Genome sequences of actinobacteriophages JorRay, Blocker23, Nibbles, and OlgasClover.

JorRay, Blocker23, Nibbles, and OlgasClover are actinobacteriophages belonging to clusters G1, B2, CT, and DJ, respectively. JorRay and Blocker23 were identified in host bacterium Mycobacterium smegmatis mc2155. Nibbles and OlgasClover were identified in host bacterium Gordonia rubripertincta NRRL B-16540.

Mitral Annulus Calcium Score in Patients With Calcific Mitral Stenosis Undergoing Invasive Hemodynamic Assessment.

BACKGROUND: Aortic valve calcium score is associated with hemodynamic severity of aortic stenosis. Whether this association is present in calcific mitral stenosis remains unknown. METHODS AND RESULTS: This study was a retrospective analysis of consecutive patients with mitral stenosis secondary to mitral annular calcification (MAC) undergoing transseptal catheterization. All patients underwent invasive mitral valve assessment via direct left atrial and left ventricular pressure measurement. Computed tomography within 1 year of cardiac catheterization and with adequate visualization of the mitral annulus was included. MAC calcium score quantification by Agatston method was obtained offline using dedicated software (Aquarius, TeraRecon, V.4). Median patient age was 66.9±11.2 years, 47% of patients were women, 50% had coronary artery disease, 40% had atrial fibrillation, 47% had prior cardiac surgery, and 33% had prior chest radiation. Median diastolic mitral valve gradient was 9.4±3.4 mm Hg on echocardiography and 8.5±4 mm Hg invasively. Invasive median mitral valve area using the Gorlin formula was 1.87±0.9 cm2. Median MAC calcium score for the cohort was 7280±7937 Hounsfield units. MAC calcium score correlated with the presence of atrial fibrillation (P=0.02) but was not associated with other comorbidities. There was no correlation between MAC calcium score and mitral valve area (r=0.07; P=0.6) or mitral valve gradient (r=-0.03; P=0.8). CONCLUSIONS: MAC calcium score did not correlate with invasively measured mitral valve gradient and mitral valve area in patients with MAC-related mitral stenosis, suggesting that calcium score should not be used as a surrogate for invasive hemodynamic parameters.

Percutaneous Removal of Left Atrial Myxoma: The FLORIDA Procedure.

Surgical resection has been the treatment of choice for cardiac myxomas, but older age and comorbidities relegate many patients to observation. Pure percutaneous removal of left atrial myxomas is both intriguing and challenging. We report a successful percutaneous technique for removal of left atrial cardiac myxoma in a nonsurgical candidate. (Level of Difficulty: Advanced.).

Impact of Pulmonary Hypertension Hemodynamic Phenotype on Incident Atrial Fibrillation.

INTRODUCTION: Atrial fibrillation/flutter (AF) is common among patients with pulmonary hypertension (PH) and is associated with poor clinical outcomes. AF has been shown to occur more commonly among patients with postcapillary PH, although AF also occurs among patients with precapillary PH. The goal of this study was to evaluate the independent impact of PH hemodynamic phenotype on incident AF among patients with PH. METHODS: We retrospectively identified 262 consecutive patients, without a prior diagnosis of atrial arrhythmias, seen at the PH clinic at Mayo Clinic, Florida, between 1997 and 2017, who had right heart catheterization and echocardiography performed, with follow-up for outcomes through 2021. Kaplan-Meier analysis and Cox-proportional hazards regression modeling were used to evaluate the independent effect of PH hemodynamic phenotype on incident AF. RESULTS: Our study population was classified into two broad PH hemodynamic groups: precapillary (64.9%) and postcapillary (35.1%). The median age was 59.5 years (Q1: 48.4, Q3: 68.4), and 72% were female. In crude models, postcapillary PH was significantly associated with incident AF (HR 2.17, 95% CI: 1.26-3.74, p = 0.005). This association was lost following multivariable adjustment, whereas left atrial volume index remained independently associated with incident AF (aHR 1.30, 95% CI: 1.09-1.54, p = 0.003). CONCLUSION: We found PH hemodynamic phenotype was not significantly associated with incident AF in our patient sample; however, echocardiographic evidence of left atrial remodeling appeared to have a greater impact on AF development. Larger studies are needed to validate these findings and identify potential modifiable risk factors for AF in this population.

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.

Cardio-Oncology for the Primary Care Provider.

Cardiovascular disease is a major cause of mortality among oncologic patients. As cancer therapies continue to evolve and advance, cancer survival rates have been increasing and so has the burden of cardiovascular disease within this population. For this reason, cardio-oncology plays an important role in promoting multidisciplinary care with the primary care provider, oncology, and cardiology. In this review, we discuss the roles of different providers, strategies to monitor patients receiving cardiotoxic therapies, and summarize cancer therapy class-specific toxicities. Continued collaboration among providers and ongoing research related to cardiotoxic cancer therapies will enable patients to receive maximal, evidence-based, comprehensive care.

Right Atrial Mass Biopsy Using Endobronchial Forceps.

A 72-year-old male with past medical history of complete heart block status post pacemaker in 2019, renal cell carcinoma, and thyroid cancer presented with a 4-cm right atrial mass incidentally found on routine transthoracic echocardiography. Cardiovascular computed tomography angiogram revealed an infiltrative mildly enhancing soft-tissue density along the right and left atrioventricular grooves, anterior interventricular groove, interatrial septum, free wall of the right ventricle, and right atria. Transesophageal echocardiography at the time of the cardiac biopsy revealed a heterogeneous mass extending along the interatrial septum into the superior vena cava, which appeared partially occluded, as well as probable involvement of the aortic root. After several attempts with traditionally used devices, an endobronchial alligator forceps was used to biopsy the right atrial mass under intracardiac echocardiographic guidance, with no complications.

Association of Neurohormonal Antagonists on Incident Cardiotoxicity in Patients With Breast Cancer.

Cardiovascular disease is the leading cause of mortality among breast cancer survivors. Anthracyclines and trastuzumab have been associated with an increased risk of cardiotoxicity, requiring close follow-up for signs of clinical heart failure or asymptomatic left ventricular systolic dysfunction. Whether neurohormonal antagonism with angiotensin-converting enzyme inhibitor (ACE-I), angiotensin receptor blockers (ARBs), or ß-blockers can prevent the development of chemotherapy-induced cardiomyopathy in this population remains unknown. We studied 459 women who were diagnosed with breast cancer at our medical center from January 2014 to December 2021 and evaluated baseline characteristics, oncologic treatment, and outcomes. The primary end point was the development of cardiotoxicity, defined as symptomatic decline in ejection fraction of ≥5% below 55% or an asymptomatic decline of ≥10% after treatment with chemotherapy. Patients who were exposed to neurohormonal antagonists were more likely to have hypertension, hyperlipidemia, and diabetes. There was an increased risk of cardiotoxicity noted for patients who were older (hazard ratio [HR] 1.04, 95% confidence interval [CI] 1.01 to 1.1), smokers within the past 10 years (HR 2.54, 95% CI 1.41 to 4.6), or who received a combination of both trastuzumab and anthracycline therapy (HR 2.52, 95% CI 1.01 to 6.3). Over a median follow-up of 12 months, there were no significant protective benefits noted for patients who were taking ACE-I/ARBs (HR 0.49, 95% CI 0.17 to 1.4), ß-blockers (HR 0.50, 95% CI 0.16 to 1.6), or both (HR 1.30, 95% CI 0.44 to 3.9). In conclusion, previous use of ACE-I/ARBs and ß-blockers, separately or in combination, was not associated with a reduction in the development of cardiotoxicity in patients receiving anthracycline or trastuzumab therapies. Older age, smoking, and combination chemotherapy were found to be associated with an increased risk.

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.

Cardio-Oncology Education and Training: JACC Council Perspectives.

The innovative development of cancer therapies has led to an unprecedented improvement in survival outcomes and a wide array of treatment-related toxicities, including those that are cardiovascular in nature. Aging of the population further adds to the number of patients being treated for cancer, especially those with comorbidities. Such pre-existing and developing cardiovascular diseases pose some of the greatest risks of morbidity and mortality in patients with cancer. Addressing the complex cardiovascular needs of these patients has become increasingly important, resulting in an imperative for an intersecting discipline: cardio-oncology. Over the past decade, there has been a remarkable rise of cardio-oncology clinics and service lines. This development, however, has occurred in a vacuum of standard practice and training guidelines, although these are being actively pursued. In this council perspective document, the authors delineate the scope of practice in cardio-oncology and the proposed training requirements, as well as the necessary core competencies. This document also serves as a roadmap toward confirming cardio-oncology as a subspecialty in medicine.

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.

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.

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 .

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.