Incidence and predictors of anthracycline-related left ventricular dysfunction in acute myeloid leukemia.

INTRODUCTION: Anthracycline-related left ventricular dysfunction (ARLVD) is a concern in patients with acute myeloid leukemia (AML) undergoing anthracyclinecontaining induction chemotherapy. However, the incidence of ARLVD in the modern era of routine pretreatment left ventricular ejection fraction (LVEF) echocardiographic assessment, as well as the clinical and genetic predictors of ARLVD are not well understood. METHODS: Consecutive adult patients with AML receiving anthracycline-containing induction chemotherapy at the Dana-Farber Cancer Institute from 2014 to 2022 were studied. Inclusion criteria included availability of a pre and post chemotherapy echocardiogram to assess the LVEF, pre-treatment LVEF > 50 %, as well as comprehensive diagnostic next generation sequencing assessing for the presence of myeloid mutations. The primary endpoint was the incidence of ARLVD defined as LVEF < 50 % post-induction. RESULTS: Out of 419 patients meeting inclusion criteria, 34 (8%) patients developed ARLVD. Among the 122/419 patients who did not undergo planned allogeneic stem cell transplantation (allo-SCT), ARLVD was the deciding factor for ineligibility in 4 patients (1%). Baseline cardiovascular comorbidities (hypertension, diabetes mellitus, hyperlipidemia, smoking and coronary artery disease) and cumulative anthracycline dose were not predictive of post-induction ARLVD. However, the presence of a JAK2 mutation (but not other myeloid mutations) was associated with an increased risk of ARLVD in multivariable analysis (OR 8.34, 95 % CI 1.55-39.3, p = 0.007). DISCUSSION: In a group of AML patients with normal LVEF prior to anthracycline-containing induction chemotherapy, ARLVD was infrequent and did not commonly preclude post-remission allo-SCT consolidation. Genetic predictors of ARLVD require further investigation in a larger patient cohort.

Effect of tafamidis on global longitudinal strain and myocardial work in transthyretin cardiac amyloidosis.

AIMS: In patients with transthyretin amyloid cardiomyopathy (ATTR-CM), the effect of tafamidis on myocardial function using serial speckle tracking echocardiography has not been reported. The purpose of this study was to describe the natural history of myocardial function in untreated ATTR-CM and determine the effect of tafamidis on myocardial functional parameters over 12 months of treatment. METHODS AND RESULTS: A total of 45 subjects with ATTR-CM were retrospectively studied: 23 treated with tafamidis and 22 untreated. Two-dimensional speckle tracking echocardiography was analysed at baseline and 1 year. Serial longitudinal, circumferential, and radial strain, twist, torsion, and myocardial work were measured. Over 1 year, absolute global longitudinal strain (GLS) deteriorated more in the untreated group by a median of 1.1% [inter-quartile range (IQR) 0.95] compared with 0.3% (IQR 1) in the tafamidis group (P = 0.02). Myocardial work index and efficiency also deteriorated to a greater degree: 142.5 mmHg% (IQR 197) and 4% (IQR 8), respectively, in the untreated group compared with 61.5 mmHg% (IQR 210) and 1% (IQR 7) in the tafamidis group (P = 0.04). There were no significant between group differences in left ventricular ejection fraction (LVEF), tissue Doppler velocities, circumferential or radial strain, LV twist or torsion at 1 year. The stabilization effect of tafamidis on myocardial function at 1 year did not differ according to baseline GLS, LVEF, or National Amyloidosis Centre disease stage. CONCLUSIONS: In ATTR-CM, tafamidis resulted in a lesser deterioration in GLS, myocardial work index, and efficiency over a 12-month period compared with a cohort not treated with tafamidis.

Multimodality Imaging in Cardiac Amyloidosis.

PURPOSE OF REVIEW: Cardiac amyloidosis is an increasingly recognized condition with a growing range of targeted therapies, but diagnosis requires a high index of suspicion and multimodality imaging expertise. Early diagnosis remains key to improving quality of life and survival. This article reviews the multimodality imaging approach to the diagnosis, differentiation, and prognosis of cardiac amyloidosis. RECENT FINDINGS: Recent advances in multimodality cardiac imaging have allowed for earlier diagnosis of cardiac amyloidosis resulting in earlier initiation of life-saving therapy in cases of light chain amyloidosis and life-prolonging therapy in transthyretin amyloidosis. With these advances in multimodality imaging, it is important for cardiologists and cardiac imagers to be aware of the subtleties of early disease, the appropriate diagnostic approach as well as understanding the practicalities and pitfalls that are encountered with each modality.

The role of endomyocardial biopsy in suspected myocarditis in the contemporary era: a 10-year National Transplant Centre experience.

BACKGROUND: Diagnostic endomyocardial biopsy (EMB) in patients with suspected myocarditis helps to direct therapy and guide prognosis. This study aimed to investigate the correlation between the 2007 clinical guideline indications for EMB and the presence of a diagnostic biopsy result and associated outcomes in patients with suspected myocarditis in a national quaternary referral center in a contemporary cohort. METHODS: All cases of suspected myocarditis referred to the National Cardiac Transplant Centre who underwent EMB between 2009 and 2019 were identified retrospectively through pathology records. Outcomes including subsequent need for inotrope and/or mechanical circulatory support (MCS), heart transplantation and in-hospital mortality were recorded. RESULTS: In total, 25 (68% male, mean age of 45 ± 15 years) EMBs were performed for this indication across this time period, 64% (n = 16) of which demonstrated diagnostic results, the majority (75%, n = 12) identifying acute lymphocytic myocarditis, 13% (n = 2) giant cell, one patient (6.3%) eosinophilic and one (6.3%) an immune checkpoint inhibitor myocarditis. The majority of those with histologically confirmed myocarditis had a Class I or IIa guideline indication for EMB (n = 12, 75%). The remaining 4 patients (25%), either met Class IIb criteria (n = 2) or would not have been accounted for in this guideline. The majority of patients requiring inotropes and/or MCS (n = 9/11), and/or heart transplant (n = 3/4), or who later died (n = 4/5) were in the diagnostic biopsy group. CONCLUSIONS: In this 10-year National referral sample, 75% of patients with histologically confirmed myocarditis had a Class I or IIa indication for EMB, reinforcing the usefulness of traditional guidelines in this contemporary era. However, 25% of patients with a subsequent confirmed histological diagnosis had either none or a less well-established indication for EMB, highlighting the need for clinical suspicion outside of accepted clinical scenarios.

Presentation of Severe Rheumatic Mitral Stenosis at the Peak of the COVID-19 Pandemic and the Presumptive Treatment as Severe Coronavirus Illness.

This case report describes a young female Caucasian patient with newly presenting severe mitral stenosis at the peak of the coronavirus pandemic in the Republic of Ireland. The initial presumptive diagnosis was of severe coronavirus illness. This case report highlights the importance of keeping an open mind to alternative diagnoses and examines some of the challenges in the diagnosis and management of a rare condition in the pandemic environment. This patient gained 10 kg of weight within 6 weeks of percutaneous balloon mitral valvuloplasty, highlighting the contribution of cardiac cachexia to her low body weight and demonstrating the exceptional benefit that this treatment can offer to patients. LEARNING POINTS: To highlight mitral stenosis as a cause of cardiac cachexia and to examine the benefits gained from percutaneous balloon commissurotomy.To highlight the potential for other serious conditions to masquerade as COVID-19 and the importance of keeping an open mind to diagnoses.To examine the use of bedside echocardiography in the patient presenting with presumed coronavirus illness.

Discovery of {4-[4,9-bis(ethyloxy)-1-oxo-1,3-dihydro-2H-benzo[f]isoindol-2-yl]-2-fluorophenyl}acetic acid (GSK726701A), a novel EP4 receptor partial agonist for the treatment of pain.

A novel series of EP4 agonists and antagonists have been identified, and then used to validate their potential in the treatment of inflammatory pain. This paper describes these novel ligands and their activity within a number of pre-clinical models of pain, ultimately leading to the identification of the EP4 partial agonist GSK726701A.

Piperidine-derived gamma-secretase modulators.

This Letter details the SAR of a novel series of piperidine-derived gamma-secretase modulators. Compound 10h was found to be a potent modulator in vitro, which on further profiling, was found to decrease Abeta42, increase Abeta38 and have no effect on Abeta40 levels. Furthermore, 10h demonstrated excellent pharmacokinetic parameters in the mouse, rat and dog in addition to good CNS penetration in the mouse.

GW627368X ((N-{2-[4-(4,9-diethoxy-1-oxo-1,3-dihydro-2H-benzo[f]isoindol-2-yl)phenyl]acetyl} benzene sulphonamide): a novel, potent and selective prostanoid EP4 receptor antagonist.

1. N-{2-[4-(4,9-diethoxy-1-oxo-1,3-dihydro-2H-benzo[f]isoindol-2-yl)phenyl]acetyl}benzene sulphonamide (GW627368X) is a novel, potent and selective competitive antagonist of prostanoid EP4 receptors with additional human TP receptor affinity. 2. At recombinant human prostanoid EP4 receptors expressed in HEK293 cells, GW627368X produced parallel rightward shifts of PGE2 concentration-effect (E/[A]) curves resulting in an affinity (pKb) estimate of 7.9 +/- 0.4 and a Schild slpoe not significantly different from unity. The affinity was independent of the agonist used. 4. In rings of phenylephrine precontracted piglet saphenous vein, GW627368X (30-300 nM) produced parallel rightward displacement of PGE2 E/[A] curves (pKb = 9.2 +/- 0.2; slope = 1). 4. GW627368X appears to bind to human prostanoid TP receptors but not the TP receptors of other species. In human washed platelets, GW627368X (10 microM) produced 100% inhibition of U-46619 (EC100)-induced aggregation (approximate pA2 approximately 7.0). However, in rings of rabbit and piglet saphenous vein and of guinea-pig aorta GW627368X (10 microM) did not displace U-46619 E/[A] curves indicating an affinity of < 5.0 for rabbit and guinea-pig prostanoid TP receptors. 5. In functional assays GW627368X is devoid of both agonism and antagonist affinity for prostanoid CRTH2, EP2, EP3, IP and FP receptors. At prostanoid EP1 receptors, GW627368X was an antagonist with a pA2 of 6.0, and at prostanoid IP receptors the compound increased the maximum effect of iloprost by 55%. At rabbit prostanoid EP2 receptors the pA2 of GW627368X was < 5.0. 6. In competition radioligand bioassays, GW627368X had affinity for human prostanoid EP4 and TP receptors (pKi = 7.0 +/- 0.2 (n = 10) and 6.8 (n = 2), respectively). Affinity for all other human prostanoid receptors was < 5.3. 7. GW627368X will be a valuable tool to explore the role of the prostanoid EP4 receptor in many physiological and pathological settings.