Echocardiographic Differences in Women Across Subtypes of Hypertensive Disorders of Pregnancy.

Background: Hypertensive disorders of pregnancy (HDP) can be classified into gestational hypertension, preeclampsia (PRE), and chronic hypertension with superimposed preeclampsia (SPE). Objectives: The purpose of this study was to retrospectively examine the echocardiographic differences in biventricular structure and function in 3 HDP groups of women in comparison to normotensive pregnant controls. Methods: Women with an echocardiogram during or within the first year of pregnancy were identified within our integrated health network. Exclusion criteria included age <18 years, diagnosis of pulmonary embolism, malignancy, autoimmune disease, and structural heart disease. Results: We identified a total of 706 subjects (cases: n = 427, normotensive controls: n = 279). Cases were divided into 3 groups: gestational hypertension (n = 57), PRE (n = 291), and SPE (n = 79). In adjusted analyses, echocardiographic parameters demonstrated a graded difference in left ventricular (LV) mass index, relative wall thickness, mitral inflow E, mitral inflow A, septal e', lateral e', E/e', left atrial volume index, tricuspid velocity, and lateral e' velocities with the most profound findings noted in the SPE group. Specifically, adjusted LV mass index (adjusted ß = 14.45, 95% CI: 9.00-19.90) and E/e' (adjusted ß = 2.97, 95% CI: 2.27-3.68) was highest in the SPE group in comparison to controls (P < 0.001). Conclusions: LV remodeling and diastolic filling abnormalities are more common in HDP and are most evident in SPE and PRE. Echocardiography during or immediately after pregnancy may be useful in these high-risk women to identify these abnormalities. The long-term implications of these echocardiographic abnormalities require further study.

Association between diseases of despair and atherosclerotic cardiovascular disease among insured adults in the USA: a retrospective cohort study from 2017 to 2021.

OBJECTIVES: To assess associations between diseases of despair (DoD) and incident atherosclerotic cardiovascular disease (ASCVD) among insured adults in the USA. DESIGN: Retrospective cohort study. SETTING: Highmark insurance claims data in the USA from 2017 to 2021. PARTICIPANTS: Adults with at least 10 months of continuous insurance enrolment, no record of ASCVD in the 2016 baseline year and no missing data on study variables. PRIMARY AND SECONDARY OUTCOME MEASURES: Cox proportional hazard regression was used to calculate crude and adjusted hazard ratios (HR) and 95% confidence intervals (CI) to assess risk of ASCVD (composite of ischaemic cardiomyopathy, non-fatal ischaemic stroke, peripheral arterial disease or non-fatal acute myocardial infarction) by baseline DoD overall, and by the component conditions comprising DoD (alcohol-related disorders, substance-related disorders, suicidality) individually and in combination. RESULTS: The DoD-exposed group had an age-adjusted rate of 20.5 ASCVD events per 1000 person-years, compared with 11.7 among the unexposed. In adjusted models, overall DoD was associated with increased risk of incident ASCVD (HR 1.42, 95% CI 1.36 to 1.47). Individually and in combination, component conditions of DoD were associated with higher risk for ASCVD relative to no DoD. Substance-related disorders were associated with 50% higher risk of incident ASCVD (HR 1.5, 95% CI 1.41 to 1.59), alcohol-related disorders and suicidality/intentional self-harm were associated with 33% and 30% higher risk, respectively (HR 1.33, 95% CI 1.26 to 1.41; HR 1.30, 95% CI 1.11 to 1.52). Co-occurring DoD components conferred higher risk still. The highest risk combination was substance-related disorders+suicidality (HR 2.01, 95% CI 1.44 to 2.82). CONCLUSIONS: Among this cohort of insured adults, documented DoD was associated with increased ASCVD risk. Further research to understand and address cardiovascular disease prevention in those with DoD could reduce costs, morbidity and mortality. Further examination of overlapping structural factors that may be contributing to concurrent rises in ASCVD and DoD in the USA is needed.

Temporal trends in cardiovascular outcomes and costs among patients with type 2 diabetes.

BACKGROUND: Type 2 diabetes (T2D) is a strong risk factor for cardiovascular (CV) disease. CV outcomes in T2D have generally been improving over time but recent data from the US suggest attenuation of trends in older adults with reversal of trends in younger adults. However, published data are only reported through 2015. OBJECTIVES: To quantify trends over time in CV outcomes from 2001 to 2018, and describe changes over time in health care costs in T2D. METHODS: This retrospective cohort study incorporated data from a regional health insurance plan. Study outcomes included acute myocardial infarction (AMI), ischemic stroke, hemorrhagic stroke, heart failure hospitalization (HFH), percutaneous coronary intervention, coronary artery bypass surgery, and all-cause mortality. Poisson regression estimated rate ratios across the entire 17-year study period (RR17). RESULTS: Among 79,392 T2D members tracked on average 4.1 years, overall trends in AMI (RR17 = 0.69; 95% CI: 0.64, 0.74), HFH (RR17 = 0.82; 0.79, 0.86), and all-cause mortality (RR17 = 0.87; 0.84, 0.91) improved while ischemic stroke (RR17 = 2.36; 2.16, 2.57) worsened. For AMI, HFH, and all-cause mortality, trends in older age groups were significantly better than in younger age groups (interaction P-values < .001). Health care costs related to pharmaceuticals (+15%/year) and emergency department (ED) visits (>15%/year) increased at faster rates than other utilization metrics (+10%/year). CONCLUSIONS: In T2D, overall trends in most CV outcomes improved but smaller improvements or worsening trends were observed in younger patients. Health care costs accelerated at faster rates for medications and ED visits.

Association between the diagnostic classification of newly diagnosed coronary artery disease and future heart failure development.

OBJECTIVE: The first clinical manifestation of coronary artery disease (CAD) varies widely from unheralded myocardial infarction (MI) to mild, incidentally detected disease. The primary objective of this study was to quantify the association between different initial CAD diagnostic classifications and future heart failure. METHODS: This retrospective study incorporated the electronic health record of a single integrated health care system. Newly diagnosed CAD was classified into a mutually exclusive hierarchy as MI, CAD with coronary artery bypass graft (CABG), CAD with percutaneous coronary intervention, CAD only, unstable angina, and stable angina. An acute CAD presentation was defined when the diagnosis was associated with a hospital admission. New heart failure was identified after the CAD diagnosis. RESULTS: Among 28 693 newly diagnosed CAD patients, initial presentation was acute in 47% and manifested as MI in 26%. Within 30 days of CAD diagnosis, MI [hazard ratio (HR) = 5.1; 95% confidence interval: 4.1-6.5] and unstable angina (3.2; 2.4-4.4) classifications were associated with the highest heart failure risk (compared to stable angina), as was acute presentation (2.9; 2.7-3.2). Among stable, heart failure-free CAD patients followed on average 7.4 years, initial MI (adjusted HR = 1.6; 1.4-1.7) and CAD with CABG (1.5; 1.2-1.8) were associated with higher long-term heart failure risk, but an initial acute presentation was not (1.0; 0.9-1.0). CONCLUSION: Nearly 50% of initial CAD diagnoses are associated with hospitalization, and these patients are at high risk of early heart failure. Among stable CAD patients, MI remained the diagnostic classification associated with the highest long-term heart failure risk, however, having an initial acute CAD presentation was not associated with long-term heart failure.

Establishing a National Cardiovascular Disease Surveillance System in the United States Using Electronic Health Record Data: Key Strengths and Limitations.

Cardiovascular disease surveillance involves quantifying the evolving population-level burden of cardiovascular outcomes and risk factors as a data-driven initial step followed by the implementation of interventional strategies designed to alleviate this burden in the target population. Despite widespread acknowledgement of its potential value, a national surveillance system dedicated specifically to cardiovascular disease does not currently exist in the United States. Routinely collected health care data such as from electronic health records (EHRs) are a possible means of achieving national surveillance. Accordingly, this article elaborates on some key strengths and limitations of using EHR data for establishing a national cardiovascular disease surveillance system. Key strengths discussed include the: (1) ubiquity of EHRs and consequent ability to create a more "national" surveillance system, (2) existence of a common data infrastructure underlying the health care enterprise with respect to data domains and the nomenclature by which these data are expressed, (3) longitudinal length and detail that define EHR data when individuals repeatedly patronize a health care organization, and (4) breadth of outcomes capable of being surveilled with EHRs. Key limitations discussed include the: (1) incomplete ascertainment of health information related to health care-seeking behavior and the disconnect of health care data generated at separate health care organizations, (2) suspect data quality resulting from the default information-gathering processes within the clinical enterprise, (3) questionable ability to surveil patients through EHRs in the absence of documented interactions, and (4) the challenge in interpreting temporal trends in health metrics, which can be obscured by changing clinical and administrative processes.

Changes over time in the cardiovascular risk profile of type 2 diabetes from 2007 to 2020: A community-based study.

AIMS: To quantify changes over time in cardiovascular (CV) risk factor control and in the uptake of glucagon-like peptide-1 receptor agonists (GLP-1RAs) and sodium-glucose cotransporter-2 (SGLT2) inhibitors from 2007 to 2020 in a real-world community-based cohort of type 2 diabetes (T2D) patients. MATERIALS AND METHODS: This study identified 95 461 T2D patients, who were followed for an average of 6.4 years through a single healthcare organization's electronic health record. The primary outcome was global risk factor control according to four factors ("ABCS"): glycated haemoglobin (HbA1c [<8%]); Blood pressure (systolic/diastolic <140/90 mmHg); Cholesterol (non-HDL cholesterol <130 mg/dL); and Smoking (not). Concomitant presence of microvascular complications and commonly used medication classes were tracked. RESULTS: According to the ABCS metric, global risk factor control did not appreciably change over time; in 2020, 40.9% (95% confidence interval 40.2, 41.5) of patients had all four factors controlled. Among individual components, HbA1c control (<8%) worsened over time from 84% in 2007 to 78% in 2020, while lipid control (non-HDL cholesterol <130 mg/dL) improved from 59% to 72%. Coexisting microvascular complications were more prevalent over time; for example, neuropathy prevalence increased from 21% (2007) to 35% (2020). Use of thiazolidinediones and sulphonylureas decreased over time while metformin, insulin, dipeptidyl peptidase-4 inhibitor, GLP-1RA and SGLT2 inhibitor use increased. In 2020, GLP-1RAs and SGLT2 inhibitors were each used by 13% of T2D patients. CONCLUSIONS: In this community-based study, global CV risk factor control in T2D did not improve, although glycaemic control worsened and lipid control improved. Given increased uptake of GLP-1RAs and SGLT2 inhibitors, the collective effect of these changes on CV outcomes warrants evaluation.

Constructing Epidemiologic Cohorts from Electronic Health Record Data.

In the United States, electronic health records (EHR) are increasingly being incorporated into healthcare organizations to document patient health and services rendered. EHRs serve as a vast repository of demographic, diagnostic, procedural, therapeutic, and laboratory test data generated during the routine provision of health care. The appeal of using EHR data for epidemiologic research is clear: EHRs generate large datasets on real-world patient populations in an easily retrievable form permitting the cost-efficient execution of epidemiologic studies on a wide array of topics. Constructing epidemiologic cohorts from EHR data involves as a defining feature the development of data machinery, which transforms raw EHR data into an epidemiologic dataset from which appropriate inference can be drawn. Though data machinery includes many features, the current report focuses on three aspects of machinery development of high salience to EHR-based epidemiology: (1) selecting study participants; (2) defining "baseline" and assembly of baseline characteristics; and (3) follow-up for future outcomes. For each, the defining features and unique challenges with respect to EHR-based epidemiology are discussed. An ongoing example illustrates key points. EHR-based epidemiology will become more prominent as EHR data sources continue to proliferate. Epidemiologists must continue to improve the methods of EHR-based epidemiology given the relevance of EHRs in today's healthcare ecosystem.

Burden and Predictors of Chest Pain-Related Health-Care Utilization Following Percutaneous Coronary Intervention.

Chest pain (CP) has been reported in 20% to 40% of patients 1 year after percutaneous coronary intervention (PCI), though rates of post-PCI health-care utilization (HCU) for CP in nonclinical trial populations are unknown. Furthermore, the contribution of noncardiac factors - such as pulmonary, gastrointestinal, and psychological - to post-PCI CP HCU is unclear. Accordingly, the objectives of this study were to describe long-term trajectories and identify predictors of post-PCI CP-related HCU in real-world patients undergoing PCI for any indication. This retrospective cohort study included patients receiving PCI for any indication from 2003 to 2017 through a single integrated health-care system. Post-PCI CP-related HCU tracked through electronic medical records included (1) office visits, (2) emergency department (ED) visits, and (3) hospital admissions with CP or angina as the primary diagnosis. The strongest predictors of CP-related HCU were identified from >100 candidate variables. Among 6386 patients followed an average of 6.7 years after PCI, 73% received PCI for acute coronary syndrome (ACS), 19% for stable angina, and 8% for other indications. Post-PCI CP-related HCU was common with 26%, 16%, and 5% of patients having ≥1 office visits, ED visits, and hospital admissions for CP within 2 years of PCI. The following factors were significant predictors of all 3 CP outcomes: ACS presentation, documented CP >7 days prior to the index PCI, anxiety, depression, and syncope. In conclusion, CP-related HCU following PCI was common, especially within the first 2 years. The strongest predictors of CP-related HCU included coronary disease attributes and psychological factors.

Quantifying the Risk Continuum for Cardiovascular Death in Adults with Type 2 Diabetes.

OBJECTIVES: In type 2 diabetes (T2D), the most common causes of death are cardiovascular (CV) related, accounting for >50% of deaths in some reports. As novel diabetes therapies reduce CV death risk, identifying patients with T2D at highest CV death risk allows for cost-effective prioritization of these therapies. Accordingly, the primary goal of this study was to quantify the risk continuum for CV death in a real-world T2D population as a means to identify patients with the greatest expected benefit from cardioprotective antidiabetes therapies. METHODS: This retrospective study included patients with T2D receiving services through an integrated health-care system and used data generated through electronic medical records (EMRs). Quantifying the risk continuum entailed developing a prediction model for CV death, creating an integer risk score based on the final prediction model and estimating future CV death risk according to risk score ranking. RESULTS: Among 59,180 patients with T2D followed for an average of 7.5 years, 15,691 deaths occurred, 6,033 (38%) of which were CV related. The EMR-based prediction model included age, established CV disease and risk factors and glycemic indices (c statistic = 0.819). The 10% highest-risk patients according to prediction model elements had an annual CV death risk of ∼5%; the 25% highest-risk patients had an annual risk of ∼2%. CONCLUSIONS: This study incorporated a prediction modelling approach to quantify the risk continuum for CV death in T2D. Prospective application allows us to rank individuals with T2D according to their CV death risk, and may guide prioritization of novel diabetes therapies with cardioprotective properties.

Trends in Atrial Fibrillation Incidence Rates Within an Integrated Health Care Delivery System, 2006 to 2018.

Importance: Atrial fibrillation (AF) is the most common cardiac arrhythmia, and multiple studies have reported increasing AF incidence rates over time, although the underlying explanations remain unclear. Objectives: To estimate AF incidence rates from 2006 to 2018 in a community-based setting and to investigate possible explanations for increasing AF by evaluating the changing features of incident AF cases and the pool of patients at risk for AF over time. Design, Setting, and Participants: This cohort study included 500 684 patients who received primary care and other health care services for more than 2 years through a single integrated health care delivery network in Pennsylvania. Data collection was conducted from January 2003 to December 2018. The base study population had no documentation of AF in the electronic medical record for at least 2 years prior to baseline. Data analysis was conducted from May to December 2019. Main Outcomes and Measures: Incident AF cases were identified through diagnostic codes recorded at inpatient or outpatient encounters. Age- and sex-adjusted AF incidence rates were estimated by calendar year from 2006 to 2018 both overall and across subgroups, including according to diagnostic setting (inpatient vs outpatient) and priority (primary vs secondary diagnosis). Results: Among 514 293 patients meeting criteria for the base study population, the mean (SD) age at baseline was 47 (18) years and 282 103 (54.9%) were women; 13 609 (2.6%) met AF diagnostic criteria on or prior to the baseline date and were excluded. Among 500 684 patients free of AF at baseline, standardized AF incidence rates from 2006 to 2018 increased from 4.74 (95% CI, 4.58-4.90) to 6.82 (95% CI, 6.65-7.00) cases per 1000 person-years, increasing significantly over time (P < .001). Incidence rates increased in all age and sex subgroups, although absolute rate increases were largest among those aged 85 years or older. The fraction of incident AF cases among individuals aged 85 years or older increased from 135 of 1075 (12.6%) in 2006 to 451 of 2427 (18.6%) in 2017. Patients with incident AF were more likely over time to have high body mass index (1351 of 3389 patients [39.9%] in 2006-2008 vs 4504 of 9214 [48.9%] in 2015-2018; P < .001), hypertension (2764 [81.6%] in 2006-2008 vs 7937 [86.1%] in 2015-2018; P < .001), and ischemic stroke (328 [9.7%] in 2006-2008 vs 1455 [15.8%] in 2015-2018; P < .001), but less likely to have coronary artery disease (1533 [45.2%] in 2006-2008 vs 3810 [41.4%] in 2015-2018; P < .001). Among 22 077 new cases of AF, 9146 (41.4%) were diagnosed as inpatients and 5731 (26.0%) as the primary diagnosis. Incidence rates of AF increased significantly in all diagnostic setting and priority pairings (eg, inpatient, primary: rate ratio, 1.07; 95% CI, 1.06-1.08; P < .001). Among patients at risk for AF, high BMI and hypertension increased over time (BMI: 71 433 of 198 245 [36.0%] in 2007 to 130 218 of 282 270 [46.1%] in 2017; hypertension: 79 977 [40.3%] in 2007 to 134 404 [47.6%] in 2017). Documentation of short-term ECG increased over time (23 297 of 207 349 [11.2%] in 2008 to 45 027 [16.0%] in 2017); however, long-term ECG monitoring showed no change (1871 [0.9%] in 2007 to 4036 [1.4%] in 2017). Conclusions and Relevance: In this community-based study, AF incidence rates increased significantly during the study period. Concurrent increases were observed in AF risk factors in the at-risk population and short-term ECG use.

A Clinical Tool to Identify Candidates for Stress-First Myocardial Perfusion Imaging.

OBJECTIVES: This study sought to develop a clinical model that identifies a lower-risk population for coronary artery disease that could benefit from stress-first myocardial perfusion imaging (MPI) protocols and that can be used at point of care to risk stratify patients. BACKGROUND: There is an increasing interest in stress-first and stress-only imaging to reduce patient radiation exposure and improve patient workflow and experience. METHODS: A secondary analysis was conducted on a single-center cohort of patients undergoing single-photon emission computed tomography (SPECT) and positron emission tomography (PET) studies. Normal MPI was defined by the absence of perfusion abnormalities and other ischemic markers and the presence of normal left ventricular wall motion and left ventricular ejection fraction. A model was derived using a cohort of 18,389 consecutive patients who underwent SPECT and was validated in a separate cohort of patients who underwent SPECT (n = 5,819), 1 internal cohort of patients who underwent PET (n=4,631), and 1 external PET cohort (n = 7,028). RESULTS: Final models were made for men and women and consisted of 9 variables including age, smoking, hypertension, diabetes, dyslipidemia, typical angina, prior percutaneous coronary intervention, prior coronary artery bypass graft, and prior myocardial infarction. Patients with a score ≤1 were stratified as low risk. The model was robust with areas under the curve of 0.684 (95% confidence interval [CI]: 0.674 to 0.694) and 0.681 (95% CI: 0.666 to 0.696) in the derivation cohort, 0.745 (95% CI: 0.728 to 0.762) and 0.701 (95% CI: 0.673 to 0.728) in the SPECT validation cohort, 0.672 (95% CI: 0.649 to 0.696) and 0.686 (95% CI: 0.663 to 0.710) in the internal PET validation cohort, and 0.756 (95% CI: 0.740 to 0.772) and 0.737 (95% CI: 0.716 to 0.757) in the external PET validation cohort in men and women, respectively. Men and women who scored ≤1 had negative likelihood ratios of 0.48 and 0.52, respectively. CONCLUSIONS: A novel model, based on easily obtained clinical variables, is proposed to identify patients with low probability of having abnormal MPI results. This point-of-care tool may be used to identify a population that might qualify for stress-first MPI protocols.

A risk prediction model for heart failure hospitalization in type 2 diabetes mellitus.

BACKGROUND: Antidiabetic therapies have shown disparate effects on hospitalization for heart failure (HHF) in clinical trials. This study developed a prediction model for HHF in type 2 diabetes mellitus (T2DM) using real world data to identify patients at high risk for HHF. HYPOTHESIS: Type 2 diabetics at high risk for HHF can be identified using information generated during usual clinical care. METHODS: This electronic medical record- (EMR-) based retrospective cohort study included patients with T2DM free of HF receiving healthcare through a single, large integrated healthcare system. The primary endpoint was HHF, defined as a hospital admission with HF as the primary diagnosis. Cox regression identified the strongest predictors of HHF from 80 candidate predictors derived from EMRs. High risk patients were defined according to the 90th percentile of estimated risk. RESULTS: Among 54,452 T2DM patients followed on average 6.6 years, estimated HHF rates at 1, 3, and 5 years were 0.3%, 1.1%, and 2.0%. The final 9-variable model included: age, coronary artery disease, blood urea nitrogen, atrial fibrillation, hemoglobin A1c, blood albumin, systolic blood pressure, chronic kidney disease, and smoking history (c = 0.782). High risk patients identified by the model had a >5% probability of HHF within 5 years. CONCLUSIONS: The proposed model for HHF among T2DM demonstrated strong predictive capacity and may help guide therapeutic decisions.

Antibody Therapies for Acute Myeloid Leukemia: Unconjugated, Toxin-Conjugated, Radio-Conjugated and Multivalent Formats.

In recent decades, therapy for acute myeloid leukemia (AML) has remained relatively unchanged, with chemotherapy regimens primarily consisting of an induction regimen based on a daunorubicin and cytarabine backbone, followed by consolidation chemotherapy. Patients who are relapsed or refractory can be treated with allogeneic hematopoietic stem-cell transplantation with modest benefits to event-free and overall survival. Other modalities of immunotherapy include antibody therapies, which hold considerable promise and can be categorized into unconjugated classical antibodies, multivalent recombinant antibodies (bi-, tri- and quad-specific), toxin-conjugated antibodies and radio-conjugated antibodies. While unconjugated antibodies can facilitate Natural Killer (NK) cell antibody-dependent cell-mediated cytotoxicity (ADCC), bi- and tri-specific antibodies can engage either NK cells or T-cells to redirect cytotoxicity against AML targets in a highly efficient manner, similarly to classic ADCC. Finally, toxin-conjugated and radio-conjugated antibodies can increase the potency of antibody therapies. Several AML tumour-associated antigens are at the forefront of targeted therapy development, which include CD33, CD123, CD13, CLL-1 and CD38 and which may be present on both AML blasts and leukemic stem cells. This review focused on antibody therapies for AML, including pre-clinical studies of these agents and those that are either entering or have been tested in early phase clinical trials. Antibodies for checkpoint inhibition and microenvironment targeting in AML were excluded from this review.

Clinical Outcomes of Selective Versus Nonselective His Bundle Pacing.

OBJECTIVES: The aim of the study was to evaluate the clinical outcomes of nonselective (NS) His bundle pacing (HBP) compared with selective (S) HBP. BACKGROUND: HBP is the most physiologic form of ventricular pacing. NS-HBP results in right ventricular septal pre-excitation due to fusion with myocardial capture in addition to His bundle capture resulting in widened QRS duration compared with S-HBP wherein there is exclusive His bundle capture and conduction. METHODS: The Geisinger and Rush University HBP registries comprise 640 patients who underwent successful HBP. Our study population included 350 consecutive patients treated with HBP for bradyarrhythmic indications who demonstrated ≥20% ventricular pacing burden 3 months post-implantation. Patients were categorized into S-HBP or NS-HBP based on QRS morphology (NS-HBP n = 232; S-HBP n = 118) at the programmed output at the 3-month follow-up. The primary analysis outcome was a combined endpoint of all-cause mortality or heart failure hospitalization. RESULTS: The NS-HBP group had a higher number of men (64% vs. 50%; p = 0.01), higher incidence of infranodal atrioventricular block (40% vs. 9%; p < 0.01), ischemic cardiomyopathy (24% vs. 14%; p = 0.03), and permanent atrial fibrillation (18% vs. 8%; p = 0.01). The primary endpoint occurred in 81 of 232 patients (35%) in the NS-HBP group compared with 23 of 118 patients (19%) in the S-HBP group (hazard ratio: 1.38; 95% confidence interval: 0.87 to 2.20; p = 0.17). Subgroup analyses of patients at greatest risk (higher pacing burden or lower left ventricular ejection fraction) revealed no incremental risk with NS-HBP. CONCLUSIONS: NS-HBP was associated with similar outcomes of death or heart failure hospitalization when compared with S-HBP. Multicenter risk-matched clinical studies are needed to confirm these findings.

Humanized anti-CD123 antibody facilitates NK cell antibody-dependent cell-mediated cytotoxicity (ADCC) of Hodgkin lymphoma targets via ARF6/PLD-1.

CD123 (IL-3Rα) is frequently expressed by malignant Hodgkin lymphoma (HL) cells. Naked monoclonal antibodies (mAb) against HL lack clinical benefit, partially due to absence of natural killer (NK) cells in the tumor microenvironment. Here we show that the combination of a fully humanized anti-CD123 mAb (CSL362) and high-affinity Fcγ-receptor NK-92 cells (haNK) effectively target and kill HL cells in vitro. First, we confirmed high expression of CD123 in 2 of the 3 HL cell lines (KM-H2 and L-428), and its absence in NK cells. Cytotoxicity of haNK cells against CD123-positive HL cells was significantly higher in the presence of CSL362. This was also shown with IL-15-activated primary NK cells, although haNK cells showed a 10.87-fold lower estimated half-maximal stimulatory effective concentration (EC50). CSL362 facilitated a significant increase in the expression of CD107a, intracellular IFN-γ and TNF-α and enhanced expression of c-JUN, PLD-1, and ARF6 by NK cells. Inhibition of the ARF6-PLD-1 axis (NAV2729), but not of the MAPK pathway (U0126), completely abrogated CSL362-facilitated antibody-dependent cell-mediated cytotoxicity (ADCC) in haNK and activated primary NK cells. Our results support CD123 as an immunotherapeutic target for HL and the combination of NK cells and CSL362 as a treatment strategy for HL.

Predicting Survival From Large Echocardiography and Electronic Health Record Datasets: Optimization With Machine Learning.

OBJECTIVES: The goal of this study was to use machine learning to more accurately predict survival after echocardiography. BACKGROUND: Predicting patient outcomes (e.g., survival) following echocardiography is primarily based on ejection fraction (EF) and comorbidities. However, there may be significant predictive information within additional echocardiography-derived measurements combined with clinical electronic health record data. METHODS: Mortality was studied in 171,510 unselected patients who underwent 331,317 echocardiograms in a large regional health system. The authors investigated the predictive performance of nonlinear machine learning models compared with that of linear logistic regression models using 3 different inputs: 1) clinical variables, including 90 cardiovascular-relevant International Classification of Diseases, Tenth Revision, codes, and age, sex, height, weight, heart rate, blood pressures, low-density lipoprotein, high-density lipoprotein, and smoking; 2) clinical variables plus physician-reported EF; and 3) clinical variables and EF, plus 57 additional echocardiographic measurements. Missing data were imputed with a multivariate imputation by using a chained equations algorithm (MICE). The authors compared models versus each other and baseline clinical scoring systems by using a mean area under the curve (AUC) over 10 cross-validation folds and across 10 survival durations (6 to 60 months). RESULTS: Machine learning models achieved significantly higher prediction accuracy (all AUC >0.82) over common clinical risk scores (AUC = 0.61 to 0.79), with the nonlinear random forest models outperforming logistic regression (p < 0.01). The random forest model including all echocardiographic measurements yielded the highest prediction accuracy (p < 0.01 across all models and survival durations). Only 10 variables were needed to achieve 96% of the maximum prediction accuracy, with 6 of these variables being derived from echocardiography. Tricuspid regurgitation velocity was more predictive of survival than LVEF. In a subset of studies with complete data for the top 10 variables, multivariate imputation by chained equations yielded slightly reduced predictive accuracies (difference in AUC of 0.003) compared with the original data. CONCLUSIONS: Machine learning can fully utilize large combinations of disparate input variables to predict survival after echocardiography with superior accuracy.

Quantifying Sex Differences in Cardiovascular Care Among Patients Evaluated for Suspected Ischemic Heart Disease.

Background: Cardiovascular care sex differences are controversial. We examined sex differences in management and clinical outcomes among patients undergoing noninvasive testing for ischemic heart disease (IHD). Methods: In a rural integrated healthcare system, we identified adults age 40-79 without diagnosed IHD who underwent initial evaluation with a cardiac stress test with imaging or coronary computed tomographic angiography (CTA), 2013-2014. We assessed sex differences in statin/aspirin therapy, revascularization, and adverse cardiovascular events. The 2013 American College of Cardiology/American Heart Association statin guidelines and U.S. Preventive Services Task Force aspirin guidelines were applied. Results: Among 2213 patients evaluated for IHD, median age was 57 years, 48.8% were women, and 9% had a positive stress test/CTA. Women were more likely to be missing lipid values than men (p < 0.001). Mean ASCVD risk score at baseline was 7.2% in women versus 12.4% in men (p < 0.001). There was no significant sex difference in statin therapy at baseline or 60-day follow-up. Women were less likely than men to be taking aspirin at baseline (adj. diff. = -8.5%; 95% CI, -4.2 to -12.9) and follow-up (adj. diff. = -7.7%; 95% CI, -3.3 to -12.1). There were no sex differences in revascularization after accounting for obstructive CAD or adverse cardiovascular outcomes during median follow-up of 33 months. Conclusion: In this contemporary cohort of patients with suspected IHD, women were less likely to receive lipid testing and aspirin therapy, but not statin therapy. Women did not experience worse outcomes. Sex differences in statin therapy reported by others may be due to inadequate accounting for baseline risk.

CD16+NK-92 and anti-CD123 monoclonal antibody prolongs survival in primary human acute myeloid leukemia xenografted mice.

Patients with acute myeloid leukemia (AML) often relapse after initial therapy because of persistence of leukemic stem cells that frequently express the IL-3 receptor alpha chain CD123. Natural killer (NK) cell-based therapeutic strategies for AML show promise and we explore the NK cell lines, NK-92 and CD16+ NK-92, as a treatment for AML. NK-92 has been tested in phase I clinical trials with minimal toxicity; irradiation prior to infusion prevents risk of engraftment. The CD16 negative NK-92 parental line was genetically modified to express the high affinity Fc gamma receptor, enabling antibody-dependent cell-mediated cytotoxicity, which we utilized in combination with an anti-CD123 antibody to target leukemic stem cells. NK-92 was preferentially cytotoxic against leukemic stem and progenitor cells compared with bulk leukemia in in vitro assays, while CD16+ NK-92 in combination with an anti-CD123 mAb mediated antibody-dependent cell-mediated cytotoxicity against CD123+ leukemic targets. Furthermore, NK-92 infusions (with or without prior irradiation) improved survival in a primary AML xenograft model. Mice xenografted with primary human AML cells had a superior survival when treated with irradiated CD16+NK-92 cells and an anti-CD123 monoclonal antibody (7G3) versus treatment with irradiated CD16+NK-92 cells combined with an isotype control antibody. In this proof-of-principle study, we show for the first time that a CD16+NK-92 cell line combined with an antibody that targets a leukemic stem cell antigen can lead to improved survival in a relevant pre-clinical model of AML.

Is There an Age When Myocardial Perfusion Imaging May No Longer Be Prognostically Useful?

BACKGROUND: Heart disease continues to be the leading cause of death, and the prevalence of coronary artery disease is expected to increase as the population ages. It is important to understand the clinical utility of medical tests, or its lack thereof, in the aging population. The objective of this study was to understand the incremental prognostic value of positron emission tomographic (PET) myocardial perfusion imaging in the elderly (≥85 years of age). METHODS AND RESULTS: A total of 3343 patients enrolled in a multicenter observational PET registry were analyzed. Participants were initially divided into 3 age categories: 65 to 74.9, 75 to 84.9, and ≥85 years of age and followed for all-cause death. Median follow-up time was 3 years. Of the total patient population, 248 patients (49% men) were ≥85 years old. When compared with younger patients, individuals ≥85 years had a higher prevalence of hypertension (79%) and a lower incidence of dyslipidemia (54%) and diabetes mellitus (24%). On multivariable analysis, %left ventricular stress defect and %left ventricular ischemia were predictors of patient outcome for those <85 years of age but was not statistically significant in those ≥85 years of age. The prognostic value of PET (%left ventricular stress defect and %left ventricular ischemia) appeared to decrease with advancing age. CONCLUSIONS: The elderly is a high-risk population irrespective of PET myocardial perfusion imaging results, and incremental prognostic value of PET myocardial perfusion imaging appears to wane in those ≥85 years of age. Although PET myocardial perfusion imaging may be diagnostically useful in the elderly, its prognostic value in this population requires further evaluation.

External validation of the TIMI risk score for secondary cardiovascular events among patients with recent myocardial infarction.

BACKGROUND AND AIMS: Risk stratification of patients with recent myocardial infarction (MI) for subsequent cardiovascular (CV) events helps identify patients most likely to benefit from secondary prevention therapies. This study externally validated a new risk score (TRS2˚P) for secondary events derived from the TRA2°P-TIMI 50 trial among post-MI patients from two large health care systems. METHODS: This retrospective cohort study included 9618 patients treated for acute MI at either the Cleveland Clinic (CC) or Geisinger Health System (GHS) between 2008 and 2013. Patients with a clinic visit within 2-52 weeks of MI were included and followed for CV death, repeat MI, and ischemic stroke through electronic medical records (EMR). The TRS2˚P is based on nine factors determined through EMR documentation. Discrimination and calibration of the TRS2˚P were quantified in both patient populations. RESULTS: MI patients at CC and GHS were older, had more comorbidities, received fewer medications, and had higher 3-year event rates compared to subjects in the TRA2°P trial: 31% (CC), 33% (GHS), and 10% (TRA2°P-TIMI 50). The proposed risk score had similar discrimination across the three cohorts with c-statistics of 0.66 (CC), 0.66 (GHS), and 0.67 (TRA2°P-TIMI 50). A strong graded relationship between the risk score and event rates was observed in all cohorts, though 3-year event rates were consistently higher within TRS2°P strata in the CC and GHS cohorts relative to TRA2˚P-TIMI 50. CONCLUSIONS: The TRS2˚P demonstrated consistent risk discrimination across trial and non-trial patients with recent MI, but event rates were consistently higher in the non-trial cohorts.