Metabolomic Profiling of Cholesterol Efflux Capacity in a Multiethnic Population: Insights From MESA.

BACKGROUND: Impaired cholesterol efflux capacity (CEC) is a novel lipid metabolism trait associated with atherosclerotic cardiovascular disease. Mechanisms underlying CEC variation are unknown. We evaluated associations of circulating metabolites with CEC to advance understanding of metabolic pathways involved in cholesterol efflux regulation. METHODS: Participants enrolled in the MESA (Multi-Ethnic Study of Atherosclerosis) who underwent nuclear magnetic resonance metabolome profiling and CEC measurement (N=3543) at baseline were included. Metabolite associations with CEC were evaluated using standard linear regression analyses. Repeated ElasticNet and multilayer perceptron regression were used to assess metabolite profile predictive performance for CEC. Features important for CEC prediction were identified using Shapley Additive Explanations values. RESULTS: Greater CEC was significantly associated with metabolite clusters composed of the largest-sized particle subclasses of VLDL (very-low-density lipoprotein) and HDL (high-density lipoprotein), as well as their constituent apo A1, apo A2, phospholipid, and cholesterol components (ß=0.072-0.081; P<0.001). Metabolite profiles had poor accuracy for predicting in vitro CEC in linear and nonlinear analyses (R2<0.02; Spearman ρ<0.18). The most important feature for CEC prediction was race, with Black participants having significantly lower CEC compared with other races. CONCLUSIONS: We identified independent associations among CEC, the largest-sized particle subclasses of VLDL and HDL, and their constituent apolipoproteins and lipids. A large proportion of variation in CEC remained unexplained by metabolites and traditional clinical risk factors, supporting further investigation into genomic, proteomic, and phospholipidomic determinants of CEC.

High-Density Lipoprotein Particle Subfractions in Heart Failure With Preserved or Reduced Ejection Fraction.

BACKGROUND: Circulating high-density lipoprotein particle (HDL-P) subfractions impact atherogenesis, inflammation, and endothelial function, all of which are implicated in the pathobiology of heart failure (HF). OBJECTIVES: The authors sought to identify key differences in plasma HDL-P subfractions between patients with HF with reduced ejection fraction (HFrEF) and HF with preserved ejection fraction (HFpEF) to determine their prognostic utility. METHODS: Patients with HFrEF (n = 782), HFpEF (n = 1,004), and no HF (n = 4,742) were identified in the CATHGEN (Catheterization Genetics) biorepository of sequential patients undergoing cardiac catheterization. Nuclear magnetic resonance-based lipoprotein profiling was performed on frozen fasting plasma obtained at catheterization. The authors used multivariable analysis of covariance to compare high-density lipoprotein particle (HDL-P) subfractions across groups, and Cox proportional hazards modeling to determine associations between HDL-P subfractions and time to death or major adverse cardiac events. RESULTS: Mean HDL-P size was greater in HFrEF than HFpEF, both of which were greater than in no HF (all 2-way p < 0.0001). By contrast, concentrations of small HDL-P and total HDL-P were lesser in HFrEF than HFpEF, which were both lesser than no HF (all 2-way p ≤ 0.0002). In both HFrEF and HFpEF, total HDL-P and small HDL-P were inversely associated with time to adverse events. These findings persisted after adjustment for 14 clinical covariates (including high-density lipoprotein cholesterol content, coronary artery disease, and the inflammatory biomarker GlycA), and in sensitivity analyses featuring alternate left ventricular ejection fraction definitions, or stricter inclusion criteria with diastolic dysfunction or left ventricular end-diastolic pressure thresholds. CONCLUSIONS: In the largest analysis of HDL-P subfractions in HF to date, derangements in HDL-P subfractions were identified that were more severe in HFrEF than HFpEF and were independently associated with adverse outcomes. These data may help refine risk assessment and provide new insights into the complex interaction of HDL and HF pathophysiology.

Discussing Health Care Expenses in the Oncology Clinic: Analysis of Cost Conversations in Outpatient Encounters.

PURPOSE: ASCO identified oncologist-patient conversations about cancer costs as an important component of high-quality care. However, limited data exist characterizing the content of these conversations. We sought to provide novel insight into oncologist-patient cost conversations by determining the content of cost conversations in breast cancer clinic visits. METHODS: We performed content analysis of transcribed dialogue from 677 outpatient appointments for breast cancer management. Encounters featured 677 patients with breast cancer visiting 56 oncologists nationwide from 2010 to 2013. RESULTS: Cost conversations were identified in 22% of visits (95% CI, 19 to 25) and had a median duration of 33 seconds (interquartile range, 19 to 62). Fifty-nine percent of cost conversations were initiated by oncologists (95% CI, 51 to 67), who most commonly brought up costs for antineoplastic agents. By contrast, patients most frequently brought up costs for diagnostic tests. Thirty-eight percent of cost conversations mentioned cost-reducing strategies (95% CI, 30 to 46), which most commonly sought to lower patient costs for endocrine therapies and symptom-alleviating treatments. The three most commonly discussed cost-reducing strategies were: switching to a lower-cost therapy/diagnostic, changing logistics of the intervention, and facilitating copay assistance. CONCLUSION: We identified cost conversations in approximately one in five breast cancer visits. Cost conversations were mostly oncologist initiated, lasted < 1 minute, and dealt with a wide range of health care expenses. Cost-reducing strategies were mentioned in more than one third of cost conversations and often involved switching antineoplastic agents for lower-cost alternatives or altering logistics of diagnostic tests.

Discussing Out-of-Pocket Expenses During Clinical Appointments: An Observational Study of Patient-Psychiatrist Interactions.

OBJECTIVE: High out-of-pocket expenses for medical treatment have been associated with worse quality of life, decreased treatment adherence, and increased risk of adverse health outcomes. Treatment of depression potentially has high out-of-pocket expenses. Limited data characterize psychiatrist-patient conversations about health care costs. METHODS: The authors conducted content analysis from 422 outpatient psychiatrist-patient visits for medication management of major depressive disorder in community-based private practices nationwide from 2010 to 2014. RESULTS: Patients' health care expenses were discussed in 38% of clinic visits (95% confidence interval [CI]= 33%-43%). Uninsured patients were significantly more likely to discuss expenses than were patients enrolled in private or public plans (64%, 44%, and 30%, respectively; p<.001). Sixty-nine percent of cost conversations lasted less than one minute (median=36 seconds; interquartile range [IQR]=16-81 seconds). Cost conversations most frequently addressed psychotropic medications (51%). Physicians initiated 50% of cost conversations and brought up costs for psychotropic medications more often than did patients (62% versus 38%, p=.009). Conversely, a greater percentage of patient-initiated cost conversations addressed provider visit costs (27% versus 10%, p=.008). Overall, 45% of cost conversations mentioned cost-reducing strategies (CI=37%-53%). The most frequently discussed cost-reducing strategies were lowering cost by changing the source or timing of an intervention (for example, changing pharmacies), providing free samples, and switching to a lower-cost therapy or diagnostic test. CONCLUSIONS: Psychiatrists and patients regularly discuss patients' health care costs in visits for depression. These discussions cover a variety of clinical topics and frequently include strategies to lower patients' costs.

Metabolomic Profiling Identifies Novel Circulating Biomarkers of Mitochondrial Dysfunction Differentially Elevated in Heart Failure With Preserved Versus Reduced Ejection Fraction: Evidence for Shared Metabolic Impairments in Clinical Heart Failure.

BACKGROUND: Metabolic impairment is an important contributor to heart failure (HF) pathogenesis and progression. Dysregulated metabolic pathways remain poorly characterized in patients with HF and preserved ejection fraction (HFpEF). We sought to determine metabolic abnormalities in HFpEF and identify pathways differentially altered in HFpEF versus HF with reduced ejection fraction (HFrEF). METHODS AND RESULTS: We identified HFpEF cases, HFrEF controls, and no-HF controls from the CATHGEN study of sequential patients undergoing cardiac catheterization. HFpEF cases (N=282) were defined by left ventricular ejection fraction (LVEF) ≥45%, diastolic dysfunction grade ≥1, and history of HF; HFrEF controls (N=279) were defined similarly, except for having LVEF <45%. No-HF controls (N=191) had LVEF ≥45%, normal diastolic function, and no HF diagnosis. Targeted mass spectrometry and enzymatic assays were used to quantify 63 metabolites in fasting plasma. Principal components analysis reduced the 63 metabolites to uncorrelated factors, which were compared across groups using ANCOVA. In basic and fully adjusted models, long-chain acylcarnitine factor levels differed significantly across groups (P<0.0001) and were greater in HFrEF than HFpEF (P=0.0004), both of which were greater than no-HF controls. We confirmed these findings in sensitivity analyses using stricter inclusion criteria, alternative LVEF thresholds, and adjustment for insulin resistance. CONCLUSIONS: We identified novel circulating metabolites reflecting impaired or dysregulated fatty acid oxidation that are independently associated with HF and differentially elevated in HFpEF and HFrEF. These results elucidate a specific metabolic pathway in HF and suggest a shared metabolic mechanism in HF along the LVEF spectrum.

Metabolic Dysfunction in Heart Failure: Diagnostic, Prognostic, and Pathophysiologic Insights From Metabolomic Profiling.

Metabolic impairment is an intrinsic component of heart failure (HF) pathophysiology. Although initially conceived as a myocardial defect, metabolic dysfunction is now recognized as a systemic process with complex interplay between the myocardium and peripheral tissues and organs. Specifically, HF-associated metabolic dysfunction includes alterations in substrate utilization, insulin resistance, defects in energy production, and imbalanced anabolic-catabolic signaling leading to cachexia. Each of these metabolic abnormalities is associated with significant morbidity and mortality in patients with HF; however, their detection and therapeutic management remains challenging. Given the difficulty in obtaining human cardiac tissue for research purposes, peripheral blood metabolomic profiling, a well-established approach for characterizing small-molecule metabolite intermediates from canonical biochemical pathways, may be a useful technology for dissecting biomarkers and mechanisms of metabolic impairment in HF. In this review, metabolic abnormalities in HF will be discussed with particular emphasis on the application of metabolomic profiling to detecting, risk stratifying, and identifying novel targets for metabolic therapy in this heterogeneous population.

Doctor Who? A Quality Improvement Project to Assess and Improve Patients' Knowledge of Their Inpatient Physicians.

Background Patient-physician communication is an integral part of high-quality patient care and an expectation of the Clinical Learning Environment Review program. Objective This quality improvement initiative evaluated the impact of an educational audit and feedback intervention on the frequency of use of 2 tools-business cards and white boards-to improve provider identification. Methods This before-after study utilized patient surveys to determine the ability of those patients to name and recognize their physicians. The before phase began in July 2013. From September 2013 to May 2014, physicians received education on business card and white board use. Results We surveyed 378 patients. Our intervention improved white board utilization (72.2% postintervention versus 54.5% preintervention, P < .01) and slightly improved business card use (44.4% versus 33.7%, P = .07), but did not improve physician recognition. Only 20.3% (14 of 69) of patients could name their physician without use of the business card or white board. Data from all study phases showed the use of both tools improved patients' ability to name physicians (OR = 1.72 and OR = 2.12, respectively; OR = 3.68 for both; P < .05 for all), but had no effect on photograph recognition. Conclusions Our educational intervention improved white board use, but did not result in improved patient ability to recognize physicians. Pooled data of business cards and white boards, alone or combined, improved name recognition, suggesting better use of these tools may increase identification. Future initiatives should target other barriers to usage of these types of tools.

Patient-physician discussions about costs: definitions and impact on cost conversation incidence estimates.

BACKGROUND: Nearly one in three Americans are financially burdened by their medical expenses. To mitigate financial distress, experts recommend routine physician-patient cost conversations. However, the content and incidence of these conversations are unclear, and rigorous definitions are lacking. We sought to develop a novel set of cost conversation definitions, and determine the impact of definitional variation on cost conversation incidence in three clinical settings. METHODS: Retrospective, mixed-methods analysis of transcribed dialogue from 1,755 outpatient encounters for routine clinical management of breast cancer, rheumatoid arthritis, and depression, occurring between 2010-2014. We developed cost conversation definitions using summative content analysis. Transcripts were evaluated independently by at least two members of our multi-disciplinary team to determine cost conversation incidence using each definition. Incidence estimates were compared using Pearson's Chi-Square Tests. RESULTS: Three cost conversation definitions emerged from our analysis: (a) Out-of-Pocket (OoP) Cost--discussion of the patient's OoP costs for a healthcare service; (b) Cost/Coverage--discussion of the patient's OoP costs or insurance coverage; (c) Cost of Illness- discussion of financial costs or insurance coverage related to health or healthcare. These definitions were hierarchical; OoP Cost was a subset of Cost/Coverage, which was a subset of Cost of Illness. In each clinical setting, we observed significant variation in the incidence of cost conversations when using different definitions; breast oncology: 16, 22, 24% of clinic visits contained cost conversation (OOP Cost, Cost/Coverage, Cost of Illness, respectively; P < 0.001); depression: 30, 38, 43%, (P < 0.001); and rheumatoid arthritis, 26, 33, 35%, (P < 0.001). CONCLUSIONS: The estimated incidence of physician-patient cost conversation varied significantly depending on the definition used. Our findings and proposed definitions may assist in retrospective interpretation and prospective design of investigations on this topic.

Study Of Physician And Patient Communication Identifies Missed Opportunities To Help Reduce Patients' Out-Of-Pocket Spending.

Some experts contend that requiring patients to pay out of pocket for a portion of their care will bring consumer discipline to health care markets. But are physicians prepared to help patients factor out-of-pocket expenses into medical decisions? In this qualitative study of audiorecorded clinical encounters, we identified physician behaviors that stand in the way of helping patients navigate out-of-pocket spending. Some behaviors reflected a failure to fully engage with patients' financial concerns, from never acknowledging such concerns to dismissing them too quickly. Other behaviors reflected a failure to resolve uncertainty about out-of-pocket expenses or reliance on temporary solutions without making long-term plans to reduce spending. Many of these failures resulted from systemic barriers to health care spending conversations, such as a lack of price transparency. For consumer health care markets to work as intended, physicians need to be prepared to help patients navigate out-of-pocket expenses when financial concerns arise during clinical encounters.

What Strategies Do Physicians and Patients Discuss to Reduce Out-of-Pocket Costs? Analysis of Cost-Saving Strategies in 1,755 Outpatient Clinic Visits.

BACKGROUND: More than 1 in 4 Americans report difficulty paying medical bills. Cost-reducing strategies discussed during outpatient physician visits remain poorly characterized. OBJECTIVE: We sought to determine how often patients and physicians discuss health care costs during outpatient visits and what strategies, if any, they discussed to lower patient out-of-pocket costs. DESIGN: Retrospective analysis of dialogue from 1,755 outpatient visits in community-based practices nationwide from 2010 to 2014. The study population included 677 patients with breast cancer, 422 with depression, and 656 with rheumatoid arthritis visiting 56 oncologists, 36 psychiatrists, and 26 rheumatologists, respectively. RESULTS: Thirty percent of visits contained cost conversations (95% confidence interval [CI], 28 to 32). Forty-four percent of cost conversations involved discussion of cost-saving strategies (95% CI, 40 to 48; median duration, 68 s). We identified 4 strategies to lower costs without changing the care plan. They were, in order of overall frequency: 1) changing logistics of care, 2) facilitating co-pay assistance, 3) providing free samples, and 4) changing/adding insurance plans. We also identified 4 strategies to reduce costs by changing the care plan: 1) switching to lower-cost alternative therapy/diagnostic, 2) switching from brand name to generic, 3) changing dosage/frequency, and 4) stopping/withholding interventions. Strategies were relatively consistent across health conditions, except for switching to a lower-cost alternative (more common in breast oncology) and providing free samples (more common in depression). LIMITATION: Focus on 3 conditions with potentially high out-of-pocket costs. CONCLUSIONS: Despite price opacity, physicians and patients discuss a variety of out-of-pocket cost reduction strategies during clinic visits. Almost half of cost discussions mention 1 or more cost-saving strategies, with more frequent mention of those not requiring care-plan changes.

Hedgehog signaling is required for differentiation of endocardial progenitors in zebrafish.

Endocardial cells form the inner endothelial layer of the heart tube, surrounded by the myocardium. Signaling pathways that regulate endocardial cell specification and differentiation are largely unknown and the origin of endocardial progenitors is still being debated. To study pathways that regulate endocardial differentiation in a zebrafish model system, we isolated zebrafish NFATc1 homolog which is expressed in endocardial but not vascular endothelial cells. We further demonstrate that Hedgehog (Hh) but not VegfA or Notch signaling is required for early endocardial morphogenesis. Pharmacological inhibition of Hh signaling with cyclopamine treatment resulted in nearly complete loss of the endocardial marker expression. Simultaneous knockdown of the two zebrafish sonic hedgehog homologs, shh and twhh or Hh co-receptor smoothened (smo) resulted in similar defects in endocardial morphogenesis. Inhibition of Hh signaling resulted in the loss of fibronectin (fn1) expression in the presumptive endocardial progenitors as early as the 10-somite stage which suggests that Hh signaling is required for the earliest stages of endocardial specification. We further show that the endoderm plays a critical role in migration but not specification or differentiation of the endocardial progenitors while notochord-derived Hh is a likely source for the specification and differentiation signal. Mosaic analysis using cell transplantation shows that Smo function is required cell-autonomously within endocardial progenitor cells. Our results argue that Hh provides a critical signal to induce the specification and differentiation of endocardial progenitors.