JAK2-mutant Clonal Hematopoiesis is Associated with Venous Thromboembolism.

Venous thromboembolism (VTE) is common among older individuals, but provoking factors are not identified in many cases. Patients with myeloid malignancies, especially myeloproliferative neoplasms, are at increased risk for venous thrombosis. Clonal hematopoiesis of indeterminate potential (CHIP), a precursor state to myeloid malignancies, is common among the elderly and may similarly predispose to venous thrombosis. We evaluated overall and genotype-specific associations between CHIP and prevalent and incident VTE in >400,000 samples from the UK Biobank. CHIP was modestly associated with incident VTE with a hazard ratio of 1.17 (95% confidence interval (CI) 1.09-1.3; p= 0.002) but was not significantly associated with prevalent VTE with an odds ratio of 1.02 (95% CI 0.81-1.23; p= 0.81). TET2-mutant CHIP was associated with incident VTE with a hazard ratio of 1.33 (95% CI 1.05-1.69; p= 0.02). JAK2 mutations were highly associated with both prevalent and incident VTE risk with odds ratio of 6.58 (95% CI 2.65-16.29; p= 4.7 x 10-5) and hazard ratio of 4.2 (95% CI 2.18-8.08; p= 1.7 x 10-5), respectively, consistent with the thrombophilia associated with JAK2-mutant myeloproliferative neoplasms. The association between JAK2-mutant CHIP and VTE remained significant after excluding potential undiagnosed myeloproliferative neoplasms based on laboratory parameters. Compared to heterozygous factor V Leiden and heterozygous prothrombin gene mutation, JAK2-mutant CHIP was more strongly associated with VTE but was less common. These results indicate that most individuals with CHIP do not have an altered risk of thrombosis, but that individuals with JAK2-mutant CHIP have a significantly elevated risk of VTE.

Proteasome Inhibitor-Related Cardiotoxicity: Mechanisms, Diagnosis, and Management.

PURPOSE OF REVIEW: Multiple myeloma is the second most common hematologic malignancy in the USA, with over 32,000 new cases and nearly 13,000 deaths expected in 2019. The past few decades in myeloma research have yielded significant advances, leading to the expansion of novel anti-myeloma agents. This review describes the incidence and mechanisms of cardiotoxicity for the FDA-approved proteasome inhibitors in myeloma and proposes strategies to assess and manage resultant cardiovascular adverse events. RECENT FINDINGS: Proteasome inhibition precipitates protein aggregation and alters transcriptional activation of NF-κB targets which contributes to a pro-apoptotic signaling cascade in myeloma cells. Similar effects in cardiomyocytes and vascular smooth muscle endothelium, along with off-target downregulation of autophagy and signaling alterations of nitric oxide homeostasis, may be linked to observed cardiotoxic effects. There is preliminary evidence for cardioprotective potential for rutin, dexrazoxane, and apremilast that could have clinical applicability in the future. Of the proteasome inhibitors used in clinical practice, carfilzomib is the most strongly associated with cardiotoxicity. Patients with anticipated carfilzomib treatment should undergo assessment and optimization of baseline cardiovascular risk, with close monitoring during treatment. Previous clinical trials were not specifically designed to assess proteasome inhibitor-related cardiotoxicity, creating a need for future studies to identify and risk stratify vulnerable individuals and to develop potential cardioprotective strategies in attenuating cardiac injury.

Clonal Hematopoiesis of Indeterminate Potential and Cardiovascular Disease.

PURPOSE OF REVIEW: The purpose of this review article is to summarize the preclinical and clinical evidence supporting the notion of clonal hematopoiesis of indeterminate potential (CHIP), highlight current knowledge gap, and provide future directions. RECENT FINDINGS: Epidemiological studies show that advanced age is a major risk factor for the development of cardiovascular disease (CVD) and cancer, the two leading causes of morbidity and mortality worldwide. While the negative effect of aging on CVD is a reflection of cumulative exposure to various established traditional CVD risk factors, genetic sequencing of whole blood-derived DNA recently revealed that clonal mutations in myeloid stem cells are associated with higher risks of cardiovascular events and hematopoietic malignancies. The clinical repercussions of this biological state, termed CHIP, are increasingly appreciated. Historically, CHIP has been associated with an increased risk of hematological malignancies. However, new research is showing that CHIP is also associated with an increased risk of several cardiac-related conditions, including atherosclerosis, myocardial infarction, aortic valve stenosis, and congestive heart failure. CHIP is increasingly being appreciated worldwide as a CVD risk factor, and further studies are needed to better understand the complex relationship between these two disorders.

Permanent lone atrial fibrillation and atrioventricular valve regurgitation: may the former lead to the latter?

BACKGROUND AND AIM OF THE STUDY: Atrioventricular valve regurgitation (AVVR) has been described in patients with long-standing atrial fibrillation (AF) despite normal valve anatomy and leaflet mobility. The study aim was to examine the association between permanent lone AF and AVVR. METHODS: A total of 47 patients with lone AF was studied. Patients provided information regarding the time since onset of arrhythmia, and mitral regurgitation (MR) and tricuspid regurgitation (TR) were graded using color-mapping Doppler echocardiography. AVVR was defined as any degree of valve regurgitation. Annular diameters (in mm) and atrial areas (in cm2) were measured at enddiastole, using digital analysis. RESULTS: Of the 47 patients, 19 (40%) had paroxysmal AF and 28 (60%) had permanent AF. Mild MR was present in nine of 19 patients (47%) with paroxysmal AF and in 15 of 28 (53%) with permanent AF (p = 0.68). Mild TR was identified in nine (47%) patients with paroxysmal AF, and in 16 (58%) of those with permanent AF (p = 0.08). None of the patients with paroxysmal AF had either moderate or severe AVVR. In 28 patients with permanent lone AF, significant MR and TR were detected in six (21%) and five (19%) patients, respectively. Patients with permanent lone AF had a 6.5-fold higher likelihood of having TR (p = 0.0031) and were marginally more likely to have MR (p = 0.053) compared to those with paroxysmal AF. Relative to patients with paroxysmal AF, those with permanent AF had larger atrial areas and annular diameters, while patients with TR had higher atrial areas and mitral annular diameters than those without. The mean follow up of patients with permanent AF and significant AVVR was 54 + 13 months, compared to 13 +/- 7 months for those without significant AVVR (p = 0.002). CONCLUSION: Permanent lone AF is associated with TR and, less strongly, with MR. Atrial size and mitral annular diameter are increased in patients with lone AF who have TR.

Cardiovascular Safety Assessment in Cancer Drug Development.

The development of cardiovascular toxicity attributable to anticancer drugs is a pivotal event that is associated with cardiovascular morbidity as well as with worse cancer-specific and overall outcomes. Although broad consensus exists regarding the importance of cardiovascular safety assessment in cancer drug development, real-world data suggest that cardiovascular events are significantly underestimated in oncology trials. This drug safety discrepancy has profound implications on drug development decisions, risk-benefit evaluation, formulation of surveillance and prevention protocols, and survivorship. In this article, we review the contemporary cardiovascular safety evaluation of new pharmaceuticals in hematology and oncology, spanning from in vitro pharmacodynamic testing to randomized clinical trials. We argue that cardiovascular safety assessment of anticancer drugs should be reformed and propose practical strategies, including development and validation of preclinical assays, expansion of oncology trial eligibility, incorporation of cardiovascular end points in early-phase studies, and design of longitudinal multi-institutional cardiotoxicity registries.

Artificial intelligence in medical imaging: switching from radiographic pathological data to clinically meaningful endpoints.

Artificial intelligence (AI) is a disruptive technology that involves the use of computerised algorithms to dissect complicated data. Among the most promising clinical applications of AI is diagnostic imaging, and mounting attention is being directed at establishing and fine-tuning its performance to facilitate detection and quantification of a wide array of clinical conditions. Investigations leveraging computer-aided diagnostics have shown excellent accuracy, sensitivity, and specificity for the detection of small radiographic abnormalities, with the potential to improve public health. However, outcome assessment in AI imaging studies is commonly defined by lesion detection while ignoring the type and biological aggressiveness of a lesion, which might create a skewed representation of AI's performance. Moreover, the use of non-patient-focused radiographic and pathological endpoints might enhance the estimated sensitivity at the expense of increasing false positives and possible overdiagnosis as a result of identifying minor changes that might reflect subclinical or indolent disease. We argue for refinement of AI imaging studies via consistent selection of clinically meaningful endpoints such as survival, symptoms, and need for treatment.

Cardiovascular Health and Outcomes in Cancer Patients Receiving Immune Checkpoint Inhibitors.

Whether cardiovascular (CV) disease is associated with clinical outcomes in cancer patients receiving immunotherapy is unknown. We reviewed the Mayo Clinic database for all cancer patients who received an immune checkpoint inhibitor (ICI). Multivariate logistic regression analysis, survival analyses, and Cox proportional-hazards models were formulated. Between March, 2010 and July, 2019, 3,326 patients received ICI. Mean patient age was 63.5 years (range: 16 to 96 years). In a Cox proportional-hazards model, obesity (hazard ratio [HR] 0.65, 95% confidence level [CI] 0.55 to 0.77, p < 0.001) and hypercholesterolemia (HR 0.80, 95% CI 0.72 to 0.89, p < 0.001) were associated with lower all-cause mortality while hypertension (HR 1.32, 95% CI 1.17 to 1.49, p < 0.001) and smoking (HR 1.17, 95% CI 1.06 to 1.29, p = 0.002) were associated with higher overall mortality. Among patients with lung cancer, multivariable-adjusted hazard ratios for death from any cause for beta blocker users, as compared with patients who had never used a beta blocker, were 1.39 (95% CI 1.10 to 1.76, p = 0.006). A total of 80 patients (2.4%) experienced CV immune-related adverse events. Event-related morality for ICI-induced myocarditis was 41.7% (5/12). Multivariable-adjusted hazard ratios for ICI-induced myocarditis were 5.2 (95% CI 1.4 to 18.7, p = 0.01) for history of heart failure, 4.06 (95% CI 1.15 to 14.3, p = 0.03) for history of acute coronary syndrome, and 1.07 (per each 1-year increase, 95% CI 1.01 to 1.14, p = 0.02) for age. In conclusion, our study shows that CV factors are associated with clinical outcomes in cancer patients receiving ICI and could be used to predict mortality. In patients with lung cancer, pretreatment beta blocker use is associated with higher all-cause mortality. Three clinical factors-history of heart failure, history of acute coronary syndrome, and age greater than 80 years-help identify patients at higher risk of ICI-induced myocarditis who might benefit from more intensive cardiac surveillance.

Characteristics and Outcomes of Patients Treated With Proprotein Convertase Subtilisin/Kexin Type 9 Inhibitors (The Mayo Clinic Experience).

Proprotein Convertase Subtilisin/Kexin Type 9 (PCSK9) inhibitors represent a novel addition to the lipid-lowering armamentarium. We attempted to characterize a real-world group of patients with a clinical indication for PCSK9 inhibitors and describe their clinical outcomes and adverse effect profile. A retrospective chart review was conducted, evaluating all patients referred to preventive cardiology at the Mayo Clinic (Minnesota) between September, 2015 and December, 2018 for management of severe dyslipidemia. A total of 222 patients were referred and a recommendation to start a PCSK9 inhibitor was given to 164 patients (73.9%). Of these, 28 patients (17.1%) declined the use of a PCSK9 inhibitor. A total of 136 previous authorizations were submitted. Of these applications, 96 (70.6%) were approved and 17 (12.5%) were rejected. The cohort's mean age was 64.1 years (range 39 to 91). High-intensity statins and ezetimibe were used in 50 (52.1%) and 80 (83.3%) of the treated patients. Mean pretreatment low-density lipoprotein cholesterol was 167.9 mg/dl. At a median follow-up of 19.0 months, the mean low-density lipoprotein reduction was 60.9% (range 0 to 90.3%). Higher low-density lipoprotein cholesterol percent reductions were seen in younger patients (p value 0.048), patients on high-intensity statins (p value 0.027), those with statin intolerance (p value 0.046), and individuals with a higher baseline triglycerides (p value 0.047). Two (2.1%) patients underwent coronary revascularization, and 1 (1.0%) patient was hospitalized for unstable angina. No cardiovascular deaths occurred. Adverse events were reported in 12 (12.5%) patients, and were all minor (injection site reactions, myalgias, and flu-like illness). In conclusion, our study shows an efficacy and safety profile that is concordant with previous investigations. The use of a standardized application form was associated with a high insurance approval rate.

Arterial events in cancer patients-the case of acute coronary thrombosis.

Patients with cancer are at high risk for both venous and arterial thrombotic complications. A variety of factors account for the greater thrombotic risk, including the underlying malignancy and numerous cancer-directed therapies. The occurrence of an acute thrombotic event in patients with cancer is associated with substantial morbidity and mortality. Acute coronary syndrome (ACS) represents a particularly important cardiovascular complication in cancer patients. With cardio-vascular risk factors becoming more prevalent in an aging cancer population that is surviving longer, questions pertaining to the appropriate management of vascular toxicity are likely to assume even greater value in the coming years. In this article, we review the current understanding of ACS in patients with cancer. The predisposition to thrombosis in a malignant host and the cancer treatments most commonly associated with vascular toxicity are reviewed. Risk prediction and management strategies are discussed, and discrepancies in the clinical evidence are highlighted.

Heart Failure with Preserved Ejection Fraction: Diagnosis and Management.

Heart failure with preserved ejection fraction (HFpEF) is a prevalent condition with substantial individual and societal burden. In this article, we review the current status of understanding of HFpEF, focusing on the challenges and uncertainties regarding diagnosis and treatment. We then propose a scientific roadmap to facilitate research that may translate into improved clinical outcomes.

Eliminating Cancer Stem Cells by Targeting Embryonic Signaling Pathways.

Dramatic advances have been made in the understanding of cancer over the past decade. Prime among those are better appreciation of the biology of cancer and the development of targeted therapies. Despite these improvements, however, most tumors remain refractory to anti-cancer medications and frequently recur. Cancer Stem Cells (CSCs), which in some cases express markers of pluripotency (e.g., Oct-4), share many of the molecular features of normal stem cells. These cells have been hypothesised to play a role in tumor resistance and relapse. They exhibit dependence on many primitive regulatory pathways and may be best viewed in the context of embryonic signaling pathways. In this article, we review important embryonic signaling cascades and their differential expression in CSCs. We also discuss these pathways as actionable targets for novel therapies in hopes that eliminating cancer stem cells will lead to an improvement in overall survival for patients.