Replication of genetic associations of chemotherapy-related cardiotoxicity in the adjuvant NSABP B-31 clinical trial.

Background: The cardiotoxic effects of doxorubicin, trastuzumab, and other anticancer agents are well known, but molecular genetic testing is lacking for the early identification of patients at risk for therapy-related cardiac toxicity. Methods: Using the Agena Bioscience MassARRAY system, we genotyped TRPC6 rs77679196, BRINP1 rs62568637, LDB2 rs55756123, RAB22A rs707557, intergenic rs4305714, LINC01060 rs7698718, and CBR3 rs1056892 (V244M) (previously associated with either doxorubicin or trastuzumab-related cardiotoxicity in the NCCTG N9831 trial of anthracycline-based chemotherapy ± trastuzumab) in 993 patients with HER2+ early breast cancer from the NSABP B-31 trial of adjuvant anthracycline-based chemotherapy ± trastuzumab. Association analyses were performed with outcomes of congestive heart failure (N = 29) and maximum decline in left ventricular ejection fraction (LVEF) using logistic and linear regression models, respectively, under an additive model with age, baseline LVEF, and previous use of hypertensive medications as covariates. Results: Associations of maximum decline in LVEF in the NCCTG N9831 patients did not replicate in the NSABP B-31 patients. However, TRPC6 rs77679196 and CBR3 rs1056892 were significantly associated with congestive heart failure, p < 0.05, with stronger associations observed in patients treated with chemotherapy only (no trastuzumab) or in the combined analysis of all patients relative to those patients treated with chemotherapy + trastuzumab. Conclusions: TRPC6 rs77679196 and CBR3 rs1056892 (V244M) are associated with doxorubicin-induced cardiac events in both NCCTG N9831 and NSABP B-31. Other variants previously associated with trastuzumab-related decline in LVEF failed to replicate between these studies.

Upregulation of Endothelin-1 May Predict Chemotherapy-Induced Cardiotoxicity in Women with Breast Cancer.

As survival in breast cancer patients from newer therapies increases, concerns for chemotherapy-induced cardiotoxicity (CIC) have offset some of these benefits, manifesting as a decline in left ventricular ejection fraction (LVEF). Patients receiving anthracycline-based chemotherapy followed by trastuzumab are at risk for CIC. Previous research evaluating whether clinical biomarkers predict cardiotoxicity has been inconsistent. Recently, angiotensin II type 1 receptor (ATR1) and endothelin 1 (ET1) have been shown to play a role in breast tumor growth. We evaluated ATR1 and ET1 expression in breast cancer tissue and its association with CIC. A total of 33 paraffin-embedded breast tissue specimens from women with breast cancer treated with anthracycline-based chemotherapy and trastuzumab were analyzed by immunohistochemistry (IHC) and qRT-PCR. We found that ET1 expression was increased in patients with an LVEF ≤ 50% (p = 0.032) with a lower LVEF correlating with higher ET1 expression (r = 0.377, p = 0.031). In patients with a change in LVEF of greater than 10%, greater ET1 expression was noted compared to those without a change in LVEF (p = 0.017). Increased ET1 expression in breast tumor tissue is associated with reduced LVEF. Future studies need to examine whether ET1 may be a tissue biomarker that helps predict the risk of developing CIC in women with breast cancer.

Macrophage Activation Led Acute Heart Failure Managed Successfully with Immunosuppression.

Macrophage activation leading to multi-organ dysfunction/failure has been described in various hematologic disorders like hemophagocytic lympho-histiocytosis (HLH), also known as macrophage activation syndrome (MAS) and macrophage activation like syndrome (MALS). Congestive heart failure (CHF) appears to be an uncommon manifestation of macrophage activation. This novel entity of macrophage activation-associated cytokine-mediated CHF has not been well reported in the medical literature. We report two young female patients with acute CHF secondary to macrophage activation-associated cytokine storm. An extensive diagnostic workup was negative for other etiologies, such as ischemia, myocarditis, or infections. Their clinical, laboratory, and pathologic findings did not meet the diagnostic criteria for hemophagocytic syndrome (HPS)/MAS. However, both had laboratory and pathologic findings which were consistent with macrophage activation and cytokine storm. One patient met criteria for MALS. Therapeutically, our patients were promptly treated with steroids with or without anti-cytokine therapy with rapid restoration of cardiac function. Macrophage activation-induced disease may not always fulfil the diagnostic criteria for the currently known macrophage activation disorders. We suggest that markers of macrophage activation and cytokine levels should be part of the diagnostic workup in patients with otherwise unexplained acute CHF. Additional research is warranted to further elucidate the underlying mechanism of this disorder.

Association of Genetic Variants at TRPC6 With Chemotherapy-Related Heart Failure.

Background: Our previous GWAS identified genetic variants at six novel loci that were associated with a decline in left ventricular ejection fraction (LVEF), p < 1 × 10-5 in 1,191 early breast cancer patients from the N9831 clinical trial of chemotherapy plus trastuzumab. In this study we sought replication of these loci. Methods: We tested the top loci from the GWAS for association with chemotherapy-related heart failure (CRHF) using 26 CRHF cases from N9831 and 984 patients from the Mayo Clinic Biobank which included CRHF cases (N = 12) and control groups of patients treated with anthracycline +/- trastuzumab without HF (N = 282) and patients with HF that were never treated with anthracycline or trastuzumab (N = 690). We further examined associated loci in the context of gene expression and rare coding variants using a TWAS approach in heart left ventricle and Sanger sequencing, respectively. Doxorubicin-induced apoptosis and cardiomyopathy was modeled in human iPSC-derived cardiomyocytes and endothelial cells and a mouse model, respectively, that were pre-treated with GsMTx-4, an inhibitor of TRPC6. Results: TRPC6 5' flanking variant rs57242572-T was significantly more frequent in cases compared to controls, p = 0.031, and rs61918162-T showed a trend for association, p = 0.065. The rs61918162 T-allele was associated with higher TRPC6 expression in the heart left ventricle. We identified a single TRPC6 rare missense variant (rs767086724, N338S, prevalence 0.0025% in GnomAD) in one of 38 patients (2.6%) with CRHF. Pre-treatment of cardiomyocytes and endothelial cells with GsMTx4 significantly reduced doxorubicin-induced apoptosis. Similarly, mice treated with GsMTx4 had significantly improved doxorubicin-induced cardiac dysfunction. Conclusions: Genetic variants that are associated with increased TRPC6 expression in the heart and rare TRPC6 missense variants may be clinically useful as risk factors for CRHF. GsMTx-4 may be a cardioprotective agent in patients with TRPC6 risk variants. Replication of the genetic associations in larger well-characterized samples and functional studies are required.

Precision Cardio-Oncology: a Systems-Based Perspective on Cardiotoxicity of Tyrosine Kinase Inhibitors and Immune Checkpoint Inhibitors.

Cancer therapies have been evolving from conventional chemotherapeutics to targeted agents. This has fulfilled the hope of greater efficacy but unfortunately not of greater safety. In fact, a broad spectrum of toxicities can be seen with targeted therapies, including cardiovascular toxicities. Among these, cardiomyopathy and heart failure have received greatest attention, given their profound implications for continuation of cancer therapies and cardiovascular morbidity and mortality. Prediction of risk has always posed a challenge and even more so with the newer targeted agents. The merits of accurate risk prediction, however, are very evident, e.g. facilitating treatment decisions even before the first dose is given. This is important for agents with a long half-life and high potential to induced life-threatening cardiac complications, such as myocarditis with immune checkpoint inhibitors. An opportunity to address these needs in the field of cardio-oncology is provided by the expanding repertoire of "-omics" and other tools in precision medicine and their integration in a systems biology approach. This may allow for new insights into patho-mechanisms and the creation of more precise and cost-effective risk prediction tools with the ultimate goals of improved therapy decisions and prevention of cardiovascular complications. Herein, we explore this topic as a future approach to translating the complexity of cardio-oncology to the reality of patient care.

Subaortic Membrane Papillary Fibroelastoma.

A 61-year-old male presented for an annual exam and received a transthoracic echocardiogram (TTE) which revealed a mobile mass arising from a subaortic membrane. Further investigations with a transesophageal echocardiogram (TEE) and cardiac computerized tomography angiography (CTA) confirmed the presence of a mobile 9 mm × 3 mm mass on a subaortic membrane. Cardiothoracic surgery was performed with an open operation removing the mass and subaortic membrane. Upon visual inspection, the mass was likened to a sea anemone and immunohistochemical staining performed pathologically confirmed the diagnosis of cardiac papillary fibroelastoma. This case represents the first reported example of a cardiac papillary fibroelastoma (PFE) arising from a subaortic membrane. Although PFEs are benign cardiac tumors, proper identification and consideration for excision of these lesions may be indicated to prevent thromboembolic complications.

Pulmonary arterial stiffness assessed by cardiovascular magnetic resonance imaging is a predictor of mild pulmonary arterial hypertension.

Early detection of mild pulmonary arterial hypertension (PAH) based on clinical evaluation and echocardiography remains quite challenging. In addition to enhanced right ventricular (RV) assessment, cardiac magnetic resonance (CMR) imaging may accurately reflect deleterious remodeling and increased stiffness of the central pulmonary arteries based on pulsatility, or percent change of the PA during the cardiac cycle. The purpose of this study is to assess the utility of measuring PA pulsatility by CMR as a potential early maker in PAH. We hypothesize that pulsatility may help discriminate mild PAH from normal control subjects. Consecutive patients with PAH (n = 51) were prospectively enrolled to receive same day CMR and right heart catheterization (RHC). PA stiffness indices including pulsatility, distensibility, compliance, and capacitance were calculated. Comparisons were made between patients with varying severities of PAH and normal controls (n = 18). Of the 51 subjects, 20 had mild PAH, and 31 moderate-severe based on hemodynamic criteria. PA pulsatility demonstrated a progressive decline from normal controls (53%), mild PAH (22%), to moderate-severe PAH (17%; p < 0.001). There was no difference in RV size, function or mass between mild PAH and normal controls. PA pulsatility below 40% had an excellent ability to discriminate between mild PAH and normal controls with a sensitivity of 95% and specificity of 94%. CMR assessment of PA stiffness may noninvasively detect adverse pulmonary vascular remodeling and mild PAH, and thus be a valuable tool for early detection of PAH. Trial Registration: ClinicalTrials.gov Identifier: NCT01451255; https://clinicaltrials.gov/ct2/show/NCT01451255 .

Eosinophillic Myocarditis Secondary to Metastatic Melanoma.

Eosinophilic myocarditis is a rare form of myocarditis that may manifest from cancer-mediated inflammation. A case of eosinophilic myocarditis secondary to metastatic melanoma is described; metastatic melanoma can cause a T helper type 2 lymphocyte-mediated increase in circulating levels of interleukin-5, which is known to stimulate eosinophil proliferation resulting in myocardial inflammation and fibrosis. Cardiac imaging with transesophageal echocardiography revealed a large immobile left ventricular apical thrombus. Cardiac MRI was then performed and revealed enhancing fibrosis along the endocardial surface. © RSNA, 2019 Supplemental material is available for this article.

Eosinophillic Myocarditis Secondary to Metastatic Melanoma.

Eosinophilic myocarditis is a rare form of myocarditis that may manifest from cancer-mediated inflammation. A case of eosinophilic myocarditis secondary to metastatic melanoma is described; metastatic melanoma can cause a T helper type 2 lymphocyte-mediated increase in circulating levels of interleukin-5, which is known to stimulate eosinophil proliferation resulting in myocardial inflammation and fibrosis. Cardiac imaging with transesophageal echocardiography revealed a large immobile left ventricular apical thrombus. Cardiac MRI was then performed and revealed enhancing fibrosis along the endocardial surface. © RSNA, 2019 Supplemental material is available for this article.

Von Willebrand factor multimer quantitation for assessment of cardiac lesion severity and bleeding risk.

BACKGROUND: von Willebrand factor (VWF) multimer quantitation has been utilized in the assessment of valvular heart disease, however, there is no standardized method for quantitation. We compared three methods of assessment which utilized a normal plasma control. METHODS: We analyzed 476 samples and their control plasma from 368 patients with valvular heart disease, hypertrophic cardiomyopathy, or LVAD therapy, and 27 normal subjects. VWF multimers were assessed as normalized VWF multimer ratios (NMR) of gel bands >15/2-15 (NMR15) or gel bands >10/2-10 (NMR10). Associations of VWF laboratory and multimeric assessments with cardiac lesion severity and acquired bleeding were investigated. RESULTS: Abnormal multimers were present in 78% of patients with moderate to severe hemodynamic abnormalities compared to 19% of patients with normal or mildly abnormal hemodynamics. NMR showed strong association with severe cardiac lesions (NMR15: OR 15.29, CI 9.04-27.18; NMR10: OR 14.18, CI 8.88-23.21). PFA-CADP was strongly associated with moderate to severe cardiac lesions (OR 14.91, CI 9.08-24.50). PFA-CADP and NMR15 showed excellent ability to discriminate ≥moderate (AUC 0.86, CI 0.83-0.89 and 0.83, CI 0.79-0.87 respectively) and severe cardiac lesions (AUC 0.84, CI 0.81-0.88 and 0.85, CI 0.81-0.88 respectively). NMR was less strongly associated with bleeding (OR 4.01 for NMR10, CI 2.49-6.58). CONCLUSION: Quantification of VWF multimers may provide clinical utility in circumstances where clinical estimation of cardiac lesion severity is challenging, such as with dysfunctional prosthetic valves. The presence of abnormal VWF multimers is associated with bleeding, however further quantitation provided only modest improvement in risk stratification.

Implementation of a New Guideline and Educational Sessions to Reduce Low-Value Continuous Pulse Oximetry Among Hospitalized Patients.

OBJECTIVES: The use of continuous pulse oximetry (CPOX) is ubiquitous among hospitalized patients, despite limited evidence that it improves clinical outcomes. The objective of this study was to reduce the use of CPOX among hospitalized patients in the nonintensive care unit and nonprogressive care unit settings. METHODS: This interventional trial included the creation a new local guideline for CPOX use and subsequent staff education. CPOX use, patient acuity, hospital length of stay, and code blue events were measured before and after the intervention. RESULTS: Postintervention there was a clinically significant and sustained decrease in CPOX use of 18% over 1 year. There were no significant changes postintervention in hospital length of stay or number of code blue events. CONCLUSIONS: Development of a guideline for CPOX use and staff education successfully led to a decrease in CPOX use, without an increase in hospital length of stay or code blue events.

The transition to value-based care.

Delivery of medical care is evolving rapidly worldwide. Over the past several years in the USA, there has been a rapid shift in reimbursement from a simple fee-for-service model to more complex models that attempt to link payment to quality and value. Change in any large system can be difficult, but with medicine, the transition to a value-based system has been particularly hard to implement because both quality and cost are difficult to quantify. Professional societies and other medical groups are developing different programs in an attempt to define high value care. However, applying a national standard of value for any treatment is challenging, since value varies from person to person, and the individual benefit must remain the central tenet for delivering best patient-centered medical care. Regardless of the specific operational features of the rapidly changing healthcare environment, physicians must first and foremost always remain patient advocates.

Syncope.

Syncope is common representing approximately 3% of ED visits and up to 6% of hospital admissions, with a cost close to 2 billion dollars per year. Diagnostic testing is often poorly sensitive and evaluations commonly lack a standardized approach. A mindful and systematic approach can increase sensitivity and improve diagnostic accuracy. A thorough history and physical exam is paramount, as conclusions drawn from the history and exam will guide further assessment. Developing a strategy for the first and, if necessary, subsequent tests will improve the accuracy of identifying the etiology of syncope and reduce cost. Although syncope has a favorable prognosis, identification of patients with structural heart disease is critical, as these patients are at greatest risk for mortality. Several risk scoring systems have been developed to help separate high risk from low risk patients.

A Case of 5-Fluorouracil-Induced Cardiac Arrest.

BACKGROUND: Coronary artery vasospasm after administration of fluorouracil (5-FU) is a rare complication. Commonly presenting as chest pain during or shortly after 5-FU infusions, vasospasm can place patients at risk for ventricular dysrhythmia, myocardial ischemia, and infarction. Although not fully understood, any 5-FU cardiotoxicity seems to be multifactorial, and patients with coronary artery disease and renal dysfunction may be at particular risk. CASE REPORT: A 46-year-old woman with no prior cardiovascular disease history presented with sudden-onset chest pain after initial administration of 5-FU continuous infusion therapy. The patient subsequently developed ventricular fibrillation arrest and underwent successful electrocardioversion. Coronary angiography was unremarkable for coronary stenosis or vasospasm. The presumed etiology was secondary to 5-FU cardiac toxicity. The patient was re-challenged with 5-FU therapy and developed repeat chest pain. The 5-FU was completely stopped and the patient's symptoms resolved, with no further dysrhythmic events 9 months after initial presentation. WHY SHOULD AN EMERGENCY PHYSICIAN BE AWARE OF THIS?: Patients who develop chest pain during or after 5-FU infusion should warrant strong consideration for admission and continuous cardiac monitoring for potential ventricular dysrhythmias and cardiac ischemia.

Rare Incidence of Ventricular Tachycardia and Torsades de Pointes in Hospitalized Patients With Prolonged QT Who Later Received Levofloxacin: A Retrospective Study.

OBJECTIVE: To determine the incidence of ventricular tachycardia and ventricular fibrillation in patients with prolonged corrected QT interval (QTc) who received levofloxacin through retrospective chart review at a tertiary care teaching hospital in the United States. PATIENTS AND METHODS: We selected 1004 consecutive hospitalized patients with prolonged QTc (>450 ms) between October 9, 2009 and June 12, 2012 at our institution. Levofloxacin was administered orally and/or intravenously and adjusted to renal function in the inpatient setting. The primary outcome measure was sustained ventricular tachycardia recorded electrocardiographically. RESULTS: With a median time from the start of levofloxacin use to hospital discharge (or death) of 4 days (range, 1-94 days), only 2 patients (0.2%; 95% CI, 0.0%-0.7%) experienced the primary outcome of sustained ventricular tachycardia after the initiation of levofloxacin use. CONCLUSION: In this study, the short-term risk for sustained ventricular tachycardia in patients with a prolonged QTc who subsequently received levofloxacin was very rare. These results suggest that levofloxacin may be a safe option in patients with prolonged QTc; however, studies with longer follow-up are needed.

A comparison of bleeding complications between warfarin, dabigatran, and rivaroxaban in patients undergoing cryoballoon ablation.

INTRODUCTION: In recent years, several novel anticoagulants have been approved for the prevention of thromboembolic strokes as an alternative to warfarin in patients with atrial arrhythmias. Studies have evaluated these medications in patients undergoing radiofrequency ablation, yet no data exists to evaluate the bleeding risk in patients undergoing cryoballoon ablation procedures. METHODS: Patients that underwent either cryoballoon ablation alone or with additional radiofrequency ablation over the past 3 years were included in the study. Patients were stratified into one of three subsets based on type of anticoagulation (warfarin, dabigatran, or rivaroxaban). Bleeding complications during the first 48 h and first 2 weeks following the ablation were recorded. Major complications were defined as hemorrhage requiring blood products or need for vascular intervention. Minor complications included prolonged bleeding from catheter insertion site, development of ecchymosis, or hematoma formation. Intraprocedural activated clotting times (ACT) were assessed and compared. RESULTS: A total of 217 patients met inclusion criteria of which 87 (40.1 %) patients were on warfarin, 90 (41.5 %) patients on dabigatran, and 40 (18.4 %) patients on rivaroxaban. The overall bleeding complication rate was 12.0 %. All complications occurred within the first 48 h post-ablation. Nine (10.3 %) complications occurred in the warfarin subset, ten (11.1 %) in the rivaroxaban subset, and seven (17.5 %) in the dabigatran subset (p = 0.49). The warfarin and dabigatran subsets had higher average ACT levels (424.9 versus 406.5) compared to the rivaroxaban subset (393.4; p < 0.01). Subanalyses found no difference in bleeding complications based on procedure type. CONCLUSION: Bleeding complications post-ablation were similar for warfarin, dabigatran, and rivaroxaban in patients undergoing cryoballoon ablation. Compared with radiofrequency ablation, cryoablation does not place patients at an increased bleeding risk.