Hypertrophic cardiomyopathy (HCM) is a common inherited heart condition characterized by abnormal thickening of the heart muscle, broadly categorized into obstructive (oHCM) and nonobstructive (nHCM) types. oHCM, accounting for 70% of cases, is identified by left ventricular outflow tract (LVOT) obstruction with a gradient of ≥30 mmHg at rest or with provocation.1Maron M.S. Maron B.J. Harrigan C. et al.Hypertrophic cardiomyopathy phenotype revisited after 50 years with cardiovascular magnetic resonance.J Am Coll Cardiol. 2009; 54: 220-228Crossref PubMed Scopus (363) Google Scholar,2Elliott P.M. Anastasakis A. Borger M.A. et al.2014 ESC Guidelines on diagnosis and management of hypertrophic cardiomyopathy.Kardiologia Polska (Polish Heart Journal). 2014; 72: 1054-1126Crossref Scopus (34) Google Scholar While surgical myectomy is considered the traditional treatment for symptomatic oHCM patients, recent advancements have introduced pharmacological alternatives. Notably, mavacamten, a novel cardiac myosin inhibitor, has demonstrated promising results in improving symptoms of individuals with oHCM.3Olivotto I. Oreziak A. Barriales-Villa R. et al.EXPLORER-HCM study investigators. Mavacamten for treatment of symptomatic obstructive hypertrophic cardiomyopathy (EXPLORER-HCM): a randomised, double-blind, placebo-controlled, phase 3 trial.Lancet. 2020 Sep 12; 396 (Epub 2020 Aug 29. Erratum in: Lancet. 2020 Sep 12;396(10253):758. PMID: 32871100): 759-769https://doi.org/10.1016/S0140-6736(20)31792-XAbstract Full Text Full Text PDF PubMed Scopus (457) Google Scholar,4Desai M.Y. Owens A. Geske J.B. et al.Myosin inhibition in patients with obstructive hypertrophic cardiomyopathy referred for septal reduction therapy.J Am Coll Cardiol. 2022; 80: 95-108Crossref PubMed Scopus (118) Google Scholar Whether mysoin inhibitors result in positive cardiac remodeling, improve phenotype severity, or reduce the burden of atrial arrythmias is still unknown. This study explores potential cardiac remodeling utilizing an artificial intelligence based electrocardiographic platform (AI-ECG) in oHCM patients treated with mavacamten. 16 consecutive oHCM patients (average age: 64 years, 56% males) who completed 12-week treatment with mavacamten were analyzed. Patients with known atrial fibrillation (AF), post-operative AF, or wide complex QRS (LBBB, paced rhythm etc.) were excluded. The primary outcomes included estimated probabilities of AF, low ejection fraction (EF) (<35%), and HCM phenotype severity as assessed by validated ECG-based AI algorithms.5Ko W.Y. Siontis K.C. Attia Z.I. et al.Detection of Hypertrophic Cardiomyopathy Using a Convolutional Neural Network-Enabled Electrocardiogram.J Am Coll Cardiol. 2020 Feb 25; 75 (PMID: 32081280): 722-733https://doi.org/10.1016/j.jacc.2019.12.030Crossref PubMed Scopus (176) Google Scholar The algorithm used was internally developed and heavily validated with an area under curve (AUC) of 0.96 (5). Thousands of EKGs from patients with confirmed HCM as well as thousands of controls were fed to a convolutional neural network (CNN). The network was then tested using the internal validation dataset. EKG segments that are thought to most influence the algorithm were atrial depolarization segment, QRS complex voltage and fragmentation and ST-T segment abnormalities. However, when saliency maps were applied, we found that the ST-T segment had the greatest impact on the algorithm rather than the QRS voltage.6Siontis K.C. Suárez A.B. Sehrawat O. et al.Saliency maps provide insights into artificial intelligence-based electrocardiography models for detecting hypertrophic cardiomyopathy.J Electrocardiol. 2023 Nov-Dec; 81 (Epub 2023 Jul 9. PMID: 37599145): 286-291https://doi.org/10.1016/j.jelectrocard.2023.07.002Crossref Scopus (2) Google Scholar Subsequent external evaluations suggested that the AI probability for HCM declines in accordance with hemodynamic measures (LVOT gradient) and circulating biomarkers (NT proBNP) of treatment response, which we used as a surrogate for phenotype severity in this paper.7Tison G.H. Siontis K.C. Abreau S. et al.PIONEER-OLE Investigators. Assessment of Disease Status and Treatment Response With Artificial Intelligence-Enhanced Electrocardiography in Obstructive Hypertrophic Cardiomyopathy.J Am Coll Cardiol. 2022 Mar 15; 79 (PMID: 35272798; PMCID: PMC10101773): 1032-1034https://doi.org/10.1016/j.jacc.2022.01.005Crossref PubMed Scopus (17) Google Scholar The patients' standard 12-lead ECGs pre-treatment and after 12 weeks of treatment were analyzed with these algorithms. We also evaluated changes in LVOT gradient, left atrial (LA) volume, and transverse LA diameter (TLAD). Continuous variables were reported as mean ± SD for normally distributed variables and median with interquartile range for non-normally distributed variables. Categorical variables were reported as frequency with percentage. Patients treated with mavacamten demonstrated a significant reduction in ECG-AI-predicted AF risk, from a median of 14.14% (IQR 22.31) to a median of 9.66% (IQR 20.42), p=0.020. Mavacamten-treated patients also showed a significant decrease in HCM phenotype severity from 71.65% (IQR 79.78) to 6.76% (IQR 86.04), (p=0.001). Finally, there was a non-significant change in AI-ECG determined reduced EF probability, from 0.7% (IQR 3.68) to 1.15% (IQR 4.00), p=0.77. When EKGs before and after treatment were directly compared, indeed the most striking changes were improvement in ST-T segments, likely due to the improvement in LVOT obstruction (Figure1). Mavacamten-treated patients showed a significant improvement in LVOT gradient from a median of 72.5 mmHg (IQR 20) at baseline to 36.5 mmHg (IQR 47.8). p=0.005 after 12 weeks of therapy. Mavacamten therapy was associated with a reduction in the TLAD from 46.81 ±4.79 to 44.08±5.22 (p=0.001). There was a non-statistically significant trend in reduction of LA volume index from 42.12 ±12.40 to 37.93 ±12.78 (p=0.07). This study investigated cardiac remodeling in oHCM patients treated with mavacamten using AI-ECG. Key findings include a significant reduction in AI-ECG determined AF risk associated with 12 weeks of mavacamten treatment. Furthermore, mavacamten utilization was associated with a significant improvement in the HCM phenotype severity as assessed by AI-ECG ability to detect HCM, despite some residual LVOT gradient at the time of analysis (12 weeks, prior to allowing dose up-titration), suggesting a potential broader impact on cardiac remodeling beyond relieving LVOT obstruction. No significant changes in the AI-ECG probability of developing low EF were observed. Clinically, there was a significant reduction in LVOT consistent with prior reports.3Olivotto I. Oreziak A. Barriales-Villa R. et al.EXPLORER-HCM study investigators. Mavacamten for treatment of symptomatic obstructive hypertrophic cardiomyopathy (EXPLORER-HCM): a randomised, double-blind, placebo-controlled, phase 3 trial.Lancet. 2020 Sep 12; 396 (Epub 2020 Aug 29. Erratum in: Lancet. 2020 Sep 12;396(10253):758. PMID: 32871100): 759-769https://doi.org/10.1016/S0140-6736(20)31792-XAbstract Full Text Full Text PDF PubMed Scopus (457) Google Scholar,4Desai M.Y. Owens A. Geske J.B. et al.Myosin inhibition in patients with obstructive hypertrophic cardiomyopathy referred for septal reduction therapy.J Am Coll Cardiol. 2022; 80: 95-108Crossref PubMed Scopus (118) Google Scholar This study highlights mavacamten's potential for positive cardiac remodeling as assessed by AI-ECG. While these results are intriguing, the analysis is limited by sample size, hence, larger and long-term studies are needed to explore myosin inhibitors' sustained effects on positive cardiac remodeling in oHCM.
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