Efficacy and Safety of Aficamten in Symptomatic Nonobstructive Hypertrophic Cardiomyopathy: Results From the REDWOOD-HCM Trial, Cohort 4.

BACKGROUND: This open-label phase 2 trial evaluated the safety and efficacy of aficamten in patients with nonobstructive hypertrophic cardiomyopathy (nHCM). METHODS: Patients with symptomatic nHCM (left ventricular outflow tract obstruction gradient ≤ 30 mmHg, left ventricular ejection fraction [LVEF] ≥ 60%, N-terminal pro-B-type natriuretic peptide [NT-proBNP] > 300 pg/mL) received aficamten 5-15 mg once daily (doses adjusted according to echocardiographic LVEF) for 10 weeks. RESULTS: We enrolled 41 patients (mean ± SD age 56 ± 16 years; 59% female). At Week 10, 22 (55%) patients experienced an improvement of ≥ 1 New York Heart Association class; 11 (29%) became asymptomatic. Clinically relevant improvements in Kansas City Cardiomyopathy Questionnaire Clinical Summary Scores occurred in 22 (55%) patients. Symptom relief was paralleled by reductions in NT-proBNP levels (56%; P < 0.001) and high-sensitivity cardiac troponin I (22%; P < 0.005). Modest reductions in LVEF (mean ± SD) of -5.4% ± 10 to 64.6% ± 9.1 were observed. Three (8%) patients had asymptomatic reduction in LVEF < 50% (range: 41%-48%), all returning to normal after 2 weeks of washout. One patient with prior history of aborted sudden cardiac death experienced a fatal arrhythmia during the study. CONCLUSIONS: Aficamten administration for symptomatic nHCM was generally safe and was associated with improvements in heart failure symptoms and cardiac biomarkers. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT04219826.

Cardiovascular magnetic resonance for evaluation of cardiac involvement in COVID-19: recommendations by the Society for Cardiovascular Magnetic Resonance.

Coronavirus disease 2019 (COVID-19) is an ongoing global pandemic that has affected nearly 600 million people to date across the world. While COVID-19 is primarily a respiratory illness, cardiac injury is also known to occur. Cardiovascular magnetic resonance (CMR) imaging is uniquely capable of characterizing myocardial tissue properties in-vivo, enabling insights into the pattern and degree of cardiac injury. The reported prevalence of myocardial involvement identified by CMR in the context of COVID-19 infection among previously hospitalized patients ranges from 26 to 60%. Variations in the reported prevalence of myocardial involvement may result from differing patient populations (e.g. differences in severity of illness) and the varying intervals between acute infection and CMR evaluation. Standardized methodologies in image acquisition, analysis, interpretation, and reporting of CMR abnormalities across would likely improve concordance between studies. This consensus document by the Society for Cardiovascular Magnetic Resonance (SCMR) provides recommendations on CMR imaging and reporting metrics towards the goal of improved standardization and uniform data acquisition and analytic approaches when performing CMR in patients with COVID-19 infection.

Diffuse myocardial fibrosis associates with incident ventricular arrhythmia in implantable cardioverter defibrillator recipients.

Background: Diffuse myocardial fibrosis (DMF) quantified by extracellular volume (ECV) may represent a vulnerable phenotype and associate with life threatening ventricular arrhythmias more than focal myocardial fibrosis. This principle remains important because 1) risk stratification for implantable cardioverter defibrillators (ICD) remains challenging, and 2) DMF may respond to current or emerging medical therapies (reversible substrate). Objectives: To evaluate the association between quantified by ECV in myocardium without focal fibrosis by late gadolinium enhancement (LGE) with time from ICD implantation to 1) appropriate shock, or 2) shock or anti-tachycardia pacing. Methods: Among patients referred for cardiovascular magnetic resonance (CMR) without congenital disease, hypertrophic cardiomyopathy, or amyloidosis who received ICDs (n=215), we used Cox regression to associate ECV with incident ICD therapy. Results: After a median of 2.9 (IQR 1.5-4.2) years, 25 surviving patients experienced ICD shock and 44 experienced shock or anti-tachycardia pacing. ECV ranged from 20.2% to 39.4%. No patient with ECV<25% experienced an ICD shock. ECV associated with both endpoints, e.g., hazard ratio 2.17 (95%CI 1.17-4.00) for every 5% increase in ECV, p=0.014 in a stepwise model for ICD shock adjusting for ICD indication, age, smoking, atrial fibrillation, and myocardial infarction, whereas focal fibrosis by LGE and global longitudinal strain (GLS) did not. Conclusions: DMF measured by ECV associates with ventricular arrhythmias requiring ICD therapy in a dose-response fashion, even adjusting for potential confounding variables, focal fibrosis by LGE, and GLS. ECV-based risk stratification and DMF representing a therapeutic target to prevent ventricular arrhythmia warrant further investigation.

Myocardial Injury on CMR in Patients With COVID-19 and Suspected Cardiac Involvement.

BACKGROUND: Myocardial injury in patients with COVID-19 and suspected cardiac involvement is not well understood. OBJECTIVES: The purpose of this study was to characterize myocardial injury in a multicenter cohort of patients with COVID-19 and suspected cardiac involvement referred for cardiac magnetic resonance (CMR). METHODS: This retrospective study consisted of 1,047 patients from 18 international sites with polymerase chain reaction-confirmed COVID-19 infection who underwent CMR. Myocardial injury was characterized as acute myocarditis, nonacute/nonischemic, acute ischemic, and nonacute/ischemic patterns on CMR. RESULTS: In this cohort, 20.9% of patients had nonischemic injury patterns (acute myocarditis: 7.9%; nonacute/nonischemic: 13.0%), and 6.7% of patients had ischemic injury patterns (acute ischemic: 1.9%; nonacute/ischemic: 4.8%). In a univariate analysis, variables associated with acute myocarditis patterns included chest discomfort (OR: 2.00; 95% CI: 1.17-3.40, P = 0.01), abnormal electrocardiogram (ECG) (OR: 1.90; 95% CI: 1.12-3.23; P = 0.02), natriuretic peptide elevation (OR: 2.99; 95% CI: 1.60-5.58; P = 0.0006), and troponin elevation (OR: 4.21; 95% CI: 2.41-7.36; P < 0.0001). Variables associated with acute ischemic patterns included chest discomfort (OR: 3.14; 95% CI: 1.04-9.49; P = 0.04), abnormal ECG (OR: 4.06; 95% CI: 1.10-14.92; P = 0.04), known coronary disease (OR: 33.30; 95% CI: 4.04-274.53; P = 0.001), hospitalization (OR: 4.98; 95% CI: 1.55-16.05; P = 0.007), natriuretic peptide elevation (OR: 4.19; 95% CI: 1.30-13.51; P = 0.02), and troponin elevation (OR: 25.27; 95% CI: 5.55-115.03; P < 0.0001). In a multivariate analysis, troponin elevation was strongly associated with acute myocarditis patterns (OR: 4.98; 95% CI: 1.76-14.05; P = 0.003). CONCLUSIONS: In this multicenter study of patients with COVID-19 with clinical suspicion for cardiac involvement referred for CMR, nonischemic and ischemic patterns were frequent when cardiac symptoms, ECG abnormalities, and cardiac biomarker elevations were present.

Phase 2 Study of Aficamten in Patients With Obstructive Hypertrophic Cardiomyopathy.

BACKGROUND: Left ventricular outflow tract (LVOT) obstruction is a major determinant of heart failure symptoms in obstructive hypertrophic cardiomyopathy (oHCM). Aficamten, a next-in-class cardiac myosin inhibitor, may lower gradients and improve symptoms in these patients. OBJECTIVES: This study aims to evaluate the safety and efficacy of aficamten in patients with oHCM. METHODS: Patients with oHCM and LVOT gradients ≥30 mm Hg at rest or ≥50 mm Hg with Valsalva were randomized 2:1 to receive aficamten (n = 28) or placebo (n = 13) in 2 dose-finding cohorts. Doses were titrated based on gradients and ejection fraction (EF). Safety and changes in gradient, EF, New York Heart Association functional class, and cardiac biomarkers were assessed over a 10-week treatment period and after a 2-week washout. RESULTS: From baseline to 10 weeks, aficamten reduced gradients at rest (mean difference: -40 ± 27 mm Hg, and -43 ± 37 mm Hg in Cohorts 1 and 2, P = 0.0003 and P = 0.0004 vs placebo, respectively) and with Valsalva (-36 ± 27 mm Hg and -53 ± 44 mm Hg, P = 0.001 and <0.0001 vs placebo, respectively). There were modest reductions in EF (-6% ± 7.5% and -12% ± 5.9%, P = 0.007 and P < 0.0001 vs placebo, respectively). Symptomatic improvement in ≥1 New York Heart Association functional class was observed in 31% on placebo, and 43% and 64% on aficamten in Cohorts 1 and 2, respectively (nonsignificant). With aficamten, N-terminal pro-B-type natriuretic peptide was reduced (62% relative to placebo, P = 0.0002). There were no treatment interruptions and adverse events were similar between treatment arms. CONCLUSIONS: Aficamten resulted in substantial reductions in LVOT gradients with most patients experiencing improvement in biomarkers and symptoms. These results highlight the potential of sarcomere-targeted therapy for treatment of oHCM.

Electroanatomic mapping in atrioventricular junction ablation during sinus rhythm for tachycardia-bradycardia syndrome with persistent left superior vena cava.

This is the first report describing atrioventricular junction ablation during sinus rhythm in a patient with persistent left superior vena cava. Electroanatomic mapping systems and awareness of anatomic and electrogram variations may decrease procedure time, decrease fluoroscopy time, and minimize delivery of ineffective ablation lesions.

Advances in Multimodality Imaging in Cardio-Oncology: JACC State-of-the-Art Review.

The population of patients with cancer is rapidly expanding, and the diagnosis and monitoring of cardiovascular complications greatly rely on imaging. Numerous advances in the field of cardio-oncology and imaging have occurred in recent years. This review presents updated and practical approaches for multimodality cardiovascular imaging in the cardio-oncology patient and provides recommendations for imaging to detect the myriad of adverse cardiovascular effects associated with antineoplastic therapy, such as cardiomyopathy, atherosclerosis, vascular toxicity, myocarditis, valve disease, and cardiac masses. Uniquely, we address the role of cardiovascular imaging in patients with pre-existing cardiomyopathy, pregnant patients, long-term survivors, and populations with limited resources. We also address future avenues of investigation and opportunities for artificial intelligence applications in cardio-oncology imaging. This review provides a uniform practical approach to cardiovascular imaging for patients with cancer.

Improved evaluation of left ventricular hypertrophy using the spatial QRS-T angle by electrocardiography.

Electrocardiographic (ECG) signs of left ventricular hypertrophy (LVH) lack sensitivity. The aim was to identify LVH based on an abnormal spatial peaks QRS-T angle, evaluate its diagnostic performance compared to conventional ECG criteria for LVH, and its prognostic performance. This was an observational study with four cohorts with a QRS duration < 120 ms. Based on healthy volunteers (n = 921), an abnormal spatial peaks QRS-T angle was defined as ≥ 40° for females and ≥ 55° for males. In other healthy volunteers (n = 461), the specificity of the QRS-T angle to detect LVH was 96% (females) and 98% (males). In patients with at least moderate LVH by cardiac imaging (n = 225), the QRS-T angle had a higher sensitivity than conventional ECG criteria (93-97% vs 13-56%, p < 0.001 for all). In clinical consecutive patients (n = 783), of those who did not have any LVH, 238/556 (43%) had an abnormal QRS-T angle. There was an association with hospitalization for heart failure or all-cause death in univariable and multivariable analysis. An abnormal QRS-T angle rarely occurred in healthy volunteers, was a mainstay of moderate or greater LVH, was common in clinical patients without LVH but with cardiac co-morbidities, and associated with outcomes.

Genetic resiliency associated with dominant lethal TPM1 mutation causing atrial septal defect with high heritability.

Analysis of large-scale human genomic data has yielded unexplained mutations known to cause severe disease in healthy individuals. Here, we report the unexpected recovery of a rare dominant lethal mutation in TPM1, a sarcomeric actin-binding protein, in eight individuals with large atrial septal defect (ASD) in a five-generation pedigree. Mice with Tpm1 mutation exhibit early embryonic lethality with disrupted myofibril assembly and no heartbeat. However, patient-induced pluripotent-stem-cell-derived cardiomyocytes show normal beating with mild myofilament defect, indicating disease suppression. A variant in TLN2, another myofilament actin-binding protein, is identified as a candidate suppressor. Mouse CRISPR knock-in (KI) of both the TLN2 and TPM1 variants rescues heart beating, with near-term fetuses exhibiting large ASD. Thus, the role of TPM1 in ASD pathogenesis unfolds with suppression of its embryonic lethality by protective TLN2 variant. These findings provide evidence that genetic resiliency can arise with genetic suppression of a deleterious mutation.

Automated In-Line Artificial Intelligence Measured Global Longitudinal Shortening and Mitral Annular Plane Systolic Excursion: Reproducibility and Prognostic Significance.

Background Global longitudinal shortening (GL-Shortening) and the mitral annular plane systolic excursion (MAPSE) are known markers in heart failure patients, but measurement may be subjective and less frequently reported because of the lack of automated analysis. Therefore, a validated, automated artificial intelligence (AI) solution can be of strong clinical interest. Methods and Results The model was implemented on cardiac magnetic resonance scanners with automated in-line processing. Reproducibility was evaluated in a scan-rescan data set (n=160 patients). The prognostic association with adverse events (death or hospitalization for heart failure) was evaluated in a large patient cohort (n=1572) and compared with feature tracking global longitudinal strain measured manually by experts. Automated processing took ≈1.1 seconds for a typical case. On the scan-rescan data set, the model exceeded the precision of human expert (coefficient of variation 7.2% versus 11.1% for GL-Shortening, P=0.0024; 6.5% versus 9.1% for MAPSE, P=0.0124). The minimal detectable change at 90% power was 2.53 percentage points for GL-Shortening and 1.84 mm for MAPSE. AI GL-Shortening correlated well with manual global longitudinal strain (R2=0.85). AI MAPSE had the strongest association with outcomes (χ2, 255; hazard ratio [HR], 2.5 [95% CI, 2.2-2.8]), compared with AI GL-Shortening (χ2, 197; HR, 2.1 [95% CI,1.9-2.4]), manual global longitudinal strain (χ2, 192; HR, 2.1 [95% CI, 1.9-2.3]), and left ventricular ejection fraction (χ2, 147; HR, 1.8 [95% CI, 1.6-1.9]), with P<0.001 for all. Conclusions Automated in-line AI-measured MAPSE and GL-Shortening can deliver immediate and highly reproducible results during cardiac magnetic resonance scanning. These results have strong associations with adverse outcomes that exceed those of global longitudinal strain and left ventricular ejection fraction.

A clinically applicable strategy to estimate the in vivo distribution of mechanical material properties of the right ventricular wall.

A clinically applicable approach to estimate the in vivo mechanical material properties of the heart wall is presented. This optimization-based inverse estimation approach applies a shape-based objective functional combined with rigid body registration and incremental parameterization of heterogeneity to use standard clinical imaging data along with simplified representations of cardiac function to provide consistent and physically meaningful solution estimates. The capability of the inverse estimation algorithm is evaluated through application to two clinically obtained human datasets to estimate the passive elastic mechanical properties of the heart wall, with an emphasis on the right ventricle. One dataset corresponded to a subject with normal heart function, while the other corresponded to a subject with severe pulmonary hypertension, and therefore expected to have a substantially stiffer right ventricle. Patient-specific pressure-driven bi-ventricle finite element analysis was used as the forward model and the endocardial surface of the right ventricle was used as the target data for the inverse problem. By using the right ventricle alone as the target of the inverse problem the relative sensitivity of the objective function to the right ventricle properties is increased. The method was able to identify material properties to accurately match the corresponding shape of the simplified forward model to the clinically obtained target data, and the properties obtained for the example cases are consistent with the clinical expectation for the right ventricle. Additionally, the material property estimates indicate significant heterogeneity in the heart wall for both subjects, and more so for the subject with pulmonary hypertension.

Right Ventricular Shape Feature Quantification for Evaluation of Pulmonary Hypertension: Feasibility and Preliminary Associations With Clinical Outcome Submitted for Publication.

This study aimed to demonstrate feasibility of statistical shape analysis techniques to identify distinguishing features of right ventricle (RV) shape as related to hemodynamic variables and outcome data in pulmonary hypertension (PH). Cardiovascular magnetic resonance images were acquired from 50 patients (33 PH, 17 non-PH). Contemporaneous right heart catheterization data were collected for all individuals. Outcome was defined by all-cause mortality and hospitalization for heart failure. RV endocardial borders were manually segmented, and three-dimensional surfaces reconstructed at end diastole and end systole. Registration and harmonic mapping were then used to create a quantitative correspondence between all RV surfaces. Proper orthogonal decomposition was performed to generate modes describing RV shape features. The first 15 modes captured over 98% of the total modal energy. Two shape modes, 8 (free wall expansion) and 13 (septal flattening), stood out as relating to PH state (mode 13: r = 0.424, p = 0.002; mode 8: r = 0.429, p = 0.002). Mode 13 was significantly correlated with outcome (r = 0.438, p = 0.001), more so than any hemodynamic variable. Shape analysis techniques can derive unique RV shape descriptors corresponding to specific, anatomically meaningful features. The modes quantify shape features that had been previously only qualitatively related to PH progression. Modes describing relevant RV features are shown to correlate with clinical measures of RV status, as well as outcomes. These new shape descriptors lay the groundwork for a noninvasive strategy for identification of failing RVs, beyond what is currently available to clinicians.

Maximal Wall Thickness Measurement in Hypertrophic Cardiomyopathy: Biomarker Variability and its Impact on Clinical Care.

OBJECTIVES: The aim of this study was to define the variability of maximal wall thickness (MWT) measurements across modalities and predict its impact on care in patients with hypertrophic cardiomyopathy (HCM). BACKGROUND: Left ventricular MWT measured by echocardiography or cardiovascular magnetic resonance (CMR) contributes to the diagnosis of HCM, stratifies risk, and guides key decisions, including whether to place an implantable cardioverter-defibrillator (ICD). METHODS: A 20-center global network provided paired echocardiographic and CMR data sets from patients with HCM, from which 17 paired data sets of the highest quality were selected. These were presented as 7 randomly ordered pairs (at 6 cardiac conferences) to experienced readers who report HCM imaging in their daily practice, and their MWT caliper measurements were captured. The impact of measurement variability on ICD insertion decisions was estimated in 769 separately recruited multicenter patients with HCM using the European Society of Cardiology algorithm for 5-year risk for sudden cardiac death. RESULTS: MWT analysis was completed by 70 readers (from 6 continents; 91% with >5 years' experience). Seventy-nine percent and 68% scored echocardiographic and CMR image quality as excellent. For both modalities (echocardiographic and then CMR results), intramodality inter-reader MWT percentage variability was large (range -59% to 117% [SD ±20%] and -61% to 52% [SD ±11%], respectively). Agreement between modalities was low (SE of measurement 4.8 mm; 95% CI 4.3 mm-5.2 mm; r = 0.56 [modest correlation]). In the multicenter HCM cohort, this estimated echocardiographic MWT percentage variability (±20%) applied to the European Society of Cardiology algorithm reclassified risk in 19.5% of patients, which would have led to inappropriate ICD decision making in 1 in 7 patients with HCM (8.7% would have had ICD placement recommended despite potential low risk, and 6.8% would not have had ICD placement recommended despite intermediate or high risk). CONCLUSIONS: Using the best available images and experienced readers, MWT as a biomarker in HCM has a high degree of inter-reader variability and should be applied with caution as part of decision making for ICD insertion. Better standardization efforts in HCM recommendations by current governing societies are needed to improve clinical decision making in patients with HCM.

Society for Cardiovascular Magnetic Resonance (SCMR) recommended CMR protocols for scanning patients with active or convalescent phase COVID-19 infection.

The aim of this document is to provide specific recommendations on the use of cardiovascular magnetic resonance (CMR) protocols in the era of the COVID-19 pandemic. In patients without COVID-19, standard CMR protocols should be used based on clinical indication as usual. Protocols used in patients who have known / suspected active COVID-19 or post COVID-19 should be performed based on the specific clinical question with an emphasis on cardiac function and myocardial tissue characterization. Short and dedicated protocols are recommended.

Society for Cardiovascular Magnetic Resonance (SCMR) guidance for re-activation of cardiovascular magnetic resonance practice after peak phase of the COVID-19 pandemic.

During the peak phase of the COVID-19 pandemic, alterations of standard operating procedures were necessary for health systems to protect patients and healthcare workers and ensure access to vital hospital resources. As the peak phase passes, re-activation plans are required to safely manage increasing clinical volumes. In the context of cardiovascular magnetic resonance (CMR), re-activation objectives include continued performance of urgent CMR studies and resumption of CMR in patients with semi-urgent and elective indications in an environment that is safe for both patients and health care workers.