Molecular mechanisms of anthracycline cardiovascular toxicity.

Anthracyclines are effective chemotherapeutic agents, commonly used in the treatment of a variety of hematologic malignancies and solid tumors. However, their use is associated with a significant risk of cardiovascular toxicities and may result in cardiomyopathy and heart failure. Cardiomyocyte toxicity occurs via multiple molecular mechanisms, including topoisomerase II-mediated DNA double-strand breaks and reactive oxygen species (ROS) formation via effects on the mitochondrial electron transport chain, NADPH oxidases (NOXs), and nitric oxide synthases (NOSs). Excess ROS may cause mitochondrial dysfunction, endoplasmic reticulum stress, calcium release, and DNA damage, which may result in cardiomyocyte dysfunction or cell death. These pathophysiologic mechanisms cause tissue-level manifestations, including characteristic histopathologic changes (myocyte vacuolization, myofibrillar loss, and cell death), atrophy and fibrosis, and organ-level manifestations including cardiac contractile dysfunction and vascular dysfunction. In addition, these mechanisms are relevant to current and emerging strategies to diagnose, prevent, and treat anthracycline-induced cardiomyopathy. This review details the established and emerging data regarding the molecular mechanisms of anthracycline-induced cardiovascular toxicity.

Hypermorphic mutation of the voltage-gated sodium channel encoding gene Scn10a causes a dramatic stimulus-dependent neurobehavioral phenotype.

The voltage-gated sodium channel Na(v)1.8 is known to function in the transmission of pain signals induced by cold, heat, and mechanical stimuli. Sequence variants of human Na(v)1.8 have been linked to altered cardiac conduction. We identified an allele of Scn10a encoding the α-subunit of Na(v)1.8 among mice homozygous for N-ethyl-N-nitrosourea-induced mutations. The allele creates a dominant neurobehavioral phenotype termed Possum, characterized by transient whole-body tonic immobility induced by pinching the skin at the back of the neck ("scruffing"). The Possum mutation enhanced Na(v)1.8 sodium currents and neuronal excitability and heightened sensitivity of mutants to cold stimuli. Striking electroencephalographic changes were observed concomitant with the scruffing-induced behavioral change. In addition, electrocardiography demonstrated that Possum mice exhibited marked sinus bradycardia and R-R variability upon scruffing, abrogated by infusion of atropine. However, atropine failed to prevent or mitigate the tonic immobility response. Hyperactive sodium conduction via Na(v)1.8 thus leads to a complex neurobehavioral phenotype, which resembles catatonia in schizophrenic humans and tonic immobility in other mammals upon application of a discrete stimulus; no other form of mechanosensory stimulus could induce the immobility phenotype. Our data confirm the involvement of Na(v)1.8 in transducing pain initiated by cold and additionally implicate Na(v)1.8 in previously unknown functions in the central nervous system and heart.

Repotrectinib in a Patient With NTRK Fusion-Positive Pancreatic Carcinoma and Congenital Long QT Syndrome.

Repotrectinib in a patient with NTRK fusion-positive pancreatic carcinoma and congenital long QT syndrome.

Regional Strain of Right Ventricle From Computed Tomography Improves Risk Stratification of Right Ventricle Failure.

Patients who undergo implantation of a left ventricular assist device (LVAD) are at a high risk for right ventricular failure (RVF), presumably due to poor right ventricular (RV) function before surgery. Cine computerized tomography (cineCT) can be used to evaluate RV size, function, and endocardial strain. However, CT-based strain measures in patients undergoing workup for LVAD implantation have not been evaluated. We quantified RV strain in the free wall (FW) and septal wall (SW) in patients with end-stage heart failure using cineCT. Compared to controls, both FW and SW strains were significantly impaired in heart failure patients. The difference between FW and SW strains predicted RV failure after LVAD implantation (area-under-the curve [AUC] = 0.82). Cine CT strain can be combined with RV volumetry to risk-stratify patients. In our study, patients with preserved RV volumes and poor strain had a higher rate of RV failure (57%), than those with preserved volume and preserved strain (0%). This suggests that CT could improve risk stratification of patients receiving LVADs and that strain metrics were particularly useful in risk-stratifying patients with preserved RV volumes.

Predictors and Risk Score for Immune Checkpoint-Inhibitor-Associated Myocarditis Severity.

Background: Immune-checkpoint inhibitors (ICI) are associated with life-threatening myocarditis but milder presentations are increasingly recognized. The same autoimmune process that causes ICI-myocarditis can manifest concurrent generalized myositis, myasthenia-like syndrome, and respiratory muscle failure. Prognostic factors for this "cardiomyotoxicity" are lacking. Methods: A multicenter registry collected data retrospectively from 17 countries between 2014-2023. A multivariable cox regression model (hazard-ratio(HR), [95%confidence-interval]) was used to determine risk factors for the primary composite outcome: severe arrhythmia, heart failure, respiratory muscle failure, and/or cardiomyotoxicity-related death. Covariates included demographics, comorbidities, cardio-muscular symptoms, diagnostics, and treatments. Time-dependent covariates were used and missing data were imputed. A point-based prognostic risk score was derived and externally validated. Results: In 748 patients (67% male, age 23-94), 30-days incidence of the primary composite outcome, cardiomyotoxic death, and overall death were 33%, 13%, and 17% respectively. By multivariable analysis, the primary composite outcome was associated with active thymoma (HR=3.60[1.93-6.72]), presence of cardio-muscular symptoms (HR=2.60 [1.58-4.28]), low QRS-voltage on presenting electrocardiogram (HR for ≤0.5mV versus >1mV=2.08[1.31-3.30]), left ventricular ejection fraction (LVEF) <50% (HR=1.78[1.22-2.60]), and incremental troponin elevation (HR=1.86 [1.44-2.39], 2.99[1.91-4.65], 4.80[2.54-9.08], for 20, 200 and 2000-fold above upper reference limit, respectively). A prognostic risk score developed using these parameters showed good performance; 30-days primary outcome incidence increased gradually from 3.9%(risk-score=0) to 81.3%(risk-score≥4). This risk-score was externally validated in two independent French and US cohorts. This risk score was used prospectively in the external French cohort to identify low risk patients who were managed with no immunosuppression resulting in no cardio-myotoxic events. Conclusions: ICI-myocarditis can manifest with high morbidity and mortality. Myocarditis severity is associated with magnitude of troponin, thymoma, low-QRS voltage, depressed LVEF, and cardio-muscular symptoms. A risk-score incorporating these features performed well. Trial registration number: NCT04294771 and NCT05454527.

Etiology of pulmonary hypertension in multiple myeloma: A case series and literature review.

BACKGROUND: Multiple myeloma is often complicated by pulmonary hypertension through a variety of mechanisms. These mechanisms include pulmonary hypertension (PH) due to concomitant cardiac amyloid, high output heart failure due to anemia or lytic bone lesions, chronic thromboembolic pulmonary hypertension (CTEPH), toxicity from medications to treat multiple myeloma, and congestive heart failure. This case series highlights the various mechanisms through which multiple myeloma patients develop pulmonary hypertension. OBJECTIVES: To identify the etiologies of pulmonary hypertension and their management among multiple myeloma patients treated at University of California San Diego. METHODS: A retrospective chart review was performed to identify patients with multiple myeloma and pulmonary hypertension who were evaluated at the University of California San Diego between July 2013 and July 2021. Patients also required a right heart catheterization to be included. Demographics, comorbidities, clinical course, and etiology of pulmonary hypertension were obtained from chart review. RESULTS: There were 11 patients included. Of the 11 patients described, two had PH due to cardiac amyloid, one had PH due to high output heart failure, one had PH due to CTEPH, two had pulmonary arterial hypertension due to medications (carfilzomib), and five had PH due to congestive heart failure. The right heart catheterization and echocardiogram findings of the various mechanisms of PH in multiple myeloma are described. CONCLUSIONS: Pulmonary hypertension in multiple myeloma is a common finding that necessitates further evaluation. The initial evaluation should include an echocardiogram and thorough medication review. Further diagnostic testing should be guided by the patient's history and can include right heart catheterization, cardiac biopsy, ventilation-perfusion scan, and bone scan.

Prognostic Value of Global Longitudinal Strain in Patients With Heart Failure With Improved Ejection Fraction.

OBJECTIVES: The authors sought to determine whether global longitudinal strain (GLS) is independently associated with the natural history of patients with heart failure (HF) with improved ejection fraction (HFimpEF). BACKGROUND: Left ventricular (LV) ejection fraction (EF) often improves in patients with reduced EF. The clinical course of patients with HFimpEF, however, is quite variable. GLS, a sensitive indicator of LV systolic function, could help predict risk of future events in this population. METHODS: Retrospective analysis of HF patients with LVEF >40% on index echocardiogram who had LVEF <40% on initial study and improvement of ≥10%. GLS was assessed by 2-dimensional speckle-tracking software on index echocardiography. Primary outcome was time to first occurrence of cardiovascular mortality or HF hospitalization/emergency treatment. RESULTS: Of the 289 patients with HFimpEF, median absolute values of GLS (aGLS) and LVEF from index echocardiography were 12.7% (IQR: 10.8%-14.7%) and 52% (IQR: 46%-58%), respectively. Over 53 months following index echocardiography, the primary endpoint occurred less frequently in patients with aGLS above the median than below it (21% vs 34%; P = 0.014); HR of 0.51; 95% CI: 0.33-0.81; P = 0.004. When assessed as a continuous variable, each 1% increase in aGLS on index echocardiogram was associated with a lower likelihood of the composite endpoint; HR of 0.86; 95% CI: 0.79-0.93; P < 0.001, an association that persisted after multivariable adjustment; HR 0.90; 95% CI: 0.82-0.97; P = 0.01. Lower aGLS was associated with increased likelihood of deterioration in LVEF. CONCLUSIONS: In patients with HFimpEF, GLS is a strong predictor for future HF events and deterioration in cardiac function.

Real-World Persistence and Time to Next Treatment With Ibrutinib in Patients With Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma Including Patients at High Risk for Atrial Fibrillation or Stroke.

BACKGROUND: Atrial fibrillation (AF) is a recognized adverse consequence associated with all Bruton's tyrosine kinase inhibitors used to treat chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL); however, real-world time to discontinuation (TTD) and time to next treatment (TTNT) of CLL/SLL patients with a high baseline AF/stroke risk remain unknown. MATERIALS AND METHODS: Patients with CLL/SLL from a nationwide electronic health record-derived database (February 12, 2013-January 31, 2021) initiating first-line (1L) or second or later-line (2L+) treatment with ibrutinib or other regimens on or after February 12, 2014 (index date) were analyzed. Kaplan-Meier survival analysis was used to assess TTD and TTNT among all patients, patients with high AF risk (CHARGE-AF risk score ≥10.0%), and patients at high risk of stroke (CHA2DS2-VASc risk score ≥3 [females] or ≥2 [males]). RESULTS: In 1L/2L+, 2190/1851 patients received ibrutinib and 4388/4135, were treated with other regimens. Median TTD for ibrutinib was similar regardless of AF/stroke-related risk (1L: all patients, 15.7 months; high AF risk, 11.7 months; high stroke risk, 13.7 months; similar results in 2L+). Median TTNT was significantly longer for ibrutinib vs. other regimens (1L: not reached vs. 45.9 months; 2L+: not reached vs. 23.6 months; both P < .05), including among those with high AF/stroke risk. TTNT was similar between all patients and high-risk cohorts in 1L and 2L+ (all P > .05). CONCLUSION: This study highlights that elevated baseline AF/stroke-related risk does not adversely impact TTD and TTNT outcomes associated with ibrutinib use. Additionally, TTNT was significantly longer for patients treated with ibrutinib vs. other regimens.

Carfilzomib-associated pulmonary arterial hypertension in multiple myeloma.

Drug-induced pulmonary arterial hypertension (PAH) is constantly evolving as new drugs are developed. Carfilzomib is a recently approved therapy for relapsed and refractory multiple myeloma. While it has been associated with cardiovascular adverse events, such as ischemic heart disease and heart failure, PAH has not been a well-described side effect. We present two patients who developed PAH associated with initiation of carfilzomib. They both initially presented with severe dyspnea, had elevated right ventricular systolic pressure on transthoracic echocardiography and ultimately underwent right heart catheterization. With discontinuation of carfilzomib, both patients had improvement in hemodynamics. However, one patient required initiation of PAH-targeted therapies and has had worsening right ventricular function again despite permanent discontinuation of carfilzomib. It is important to recognize the association between carfilzomib and PAH. Echocardiography can be an important initial screening tool. PAH from carfilzomib therapy may be reversible, especially if diagnosed early; however, extended follow-up is essential.

Automated cardiac volume assessment and cardiac long- and short-axis imaging plane prediction from electrocardiogram-gated computed tomography volumes enabled by deep learning.

AIMS: To develop an automated method for bloodpool segmentation and imaging plane re-slicing of cardiac computed tomography (CT) via deep learning (DL) for clinical use in coronary artery disease (CAD) wall motion assessment and reproducible longitudinal imaging. METHODS AND RESULTS: One hundred patients who underwent clinically indicated cardiac CT scans with manually segmented left ventricle (LV) and left atrial (LA) chambers were used for training. For each patient, long-axis (LAX) and short-axis planes were manually defined by an imaging expert. A DL model was trained to predict bloodpool segmentations and imaging planes. Deep learning bloodpool segmentations showed close agreement with manual LV [median Dice: 0.91, Hausdorff distance (HD): 6.18 mm] and LA (Dice: 0.93, HD: 7.35 mm) segmentations and a strong correlation with manual ejection fraction (Pearson r: 0.95 LV, 0.92 LA). Predicted planes had low median location (6.96 mm) and angular orientation (7.96 ° ) errors which were comparable to inter-reader differences (P > 0.71). 84-97% of DL-prescribed LAX planes correctly intersected American Heart Association segments, which was comparable (P > 0.05) to manual slicing. In a test cohort of 144 patients, we evaluated the ability of the DL approach to provide diagnostic imaging planes. Visual scoring by two blinded experts determined ≥94% of DL-predicted planes to be diagnostically adequate. Further, DL-enabled visualization of LV wall motion abnormalities due to CAD and provided reproducible planes upon repeat imaging. CONCLUSION: A volumetric, DL approach provides multiple chamber segmentations and can re-slice the imaging volume along standardized cardiac imaging planes for reproducible wall motion abnormality and functional assessment.

Inhibition of Coxsackievirus-associated dystrophin cleavage prevents cardiomyopathy.

Heart failure in children and adults is often the consequence of myocarditis associated with Coxsackievirus (CV) infection. Upon CV infection, enteroviral protease 2A cleaves a small number of host proteins including dystrophin, which links actin filaments to the plasma membrane of muscle fiber cells (sarcolemma). It is unknown whether protease 2A-mediated cleavage of dystrophin and subsequent disruption of the sarcolemma play a role in CV-mediated myocarditis. We generated knockin mice harboring a mutation at the protease 2A cleavage site of the dystrophin gene, which prevents dystrophin cleavage following CV infection. Compared with wild-type mice, we found that mice expressing cleavage-resistant dystrophin had a decrease in sarcolemmal disruption and cardiac virus titer following CV infection. In addition, cleavage-resistant dystrophin inhibited the cardiomyopathy induced by cardiomyocyte-restricted expression of the CV protease 2A transgene. These findings indicate that protease 2A-mediated cleavage of dystrophin is critical for viral propagation, enteroviral-mediated cytopathic effects, and the development of cardiomyopathy.

High-frequency epigenetic repression and silencing of retroviruses can be antagonized by histone deacetylase inhibitors and transcriptional activators, but uniform reactivation in cell clones is restricted by additional mechanisms.

Integrated retroviral DNA is subject to epigenetic gene silencing, but the viral and host cell properties that influence initiation, maintenance, and reactivation are not fully understood. Here we describe rapid and high-frequency epigenetic repression and silencing of integrated avian sarcoma virus (ASV)-based vector DNAs in human HeLa cells. Initial studies utilized a vector carrying the strong human cytomegalovirus (hCMV) immediate-early (IE) promoter to drive expression of a green fluorescent protein (GFP) reporter gene, and cells were sorted into two populations based on GFP expression [GFP(+) and GFP(-)]. Two potent epigenetic effects were observed: (i) a very broad distribution of GFP intensities among cells in the GFP(+) population as well as individual GFP(+) clones and (ii) high-frequency GFP reporter gene silencing in GFP(-) cells. We previously showed that histone deacetylases (HDACs) can associate with ASV DNA soon after infection and may act to repress viral transcription at the level of chromatin. Consistent with this finding, we report here that treatment with the histone deacetylase inhibitor trichostatin A (TSA) induces GFP activation in GFP(-) cells and can also increase GFP expression in GFP(+) cells. In the case of the GFP(-) populations, we found that after removal of TSA, GFP silencing was reestablished in a subset of cells. We used that finding to enrich for stable GFP(-) cell populations in which viral GFP reporter expression could be reactivated by TSA; furthermore, we found that the ability to isolate such populations was independent of the promoter driving the GFP gene. In such enriched cultures, hCMV IE-driven, but not the viral long terminal repeat-driven, silent GFP reporter expression could be reactivated by the transcriptional activator prostratin. Microscopy-based studies using synchronized cells revealed variegated reactivation in cell clones, indicating that secondary epigenetic effects can restrict reactivation from silencing. Furthermore we found that entry into S phase was not required for reactivation. We conclude that HDACs can act rapidly to initiate and maintain promoter-independent retroviral epigenetic repression and silencing but that reactivation can be restricted by additional mechanisms.

Genome-wide analyses of avian sarcoma virus integration sites.

The chromosomal features that influence retroviral integration site selection are not well understood. Here, we report the mapping of 226 avian sarcoma virus (ASV) integration sites in the human genome. The results show that the sites are distributed over all chromosomes, and no global bias for integration site selection was detected. However, RNA polymerase II transcription units (protein-encoding genes) appear to be favored targets of ASV integration. The integration frequency within genes is similar to that previously described for murine leukemia virus but distinct from the higher frequency observed with human immunodeficiency virus type 1. We found no evidence for preferred ASV integration sites over the length of genes and immediate flanking regions. Microarray analysis of uninfected HeLa cells revealed that the expression levels of ASV target genes were similar to the median level for all genes represented in the array. Although expressed genes were targets for integration, we found no preference for integration into highly expressed genes. Our results provide a more detailed description of the chromosomal features that may influence ASV integration and support the idea that distinct, virus-specific mechanisms mediate integration site selection. Such differences may be relevant to viral pathogenesis and provide utility in retroviral vector design.