Efficacy and Safety of Acoramidis in Transthyretin Amyloid Cardiomyopathy.

BACKGROUND: Transthyretin amyloid cardiomyopathy is characterized by the deposition of misfolded monomeric transthyretin (TTR) in the heart. Acoramidis is a high-affinity TTR stabilizer that acts to inhibit dissociation of tetrameric TTR and leads to more than 90% stabilization across the dosing interval as measured ex vivo. METHODS: In this phase 3, double-blind trial, we randomly assigned patients with transthyretin amyloid cardiomyopathy in a 2:1 ratio to receive acoramidis hydrochloride at a dose of 800 mg twice daily or matching placebo for 30 months. Efficacy was assessed in the patients who had an estimated glomerular filtration rate of at least 30 ml per minute per 1.73 m2 of body-surface area. The four-step primary hierarchical analysis included death from any cause, cardiovascular-related hospitalization, the change from baseline in the N-terminal pro-B-type natriuretic peptide (NT-proBNP) level, and the change from baseline in the 6-minute walk distance. We used the Finkelstein-Schoenfeld method to compare all potential pairs of patients within strata to generate a P value. Key secondary outcomes were death from any cause, the 6-minute walk distance, the score on the Kansas City Cardiomyopathy Questionnaire-Overall Summary, and the serum TTR level. RESULTS: A total of 632 patients underwent randomization. The primary analysis favored acoramidis over placebo (P<0.001); the corresponding win ratio was 1.8 (95% confidence interval [CI], 1.4 to 2.2), with 63.7% of pairwise comparisons favoring acoramidis and 35.9% favoring placebo. Together, death from any cause and cardiovascular-related hospitalization contributed more than half the wins and losses to the win ratio (58% of all pairwise comparisons); NT-proBNP pairwise comparisons yielded the highest ratio of wins to losses (23.3% vs. 7.0%). The overall incidence of adverse events was similar in the acoramidis group and the placebo group (98.1% and 97.6%, respectively); serious adverse events were reported in 54.6% and 64.9% of the patients. CONCLUSIONS: In patients with transthyretin amyloid cardiomyopathy, the receipt of acoramidis resulted in a significantly better four-step primary hierarchical outcome containing components of mortality, morbidity, and function than placebo. Adverse events were similar in the two groups. (Funded by BridgeBio Pharma; ATTRibute-CM ClinicalTrials.gov number, NCT03860935.).

Aficamten for Symptomatic Obstructive Hypertrophic Cardiomyopathy.

BACKGROUND: One of the major determinants of exercise intolerance and limiting symptoms among patients with obstructive hypertrophic cardiomyopathy (HCM) is an elevated intracardiac pressure resulting from left ventricular outflow tract obstruction. Aficamten is an oral selective cardiac myosin inhibitor that reduces left ventricular outflow tract gradients by mitigating cardiac hypercontractility. METHODS: In this phase 3, double-blind trial, we randomly assigned adults with symptomatic obstructive HCM to receive aficamten (starting dose, 5 mg; maximum dose, 20 mg) or placebo for 24 weeks, with dose adjustment based on echocardiography results. The primary end point was the change from baseline to week 24 in the peak oxygen uptake as assessed by cardiopulmonary exercise testing. The 10 prespecified secondary end points (tested hierarchically) were change in the Kansas City Cardiomyopathy Questionnaire clinical summary score (KCCQ-CSS), improvement in the New York Heart Association (NYHA) functional class, change in the pressure gradient after the Valsalva maneuver, occurrence of a gradient of less than 30 mm Hg after the Valsalva maneuver, and duration of eligibility for septal reduction therapy (all assessed at week 24); change in the KCCQ-CSS, improvement in the NYHA functional class, change in the pressure gradient after the Valsalva maneuver, and occurrence of a gradient of less than 30 mm Hg after the Valsalva maneuver (all assessed at week 12); and change in the total workload as assessed by cardiopulmonary exercise testing at week 24. RESULTS: A total of 282 patients underwent randomization: 142 to the aficamten group and 140 to the placebo group. The mean age was 59.1 years, 59.2% were men, the baseline mean resting left ventricular outflow tract gradient was 55.1 mm Hg, and the baseline mean left ventricular ejection fraction was 74.8%. At 24 weeks, the mean change in the peak oxygen uptake was 1.8 ml per kilogram per minute (95% confidence interval [CI], 1.2 to 2.3) in the aficamten group and 0.0 ml per kilogram per minute (95% CI, -0.5 to 0.5) in the placebo group (least-squares mean between-group difference, 1.7 ml per kilogram per minute; 95% CI, 1.0 to 2.4; P<0.001). The results for all 10 secondary end points were significantly improved with aficamten as compared with placebo. The incidence of adverse events appeared to be similar in the two groups. CONCLUSIONS: Among patients with symptomatic obstructive HCM, treatment with aficamten resulted in a significantly greater improvement in peak oxygen uptake than placebo. (Funded by Cytokinetics; SEQUOIA-HCM ClinicalTrials.gov number, NCT05186818.).

In adults with ATTR cardiac amyloidosis, patisiran reduced decline in functional capacity at 12 mo.

SOURCE CITATION: Maurer MS, Kale P, Fontana M, et al; APOLLO-B Trial Investigators. Patisiran treatment in patients with transthyretin cardiac amyloidosis. N Engl J Med. 2023;389:1553-1565. 37888916.

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.

EstimATTR: A Simplified, Machine-Learning-Based Tool to Predict the Risk of Wild-Type Transthyretin Amyloid Cardiomyopathy.

BACKGROUND: Wild-type transthyretin amyloid cardiomyopathy (ATTRwt-CM), an increasingly recognized cause of heart failure (HF), often remains undiagnosed until later stages of the disease. METHODS AND RESULTS: A previously developed machine learning algorithm was simplified to create a random forest model based on 11 selected phenotypes predictive of ATTRwt-CM to estimate ATTRwt-CM risk in hypothetical patient scenarios. Using U.S. medical claims datasets (IQVIA), International Classification of Diseases codes were extracted to identify a training cohort of patients with ATTRwt-CM (cases) or nonamyloid HF (controls). After assessment in a 20% test sample of the training cohort, model performance was validated in cohorts of patients with International Classification of Diseases codes for ATTRwt-CM or cardiac amyloidosis vs nonamyloid HF derived from medical claims (IQVIA) or electronic health records (Optum). The simplified model performed well in identifying patients with ATTRwt-CM vs nonamyloid HF in the test sample, with an accuracy of 74%, sensitivity of 77%, specificity of 72%, and area under the curve of 0.82; robust performance was also observed in the validation cohorts. CONCLUSIONS: This simplified machine learning model accurately estimated the empirical probability of ATTRwt-CM in administrative datasets, suggesting it may serve as an easily implementable tool for clinical assessment of patient risk for ATTRwt-CM in the clinical setting. BRIEF LAY SUMMARY: Wild-type transthyretin amyloid cardiomyopathy (ATTRwt-CM for short) is a frequently overlooked cause of heart failure. Finding ATTRwt-CM early is important because the disease can worsen rapidly without treatment. Researchers developed a computer program that predicts the risk of ATTRwt-CM in patients with heart failure. In this study, the program was used to check for 11 medical conditions linked to ATTRwt-CM in the medical claims records of patients with heart failure. The program was 74% accurate in identifying ATTRwt-CM in patients with heart failure and was then used to develop an educational online tool for doctors (the wtATTR-CM estimATTR).

Effect of Eplontersen on Cardiac Structure and Function in Patients With Hereditary Transthyretin Amyloidosis.

BACKGROUND: Hereditary transthyretin amyloidosis (ATTRv) is associated with polyneuropathy, cardiomyopathy, or both. The effects of eplontersen on cardiac structure and function were assessed. METHODS AND RESULTS: NEURO-TTRansform was an open-label trial involving 144 adults with ATTRv polyneuropathy (49 patients [34%] with cardiomyopathy) receiving eplontersen throughout and compared with a historical placebo group (n = 60; 30 patients [50%] with cardiomyopathy) from the NEURO-TTR trial at week 65. Treatment effect (eplontersen vs placebo), presented as mean difference (95% confidence interval) was analyzed after adjusting for age, sex, region, baseline value, ATTRv disease stage, previous ATTRv treatment, and V30M transthyretin variant. There were notable differences at baseline between the eplontersen group and historical placebo. In the cardiomyopathy subgroup, 65 weeks of eplontersen treatment was associated with improvement from baseline relative to placebo in left ventricular ejection fraction of 4.3% (95% confidence interval 1.40-21.01; P = .049) and stroke volume 10.64 mL (95% confidence interval 3.99-17.29; P = .002) while the remainder of echocardiographic parameters remained stable. CONCLUSIONS: Eplontersen was associated with stable or improved measures of cardiac structure and function vs historical placebo in patients with ATTRv polyneuropathy and cardiomyopathy. Further investigation into eplontersen's effect on transthyretin amyloid cardiomyopathy is being conducted in the CARDIO-TTRansform trial.

Imaging cardiac hypertrophy in hypertrophic cardiomyopathy and its differential diagnosis.

PURPOSE OF REVIEW: The aim of this study was to review imaging of myocardial hypertrophy in hypertrophic cardiomyopathy (HCM) and its phenocopies. The introduction of cardiac myosin inhibitors in HCM has emphasized the need for careful evaluation of the underlying cause of myocardial hypertrophy. RECENT FINDINGS: Advances in imaging of myocardial hypertrophy have focused on improving precision, diagnosis, and predicting prognosis. From improved assessment of myocardial mass and function, to assessing myocardial fibrosis without the use of gadolinium, imaging continues to be the primary tool in understanding myocardial hypertrophy and its downstream effects. Advances in differentiating athlete's heart from HCM are noted, and the increasing rate of diagnosis in cardiac amyloidosis using noninvasive approaches is especially highlighted due to the implications on treatment approach. Finally, recent data on Fabry disease are shared as well as differentiating other phenocopies from HCM. SUMMARY: Imaging hypertrophy in HCM and ruling out other phenocopies is central to the care of patients with HCM. This space will continue to rapidly evolve, as disease-modifying therapies are under investigation and being advanced to the clinic.

Baseline and Longitudinal Imaging of Hypertrophic Cardiomyopathy in the Era of Emerging Therapeutics.

PURPOSE OF REVIEW: In this review, we will overview the baseline and longitudinal imaging modalities utilized in the care of patients with hypertrophic cardiomyopathy (HCM) with a focus on echocardiography and cardiac magnetic resonance (CMR) imaging, especially in the new era of cardiac myosin inhibitors (CMIs). RECENT FINDINGS: Traditional therapies for hypertrophic cardiomyopathy (HCM) have been well established for decades. Attempts to investigate new drug therapy in HCM resulted in neutral clinical trials, until the discovery of cardiac myosin inhibitors (CMIs). The introduction of this new class of small oral molecules which target the hypercontractility resulting from excessive actin-myosin cross-bridging at the sarcomere level is the first therapeutic option which directly addresses the underlying pathophysiology of HCM. While imaging has always played a central role in HCM diagnosis and management, CMIs introduced a new paradigm in the use of imaging to evaluate and monitor patients with HCM. Echocardiography and cardiac magnetic resonance imaging (CMR) are the central modalities in the care of patients with HCM, but their roles and our understanding of their strengths and limitations are evolving as newer therapeutics are being investigated in clinical trials and in daily practice. In this review, we will focus the recent CMI trials and discuss the role of baseline and longitudinal imaging with echocardiography and CMR in the care of patients with HCM in the era of CMIs.

Differentiating Cardiac Troponin Levels During Cardiac Myosin Inhibition or Cardiac Myosin Activation Treatments: Drug Effect or the Canary in the Coal Mine?

PURPOSE OF REVIEW: Cardiac myosin inhibitors (CMIs) and activators are emerging therapies for hypertrophic cardiomyopathy (HCM) and heart failure with reduced ejection fraction (HFrEF), respectively. However, their effects on cardiac troponin levels, a biomarker of myocardial injury, are incompletely understood. RECENT FINDINGS: In patients with HCM, CMIs cause substantial reductions in cardiac troponin levels which are reversible after stopping treatment. In patients with HFrEF, cardiac myosin activator (omecamtiv mecarbil) therapy cause modest increases in cardiac troponin levels which are reversible following treatment cessation and not associated with myocardial ischaemia or infarction. Transient changes in cardiac troponin levels might reflect alterations in cardiac contractility and mechanical stress. Such transient changes might not indicate cardiac injury and do not appear to be associated with adverse outcomes in the short to intermediate term. Longitudinal changes in troponin levels vary depending on the population and treatment. Further research is needed to elucidate mechanisms underlying changes in troponin levels.

Eplontersen for Hereditary Transthyretin Amyloidosis With Polyneuropathy.

Importance: Transthyretin gene silencing is an emerging treatment strategy for hereditary transthyretin (ATTRv) amyloidosis. Objective: To evaluate eplontersen, an investigational ligand-conjugated antisense oligonucleotide, in ATTRv polyneuropathy. Design, Setting, and Participants: NEURO-TTRansform was an open-label, single-group, phase 3 trial conducted at 40 sites across 15 countries (December 2019-April 2023) in 168 adults with Coutinho stage 1 or 2 ATTRv polyneuropathy, Neuropathy Impairment Score 10-130, and a documented TTR variant. Patients treated with placebo from NEURO-TTR (NCT01737398; March 2013-November 2017), an inotersen trial with similar eligibility criteria and end points, served as a historical placebo ("placebo") group. Interventions: Subcutaneous eplontersen (45 mg every 4 weeks; n = 144); a small reference group received subcutaneous inotersen (300 mg weekly; n = 24); subcutaneous placebo weekly (in NEURO-TTR; n = 60). Main Outcomes and Measures: Primary efficacy end points at week 65/66 were changes from baseline in serum transthyretin concentration, modified Neuropathy Impairment Score +7 (mNIS+7) composite score (scoring range, -22.3 to 346.3; higher scores indicate poorer function), and Norfolk Quality of Life Questionnaire-Diabetic Neuropathy (Norfolk QoL-DN) total score (scoring range, -4 to 136; higher scores indicate poorer quality of life). Analyses of efficacy end points were based on a mixed-effects model with repeated measures adjusted by propensity score weights. Results: Among 144 eplontersen-treated patients (mean age, 53.0 years; 69% male), 136 (94.4%) completed week-66 follow-up; among 60 placebo patients (mean age, 59.5 years; 68% male), 52 (86.7%) completed week-66 follow-up. At week 65, adjusted mean percentage reduction in serum transthyretin was -81.7% with eplontersen and -11.2% with placebo (difference, -70.4% [95% CI, -75.2% to -65.7%]; P < .001). Adjusted mean change from baseline to week 66 was lower (better) with eplontersen vs placebo for mNIS+7 composite score (0.3 vs 25.1; difference, -24.8 [95% CI, -31.0 to -18.6; P < .001) and for Norfolk QoL-DN (-5.5 vs 14.2; difference, -19.7 [95% CI, -25.6 to -13.8]; P < .001). Adverse events by week 66 that led to study drug discontinuation occurred in 6 patients (4%) in the eplontersen group vs 2 (3%) in the placebo group. Through week 66, there were 2 deaths in the eplontersen group consistent with known disease-related sequelae (cardiac arrhythmia; intracerebral hemorrhage); there were no deaths in the placebo group. Conclusions and Relevance: In patients with ATTRv polyneuropathy, the eplontersen treatment group demonstrated changes consistent with significantly lowered serum transthyretin concentration, less neuropathy impairment, and better quality of life compared with a historical placebo. Trial Registration: ClinicalTrials.gov Identifier: NCT04136184; EU Clinical Trials Register: EudraCT 2019-001698-10.

Clinical management of amyloid cardiomyopathy.

Clinical heart failure, restrictive cardiomyopathy, and arrhythmias are hallmark features of amyloid cardiomyopathy. In contrast to the advancements in targeted therapies, there is a general lack of evidence-based practice guidelines for clinical management of amyloid cardiomyopathy. In this review, we review the role of routine medical therapy in amyloid cardiomyopathy, from heart failure management to orthostatic hypotension, atrial arrhythmias, thromboembolic complications, and prevention of sudden death. We conclude by discussing approaches to patients with end-stage disease.

Liver-directed drugs for transthyretin-mediated amyloidosis.

Transthyretin-mediated amyloidosis (ATTR) is a rare, under-recognized, progressively debilitating, fatal disease caused by the aggregation and extracellular deposition of amyloid transthyretin (TTR) fibrils in multiple organs and tissues throughout the body. TTR is predominantly synthesized by the liver and normally circulates as a homotetramer, while misfolded monomers aggregate to form amyloid fibrils. One strategy to treat ATTR amyloidosis is to reduce the amount of TTR produced by the liver using drugs that directly target the TTR mRNA or gene. This narrative review focuses on how TTR gene silencing tools act to reduce TTR production, describing strategies for improved targeted delivery of these agents to hepatocytes where TTR is preferentially expressed. Antisense oligonucleotides (ASOs) and small interfering RNAs (siRNAs), termed RNA silencers, cause selective degradation of TTR mRNA, while a TTR gene editing tool reduces TTR expression by introducing nonsense mutations into the TTR gene. Two strategies to facilitate tissue-specific delivery of these nucleic acid-based drugs employ endogenous receptors expressed by hepatocytes. Lipid nanoparticles (LNPs) that recruit apolipoprotein E support low-density lipoprotein receptor-mediated uptake of unconjugated siRNA and are now used for CRISPR gene editing tools. Additionally, conjugating N-acetylgalactosamine (GalNAc) moieties to ASOs or siRNAs facilitates receptor-mediated uptake by the asialoglycoprotein receptor. In summary, ATTR is a progressive disease with various clinical manifestations due to TTR aggregation, deposition, and amyloid formation. Receptor-targeted ligands (eg, GalNAc) and nanoparticle encapsulation (eg, LNPs) are technologies to deliver ASOs, siRNAs, and gene editing tools to hepatocytes, the primary location of TTR synthesis.

Implantable cardioverter-defibrillators with end stage renal disease: Nationwide inpatient sample database results.

BACKGROUND: When compared to patients with normal renal function, patients with chronic kidney disease develop higher in-hospital complications post implantable cardioverter-defibrillator (ICD) therapy. However, real world data on in-hospital complications post ICD therapy in patients with end stage renal disease (ESRD) is limited. In this study, we aim to explore the procedure-related complications of ICD therapy in patients with ESRD. METHODS: Using the nationwide inpatient sample (NIS) database, we conducted a retrospective analysis on ESRD patients who underwent inpatient ICD placement from 2010 to 2016. Using 1:2 propensity score matching, we compared ESRD patients to those with normal renal function. Outcomes of interest were postoperative hemorrhage and hematoma formation, blood transfusion, pericardial complications, mechanical complications requiring lead revision, vascular injury, in-hospital mortality, and length of stay. RESULTS: Our sample included 40,075 cases with subsequent propensity score matching between ESRD and normal renal function. Comparatively, patients with ESRD had higher odds of postoperative hemorrhage (Odds ratio [OR] = 1.67, 95% confidence interval [CI] 1.4-1.99, p = < .0001), blood transfusion (OR, 3.88; CI 3.29-4.56; p = < .0001), mechanical complications requiring lead revision (OR, 1.24; CI 1.01-1.51; p = .035), vascular injury (OR, 2.02; CI 1.27-3.24; p = .0027), in-hospital mortality (OR, 4.56; CI 3.08-6.76; p = < .0001), and longer hospitalization (11 vs. 7 days, p = < .0001), but without significant difference in pericardial complications (OR, 1.9; CI 0.92-1.54; p = < .18). CONCLUSION: In this large contemporary cohort, patients with ESRD undergoing inpatient ICD therapy are at higher risk of developing postprocedural complications including hemorrhage and hematoma, blood transfusion, mechanical complications requiring lead revision, and in hospital mortality, without increased risk of pericardial complications.

Myocardial contrast echocardiography assessment of perfusion abnormalities in hypertrophic cardiomyopathy.

BACKGROUND: Perfusion defects during stress can occur in hypertrophic cardiomyopathy (HCM) from either structural or functional abnormalities of the coronary microcirculation. In this study, vasodilator stress myocardial contrast echocardiography (MCE) was used to quantify and spatially characterize hyperemic myocardial blood flow (MBF) deficits in HCM. METHODS: Regadenoson stress MCE was performed in patients with septal-variant HCM (n = 17) and healthy control subjects (n = 15). The presence and spatial distribution (transmural diffuse, patchy, subendocardial) of perfusion defects was determined by semiquantitative analysis. Kinetic analysis of time-intensity data was used to quantify MBF, microvascular flux rate (ß), and microvascular blood volume. In patients undergoing septal myectomy (n = 3), MCE was repeated > 1 years after surgery.  RESULTS: In HCM subjects, perfusion defects during stress occurred in the septum in 80%, and in non-hypertrophied regions in 40%. The majority of septal defects (83%) were patchy or subendocardial, while 67% of non-hypertrophied defects were transmural and diffuse. On quantitative analysis, hyperemic MBF was approximately 50% lower (p < 0.001) in the hypertrophied and non-hypertrophied regions of those with HCM compared to controls, largely based on an inability to augment ß, although hypertrophic regions also had blood volume deficits. There was no correlation between hyperemic MBF and either percent fibrosis on magnetic resonance imaging or outflow gradient, yet those with higher degrees of fibrosis (≥ 5%) or severe gradients all had low septal MBF during regadenoson. Substantial improvement in hyperemic MBF was observed in two of the three subjects undergoing myectomy, both of whom had severe pre-surgical outflow gradients at rest. CONCLUSION: Perfusion defects on vasodilator MCE are common in HCM, particularly in those with extensive fibrosis, but have a different spatial pattern for the hypertrophied and non-hypertrophied segments, likely reflecting different contributions of functional and structural abnormalities. Improvement in hyperemic perfusion is possible in those undergoing septal myectomy to relieve obstruction.  TRIAL REGISTRATION: ClinicalTrials.gov NCT02560467.

Approach to echocardiography in ARDS patients in the prone position: A systematic review.

Echocardiography is commonly utilized in patients with acute respiratory distress syndrome (ARDS) for assessment of cardiac function, volume status, and the potential development of acute cor pulmonale. In severe ARDS, prone positioning is frequently used, which imposes technical challenges during transthoracic echocardiography (TTE) image acquisition. Moreover, prone positioning can affect cardiopulmonary function in ways that are reflected on the echocardiographic findings in this position. Historically, a transesophageal approach was recommended when a patient is prone, with few studies reporting utility of TTE in this setting. However, recent publications have begun to address this knowledge gap. This review explores recent literature addressing the use of TTE in prone patients with ARDS, with a special focus on the cardiopulmonary effects of proning and potential solutions to the technical difficulties that arise in this position.

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.

Assessment of right ventricular function following left ventricular assist device (LVAD) implantation-The role of speckle-tracking echocardiography: A meta-analysis.

BACKGROUND: Right ventricular failure (RVF) following left ventricular assist device (LVAD) implantation is associated with worse outcomes. Prediction of RVF is difficult with routine transthoracic echocardiography (TTE), while speckle-tracking echocardiography (STE) showed promising results. We performed systematic review and meta-analysis of published literature. METHODS: We queried multiple databases to compile articles reporting preoperative or intraoperative right ventricle global longitudinal strain (RVGLS) or right ventricle free wall strain (RVFWS) in LVAD recipients. The standard mean difference (SMD) in RVGLS and RVFWS in patients with and without RVF postoperatively was pooled using random-effects model. RESULTS: Seventeen studies were included. Patients with RVF had significantly lower RVGLS and RVFWS as compared to non-RVF patients; SMD: 2.79 (95% CI: -4.07 to -1.50; P: <.001) and -3.05 (95% CI: -4.11 to -1.99; P: <.001), respectively. The pooled odds ratio (OR) for RVF per percentage increase of RVGLS and RVFWS were 1.10 (95 CI: 0.98-1.25) and 1.63 (95% CI 1.07-2.47), respectively. In a subgroup analysis, TTE-derived GLS and FWS were significantly lower in RVF patients as compared to non-RVF patients; SMD of -3.97 (95% CI: -5.40 to -2.54; P: <.001) and -3.05 (95% CI: -4.11 to -1.99; P: <.001), respectively. There was no significant difference between RVF and non-RVF groups in TEE-derived RVGLS and RVFWS. CONCLUSION: RVGLS and RVFWS were lower in patients who developed RVF as compared to non-RVF patients. In a subgroup analysis, TTE-derived RVGLS and RVFWS were reduced in RVF patients as compared to non-RVF patients. This difference was not reported with TEE.

A rare case of bowel intussusception due to adenocarcinomatous polyp in a 14 year-old child: case report.

BACKGROUND: Intussusception is a form of intestinal obstruction in which a segment of the bowel prolapses into a more distal segment. It is an uncommon condition in children older than 2 years and causes intestinal obstruction. On the contrary of adult intussusception, childhood intussusception does not usually happen on a lead point of a malignant organic lesion. CASE PRESENTATION: A 14-year-old male presented with complaints of heavy, bilious emesis and periumbilical colicky pain. Ultrasonography showed a dilated intestinal loop with absent bowel movement. CT scan revealed two masses in the abdomen. We performed an exploratory laparotomy that revealed invaginated intestines and showed a polyp near the area of interest. Necrotic segments and the polyp were removed and examined pathologically. Pathology showed adenocarcinoma in the polyp. After surgery, the general condition of the patient was normal and no complications occurred. CONCLUSIONS: Intussusception mainly occurs during infancy and early childhood. Mostly it is an idiopathic ileo-colic invagination. In our case, the patient had a jejuno-jejunal intussusception in his late childhood, and the lead point was an adenocarcinomatous polyp, which is rare in children. Amongst the many types of treatment, we chose surgical resection because of patient's age.