RDCS, Amy Kanta, RDCS, Maureen Martin, RDCS, Margaret Park, RDCS, Jill Odabashian, RDCS, Cathy McDowell, Michelle Baksar, Eva Balazs. C5Research Stats: Kathy Wolski, MPH (Lead Statistician), Qiuqing Wang (statistician), Craig Balog (statistical programming support). Medpace Contract Research Organization: Dr Richard Lee (Medical Monitor), James Creager (Clinical Trial Manager), Brian Knauf (Data Manager). Dr Desai acknowledges the Haslam Family Endowed Chair in Cardiovascular Medicine at the Cleveland Clinic. Dr Desai also acknowledges the contribution of Barbara Bittel, RN, BSN, and Susan Ospina, MSN, CNP, in the conduct of the trial.

Sources of Funding

The VALOR-HCM study (A Study to Evaluate Mavacamten in Adults With Symptomatic Obstructive Hypertrophic Cardiomyopathy Who Are Eligible for Septal Reduction Therapy) was funded by Bristol Myers Squibb, Princeton, NJ.

Disclosures

Dr Desai reports consulting for Bristol Myers Squibb, Cytokinetics, Tenaya, Edgewise, and viz.AI and research support to Cleveland Clinic from Bristol Myers Squibb, Cytokinetics, and Tenaya. Dr Owens reports consulting for Bristol Myers Squibb, Cytokinetics, Pfizer, Biomarin, Tenaya, Lexicon, Stealth, Edgewise, and Renovacor and grant support for research from BMS. Dr Saberi reports consulting for Bristol Myers Squibb and Cytokinetics. Dr Lakdawala has received consulting incomes from Bristol Myers Squibb, Pfizer, Tenaya, Cytokinetics, and Akros and research support from Bristol Myers Squibb and Pfizer. Dr Wang reports research grants (to institution) from Bristol Myers Squibb, Cytokinetics, and Abbott Vascular; being on the consulting/advisory board from Bristol Myers Squibb; being on the steering committee for Bristol Myers Squibb and Cytokinetics; and speaker fees from Bristol Myers Squibb. Drs Naidu, Sherrid, and Tower-Rader report consulting for Bristol Myers Squibb and Cytokinetics. Dr Geske reports consultation with Bristol Myers Squibb. Dr Fermin reports conflicts from Bristol Myers Squibb (consulting, speaking), Pfizer (consulting), and BridgeBio (consulting, speaking). Drs Gaballa, Cremer, Popovic, and Yokushi report no conflicts of interest. Dr Nissen and Wang work for C5 Research and are employees of Cleveland Clinic, which received payments for current research from Bristol Myers Squibb. Drs Lampl and Sehnert are employed by and have stock ownership at Bristol Myers Squibb.

Supplemental Material

Tables S1–S4

Trial Leadership

APPENDIX

VALOR-HCM site investigators: M. Desai (Cleveland Clinic), J. Geske (Mayo Clinic-Rochester), M. Sherrid (New York University Langone Medical Center), A.T. Owens (University of Pennsylvania-Heart and Vascular Center), S. Saberi (University of Michigan Cardiovascular Center), A. Wang (Duke University School of Medicine), A. Tower-Rader (Massachusetts General Hospital), D. Fermin (Corewell Health), N. Lakdawala (Brigham and Women’s Hospital), A. Masri (Oregon Health & Science University), M. Zenker (Saint Thomas West Hospital), J. Stendahl (Yale University School of Medicine), M. Wheeler (Stanford University Medical Center), R. Bach (Washington University School of Medicine), J. Orford (Intermountain Medical Center), S. Naidu (Westchester Medical Center), F. Rader (Cedars-Sinai Medical Center), P. Bajona (Allegheny General Hospital), and M. Desai (Cleveland Clinic Florida-Weston).

Supplementary Material

Nonstandard Abbreviations and Acronyms

GLS global longitudinal strain

HCM hypertrophic cardiomyopathy

KCCQ-23 CSS Kansas City Cardiomyopathy Questionnaire 23-item Clinical Summary Score

LV left ventricle

LVEF left ventricular ejection fraction

LVOT left ventricular outflow tract

NT-proBNP N-terminal pro-B-type natriuretic peptide

SRT septal reduction therapy

VALOR-HCM A Study to Evaluate Mavacamten in Adults With Symptomatic Obstructive Hypertrophic Cardiomyopathy Who Are Eligible for Septal Reduction Therapy

A list of the VALOR-HCM investigators is provided in the Appendix.

This work was presented as an abstract at the ESC Congress 2024, London, England, August 30-September 2, 2024.

For Sources of Funding and Disclosures, see page 744.

This manuscript was sent to Linda D. Gillam, MD, MPH, Senior Guest Editor, for review by expert referees, editorial decision, and final disposition.

Supplemental Material is available at https://www.ahajournals.org/doi/suppl/10.1161/CIRCIMAGING.124.017185.
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