Left Ventricular Outflow Research Articles

Mavacamten: Real-World Experience from 22 Months of the Risk Evaluation and Mitigation Strategy (REMS) Program.

Background: Mavacamten is the only cardiac myosin inhibitor approved by the US FDA for treatment of symptomatic New York Heart Association class II-III obstructive hypertrophic cardiomyopathy (HCM) patients. Under the risk evaluation and mitigation strategy (REMS) program for mavacamten, patients are required to be monitored for development of systolic heart failure, and reduction of left ventricular ejection fraction (LVEF) to <50%. We report results from the mavacamten REMS database (28-Apr-2022 to 27-Feb-2024). Methods: Data on healthcare providers and pharmacy certification, patient monitoring (from Patient Status Forms, based partly on echocardiograms), and screening for drug interactions prior to each dispense were collected. Results: Of 6,299 patients who received ≥1 dose of mavacamten, 60.0% were women; 64.6% were >60 years of age. Of 5,573 patients with submitted Patient Status Forms, 256 (4.6%) developed LVEF <50% and 71 (1.3%) experienced heart failure requiring hospitalization (HFH). On the 29,111 status forms in these patients, each representing an assessment of an echocardiogram, LVEF <50% was reported on 276 (0.9%) and HFH was reported on 86 (0.3%). Of 1,929 patients with ≥1 year of treatment, 78 (4.0%) had an LVEF reduction to <50% and 4 (0.2%) experienced LVEF <50% + HFH but later resumed treatment. Of 3,228 patients initiated on 5 mg/day mavacamten and were treated for at least 6 months, 2,391 (74.1%) remained at 5 or 10 mg/day. At 3- and 6-months following mavacamten treatment initiation, 57.2% and 70.3%, respectively, demonstrated post-Valsalva LV outflow tract gradient <30 mmHg. Conclusions: We describe the feasibility and experience of the first 22 months of the REMS program for prescribing mavacamten in >6,000 symptomatic obstructive HCM patients. The need for temporary interruption for LVEF <50% was low, including for patients on therapy ≥1 year, with even fewer LVEF reductions associated with HFH.

Loss of quality of life and increased societal costs in patients with hypertrophic cardiomyopathy: the AFFECT-HCM study.

Hypertrophic cardiomyopathy (HCM) is the most prevalent inherited cardiac disease. The impact of HCM on quality of life (QoL) and societal costs remains poorly understood. This prospective multi-centre burden of disease study estimated QoL and societal costs of genotyped HCM patients and genotype-positive phenotype-negative (G+/P-) subjects. Participants were categorized into three groups based on genotype and phenotype: 1) G+/P- (left ventricular (LV) wall thickness <13 mm), 2) non-obstructive HCM (nHCM, LV outflow tract (LVOT) gradient <30 mmHg), and 3) obstructive HCM (oHCM, LVOT gradient ≥30 mmHg). We assessed QoL with EQ-5D-5L and Kansas City Cardiomyopathy Questionnaires (KCCQ). Societal costs were measured using medical consumption (iMCQ) and productivity cost (iPCQ) questionnaires. We performed subanalyses within three age groups: <40, 40-59, and ≥60 years. From three Dutch hospitals, 506 subjects were enrolled (84 G+/P-, 313 nHCM, 109 oHCM; median age 59 years, 39% female). HCM (both nHCM and oHCM) patients reported reduced QoL vs G+/P- subjects (KCCQ: 88 vs 98, EQ-5D-5L: 0.88 vs 0.96; both p<0.001). oHCM patients reported lower KCCQ scores than nHCM patients (83 vs 89, p=0.036). Societal costs were significantly higher in HCM patients (€19,035/year vs €7,385/year) compared to G+/P- controls, mainly explained by higher healthcare costs and productivity losses. Being symptomatic and of younger age (<60 years) particularly led to decreased QoL and increased costs. HCM is associated with decreased QoL and increased societal costs, especially in younger and symptomatic patients. oHCM patients were more frequently symptomatic than nHCM patients. This study highlights the substantial disease burden of HCM and can aid in assessing new therapy cost-effectiveness for HCM in the future.

Perfusion metabolism mismatch predicts short-term complications in Takotsubo syndrome

Abstract Background Takotsubo syndrome (TTS) is a transient cardiac condition triggered by sudden emotional or physical stress characterized by LV dysfunction in the absence of obstructive epicardial coronary artery disease. 123I-BMIPP, an iodinated fatty acid analogue, can identify impaired myocardial metabolic activity. With the use of dual SPECT protocol, reduced uptake of 123I-BMIPP compared to perfusion which is called perfusion-metabolic mismatch is observed in apical regions in TTS. The mismatch may indicate jeopardized but viable myocardium, reflecting transient ischemic damage or metabolically stunned myocardium. However, the association between the perfusion metabolism mismatch in TTS and its complications remains underexplored. Purpose Our study aimed to analyze the degree of perfusion metabolism mismatch at the acute phase in TTS and investigate its association with short-term complications. Methods This retrospective study conducted between 2012 and 2024 at a single center included 82 patients diagnosed with TTS. Patients underwent dual SPECT imaging using 99mTc or 201 Tl and 123I-BMIPP within two weeks of admission. We applied quantitative analysis using QGS/QPS software from Cedars-Sinai. Total perfusion deficit ("TPD") was calculated based on sex-matched normal limits providing the extent of perfusion abnormality. Meanwhile, perfusion-metabolism mismatch scores ("worsen") were determined by comparing the total BMIPP counts to the total counts of perfusion. We then assessed the correlation of these imaging findings with biomarkers, regional wall motion abnormalities, and the occurrence of short-term complications. Short-term complications included heart failure, left ventricular outflow (LVOT) obstruction, mitral regurgitation, cardiac arrhythmia, cardiogenic shock, left ventricle (LV) rupture, and cardiac death during the hospitalization period. Results All study patients exhibited wall motion abnormalities seen in apical segments. The count of myocardial segments with regional wall motion abnormality was correlated with both TPD (r=0.34, p=0.002) and perfusion metabolic mismatch score (r=0.40, p&amp;lt;0.001). TPD had a moderate correlation coefficient with max CK-MB (r=0.44, p&amp;lt;0.001) and troponin T (r=0.40, p&amp;lt;0.001) levels. However, perfusion metabolic mismatch did not display correlations with max CK-MB (r=0.05, p=0.65), and Troponin T (r=0.12, p=0.28) levels. Among 82 patients, 37 patients experienced any short-term complications. Importantly, patients with short-term complications had elevated perfusion mismatch scores compared to those without short-term complications (14.0 [6.0-22.5] vs. 5.0 [3.0-10.0], p&amp;lt;0.001). However, no significant difference was observed in TPD between the two groups (9.0 [4.5-20.0] vs. 7.0 [3.0-12.0], p=0.130). Conclusions Our research highlights a significant association between perfusion-metabolism mismatch and an increased risk for short-term complications in patients with Takotsubo syndrome.

Exploring the effects of mavacamten through hemodynamic force analysis in patients with obstructive hypertrophic cardiomyopathy

Abstract Introduction Mavacamten is a first-in-class allosteric myosin inhibitor effective in relieving left ventricular (LV) outflow tract obstruction in patients with obstructive hypertrophic cardiomyopathy (oHCM). To date, however, its effect on cardiac mechanics is still unclear. Hemodynamic force (HDF) analysis represents the fluid dynamics correlate of deformation imaging, showing a greater sensitivity in detecting early mechanical abnormalities or response to treatment [1]. Purpose To explore the in vivo effect of mavacamten on cardiac mechanics in patients with HCM after a 3 year-treatment, using HDF analysis. Methods LV HDF analysis was performed in 6 patients with oHCM (representing a cohort of the MAVA-LTE study) at baseline and after 3 years of treatment. Apical 4-, 2-, and 3-chamber echocardiographic views were analysed using a dedicated and sofisticated software. Base-apex forces (where positive deflections represent a force directed from the apex to the base of LV, whilst negative ones are directed toward the LV apex) were assessed in terms of timing indexed to cardiac cycle duration. HDF curves from the 6 patients treated with macavamten were compared to those obtained from oHCM patients (n=20), non-obstructive HCM (noHCM) patients (n=20), and healthy controls (n=22). Results Figure 1 shows a different pattern of transition between diastole and systole in HCM patients compared to controls. Specifically, HCM patients exhibited an earlier onset of the systolic phase, expressed as a fusion of late diastolic deceleration and systolic thrust. This was numerically represented as a decrease in diastolic-systolic transition time, which is 0.22 [0.20-0.24] for oHCM, 0.23 [0.21-0.25] for noHCM and 0.26 [0.26-0.30] for controls (p ≤0.001 for control vs oHCM, p ≤0.01 for control vs noHCM). Additionally, HCM patients showed an increased rate of force generation. The time to systolic peak (i.e., time interval from the onset of systole to the maximum force) was reduced in HCM patients compared to controls, and was shorter in oHCM than in noHCM patients (0.13 [0.11-0.15] vs 0.16 [0.14-0.17], p ≤0.01), thus reflecting an increased clinotropism in HCM. After 3 years of mavacamten treatment, the diastolic-systolic transition time and the time to systolic peak returned to a level similar to that of healthy controls (0.30 [0.27-0.30] in mavacamten group vs 0.26 [0.26-0.30], p &amp;gt;0.05, and 0.21 [0.20-0.22] vs 0.19[0.17-0.20], p=0.04, respectively) (Figure 2). Conclusion HDF analysis reveals that mavacamten affects the duration of transition from diastole to systole and prolongs time from the onset to the peak in systole. These findings may explain the removal of the mechanical coupling substrate responsible for the systolic anterior movement of mitralic leaflets and the subsequent resolution of LV outflow tract obstruction by mavacamten.Distribution of time parameters

Trans catheter edge to edge repair for mitral regurgitation and left ventricular outflow obstruction in hypertrophic cardiomyopathy

Abstract Background Based on previous reports, mitral valve transcatheter edge to edge repair (TEER) may be considered in patients with severe mitral regurgitation (MR) and left ventricular obstruction in patients with hypertrophic obstructive cardiomyopathy (HOCM) that are high risk for surgery. Objective We aimed to evaluate the feasibility, and immediate and short-term outcomes of mitral TEER in symptomatic patients with severe MR and HOCM. Methods Five patients (age 75±6, 3 men) with severe MR and HOCM with high surgical risk, and anatomy not suitable for septal ethanol ablation, who remained symptomatic despite maximally tolerated drug therapy were selected for TEER using the MitrClip system. Result The procedure was performed successfully on all 5 patients. Devices were deployed at the A2-P2 scallops of the mitral valve. MR severity declined from severe to mild in all patients, left ventricular outflow (LVOT) maximal gradient decreased from 140±46 to 8±5 mmHg after TEER, and was 41±32 mmHg at 4±2 month follow- up, Clinically, all patients reported improvement of their symptoms to Class I-II NYHA functional Class. Conclusion TEER may be a beneficial procedure for severely symptomatic patients with severe MR and obstructive HOCM on maximal tolerated medical therapy, who are not amenable to surgery because of excessive risk, old age, and frailty.Pre and Post procedure EchoPre and Post Cath

Echocardiographic associates of impaired sleep quality in patients with anxiety and depression

Abstract Objective Sleep health, mental health and cardiovascular health are multidimensional constructs that are strongly associated with each other. Anxiety and depression are the most common psychiatric diseases in the community and frequently comorbid in routine clinical practice. This study sought to investigate whether there is an association between sleep quality and echocardiographic parameters in patients with anxiety and/or depression. Methods The clinical and instrumental find­ings of consecutive patients diagnosed with either of anxiety disorders and/or depressive disorders and underwent cardiac examination in our tertiary center on the same day were retrospectively reviewed. The diagnosis was made by a psychiatrist according to the criteria listed in the fifth edition of The Diagnostic and Statistical Manual of Mental Disorders. Afterwards, Hospital Anxiety and Depression Scale (HADS) and Pittsburgh Sleep Quality Index (PSQI) were applied to patients to assess symptom severity and sleep quality, respectively. Subsequent to psychiatric examination, the patients underwent echocardiographic examination that includes two-dimensional conventional echocardiography, tissue doppler imaging (TDI) echocardiography, atrial conduction times, and left atrium (LA) volumes and functions. Results The final study population consisted of 167 patients and divided into two groups according to their PSQI score: PSQI&amp;lt;5 (normal sleep quality) (n=32) and PSQI≥5 (impaired sleep quality) (n=135). Aortic diameter, left ventricular (LV) end-systolic diameter, LV end-diastolic and -systolic volume, LV stroke volume and LV stroke volume index, LV outflow tract velocity–time integral (LVOT-VTI), and LA conduit volume calculations were significantly lower in patients with impaired sleep quality compared to patients with normal sleep quality. The other echocardiographic parameters including LV systolic functions, doppler and TDI echocardiography indices, atrial conduction times, atrial mechanical functions including LA function index (LAFI) were similar among groups. Correlation analysis yielded a negative, weak but statistically significant correlation between LAFI and PSQI score (r=-0.17, p=.030) (Figure 1A). Left intra-AEMD positively and significantly correlated with PSQI score at a weak level (r=0.16, p=.043) (Figure 1B). Aortic diameter, LV stroke volume index, LVOT-VTI and conduit volume were determined as echocardiographic parameters significantly associated with impaired sleep quality in univariate analysis. Among these parameters, only conduit volume remained as significant and independent associate of impaired sleep quality in multivariate logistic regression analysis (Odds ratio:0.91, 95% Confidence interval:0.85-0.98, p=.018) (Table 1). Conclusion There is an independent association between LA conduit volume and impaired sleep quality in patients suffering from anxiety and/or depressive disorders.Figure 1Table 1

Acute echocardiographic assessment of patients with ST-elevation myocardial infarction in detecting clinically hidden hemodynamic deterioration

Abstract Background Transthoracic echocardiography (TTE) offers an immediate non-invasive assessment of cardiac morphology and function that can be performed bedside. Acute TTE in the catheterization laboratory (cath.lab.) may be helpful to identify markers of subsequent development of cardiogenic shock (CS) in patients with ST-elevation myocardial infarction (STEMI) in addition to the previously validated ORBI risk score. This relationship has not been investigated thoroughly previously. Purpose To investigate the association between acute TTE estimates of left ventricular (LV) function prior to primary percutaneous coronary intervention (pPCI) in STEMI patients and pro-B-type natriuretic peptide (proBNP) as a proxy associated with of CS development. Method From September 2023 all non-CS STEMI patients at one tertiary heart center underwent acute bedside TTE in the cath.lab. and ORBI risk score assessing the risk of CS development aiming for inclusion of 500 patients. The 5 minutes TTE-protocol consisted of LV ejection fraction (EF), LV outflow tract velocity time integral (LVOT VTI), mitral inflow (E and E/A), mitral deceleration time, and mitral annular early diastolic velocity é lateral. The primary endpoint was proBNP measured 24 hours (h) after pPCI (12-36h) stratified in quartiles (Q4 vs. Q1-3). The correlation between proBNP and TTE measurements and proBNP and ORBI risk score was examined using univariate linear regression models. Results Until now 153 STEMI patients (mean age 64 years, 25% female) were studied. Anterior STEMI was present in 36%, and median time from cath. lab. arrival to first wire over the culprit lesion was 28 minutes (IQR 24; 37). Patients with high proBNP level (Q4 vs. Q1-3) had significantly higher heart rate (median 84 bpm vs. 72 bpm) and Killip Class&amp;gt;1 (16% vs. 0%) at admission, but similar lactate levels (1.8mM vs. 1.5mM), systolic blood pressure (130 mmHg vs. 137 mmHg), and out-of-hospital cardiac arrest (11% vs. 12%). Patients with high proBNP levels (Q4 vs. Q1-3) had significantly lower LVEF (35% vs. 50%), higher E/é lateral (median 11.4 vs. 7.9), and higher ORBI risk score (median 8 vs. 4). LVEF, LVOT VTI, E/é lateral, and ORBI risk score were significantly associated with proBNP (Figure 1). Two patients developed CS after the pPCI; one with high proBNP level Q4, and one deceased prior to proBNP measurement. Conclusion Acute TTE is an easy tool for assessment of the acute hemodynamic status in STEMI patients bedside in the cath.lab., and it can be without delaying time to revascularization. LVEF, LVOT VTI, E/é lateral, and ORBI were all parameters associated with increased levels of the hemodynamic biomarker proBNP, and may together with the ORBI risk score improve the assessment and risk stratification of STEMI-patients at risk of CS-development.Figure 1.

Clinical profile of patients undergoing percutaneous stellate ganglion block for electrical storm and association with antiarrhythmic efficacy

Abstract Background Percutaneous stellate ganglion block (PSGB) usage for patients with refractory ventricular arrhythmias (VAs) in form of electrical storm (ES) is in quickly expanding. The clinical profile of patients and the potential association with the antiarrhythmic efficacy of the procedure are mostly unexplored. Purpose To better characterize clinical profile and potential association with antiarrhythmic efficacy of patients undergoing PSGB for ES. Methods Patients undergoing PSGB for ES in our Center from 2/2021 to 2/2024 were enrolled; all the dynamic variables were evaluated in a per procedure analysis. Results 45 patients (93% male, 64 ± 10 years) received a total of 80 PSGB performed with the lateral, ultrasound (US) guided technique; most PSGB consisted of a single bolus anesthetic injection (lidocaine + ropivacaine), 26% in an additional continuous infusion, mostly with ropivacaine. All procedures except for 3 in a single patient who had previously received left cardiac sympathetic denervation, were performed on the left side. Most of the patients (60%) suffered ischemic cardiomyopathy (CMP), including 10 with an acute coronary syndrome; the rest had non-ischemic CMP; 60% had an ICD. The type of VAs was ventricular tachycardia (VTs) only in 86% of the procedures (cycle length 404 ± 143 msec), VT and VF in 10% and VF only in 3 (4%). Most PSGB (81%) were performed in the setting of impending or manifest cardiogenic shock (SCAI classification B or more), including 20% with sepsis. Cardiac US performed before (within 12 hours) each PSGB showed a severely depressed left ventricular (LV) function (mean LVEF 22 ± 10%, mean LV outflow tract velocity time integral 12 ± 4 cm), calculated at a mean heart rate of 81 ± 16 bpm. Mean LVEDV was 252 ± 104 ml, 79% had mitral regurgitation (MR) ≥2+/4+ (including 39% severe MR), 50% had ≥ moderate diastolic dysfunction, 29% had right ventricular dysfunction (mean fractional areal change 33± 7%). Most cases (75%) experienced a complete VAs suppression (sustained or treated) in the 12 hours after PSGB; only 3/80 cases required additional urgent antiarrhythmic strategies (intra-aortic ballon pump in one case, urgent pacing in another one, urgent revascularization in the last one). None of the assessed clinical or echocardiographic characteristics was significantly associated with VT cycle length or the response to PSGB. Only 1 (1%) major complication occurred (respiratory arrest), that was quickly and effectively treated with lipid emulsion. Conclusions PSGB in our Center was mostly performed in the setting of primary impending or manifest cardiogenic shock with severely impaired cardiac function, with an excellent safety profile. None of the assessed clinical or echocardiographic variables were associated with response to PSGB. Our data, despite preliminary and requiring confirmation, suggests always considering PSGB in the urgent/emergent setting independently from patients’ characteristics.

Association between impaired left ventricular global longitudinal strain and B-type natriuretic peptide in obstructive hypertrophic cardiomyopathy

Abstract Background Left ventricular global longitudinal strain (LV-GLS) is considered valuable in explaining impaired left ventricular contractility in hypertrophic cardiomyopathy (HCM) with preserved ejection fraction and is associated with worse outcome. Elevated B-type natriuretic peptide (BNP) is a biomarker of increased LV wall stretch and a risk factor of heart failure, mortality, and other adverse cardiovascular events. However, relationship between GLS and BNP has not received sufficient attention in the obstructive variant of HCM. Purpose This study aimed to determine the association between echocardiographic LV-GLS and plasma BNP in patients with hypertrophic obstructive cardiomyopathy (HOCM). Methods A total of 145 consecutive patients (32% females) with symptomatic HOCM were enrolled in the retrospective study. HOCM was defined with a maximum end-diastolic wall thickness ≥15mm without other etiologies for LV hypertrophy, and peak LV outflow tract (LVOT) gradient ≥30mmHg. The echocardiographic parameters regarding LV geometry, loading conditions, and GLS were evaluated according to guidelines. Patients were divided into two groups according to absolute GLS values (greater or lower than median LV-GLS). Patient baseline clinical data, echocardiographic parameters, and BNP were compared. Univariate and multivariable regression analysis were applied to identify the independent determinator of LV-GLS. Results The median value of LV-GLS of this study cohort was -13.4%. Eighty-one patients (47.6±13.4 years-old) had a |GLS|≥13.4% and 64 individuals (48.7±12.6 years-old) had a |GLS|&amp;lt;13.4%. No differences were found in age, gender, physical examinations, LVEF, cardiovascular comorbidities, or active medications between the two groups, except for body mass index (BMI). Patients with |GLS|≥13.4% had statistically lower BMI (24.58±2.42 vs. 26.00±3.12kg/m², p=0.030). BNP was found significantly elevated in patients with |GLS|&amp;lt;13.4% when compared with individuals with |GLS|≥13.4% {median (IQR); 550.05 (214.50, 899.35) vs. 182.40 (78.90, 479.90)pg/mL, p=0.004}. In univariate regression analysis, decreased |GLS| was associated with male gender, maximum and mean LV wall thickness, peak LVOT gradient, reduced mitral annular e’ velocity, elevated BNP and cardiac troponin I. In multivariable regression analysis, GLS was found independently associated with mean LV wall thickness and BNP. Conclusions In patients with symptomatic HOCM with preserved ejection fraction, impaired LV-GLS was found to be associated with plasma BNP and mean LV wall thickness, independent of gender, age, loading conditions, LVEF, or LVOT gradient. Reduced GLS may be a more sensitive surrogate in assessing increased myocardial wall tension or stretch, rather than LV contractility in these patients. Therefore, the interpretation of GLS in HOCM should shift away from systolic interest toward emphasizing its potential value in risk stratification of diastolic heart failure with preserved LVEF.Figure 1

The mitral to aortic/pulmonary velocity-time integral ratio is a simple, feasible and accurate discriminator for echocardiographic evaluation of severe isolated mitral regurgitation.

Echocardiographic quantification of mitral regurgitation (MR) remains challenging, requiring dedicated image acquisition, and is limited by potential error from geometric assumptions of annular dimensions. Volume is a product of area and flow and assuming proportional mitral/aortic areas, an increased mitral-inflow volume compared to LV/RV-outflow semi-quantitatively represents greater MR regurgitant volume. Therefore, we investigated the feasibility and diagnostic performance of the mitral-aortic velocity-time integral(VTI) ratio in isolated MR. We also investigated the use of the mitral-pulmonary VTI ratio as an alternative in clinical situations where the LV outflow tract(LVOT) VTI could not be used. We reviewed 166 consecutive patients (33%, n = 54 severe MR by multi-parameter integrated expert opinion). Pulsed wave Doppler VTI at the mitral leaflet tips and the left ventricular outflow and continuous-wave Doppler of the RV outflow tract were measured individually and independently by blinded readers(expert and trainee status) to derive the ratio. Receiver operator characteristic area under the curve(AUC) comparison was calculated and compared with effective regurgitant orifice area(EROA > 40mm), regurgitant volume(RVol > 60mL), vena contracta(VC > 0.7cm), E-velocity > 1.2cm, systolic flow reversal(SFR), left atrial and ventricular dilatation. Increasing ratio was associated with severe MR(AUC 0.94) with optimal threshold defined at 1.3. This provided significant discrimination for severe MR(AUC 0.81) compared to EROA(0.68), VC(0.52), LV dilatation(0.69), LA dilatation(0.70), SFR(0.73), E-velocity(0.68) all p < 0.05, with sensitivity 82% and specificity 94%. The mitral-pulmonary VTI ratio demonstrated similar discrimination(AUC 0.92) with optimal threshold defined at 1.14. Excellent inter-observer reproducibility(intra-class correlation 0.97) was seen between trainee and expert readers. There was no difference in AUC comparison by MR mechanism or patient rhythm. The mitral-aortic and mitral-pulmonary VTI ratios are simple, geometric-free parameters feasibly reproducible from routine echocardiographic datasets and are excellent discriminative tools for severe MR. Readers should consider integration of this parameter in routine reporting.

Deep learning of echocardiography distinguishes between presence and absence of late gadolinium enhancement on cardiac magnetic resonance in patients with hypertrophic cardiomyopathy

BackgroundHypertrophic cardiomyopathy (HCM) can cause myocardial fibrosis, which can be a substrate for fatal ventricular arrhythmias and subsequent sudden cardiac death. Although late gadolinium enhancement (LGE) on cardiac magnetic resonance (CMR) represents myocardial fibrosis and is associated with sudden cardiac death in patients with HCM, CMR is resource-intensive, can carry an economic burden, and is sometimes contraindicated. In this study for patients with HCM, we aimed to distinguish between patients with positive and negative LGE on CMR using deep learning of echocardiographic images.MethodsIn the cross-sectional study of patients with HCM, we enrolled patients who underwent both echocardiography and CMR. The outcome was positive LGE on CMR. Among the 323 samples, we randomly selected 273 samples (training set) and employed deep convolutional neural network (DCNN) of echocardiographic 5-chamber view to discriminate positive LGE on CMR. We also developed a reference model using clinical parameters with significant differences between patients with positive and negative LGE. In the remaining 50 samples (test set), we compared the area under the receiver-operating-characteristic curve (AUC) between a combined model using the reference model plus the DCNN-derived probability and the reference model.ResultsAmong the 323 CMR studies, positive LGE was detected in 160 (50%). The reference model was constructed using the following 7 clinical parameters: family history of HCM, maximum left ventricular (LV) wall thickness, LV end-diastolic diameter, LV end-systolic volume, LV ejection fraction < 50%, left atrial diameter, and LV outflow tract pressure gradient at rest. The discriminant model combining the reference model with DCNN-derived probability significantly outperformed the reference model in the test set (AUC 0.86 [95% confidence interval 0.76–0.96] vs. 0.72 [0.57–0.86], P = 0.04). The sensitivity, specificity, positive predictive value, and negative predictive value of the combined model were 0.84, 0.76, 0.78, and 0.83, respectively.ConclusionCompared to the reference model solely based on clinical parameters, our new model integrating the reference model and deep learning-based analysis of echocardiographic images demonstrated superiority in distinguishing LGE on CMR in patients with HCM. The novel deep learning-based method can be used as an assistive technology to facilitate the decision-making process of performing CMR with gadolinium enhancement.

Mavacamten for Obstructive Hypertrophic Cardiomyopathy: Rationale for Clinically Guided Dose Titration to Optimize Individual Response.

Mavacamten is the first and only cardiac myosin inhibitor approved in 5 continents for the treatment of adults with symptomatic New York Heart Association class II and III obstructive hypertrophic cardiomyopathy. An evidence-based rationale was used to develop individualized mavacamten dosing, guided by commonly used clinical parameters. Echocardiography is recommended as part of routine clinical assessment of patients with hypertrophic cardiomyopathy, and left ventricular (LV) outflow tract gradient and LV ejection fraction are parameters that can be readily assessed and monitored by echocardiography. Therefore, an echocardiography-based, clinically guided dose-titration strategy was developed to optimize patient benefit from mavacamten for the treatment of symptomatic obstructive hypertrophic cardiomyopathy while minimizing the risk of LV ejection fraction reduction. Results from clinical trials paired with extensive modeling and simulation analyses support a dose-titration and monitoring strategy based on serial echocardiographic measures of Valsalva LV outflow tract gradient and LV ejection fraction. This dosing approach allows for the identification of the lowest individualized mavacamten dose and exposure required to provide improvements in LV outflow tract obstruction, functional capacity, and symptoms. Mavacamten is primarily metabolized by CYP2C19 (cytochrome P450 2C19), and CYP2C19 metabolizer phenotype has an effect on mavacamten exposure. Therefore, this approach has also been demonstrated to provide a favorable safety profile irrespective of patients' CYP2C19 metabolizer status. The dose-titration strategy includes additional considerations for the potential onset of systolic dysfunction in the context of intercurrent illness, and for the potential of drug-drug interactions with inhibitors and substrates of cytochrome P450 enzymes. This posology is reflected in the mavacamten US prescribing information.

Impact of Aficamten on Echocardiographic Cardiac Structure and Function in Symptomatic Obstructive Hypertrophic Cardiomyopathy

BackgroundAficamten, a next-in-class cardiac myosin inhibitor, improved peak oxygen uptake (pVO2) and lowered resting and Valsalva left ventricular outflow (LVOT) gradients in adults with symptomatic obstructive hypertrophic cardiomyopathy (oHCM) in SEQUOIA-HCM (Phase 3 Trial to Evaluate the Efficacy and Safety of Aficamten Compared to Placebo in Adults With Symptomatic oHCM), a phase 3, multicenter, randomized, double-blinded, placebo-controlled study. ObjectivesThe authors sought to evaluate the effect of aficamten on echocardiographic measures of cardiac structure and function in SEQUOIA-HCM. MethodsSerial echocardiograms were performed over 28 weeks in patients randomized to receive placebo or aficamten in up to 4 individually titrated escalating doses (5-20 mg daily) over 24 weeks based on Valsalva LVOT gradients and left ventricular ejection fraction (LVEF). ResultsAmong 282 patients (mean age 59 ± 13 years; 41% female, 79% White, 19% Asian), mean LVEF was 75% ± 6% with resting and Valsalva LVOT gradients of 55 ± 30 mm Hg and 83 ± 32 mm Hg, respectively. Over 24 weeks, aficamten significantly lowered resting and Valsalva LVOT gradients, and improved left atrial volume index, lateral and septal eʹ velocities, and lateral and septal E/eʹ (all P ≤ 0.001). LV end-systolic volume increased and wall thickness decreased (all P ≤ 0.003). Aficamten resulted in a mild reversible decrease in LVEF (−4.8% [95% CI: −6.4% to −3.3%]; P < 0.001) and absolute LV global circumferential strain (−3.7% [95% CI: 1.8%-5.6%]; P < 0.0010), whereas LV global longitudinal strain was unchanged. Several measures, including LVEF, LVOT gradients, and E/eʹ returned to baseline following washout. Among those treated with aficamten, improved pVO2 and reduction in N-terminal pro–B-type natriuretic peptide (NT-proBNP) were associated with improvement in lateral eʹ velocity and septal and lateral E/eʹ (all P < 0.03), whereas improvement in Kansas City Cardiomyopathy Questionnaire Clinical Summary Scores (KCCQ-CSS) was associated with a decrease in both LVOT gradients (all P < 0.001). ConclusionsCompared with placebo, patients receiving aficamten demonstrated significant improvement in LVOT gradients and measures of LV diastolic function, and several of these measures were associated with improvements in pVO2, KCCQ-CSS, and NT-proBNP. A modest decrease in LVEF occurred yet remained within normal range. These findings suggest aficamten improved multiple structural and physiological parameters in oHCM without significant adverse changes in LV systolic function. (Phase 3 Trial to Evaluate the Efficacy and Safety of Aficamten Compared to Placebo in Adults With Symptomatic oHCM [SEQUOIA-HCM]; NCT05186818)

Effect of Aficamten on Cardiac Structure and Function in Obstructive Hypertrophic Cardiomyopathy: SEQUOIA-HCM CMR Substudy

BackgroundObstructive hypertrophic cardiomyopathy (oHCM) is characterized by left ventricular (LV) hypertrophy, LV outflow tract obstruction, and left atrial dilation, which can be associated with progressive heart failure, atrial fibrillation, and stroke. Aficamten is a next-in-class cardiac myosin inhibitor that reduces outflow tract obstruction by modulating cardiac contractility, with the potential to reverse pathological remodeling and, in turn, reduce cardiovascular events. ObjectivesThis study sought to investigate the effect of aficamten on cardiac remodeling compared with placebo using cardiovascular magnetic resonance (CMR) and its association with key clinical endpoints in the SEQUOIA-HCM (Safety, Efficacy, and Quantitative Understanding of Obstruction Impact of Aficamten in HCM) CMR substudy. MethodsSEQUOIA-HCM was a phase 3 double-blind, placebo-controlled trial for adults with symptomatic oHCM who were randomized 1:1 to 24 weeks of aficamten (dose range: 5-20 mg) or placebo. Eligible participants were offered enrollment in the CMR substudy with studies performed at baseline and week 24. Image analysis was performed in a blinded fashion by a core laboratory. ResultsOf the 282 randomized patients, 57 (20%) participated in the substudy, and of those, 50 (88%) completed both baseline and week 24 CMR. Baseline characteristics of the CMR cohort were similar to the overall study population. Of these 50 patients, 21 received aficamten and 29 received placebo. Relative to placebo, patients receiving aficamten demonstrated significant reductions (Δ least-squares mean) in LV mass index (−15 g/m2; 95% CI: −25 to −6 g/m2; P = 0.001), maximal LV wall thickness (−2.1 mm; 95% CI: −3.1 to −1.1 mm; P < 0.001), left atrial volume index (−13 mL/m2; 95% CI: −19 to −7 mL/m2; P < 0.001), native T1 relaxation time (−37 ms; 95% CI: −69 to −5 ms; P = 0.026), indexed extracellular volume fraction (−3.9 g/m2; 95% CI: −7.0 to −0.9 g/m2; P = 0.014), and indexed myocyte mass (−14 g/m2; 95% CI: −23 to −4 g/m2; P = 0.004), while there were no significant changes in LV chamber volumes, LV replacement fibrosis (late gadolinium enhancement mass −0.7 g; 95% CI: −2.9 to 1.6 g; P = 0.54), or extracellular volume (0.7%; 95% CI: −2.2% to 3.6%; P = 0.61). ConclusionsThe CMR substudy of SEQUOIA-HCM demonstrated that treatment with aficamten relative to placebo for 24 weeks resulted in favorable cardiac remodeling. These changes, particularly with regard to LV mass, wall thickness, and left atrial size, could potentially lead to reduced cardiovascular events including heart failure and atrial fibrillation with longer follow-up. (Phase 3 Trial to Evaluate the Efficacy and Safety of Aficamten Compared to Placebo in Adults With Symptomatic oHCM [SEQUOIA-HCM]; NCT05186818)

Diastolic Stress Echocardiography in Patients With Hypertrophy Cardiomyopathy: Association With Exercise Capacity

Diastolic dysfunction plays a major role in precipitating congestive heart failure (CHF) in hypertrophic cardiomyopathy (HCM) patients. In many such patients, symptoms are unmasked only during exercise, as left ventricular (LV) filling pressure is normal at rest but increase with exercise. We sought to establish if abnormal post-exercise diastolic parameters are associated with reduced exercise capacity in patients with HCM. We examined 590 asymptomatic/minimally symptomatic HCM patients (54±14 years, 57% men, body mass index 30±6 kg/m2, 84% on betablockers) with HCM by two-dimensional and Doppler echocardiography at rest and following maximal treadmill exercise echocardiography (TSE). A complete echocardiogram (including LV ejection fraction, LV thickness, LV outflow tract [LVOT] gradient, degree of mitral regurgitation [MR]) was recorded. Diastolic parameters (septal and lateral [e’] velocities of the mitral annulus, peak early [E] and late [A] mitral inflow velocity, E/A ratio, E/e’, right ventricular systolic pressure [RVSP] and left atrial volume index [LAVI]) were recorded at rest and post-TSE. Exercise functional capacity was recorded and divided into <85% or >85% of age-gender predicted metabolic equivalents (AGP-METs). Following maximal exercise, 32% patients had at least moderate MR, mean LVOT gradient was 61±59 mmHg, E/A ratio was 1.2± 1.0, average E/e’ ratio 12.9±1.0 and peak RVSP was 36±15 mm Hg. Only 42% patients achieved >85% of AGP-METs; mean Mets were 7±3. On multivariable logistic regression analysis, higher body mass index (odds ratio [OR] 1.05), betablocker use (OR 2.58), higher LAVI (OR 1.02), higher peak-stress LVOTG (OR 1.06), peak-stress E/e’ (OR 1.04) and higher RVSP (OR 1.03) were independently associated with <85% AGP-METs achieved (all p<0.05). In conclusion, in asymptomatic/minimally symptomatic patients with HCM undergoing TSE, there is a significant and independent association between abnormal diastolic response to exercise and reduced exercise capacity in HCM. Incorporating diastolic parameters during stress echocardiography could provide incremental diagnostic utility in deciphering the exact etiology of dyspnea in such patients.

Echocardiographic assessment of left ventricular volumes: a comparison of different methods in athletes.

Cardiac magnetic resonance imaging (cMRI) is considered the gold standard for the assessment of left ventricular (LV) systolic function. However, discrepancies have been reported in the literature between LV volumes assessed by transthoracic echocardiography (TTE) and cMRI. The objective of this study was to analyze the differences in LV volumes between different echocardiographic techniques and cMRI. In 64 male athletes (21.1 ± 4.9years), LV volumes were measured by TTE using the following methods: Doppler echocardiography, anatomical M-Mode, biplane/triplane planimetry and 3D volumetry. In addition, LV end-diastolic (LVEDV), end-systolic (LVESV), and stroke volumes (LVSV) were assessed in 11 athletes by both TTE and cMRI. There was no significant difference between LVEDV and LVESV determined by biplane/triplane planimetry and 3D volumetry. LVEDV and LVESV measured by M-Mode were significantly lower compared to 3D volumetry. LVSV determined by Doppler with 3D planimetry of LV outflow tract was significantly higher than 2D planimetry and 3D volumetry, whereas none of the planimetric or volumetric methods for determining LVSV differed significantly. There were no significant differences for LVEDV, LVESV, LVSV and LVEF between cMRI and TTE determined by biplane planimetry in the subgroup of 11 athletes. The choice of echocardiographic method used has an impact on LVSV in athletes, so the LVSV should always be checked for plausibility. The same echocardiographic method should be used to assess LVSV at follow-ups to ensure good comparability. The data suggest that biplane LV planimetry by TTE is not inferior to cMRI.

Flow inefficiencies in non-obstructive HCM revealed by kinetic energy and hemodynamic forces on 4D-flow CMR.

Patients with non-obstructive hypertrophic cardiomyopathy (HCM) exhibit myocardial changes which may cause flow inefficiencies not detectable on echocardiogram. We investigated whether left ventricular (LV) kinetic energy (KE) and hemodynamic forces (HDF) on 4D-flow cardiovascular magnetic resonance (CMR) can provide more sensitive measures of flow in non-obstructive HCM. Ninety participants (70 with non-obstructive HCM and 20 healthy controls) underwent 4D-flow CMR. Patients were categorized as phenotype positive (P+) based on maximum wall thickness (MWT) ≥ 15 mm or ≥13 mm for familial HCM, or pre-hypertrophic sarcomeric variant carriers (P-). LV KE and HDF were computed from 4D-flow CMR. Stroke work was computed using a previously validated non-invasive method. P+ and P- patients and controls had comparable diastolic velocities and LV outflow gradients on echocardiography, LV ejection fraction, and stroke volume on CMR. P+ patients had greater stroke work than P- patients, higher systolic KE compared with controls (5.8 vs. 4.1 mJ, P = 0.0009), and higher late diastolic KE relative to P- patients and controls (2.6 vs. 1.4 vs. 1.9 mJ, P < 0.0001, respectively). MWT was associated with systolic KE (r = 0.5, P < 0.0001) and diastolic KE (r = 0.4, P = 0.005), which also correlated with stroke work. Systolic HDF ratio was increased in P+ patients compared with controls (1.0 vs. 0.8, P = 0.03) and correlated with MWT (r = 0.3, P = 0.004). Diastolic HDF was similar between groups. Sarcomeric variant status was not associated with KE or HDF. Despite normal flow velocities on echocardiography, patients with non-obstructive HCM exhibited greater stroke work, systolic KE and HDF ratio, and late diastolic KE relative to controls. 4D-flow CMR provides more sensitive measures of haemodynamic inefficiencies in HCM, holding promise for clinical trials of novel therapies and clinical surveillance of non-obstructive HCM.

Echocardiography-Derived Forward Left Ventricular Output Improves Risk Prediction in Systolic Heart Failure

Although it is widely used to classify patients with heart failure (HF), the prognostic role of left ventricular ejection fraction (LVEF) is debated. The aim of this study was to test the hypothesis that echocardiographic measures of forward left ventricular (LV) output, being more representative of cardiac hemodynamics, might improve risk prediction in a large cohort of patients with HF with systolic dysfunction. Consecutive stable patients with HF with LVEF <50% on guideline-recommended therapies undergoing echocardiography including the evaluation of forward LV output (i.e., LV outflow tract [LVOT] velocity-time integral [VTI], stroke volume index [SVi], and cardiac index) over a 6-year period were selected and followed for the end point of cardiac and all-cause death. Among the 1,509 patients analyzed (mean age, 71±12years; 75% men; mean LVEF, 35±9%), 328 (22%) died during a median follow-up period of 28 months (interquartile range, 14-40 months), 165 (11%) of cardiac causes. On multivariable regression analysis, LVOT VTI (P<.001), SVi (P<.001), and cardiac index (P<.001), but not LVEF (P>.05), predicted cardiac and all-cause death. The optimal prognostic cutoffs for LVOT VTI, SVi, and cardiac index were 15cm, 38mL/m2, and 2L/min/m2, respectively. Adding each of these measures to a multivariable risk model (including clinical, biohumoral, and echocardiographic markers) improved risk prediction (P<.001). Among the different measures of forward LV output, cardiac index was less accurate than LVOT VTI and SVi. The echocardiographic evaluation of forward LV output improves risk prediction in patients with HF across a wide LVEF spectrum over other well-established clinical, biohumoral, and echocardiographic prognostic markers.

Changes in left ventricular-aortic angulation are associated with the development of obstruction in hypertrophic cardiomyopathy

ObjectiveTo characterize changes in ventricular morphology in patients with hypertrophic cardiomyopathy who develop left ventricular (LV) outflow tract obstruction. MethodsWe reviewed patients with hypertrophic cardiomyopathy with LV outflow tract obstruction who underwent septal myectomy from May 2012 to June 2023. Among 68 patients initially without obstruction documented up to 7.6 years (interquartile range, 6.3-9.4 years) before the operation, a comparison was made with 78 patients with nonobstructive hypertrophic cardiomyopathy over a similar period. Patients who did not develop obstruction were matched with those who did on sex, age, and maximum septal wall thickness during the initial echocardiography, identifying 41 matched pairs. Echocardiographic data, including 5 measures of angulation, were compared between the groups. ResultsThe median interval between echocardiographic assessments was 7.5 years (interquartile range, 6.3-8.1 years) among patients with obstruction versus 7.3 years (interquartile range, 6.2-9.0 years) in patients without nonobstruction. Patients with obstruction were more likely to have hypertension at both times. The maximum septal wall thickness increased within both groups (both P values < .001), but the magnitude of increase was not different between groups (P = .130). Patients with obstruction exhibited a greater increase in LV mass (P < .001) compared with patients without obstruction (P = .004). Aortic angulation significantly increased in 4 of the 5 measurements (all P values < .001) in patients with obstruction, whereas patients with no obstruction showed no change. Anterior and posterior mitral valve leaflet lengths and coaptation lengths remained similar in both groups over time. ConclusionsThe development of LV outflow tract obstruction in patients with hypertrophic cardiomyopathy was associated with progressive LV outflow tract angulation and increased LV hypertrophy, as reflected by LV mass. Progression to obstruction was not related to changes in the mitral valve leaflet morphology.

Conduction system pacing preserves both electrical and mechanical interventricular synchrony, a UHF ECG validation study

Abstract Background Interventricular mechanical delay (IVMD) is an established echocardiographic risk factor for pacing-induced cardiomyopathy development. Ultra-high-frequency ECG (UHF-ECG) is a non-invasive tool visualizing the ventricular activation sequence. Purpose To compare UHF-ECG interventricular dyssynchrony with echocardiography and to establish interventricular dyssynchrony related to conductive system pacing (CSP) and right ventricular myocardial pacing (RVP). Methods 53 patients with advanced AV conduction disease, without organic heart disease, and preserved LV systolic function were prospectively included. Thirty-two had RVP, and twenty-one had CSP. CSP included both His bundle pacing (n=5) and left bundle branch area pacing (n=16). UHF-ECG and echocardiography were obtained at the baseline (during spontaneous rhythm) and after 1 year (during pacing). IVMD was manually calculated as a difference between the time from a distinct point of the QRS until the onset of the flow through LV and RV outflow tract using pulsed wave doppler imaging. Analysis was performed by two experienced and blinded cardiologists. Interventricular e-DYS was calculated automatically by a software as a time difference between activation in V8 (LV free wall) and V1 electrode (RV free wall). Results The average age of all included patients was 76 ± 6 years old and patients in both RVP and CSP group had similar clinical characteristics. The values of IVMD and interventricular e-DYS were similar in the whole study population both before the pacemaker implantation (-2 ± 21 ms for IVMD vs. 0 ± 20 ms for interventricular e-DYS; p=0.31) and after one year (14 ± 23 ms for IVMD vs. 14 ± 24 ms for UHF; p = 0.7). There were no significant differences in the baseline IVMD and interventricular e-DYS between those receiving CSP vs. RVP (IVMD -6 ± 22 ms for CSP vs 2 ± 20 ms for RVP, p=0.22) and interventricular e-DYS (e-DYS -5 ± 20 ms for CSP vs. 3 ± 20 ms for RVP, p=0.34). After one year of pacing, the patients with CSP preserved similar levels of both IVMD (mean change -2 ± 5 ms, p=0.74) and interventricular e-DYS V8-V1 (mean change 0 ± 4 ms, p = 0.95) – Figure 1. There was no difference between IVMD and interventricular e-DYS in CSP patients after one year (p=0.92). On the contrary, in the RVP group IVMD increased for 27 ± 5 ms (p &amp;lt;0.0001) and interventricular e-DYS for 24 ± 5 ms (p &amp;lt;0.0001) compared to the baseline - Figure 1. There was no difference between IVMD and interventricular e-DYS in RVP patients after one year (p=0.75). There was a moderate overall correlation between IVMD and e-DYS V8-V1 in all studied ventricular rhythms (R=0.73, p&amp;lt;0.0001) – Figure 2. Conclusions UHF-ECG expresses the interventricular dyssynchrony noninvasively by measuring the activation difference between V8-V1 chest leads. RV myocardial pacing increases interventricular dyssynchrony, while CSP preserves synchronous ventricular activation.CSP vs RVPcorrelation of dyssynchrony