Lipoprotein (a) as a Cardiovascular Risk Factor in Controversial Clinical Scenarios: A Narrative Review.

Lipoprotein (a) is a complex lipid molecule that has sparked immense interest in recent years, after studies demonstrated its significant association with several cardiovascular conditions. Lp(a) promotes cardiovascular disease through its combined proatherogenic, pro-inflammatory, and prothrombotic effects. While the measurement of Lp(a) has become widely available, effective methods to reduce its concentration are currently limited. However, emerging data from ongoing clinical trials involving antisense oligonucleotides have indicated promising outcomes in effectively reducing Lp(a) concentrations. This may serve as a potential therapeutic target in the management and prevention of myocardial infarction, calcific aortic stenosis, and cerebrovascular accidents. In contrast, the role of Lp(a) in atrial fibrillation, in-stent restenosis, cardiac allograft vasculopathy, and bioprosthetic aortic valve degeneration remains unclear. This review article aims to thoroughly review the existing literature and provide an updated overview of the evidence surrounding the association of Lp(a) and these cardiovascular diseases. We seek to highlight controversies in the existing literature and offer directions for future investigations to better understand Lp(a)'s precise role in these conditions, while providing a summary of its unique molecular characteristics.

The Role of Cardiovascular Imaging in the Diagnosis of Athlete's Heart: Navigating the Shades of Grey.

Athlete's heart (AH) represents the heart's remarkable ability to adapt structurally and functionally to prolonged and intensive athletic training. Characterized by increased left ventricular (LV) wall thickness, enlarged cardiac chambers, and augmented cardiac mass, AH typically maintains or enhances systolic and diastolic functions. Despite the positive health implications, these adaptations can obscure the difference between benign physiological changes and early manifestations of cardiac pathologies such as dilated cardiomyopathy (DCM), hypertrophic cardiomyopathy (HCM), and arrhythmogenic cardiomyopathy (ACM). This article reviews the imaging characteristics of AH across various modalities, emphasizing echocardiography, cardiac magnetic resonance (CMR), and cardiac computed tomography as primary tools for evaluating cardiac function and distinguishing physiological adaptations from pathological conditions. The findings highlight the need for precise diagnostic criteria and advanced imaging techniques to ensure accurate differentiation, preventing misdiagnosis and its associated risks, such as sudden cardiac death (SCD). Understanding these adaptations and employing the appropriate imaging methods are crucial for athletes' effective management and health optimization.

Association between echocardiographic velocity time integral ratio of mitral valve and left ventricular outflow tract and clinical outcomes post transcatheter edge-to-edge mitral valve repair.

Background: Residual mitral regurgitation (MR) is frequent after transcatheter edge-to-edge repair (TEER). There is controversy regarding the clinical impact of residual MR and its quantitative assessment by transthoracic echocardiography (TTE), which is often challenging with multiple eccentric jets and artifact from the clip. The utility of the velocity time integral (VTI) ratio between the mitral valve (MV) and left ventricular outflow tract (LVOT), (VTIMV/LVOT), a simple Doppler measurement that increases with MR, has not been assessed post TEER. Methods: Baseline characteristics, clinical outcomes, and TTE data from patients who underwent TEER between 2014 and 2021 across three academic centers were retrospectively analyzed. Post-procedure TTEs were evaluated for VTIMV/LVOT in the first three months after TEER. One-year outcomes including all-cause and cardiac mortality, major adverse cardiac events, and MV reintervention were compared between patients with high VTIMV/LVOT (≥2.5) and low (<2.5). Results: In total, 372 patients were included (mean age 78.7 ± 8.8 years, 68 % male, mean pre-TEER ejection fraction of 50.5 ± 14.7 %). Follow up TTEs were performed at a median of 37.5 (IQR 30-48) days post-procedure. Patients with high VTIMV/LVOT had significantly higher all-cause mortality (HR 2.10, p = 0.003), cardiac mortality (HR 3.03, p = 0.004) and heart failure admissions (HR 2.28, p < 0.001) at one-year post-procedure. There was no association between raised VTIMV/LVOT and subsequent MV reintervention. Conclusion: High VTIMV/LVOT has clinically significant prognostic value at one year post TEER. This tool could be used to select patients for consideration of repeat intervention.

Lipoprotein(a) and Long-term In-stent Restenosis after Percutaneous Coronary Intervention.

AIM: Lipoprotein(a) [Lp(a)] has demonstrated its association with atherosclerosis and myocardial infarction. However, its role in the development of in-stent restenosis (ISR) after percutaneous coronary intervention (PCI) is not clearly established. The aim of this study is to investigate the association between Lp(a) and ISR. METHODS: A retrospective study of adult patients who underwent successful PCI between January 2006 and December 2017 at the three Mayo Clinic sites and had a preprocedural Lp(a) measurement was conducted. Patients were divided into two groups according to the serum Lp(a) concentration (high Lp(a) ≥50 mg/dl and low Lp(a) <50 mg/dl). Univariable and multivariable analyses were performed to compare risk of ISR between patients with high Lp(a) versus those with low Lp(a). RESULTS: A total of 1209 patients were included, with mean age 65.9 ±11.7 years and 71.8% were male. Median follow-up after baseline PCI was 8.8 (IQR 7.4) years. Restenosis was observed in 162 (13.4%) patients. Median serum levels of Lp(a) were significantly higher in patients affected by ISR versus non-affected cases: 27 (IQR 73.8) vs. 20 (IQR 57.5) mg/dL, p=0.008. The rate of ISR was significantly higher among patients with high Lp(a) versus patients with low Lp(a) values (17.0% vs 11.6%, p=0.010). High Lp(a) values were independently associated with ISR events (HR 1.67, 95%CI 1.18 to 2.37, p=0.004), and this association was more prominent after the first year following the PCI. CONCLUSION: Lipoprotein(a) is an independent predictor for long-term in-stent restenosis and should be considered in the evaluation of patients undergoing PCI.

The role of Lp(a) in the development of in-stent restenosis is not clearly established. In this study including 1209 patients who underwent successful percutaneous coronary intervention and had a preprocedural Lp(a) measurement between 2006 and 2017, the rates of restenosis were significantly higher among patients with high Lp(a) versus patients with low Lp(a) values and high Lp(a) concentrations were independently associated with restenosis events. Lp(a) should be considered as a risk factor for long term in-stent restenosis in the evaluation of patients undergoing percutaneous coronary intervention and assessed as a potential therapeutic target for reducing residual cardiovascular risk in this population.

Long-Term Safety and Efficacy of Mavacamten in Symptomatic Obstructive Hypertrophic Cardiomyopathy: Interim Results of the PIONEER-OLE Study.

BACKGROUND: The phase 2 PIONEER-HCM (Phase 2 Open-label Pilot Study Evaluating Mavacamten in Subjects With Symptomatic Hypertrophic Cardiomyopathy and Left Ventricular Outflow Tract Obstruction) study showed that mavacamten improved left ventricular outflow tract gradients, exercise capacity, and symptoms in patients with obstructive hypertrophic cardiomyopathy (HCM), but the results of longer-term treatment are less well described. We report interim results from the PIONEER-OLE (PIONEER Open-Label Extension) study, the longest-term study of mavacamten in patients with symptomatic obstructive HCM. METHODS AND RESULTS: Patients who previously completed PIONEER-HCM (n=20) were eligible to enroll in PIONEER-OLE. Patients received oral mavacamten, 5 mg once daily (starting dose), with individualized dose titration at week 6. Evaluations included serial monitoring of safety, echocardiography, Kansas City Cardiomyopathy Questionnaire-Overall Summary Score, and serum NT-proBNP (N-terminal pro-B-type natriuretic peptide) levels. Thirteen patients enrolled and received mavacamten (median study duration at data cutoff, 201 weeks). Most patients (92.3%) received ß-blockers concomitantly. Treatment-emergent adverse events were predominantly mild/moderate. One patient had an isolated reduction in left ventricular ejection fraction to 47%, which recovered and remained normal with continued treatment at a reduced dose. At week 180, mavacamten was associated with New York Heart Association class improvements from baseline (class II to I, n=9; class III to II, n=1; and unchanged, n=2), sustained reductions in left ventricular outflow tract gradients (mean [SD] change from baseline: resting, -50 [55] mm Hg; Valsalva, -70 [41] mm Hg), and serum NT-proBNP levels (median [interquartile range] change from baseline: -498 [-2184 to -76] ng/L), and improved Kansas City Cardiomyopathy Questionnaire-Overall Summary Score (mean [SD] change from baseline: +17 [16]). CONCLUSIONS: This long-term analysis supports the continued safety and effectiveness of mavacamten for >3 years in obstructive HCM. REGISTRATION: URL: https://www.clinicaltrials.gov; Unique identifier: NCT03496168.

Role of Genetics in Diagnosis and Management of Hypertrophic Cardiomyopathy: A Glimpse into the Future.

Hypertrophic cardiomyopathy (HCM) is the most common inherited cardiomyopathy. It follows an autosomal dominant inheritance pattern in most cases, with incomplete penetrance and heterogeneity. It is familial in 60% of cases and most of these are caused by pathogenic variants in the core sarcomeric genes (MYH7, MYBPC3, TNNT2, TNNI3, MYL2, MYL3, TPM1, ACTC1). Genetic testing using targeted disease-specific panels that utilize next-generation sequencing (NGS) and include sarcomeric genes with the strongest evidence of association and syndrome-associated genes is highly recommended for every HCM patient to confirm the diagnosis, identify the molecular etiology, and guide screening and management. The yield of genetic testing for a disease-causing variant is 30% in sporadic cases and up to 60% in familial cases and in younger patients with typical asymmetrical septal hypertrophy. Genetic testing remains challenging in the interpretation of results and classification of variants. Therefore, in 2015 the American College of Medical Genetics and Genomics (ACMG) established guidelines to classify and interpret the variants with an emphasis on the necessity of periodic reassessment of variant classification as genetic knowledge rapidly expands. The current guidelines recommend focused cascade genetic testing regardless of age in phenotype-negative first-degree relatives if a variant with decisive evidence of pathogenicity has been identified in the proband. Genetic test results in family members guide longitudinal clinical surveillance. At present, there is emerging evidence for genetic test application in risk stratification and management but its implementation into clinical practice needs further study. Promising fields such as gene therapy and implementation of artificial intelligence in the diagnosis of HCM are emerging and paving the way for more effective screening and management, but many challenges and obstacles need to be overcome before establishing the practical implications of these new methods.

Identifying the Causes of Unexplained Dyspnea at High Altitude Using Normobaric Hypoxia with Echocardiography.

Exposure to high altitude results in hypobaric hypoxia, leading to physiological changes in the cardiovascular system that may result in limiting symptoms, including dyspnea, fatigue, and exercise intolerance. However, it is still unclear why some patients are more susceptible to high-altitude symptoms than others. Hypoxic simulation testing (HST) simulates changes in physiology that occur at a specific altitude by asking the patients to breathe a mixture of gases with decreased oxygen content. This study aimed to determine whether the use of transthoracic echocardiography (TTE) during HST can detect the rise in right-sided pressures and the impact of hypoxia on right ventricle (RV) hemodynamics and right to left shunts, thus revealing the underlying causes of high-altitude signs and symptoms. A retrospective study was performed including consecutive patients with unexplained dyspnea at high altitude. HSTs were performed by administrating reduced FiO2 to simulate altitude levels specific to patients' history. Echocardiography images were obtained at baseline and during hypoxia. The study included 27 patients, with a mean age of 65 years, 14 patients (51.9%) were female. RV systolic pressure increased at peak hypoxia, while RV systolic function declined as shown by a significant decrease in the tricuspid annular plane systolic excursion (TAPSE), the maximum velocity achieved by the lateral tricuspid annulus during systole (S' wave), and the RV free wall longitudinal strain. Additionally, right-to-left shunt was present in 19 (70.4%) patients as identified by bubble contrast injections. Among these, the severity of the shunt increased at peak hypoxia in eight cases (42.1%), and the shunt was only evident during hypoxia in seven patients (36.8%). In conclusion, the use of TTE during HST provides valuable information by revealing the presence of symptomatic, sustained shunts and confirming the decline in RV hemodynamics, thus potentially explaining dyspnea at high altitude. Further studies are needed to establish the optimal clinical role of this physiologic method.

Opportunistic screening for coronary artery calcium deposition using chest radiographs - a multi-objective models with multi-modal data fusion.

Background: To create an opportunistic screening strategy by multitask deep learning methods to stratify prediction for coronary artery calcium (CAC) and associated cardiovascular risk with frontal chest x-rays (CXR) and minimal data from electronic health records (EHR). Methods: In this retrospective study, 2,121 patients with available computed tomography (CT) scans and corresponding CXR images were collected internally (Mayo Enterprise) with calculated CAC scores binned into 3 categories (0, 1-99, and 100+) as ground truths for model training. Results from the internal training were tested on multiple external datasets (domestic (EUH) and foreign (VGHTPE)) with significant racial and ethnic differences and classification performance was compared. Findings: Classification performance between 0, 1-99, and 100+ CAC scores performed moderately on both the internal test and external datasets, reaching average f1-score of 0.66 for Mayo, 0.62 for EUH and 0.61 for VGHTPE. For the clinically relevant binary task of 0 vs 400+ CAC classification, the performance of our model on the internal test and external datasets reached an average AUCROC of 0.84. Interpretation: The fusion model trained on CXR performed better (0.84 average AUROC on internal and external dataset) than existing state-of-the-art models on predicting CAC scores only on internal (0.73 AUROC), with robust performance on external datasets. Thus, our proposed model may be used as a robust, first-pass opportunistic screening method for cardiovascular risk from regular chest radiographs. For community use, trained model and the inference code can be downloaded with an academic open-source license from https://github.com/jeong-jasonji/MTL_CAC_classification . Funding: The study was partially supported by National Institute of Health 1R01HL155410-01A1 award.

Role of lipoprotein(a) concentrations in bioprosthetic aortic valve degeneration.

OBJECTIVES: Lipoprotein(a) (Lp(a)) is associated with an increased incidence of native aortic stenosis, which shares similar pathological mechanisms with bioprosthetic aortic valve (bAV) degeneration. However, evidence regarding the role of Lp(a) concentrations in bAV degeneration is lacking. This study aims to evaluate the association between Lp(a) concentrations and bAV degeneration. METHODS: In this retrospective multicentre study, patients who underwent a bAV replacement between 1 January 2010 and 31 December 2020 and had a Lp(a) measurement were included. Echocardiography follow-up was performed to determine the presence of bioprosthetic valve degeneration, which was defined as an increase >10 mm Hg in mean gradient from baseline with concomitant decrease in effective orifice area and Doppler Velocity Index, or new moderate/severe prosthetic regurgitation. Levels of Lp(a) were compared between patients with and without degeneration and Cox regression analysis was performed to investigate the association between Lp(a) levels and bioprosthetic valve degeneration. RESULTS: In total, 210 cases were included (mean age 74.1±9.4 years, 72.4% males). Median time between baseline and follow-up echocardiography was 4.4 (IQR 3.7) years. Bioprostheses degeneration was observed in 33 (15.7%) patients at follow-up. Median serum levels of Lp(a) were significantly higher in patients affected by degeneration versus non-affected cases: 50.0 (IQR 72.0) vs 15.6 (IQR 48.6) mg/dL, p=0.002. In the regression analysis, high Lp(a) levels (≥30 mg/dL) were associated with degeneration both in a univariable analysis (HR 3.6, 95% CI 1.7 to 7.6, p=0.001) and multivariable analysis adjusted by other risk factors for bioprostheses degeneration (HR 4.4, 95% CI 1.9 to 10.4, p=0.001). CONCLUSIONS: High serum Lp(a) is associated with bAV degeneration. Prospective studies are needed to confirm these findings and to investigate whether lowering Lp(a) levels could slow bioprostheses degradation.

Patient-Level Artificial Intelligence-Enhanced Electrocardiography in Hypertrophic Cardiomyopathy: Longitudinal Treatment and Clinical Biomarker Correlations.

BACKGROUND: Artificial intelligence (AI) applied to 12-lead electrocardiographs (ECGs) can detect hypertrophic cardiomyopathy (HCM). OBJECTIVES: The purpose of this study was to determine if AI-enhanced ECG (AI-ECG) can track longitudinal therapeutic response and changes in cardiac structure, function, or hemodynamics in obstructive HCM during mavacamten treatment. METHODS: We applied 2 independently developed AI-ECG algorithms (University of California-San Francisco and Mayo Clinic) to serial ECGs (n = 216) from the phase 2 PIONEER-OLE trial of mavacamten for symptomatic obstructive HCM (n = 13 patients, mean age 57.8 years, 69.2% male). Control ECGs from 2,600 age- and sex-matched individuals without HCM were obtained. AI-ECG output was correlated longitudinally to echocardiographic and laboratory metrics of mavacamten treatment response. RESULTS: In the validation cohorts, both algorithms exhibited similar performance for HCM diagnosis, and exhibited mean HCM score decreases during mavacamten treatment: patient-level score reduction ranged from approximately 0.80 to 0.45 for Mayo and 0.70 to 0.35 for USCF algorithms; 11 of 13 patients demonstrated absolute score reduction from start to end of follow-up for both algorithms. HCM scores were significantly associated with other HCM-relevant parameters, including left ventricular outflow tract gradient at rest, postexercise, and with Valsalva, and NT-proBNP level, independent of age and sex (all P < 0.01). For both algorithms, the strongest longitudinal correlation was between AI-ECG HCM score and left ventricular outflow tract gradient postexercise (slope estimate: University of California-San Francisco 0.70 [95% CI: 0.45-0.96], P < 0.0001; Mayo 0.40 [95% CI: 0.11-0.68], P = 0.007). CONCLUSIONS: AI-ECG analysis longitudinally correlated with changes in echocardiographic and laboratory markers during mavacamten treatment in obstructive HCM. These results provide early evidence for a potential paradigm for monitoring HCM therapeutic response.

Using Augmented Mean Arterial Pressure to Identify High Mortality Risk Patients With Moderate Aortic Stenosis.

OBJECTIVE: To study the usefulness of a novel echocardiographic marker, augmented mean arterial pressure (AugMAP = [(mean aortic valve gradient + systolic blood pressure) + (2 × diastolic blood pressure)] / 3), in identifying high-risk patients with moderate aortic stenosis (AS). PATIENTS AND METHODS: Adults with moderate AS (aortic valve area, 1.0-1.5 cm2) at Mayo Clinic sites from January 1, 2010, through December 31, 2020, were identified. Baseline demographic, echocardiographic, and all-cause mortality data were retrieved. Patients were grouped into higher and lower AugMAP groups using a cutoff value of 80 mm Hg for analysis. Kaplan-Meier and Cox regression models were used to assess the performance of AugMAP. RESULTS: A total of 4563 patients with moderate AS were included (mean ± SD age, 73.7±12.5 years; 60.5% men). Median follow-up was 2.5 years; 36.0% of patients died. The mean ± SD left ventricular ejection fraction (LVEF) was 60.1%±11.4%, and the mean ± SD AugMAP was 99.1±13.1 mm Hg. Patients in the lower AugMAP group, with either preserved or reduced LVEF, had significantly worse survival performance (all P<.001). Multivariate Cox regression showed that AugMAP (hazard ratio, 0.962; 95% CI, 0.942 to 0.981 per 5-mm Hg increase; P<.001) and AugMAP less than 80 mm Hg (hazard ratio, 1.477; 95% CI, 1.241 to 1.756; P<.001) were independently associated with all-cause mortality. CONCLUSION: AugMAP is a simple and effective echocardiographic marker to identify high-risk patients with moderate AS independent of LVEF. It can potentially be used in the candidate selection process if moderate AS becomes indicated for aortic valve intervention in the future.

Transcatheter Aortic Valve Replacement Prognostication with Augmented Mean Arterial Pressure.

BACKGROUND: Post-transcatheter aortic valve replacement (TAVR) patient outcome is an important research topic. To accurately assess post-TAVR mortality, we examined a family of new echo parameters (augmented systolic blood pressure (AugSBP) and arterial mean pressure (AugMAP)) derived from blood pressure and aortic valve gradients. METHODS: Patients in the Mayo Clinic National Cardiovascular Diseases Registry-TAVR database who underwent TAVR between 1 January 2012 and 30 June 2017 were identified to retrieve baseline clinical, echocardiographic and mortality data. AugSBP, AugMAP and valvulo-arterial impedance (Zva) (Zva) were evaluated using Cox regression. Receiver operating characteristic curve analysis and the c-index were used to assess the model performance against the Society of Thoracic Surgeons (STS) risk score. RESULTS: The final cohort contained 974 patients with a mean age of 81.4 ± 8.3 years old, and 56.6% were male. The mean STS risk score was 8.2 ± 5.2. The median follow-up duration was 354 days, and the one-year all-cause mortality rate was 14.2%. Both univariate and multivariate Cox regression showed that AugSBP and AugMAP parameters were independent predictors for intermediate-term post-TAVR mortality (all p < 0.0001). AugMAP1 < 102.5 mmHg was associated with a 3-fold-increased risk of all-cause mortality 1-year post-TAVR (hazard ratio 3.0, 95%confidence interval 2.0-4.5, p < 0.0001). A univariate model of AugMAP1 surpassed the STS score model in predicting intermediate-term post-TAVR mortality (area under the curve: 0.700 vs. 0.587, p = 0.005; c-index: 0.681 vs. 0.585, p = 0.001). CONCLUSIONS: Augmented mean arterial pressure provides clinicians with a simple but effective approach to quickly identify patients at risk and potentially improve post-TAVR prognosis.

A Practical Approach to Echocardiographic Imaging in Patients With Hypertrophic Cardiomyopathy.

Hypertrophic cardiomyopathy (HCM) is frequently unrecognized or misdiagnosed. The recently published consensus recommendations from the American Society of Echocardiography provided recommendations for the utilization of multimodality imaging in the care of patients with HCM. This document provides an additional practical framework for optimal image and measurement acquisition and guidance on how to tailor the echocardiography examination for individuals with HCM. It also provides resources for physicians and sonographers to use to develop HCM imaging protocols.

Recommendations for Multimodality Cardiovascular Imaging of Patients with Hypertrophic Cardiomyopathy: An Update from the American Society of Echocardiography, in Collaboration with the American Society of Nuclear Cardiology, the Society for Cardiovascular Magnetic Resonance, and the Society of Cardiovascular Computed Tomography.

Hypertrophic cardiomyopathy (HCM) is defined by the presence of left ventricular hypertrophy in the absence of other potentially causative cardiac, systemic, syndromic, or metabolic diseases. Symptoms can be related to a range of pathophysiologic mechanisms including left ventricular outflow tract obstruction with or without significant mitral regurgitation, diastolic dysfunction with heart failure with preserved and heart failure with reduced ejection fraction, autonomic dysfunction, ischemia, and arrhythmias. Appropriate understanding and utilization of multimodality imaging is fundamental to accurate diagnosis as well as longitudinal care of patients with HCM. Resting and stress imaging provide comprehensive and complementary information to help clarify mechanism(s) responsible for symptoms such that appropriate and timely treatment strategies may be implemented. Advanced imaging is relied upon to guide certain treatment options including septal reduction therapy and mitral valve repair. Using both clinical and imaging parameters, enhanced algorithms for sudden cardiac death risk stratification facilitate selection of HCM patients most likely to benefit from implantable cardioverter-defibrillators.

Effect of Mavacamten on Echocardiographic Features in Symptomatic Patients With Obstructive Hypertrophic Cardiomyopathy.

BACKGROUND: EXPLORER-HCM (Clinical Study to Evaluate Mavacamten [MYK-461] in Adults With Symptomatic Obstructive Hypertrophic Cardiomyopathy) demonstrated that mavacamten, a cardiac myosin inhibitor, improves symptoms, exercise capacity, and left ventricular outflow tract (LVOT) obstruction in patients with obstructive hypertrophic cardiomyopathy (oHCM). OBJECTIVES: The purpose of this study was to evaluate mavacamten's effect on measures of cardiac structure and function and its association with changes in other clinical measures. METHODS: Key echocardiographic parameters from serial echocardiograms over 30 weeks from 251 symptomatic oHCM patients (mavacamten [n = 123], placebo [n = 128]) were assessed in a core laboratory. RESULTS: More patients on mavacamten (80.9%; n = 76 of 94) vs placebo (34.0%; n = 33 of 97) showed complete resolution of mitral valve systolic anterior motion after 30 weeks (difference, 46.8%; P < 0.0001). Mavacamten also improved measures of diastolic function vs placebo, including left atrial volume index (LAVI) (mean ± SD baseline: 40 ± 12 mL/m2 vs 41 ± 14 mL/m2; mean change from baseline of -7.5 mL/m2 [95% CI: -9.0 to -6.1 mL/m2] vs -0.09 mL/m2 [95% CI: -1.6 to 1.5 mL/m2]; P < 0.0001) and lateral E/e' (baseline, 15 ± 6 vs 15 ± 8; change of -3.8 [95% CI: -4.7 to -2.8] vs 0.04 [95% CI: -0.9 to 1.0]; P < 0.0001). Among mavacamten-treated patients, improvement in resting, Valsalva, and post-exercise LVOT gradients, LAVI, and lateral E/e' was associated with reduction in N-terminal pro-B-type natriuretic peptide (P ≤ 0.03 for all). Reduction in LAVI was associated with improved peak exercise oxygen consumption (P = 0.04). CONCLUSIONS: Mavacamten significantly improved measures of left ventricular diastolic function and systolic anterior motion. Improvement in LVOT obstruction, LAVI, and E/e' was associated with reduction in a biomarker of myocardial wall stress (N-terminal pro-B-type natriuretic peptide). These findings demonstrate improvement in important markers of the pathophysiology of oHCM with mavacamten. (Clinical Study to Evaluate Mavacamten [MYK-461] in Adults With Symptomatic Obstructive Hypertrophic Cardiomyopathy; NCT03470545).

Mavacamten for treatment of symptomatic obstructive hypertrophic cardiomyopathy (EXPLORER-HCM): a randomised, double-blind, placebo-controlled, phase 3 trial.

BACKGROUND: Cardiac muscle hypercontractility is a key pathophysiological abnormality in hypertrophic cardiomyopathy, and a major determinant of dynamic left ventricular outflow tract (LVOT) obstruction. Available pharmacological options for hypertrophic cardiomyopathy are inadequate or poorly tolerated and are not disease-specific. We aimed to assess the efficacy and safety of mavacamten, a first-in-class cardiac myosin inhibitor, in symptomatic obstructive hypertrophic cardiomyopathy. METHODS: In this phase 3, randomised, double-blind, placebo-controlled trial (EXPLORER-HCM) in 68 clinical cardiovascular centres in 13 countries, patients with hypertrophic cardiomyopathy with an LVOT gradient of 50 mm Hg or greater and New York Heart Association (NYHA) class II-III symptoms were assigned (1:1) to receive mavacamten (starting at 5 mg) or placebo for 30 weeks. Visits for assessment of patient status occurred every 2-4 weeks. Serial evaluations included echocardiogram, electrocardiogram, and blood collection for laboratory tests and mavacamten plasma concentration. The primary endpoint was a 1·5 mL/kg per min or greater increase in peak oxygen consumption (pVO2) and at least one NYHA class reduction or a 3·0 mL/kg per min or greater pVO2 increase without NYHA class worsening. Secondary endpoints assessed changes in post-exercise LVOT gradient, pVO2, NYHA class, Kansas City Cardiomyopathy Questionnaire-Clinical Summary Score (KCCQ-CSS), and Hypertrophic Cardiomyopathy Symptom Questionnaire Shortness-of-Breath subscore (HCMSQ-SoB). This study is registered with ClinicalTrials.gov, NCT03470545. FINDINGS: Between May 30, 2018, and July 12, 2019, 429 adults were assessed for eligibility, of whom 251 (59%) were enrolled and randomly assigned to mavacamten (n=123 [49%]) or placebo (n=128 [51%]). 45 (37%) of 123 patients on mavacamten versus 22 (17%) of 128 on placebo met the primary endpoint (difference +19·4%, 95% CI 8·7 to 30·1; p=0·0005). Patients on mavacamten had greater reductions than those on placebo in post-exercise LVOT gradient (-36 mm Hg, 95% CI -43·2 to -28·1; p<0·0001), greater increase in pVO2 (+1·4 mL/kg per min, 0·6 to 2·1; p=0·0006), and improved symptom scores (KCCQ-CSS +9·1, 5·5 to 12·7; HCMSQ-SoB -1·8, -2·4 to -1·2; p<0·0001). 34% more patients in the mavacamten group improved by at least one NYHA class (80 of 123 patients in the mavacamten group vs 40 of 128 patients in the placebo group; 95% CI 22·2 to 45·4; p<0·0001). Safety and tolerability were similar to placebo. Treatment-emergent adverse events were generally mild. One patient died by sudden death in the placebo group. INTERPRETATION: Treatment with mavacamten improved exercise capacity, LVOT obstruction, NYHA functional class, and health status in patients with obstructive hypertrophic cardiomyopathy. The results of this pivotal trial highlight the benefits of disease-specific treatment for this condition. FUNDING: MyoKardia.

Study Design and Rationale of EXPLORER-HCM: Evaluation of Mavacamten in Adults With Symptomatic Obstructive Hypertrophic Cardiomyopathy.

BACKGROUND: Obstructive hypertrophic cardiomyopathy (oHCM) is characterized by unexplained left ventricular (LV) hypertrophy associated with dynamic LV outflow tract obstruction. Current medical therapies are nonspecific and have limited efficacy in relieving symptoms. Mavacamten is a first-in-class targeted inhibitor of cardiac myosin, which has been shown to reduce LV outflow tract obstruction, improve exercise capacity, and relieve symptoms of oHCM in the PIONEER-HCM phase 2 study. METHODS: EXPLORER-HCM is a multicenter, phase 3, randomized, double-blind, placebo-controlled trial to investigate the efficacy and safety of mavacamten in treating symptomatic oHCM. Eligible adults with oHCM and New York Heart Association Functional Class II or III are randomized 1:1 to receive once-daily, oral mavacamten, or matching placebo for 30 weeks. The primary composite functional end point is clinical response at week 30 compared to baseline defined as either (1) an increase in peak oxygen consumption ≥1.5 mL/kg/min and reduction of at least one New York Heart Association class; or (2) an improvement of ≥3.0 mL/kg/min in peak oxygen consumption with no worsening of New York Heart Association class. Secondary end points include change in postexercise LV outflow tract gradient, New York Heart Association class, peak oxygen consumption, and patient-reported outcomes assessed by the Kansas City Cardiomyopathy Questionnaire and a novel HCM-specific instrument. Exploratory end points aim to characterize the effect of mavacamten on multiple aspects of oHCM pathophysiology. CONCLUSIONS: EXPLORER-HCM is a phase 3 trial in oHCM testing a first-in-class, targeted strategy of myosin inhibition to improve symptom burden and exercise capacity through reducing LV outflow tract obstruction. Results of this trial will provide evidence to support the first disease-specific treatment for HCM. Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT03470545.