HCM-linked ∆160E cardiac troponin T mutation causes unique progressive structural and molecular ventricular remodeling in transgenic mice.

Hypertrophic cardiomyopathy (HCM) is a primary disease of the cardiac muscle, and one of the most common causes of sudden cardiac death (SCD) in young people. Many mutations in cardiac troponin T (cTnT) lead to a complex form of HCM with varying degrees of ventricular hypertrophy and ~65% of all cTnT mutations occur within or flanking the elongated N-terminal TNT1 domain. Biophysical studies have predicted that distal TNT1 mutations, including Δ160E, cause disease by a novel, yet unknown mechanism as compared to N-terminal mutations. To begin to address the specific effects of this commonly observed cTnT mutation we generated two independent transgenic mouse lines carrying variant doses of the mutant transgene. Hearts from the 30% and 70% cTnT Δ160E lines demonstrated a highly unique, dose-dependent disruption in cellular and sarcomeric architecture and a highly progressive pattern of ventricular remodeling. While adult ventricular myocytes isolated from Δ160E transgenic mice exhibited dosage-independent mechanical impairments, decreased sarcoplasmic reticulum calcium load and SERCA2a calcium uptake activity, the observed decreases in calcium transients were dosage-dependent. The latter findings were concordant with measures of calcium regulatory protein abundance and phosphorylation state. Finally, studies of whole heart physiology in the isovolumic mode demonstrated dose-dependent differences in the degree of cardiac dysfunction. We conclude that the observed clinical severity of the cTnT Δ160E mutation is caused by a combination of direct sarcomeric disruption coupled to a profound dysregulation of Ca(2+) homeostasis at the cellular level that results in a unique and highly progressive pattern of ventricular remodeling.

The Association Between Social Isolation and Memory Loss Among Older Adults.

INTRODUCTION: Social isolation among older individuals is associated with poor health outcomes. However, less is known about the association between social isolation and memory loss, specifically among Medicare enrollees in large, integrated health care systems. METHODS: We conducted a cross-sectional, observational study. From a cohort of 46,240 Medicare members aged 65 years and older at Kaiser Permanente Northwest (KPNW) who completed a health questionnaire, we compared self-reported memory loss of those who reported feeling lonely or socially isolated and those who did not, adjusting for demographic factors, health conditions, and use of health services in the 12 months before the survey. RESULTS: Patients who reported sometimes experiencing social isolation were more likely than those who rarely or never experienced social isolation to report memory loss in both unadjusted (odds ratio [ORsometimes]: 2.56, 95% CI= 2.42-2.70, P = 0.0076) and adjusted (ORsometimes: 2.45, 95% CI= 2.32-2.60, P = .0298) logistic regression models. Similarly, those who reported social isolation often or always were more likely to report memory loss than those who reported rarely or never experiencing isolation in both unadjusted (ORoften/always: 5.50, 95% CI = 5.06-5.99, P < .0001) and adjusted logistic regression models (ORoften/always: 5.20, 95% CI = 4.75-5.68, P < .0001). CONCLUSIONS: The strong association between social isolation and memory loss suggest the need to develop interventions to reduce isolation and to evaluate their effects on potential future memory loss.

The Association Between Social Isolation and Memory Loss Among Older Adults.

INTRODUCTION: Social isolation among older individuals is associated with poor health outcomes. However, less is known about the association between social isolation and memory loss, specifically among Medicare enrollees in large, integrated health care systems. METHODS: We conducted a cross-sectional, observational study. From a cohort of 46,240 Medicare members aged 65 years and older at Kaiser Permanente Northwest (KPNW) who completed a health questionnaire, we compared self-reported memory loss of those who reported feeling lonely or socially isolated and those who did not, adjusting for demographic factors, health conditions, and use of health services in the 12 months before the survey. RESULTS: Patients who reported sometimes experiencing social isolation were more likely than those who rarely or never experienced social isolation to report memory loss in both unadjusted (odds ratio [ORsometimes]: 2.56, 95% CI= 2.42-2.70, P = 0.0076) and adjusted (ORsometimes: 2.45, 95% CI= 2.32-2.60, P = 0.0298) logistic regression models. Similarly, those who reported social isolation often or always were more likely to report memory loss than those who reported rarely or never experiencing isolation in both unadjusted (ORoften/always: 5.50, 95% CI = 5.06-5.99, P < 0.0001) and adjusted logistic regression models (ORoften/always: 5.20, 95% CI = 4.75-5.68, P < 0.0001). CONCLUSIONS: The strong association between social isolation and memory loss suggests the need to develop interventions to reduce isolation and to evaluate their effects on potential future memory loss.

Social Isolation Associated with Future Health Care Utilization.

Social isolation among individuals ages 65 years and older is associated with poor health outcomes. However, little is known about health care utilization patterns of socially isolated individuals. This retrospective, observational study evaluated associations between social isolation and hospital and emergency department (ED) utilization among Medicare patients ages 65 years and older. In a cohort of 18,557 Medicare members age 65 years and older at Kaiser Permanente Northwest, the authors compared rates of hospitalization and ED visits in the 12 months following a baseline survey between respondents who reported feeling lonely or socially isolated and those who did not, controlling for demographic and health variables and utilization in the 12 months prior to the survey. Statistical analysis was conducted in February 2020. In adjusted models, those who reported "sometimes" experiencing social isolation were more likely to have at least 1 hospital admission (odds ratio [ORsometimes]: 1.17, 95% confidence interval [CI]: 1.01-1.35, P = 0.04), than those who "rarely" or "never" experienced social isolation. Those who experienced social isolation "sometimes" or "often/always" were more likely to have at least 1 ED visit (ORsometimes: 1.28, 95% CI: 1.15-1.41, P < 0.0001, and ORoften/always: 1.51, 95% CI: 1.25-1.84, P < 0.0001, respectively) than those who "rarely" or "never" experienced social isolation. These findings suggest that self-reported social isolation may be predictive of future hospital admissions and ED utilization. Research is needed to determine how addressing social isolation needs within the health care system affects health care utilization and health outcomes.

Association Between Social and Economic Needs With Future Healthcare Utilization.

INTRODUCTION: Unmet social and economic needs are associated with poor health outcomes, but little is known about how these needs are predictive of future healthcare utilization. This study examined the association of social and economic needs identified during medical visits with future hospitalizations and emergency department visits. METHODS: Individuals with electronic health record-coded social and economic needs during a primary care, emergency department, or urgent care visit at Kaiser Permanente Northwest from October 1, 2016 to November 31, 2017 (case patients) were identified, as well as individuals who had visits during that time period but had no electronic health record-coded needs (control patients). The 2 groups were compared on sociodemographic characteristics, comorbidities, and healthcare utilization in the prior year. Finally, logistic regression assessed the relationship between documented needs and hospitalizations and emergency department visits in the 12 months following the index visit, controlling for sociodemographic characteristics, comorbidities, and prior healthcare utilization. Statistical analysis was completed in April 2019. RESULTS: Case patients differed significantly from control patients on sociodemographic characteristics and had higher rates of comorbidities and prior healthcare utilization. Social and economic needs documented during the index visit were associated with significantly higher rates of hospitalization and emergency department visits in the 12 months following the visit, controlling for sociodemographic characteristics, comorbidities, and prior utilization. CONCLUSIONS: These results demonstrate that documented social and economic needs are a powerful predictor of future hospitalization and emergency department use and suggest the need for research into whether interventions to address these needs can influence healthcare utilization.

Pilot of urgent care center evaluation for acute coronary syndrome.

OBJECTIVES: Patients with chest pain and concern for potential coronary ischemia are frequently referred to the emergency department (ED), resulting in substantial resource utilization and cost. The objective of this study was to implement a protocol for urgent care center (UCC) evaluation of potential acute coronary syndrome (ACS) and describe its performance. STUDY DESIGN: This is a descriptive, retrospective review of consecutive cases included in a protocol for UCC evaluation of ACS. METHODS: Consecutive patient encounters from 4 urgent care facilities of our regional integrated health system were reviewed from a period spanning 4.5 months of the 2017 calendar year. The primary outcome was avoidance of an ED visit within 30 days of the index visit, and the primary safety outcome was serious adverse events (AEs) occurring in the UCC setting. RESULTS: There were 802 patients evaluated, with a median age of 55 years, and 58% were female. Seventy-three (9.1%) patients were referred to the ED or hospitalized for any reason at the index visit, 10 (1.2%) of whom were ultimately diagnosed with ACS. Within 30 days, 56 (7.7%) of the remaining 729 patients had ED visits or hospitalization for any reason, 2 (0.2%) of whom received a diagnosis of ACS. Overall, 673 (83.9%) patients were managed without any ED visit. No serious AEs were recorded. CONCLUSIONS: Our initial pilot data demonstrate the feasibility of an outpatient UCC evaluation for ACS without refuting the underlying premise of safety.

Changes in the chemical and dynamic properties of cardiac troponin T cause discrete cardiomyopathies in transgenic mice.

Cardiac troponin T (cTnT) is a central component of the regulatory thin filament. Mutations in cTnT have been linked to severe forms of familial hypertrophic cardiomyopathy. A mutational "hotspot" that leads to distinct clinical phenotypes has been identified at codon 92. Although the basic functional and structural roles of cTnT in modulating contractility are relatively well understood, the mechanisms that link point mutations in cTnT to the development of this complex cardiomyopathy are unknown. To address this question, we have taken a highly interdisciplinary approach by first determining the effects of the residue 92 mutations on the molecular flexibility and stability of cTnT by means of molecular dynamics simulations. To test whether the predicted alterations in thin filament structure could lead to distinct cardiomyopathies in vivo, we developed transgenic mouse models expressing either the Arg-92-Trp or Arg-92-Leu cTnT proteins in the heart. Characterization of these models at the cellular and whole-heart levels has revealed mutation-specific early alterations in transcriptional activation that result in distinct pathways of ventricular remodeling and contractile performance. Thus, our computational and experimental results show that changes in thin filament structure caused by single amino acid substitutions lead to differences in the biophysical properties of cTnT and alter disease pathogenesis.