Proportion and predictors of FVC decline in patients with interstitial lung disease.

RATIONALE: The proportion of patients who develop progressive pulmonary fibrosis (PPF), along with risk factors for progression remain poorly understood. OBJECTIVES: To examine factors associated with an increased risk of developing PPF among patients at a referral center. METHODS: We identified patients with a diagnosis of interstitial lung disease (ILD) seen within the Cleveland Clinic Health System. Utilizing a retrospective observational approach we estimated the risk of developing progression by diagnosis group and identified key clinical predictors using the FVC component of both the original progressive fibrotic interstitial lung disease (PFILD) and the proposed PPF (ATS) criteria. RESULTS: We identified 5934 patients with a diagnosis of ILD. The cumulative incidence of progression over the 24 months was similar when assessed with the PFILD and PPF criteria (33.1 % and 37.9 % respectively). Of those who met the ATS criteria, 9.5 % did not meet the PFILD criteria. Conversely, 4.3 % of patients who met PFILD thresholds did not achieve the 5 % absolute FVC decline criteria. Significant differences in the rate of progression were seen based on underlying diagnosis. Steroid therapy (HR 1.46, CI 1.31-1.62) was associated with an increased risk of progressive fibrosis by both PFILD and PPF criteria. CONCLUSION: Regardless of the definition used, the cumulative incidence of progressive disease is high in patients with ILD in the 24 months following diagnosis. Some differences are seen in the risk of progression when assessed by PFILD and PPF criteria. Further work is needed to identify modifiable risk factors for the development of progressive fibrosis.

Real-world impact of empagliflozin on total cost of care in adults with type 2 diabetes: Results from an outcomes-based agreement.

BACKGROUND: Value-based health care is expanding through payment models such as outcomes-based agreements between manufacturers and payers. OBJECTIVE: To describe the total-cost-of-care outcomes of an outcomes-based agreement evaluating the real-world impact of empagliflozin vs other type 2 diabetes mellitus (T2DM) drugs among all patients with T2DM, with and without cardiovascular disease (within and beyond the requirement of the agreement). METHODS: In this prospective real-world analysis, members from the health plan of an integrated health care delivery system from the commercial and Medicare Advantage lines of business, who qualify under the confines of the contract, were included for analysis. Thus, members aged 18 years and older who were continuously enrolled in the identification (January 1, 2018, to December 31, 2018) and measurement periods (≤1 year post-index) with a T2DM diagnosis were retained. Patients using empagliflozin and empagliflozin-combination drugs constituted the empagliflozin group; those using all other antihyperglycemics, the nonempagliflozin group. Patients with type 1 diabetes, or those using metformin or insulin monotherapy, at index were excluded. Eligible members were followed for up to the earliest occurrence of disenrollment date, discontinuation (60-day medication fill gap allowed) of empagliflozin (or nonempagliflozin containing) medication, or the end of the measurement period. We compared, using Student's t-test and summary statistics (for reporting the outcomes agreement) and a propensity-matched difference-in-difference model (for the followup evaluation beyond the requirement of the agreement), the mean all-cause total cost of care (pharmacy plus medical) per patient per month (PPPM) between the 2 groups, including a subgroup of members with a baseline cardiovascular disease diagnosis. RESULTS: There were 4,577 (3,069 and 1,508 in the commercial and Medicare) and 33,712 (15,571 and 18,141 in the commercial and Medicare) in the empagliflozin and nonempagliflozin groups, respectively. The difference in mean total cost PPPM was $75 lower for empagliflozin vs nonempagliflozin groups, driven mainly by lower medical costs in the empagliflozin group (-$465 PPPM). However, the difference was not statistically significant in the propensity score-matched model. CONCLUSIONS: Although empagliflozin had higher pharmacy costs, the total cost of care for patients with T2DM and with established cardiovascular disease were comparable to the group of patients with all other T2DM, driven mainly by lower medical costs. DISCLOSURES: The authors report no conflicts of interest beyond being employees of the 2 organizations involved in this outcomes-based agreement. Ms. Palli is a former employee of Boehringer Ingelheim Pharmaceuticals, Inc., who was affiliated at the time of study conduct.

Burden of hospitalization for heart failure in the United States: a systematic literature review.

BACKGROUND: Heart failure (HF) affects approximately 6 million Americans, with prevalence projected to increase by 46% and direct medical costs to reach $53 billion by 2030. Hospitalizations are the largest component of direct costs for HF; however, recent syntheses of the economic and clinical burden of hospitalization for heart failure (HHF) are lacking. OBJECTIVE: To synthesize contemporary estimates of cost and clinical outcomes of HHF in the United States. METHODS: A systematic literature review was conducted using MEDLINE and Embase to identify articles reporting cost or charge per HHF in the United States published between January 2014 and May 2019. Subgroups of interest were those with both HF and renal disease or diabetes, as well as HF with reduced or preserved ejection fraction (HFrEF or HFpEF). RESULTS: 23 studies reporting cost and/or charge per HHF were included. Sample sizes ranged from 989 to approximately 11 million (weighted), mean age from 65 to 83 years, and 39% to 74% were male. Cost per HHF ranged from $7,094 to $9,769 (median) and $10,737 to $17,830 (mean). Charge per HHF ranged from $22,162 to $40,121 (median), and $50,569 to $50,952 (mean). Among patients with renal disease, HHF mean cost ranged from $9,922 to $41,538. For those with HFrEF or HFpEF, mean cost ranged from $11,600 to $17,779 and $7,860 to $10,551, respectively. No eligible studies were identified that reported HHF costs or charges among patients with HF and diabetes. Cost and charge per HHF increased with length of stay, which ranged from 3 to 5 days (median) and 4 to 7 days (mean). CONCLUSIONS: This synthesis demonstrates the substantial economic burden of HHF and the variability in estimates of this burden. Factors contributing to variability in estimates include length of stay, age and sex of the sample, HF severity, and frequencies of comorbidities. Further research into cost drivers of HHF is warranted to understand potential mechanisms to reduce associated costs. DISCLOSURES: This study was funded by Boehringer Ingelheim Pharmaceuticals. Osenenko, Deighton, and Szabo are employees of Broadstreet HEOR, which received funds from Boehringer Ingelheim Pharmaceuticals for this work. Kuti and Pimple are employees of Boehringer Ingelheim Pharmaceuticals. This study was presented in abstract form at the 2020 American Heart Association (AHA) Quality of Care and Outcomes Research (QCOR) 2020 Scientific Sessions (May 15-16, Virtual Meeting).

Healthcare Costs and Resource Utilization Associated with the Use of Empagliflozin Versus Other Antihyperglycemic Agents Among Patients with Type 2 Diabetes Mellitus and Cardiovascular Disease: A Real-World Retrospective Cohort Analysis.

INTRODUCTION: Empagliflozin has demonstrated lower rates of cardiovascular outcomes vs. standard of care among patients with type 2 diabetes mellitus (T2DM) and cardiovascular disease (CVD). However, the impact of empagliflozin compared to other branded antihyperglycemic agents (AHAs) on total cost of care has yet to be quantified. METHODS AND RESULTS: This retrospective cohort study evaluated the impact of empagliflozin (n = 441) on costs and healthcare resource utilization (HCRU) vs. other branded AHAs (n = 13,122) among patients with T2DM and CVD, using the IQVIA PharMetrics® Plus Claims Database (1 August 2013-31 December 2017). Date of the first prescription (index date) for empagliflozin or other branded AHAs was used to classify patients into study cohorts. All-cause costs and HCRU were computed on a per patient per month (PPPM) basis and compared across study cohorts using outcome-appropriate statistical models. Overall, the empagliflozin cohort was younger and had a lower comorbidity burden. After covariate adjustment, the total all-cause costs (mean difference - $412 PPPM; 95% CI - $593, - $214) were significantly lower for the empagliflozin cohort. These cost differences were mainly driven by lower all-cause medical costs (mean difference - $400 PPPM; 95% CI - $577, - $196). For HCRU, the mean adjusted all-cause visits in the physician office and other outpatient settings were lower with empagliflozin vs. other branded AHAs (p < 0.001). CONCLUSIONS: This study demonstrated that the all-cause healthcare costs and HCRU were significantly lower for patients with T2DM and CVD who initiated empagliflozin vs. other branded AHAs. Along with the positive clinical evidence base of empagliflozin, these results can guide healthcare decision makers during therapy selection.

Cost-effectiveness of second-line empagliflozin versus liraglutide for type 2 diabetes in the United States.

AIM: To estimate the cost-effectiveness of sequential use of the sodium-glucose co-transporter-2 inhibitor empagliflozin and glucagon-like peptide-1 receptor agonist liraglutide after metformin in patients with type 2 diabetes (T2D) from the US payer perspective. MATERIALS AND METHODS: An economic simulation model with a lifetime horizon was developed to estimate T2D-related complications (including cardiovascular [CV] death, myocardial infarction, stroke, and renal outcomes) using EMPA-REG OUTCOME data or UK Prospective Diabetes Study risk equations, in patients with or without a history of cardiovascular disease (CVD), respectively. Evidence synthesis methods were used to provide effectiveness inputs for empagliflozin and liraglutide. Population characteristics, adverse event rates, treatment escalation, costs ($2019), and utilities (both discounted 3%/year) were taken from US sources. RESULTS: Compared with second-line liraglutide in the overall T2D population, second-line empagliflozin was dominant as it was associated with lower total lifetime cost ($11 244/patient less) and resulted in a quality-adjusted life-year (QALY) gain (0.32/patient). Second-line empagliflozin was associated with reductions in CV death (by 5%) and lower cumulative complication rates in patients with CVD (by 2%), relative to second-line liraglutide. These findings were consistent among patients with co-morbid CVD, with gains in incremental QALYs (0.43/patient) and lower lifetime cost (by $10 175/patient) relative to second-line liraglutide. Scenario analyses consistently showed dominance for second-line empagliflozin. CONCLUSION: For patients with T2D, use of second-line empagliflozin combined with metformin was a dominant strategy for US payers, associated with extended survival, improved QALYs, and lower costs compared with second-line liraglutide.

Cardiovascular risk prediction model and stratification in patients with type 2 diabetes enrolled in a Medicare Advantage plan.

BACKGROUND: Cardiovascular (CV) risk tools have been developed both nationally and internationally to identify patients at risk for developing CV disease or experiencing a CV event. However, these tools vary widely in the definitions of endpoints, the time at which the endpoints are measured, patient populations, and their validity. The primary limitation of some of the most commonly utilized tools is the lack of specificity for a type 2 diabetes (T2D) population and/or among older patients. OBJECTIVE: To develop a predictive model within an older population of patients with T2D to identify patients at risk for CV events. METHODS: This retrospective cohort study used claims, laboratory, and enrollment data during the 2011-2018 study period. Patients with T2D were identified based on diagnoses and/or medications from 2012-2013. The patient cohort was split into 3 different datasets. The holdout dataset included only those patients residing in the northeastern United States. The rest of the sample was then randomly split: 70% for the training dataset, which were used to fit the predictive model, and 30% for the test dataset to assess internal validity. The primary outcome was the first composite CV event defined as at least 1 of the following: inpatient hospitalization for myocardial infarction, ischemic stroke, unstable angina, or heart failure; or any evidence of revascularization. A survival model for the composite outcome was fitted with baseline demographic and clinical characteristics prognostic for the dependent variable utilizing augmented backwards elimination. For assessing model performance, accuracy, sensitivity, specificity, and the c-statistic were used. Patients were ranked as having a low, moderate, or high probability of a future CV event. RESULTS: A total of 362,791 patients were identified. The holdout dataset included only those patients residing in the northeastern United States (n = 8,303). There were 248,142 patients included in the training dataset and 106,346 patients in the test dataset. The proportion with at least 1 observed composite CV event was 20.9%. The final model included 42 variables. The c-statistic was 0.68, and the accuracy, sensitivity, and specificity were approximately 63%. Results were consistent across the training, test, and holdout samples. The optimal cut points minimizing the difference in sensitivity and specificity for low-, moderate-, and high-risk future CV events were determined to be less than 0.18, 0.18-0.63, and greater than 0.63, respectively, in the training dataset at 5 years. The 5-year observed event risk was 11%, 27%, and 51% for patients classified as low, moderate, and high risk of a future CV event, respectively. CONCLUSIONS: A model predicting CV events among older patients with T2D using administrative claims to identify those at risk may be used for focusing interventions to prevent future events. DISCLOSURES: This study was funded by Boehringer Ingelheim (BI) and conducted as part of the BI-Humana Research Collaboration. Caplan is employed by Humana Healthcare Research, Inc., a wholly owned subsidiary of Humana Inc., which received fees to conduct the study from the sponsor BI. At the time of the study, Hayden and Harvey were employees of Humana Healthcare Research, Inc. Additionally, Prewitt, who owns stock in Humana Inc, and Chiguluri are employees of Humana Inc. Kattan, associated with the Cleveland Clinic in Ohio, served as a consultant to BI, and Pimple and Goss are employees of BI. Luthra was employed by BI for the duration of the study. Portions of this work were accepted as an abstract and presented as a poster at the American Diabetes Association 2020 virtual meeting, June 12-16, 2020.

Cost-effectiveness analysis of empagliflozin versus sitagliptin as second-line therapy for treatment in patients with type 2 diabetes in the United States.

AIM: To estimate the cost-effectiveness of sequential addition of empagliflozin versus sitagliptin after metformin in patients with type 2 diabetes (T2D) with or without cardiovascular disease (CVD) from the perspective of the US healthcare payer. METHODS: An individual simulation model predicted lifetime diabetes-related complications, using UKPDS-OM2 equations in patients without CVD, and EMPA-REG OUTCOME equations in patients with CVD. Additional US-based sources informed inputs for population characteristics, adverse events, non-CV death, treatment escalation, quality of life and costs. Costs and quality-adjusted life-years (QALYs) were discounted 3.0% annually. RESULTS: The incremental cost-effectiveness ratio (ICER) for second-line empagliflozin versus sitagliptin in the overall T2D population was $6967/QALY. Empagliflozin led to longer CVD-free survival (0.07 years) and an 11% reduction in CV death in patients with CVD compared with sitagliptin. Empagliflozin resulted in greater benefits with greater costs in patients with versus without baseline CVD, yielding ICERs of $3589/QALY versus $12 577/QALY, respectively. Results were consistent across a range of deterministic and probabilistic sensitivity analyses and scenarios. CONCLUSION: Compared with sitagliptin, empagliflozin was cost-effective (at $50 000/QALY US threshold) as a second-line treatment to metformin for T2D patients with or without CVD in the United States. Our findings lend additional support for more widespread adoption of guidelines by healthcare decision-makers for T2D treatment.

Longitudinal associations between self-reported experiences of discrimination and depressive symptoms in young women and men post- myocardial infarction.

Objectives: Research suggests that following a myocardial infarction (MI), women under the age of 60 have more elevated depressive symptoms and adverse outcomes than similarly aged men. Identifying risk factors that contribute to gender differences in depressive symptoms among this group may be critical to the development of psychosocial interventions. Experiences of discrimination may be an important correlate of depressive symptoms in this group; however, studies of this relationship have largely been cross-sectional and focused on healthy populations. This study examines longitudinal associations among gender, discrimination, and depressive symptoms in a young post-MI cohort. Methods: Participants were 313 adults from the Myocardial Infarction and Mental Stress Ischemia Study 2 of young (≤60 yrs) post-MI patients. At baseline and 6 month follow-up, depressive symptoms were measured with the Beck Depression Inventory-II and discrimination was assessed with the 10-item version Everyday Discrimination scale. Linear regression models were used to assess the longitudinal association between reports of discrimination and depressive symptoms adjusted for sociodemographic characteristics, psychosocial factors and health status indicators and tested for gender differences. Results: The mean age was 51.2, 49.6% were women, and 69.5% were African-American. Although the discrimination-by-gender interaction was marginally significant (p=.09) in the fully adjusted model, findings suggest that the association between changes in reports of discrimination and depressive symptoms over time may be more pronounced for women (ß=.61, standard error=.15, p<.001) than men (ß=.27, standard error=.13, p=.033). Conclusion: Our findings suggest that discrimination is a risk factor for depressive symptoms in young post-MI populations over time.

Psychological Distress and Subsequent Cardiovascular Events in Individuals With Coronary Artery Disease.

Background Higher symptom levels of a variety of measures of emotional distress have been associated with cardiovascular disease ( CVD ), especially among women. Here, our goal was to investigate the association between a composite measure of psychological distress and incident cardiovascular events. Methods and Results In a prospective cohort study, we assessed 662 individuals (28% women; 30% blacks) with stable coronary artery disease. We used a composite score of psychological distress derived through summation of Z-transformed psychological distress symptom scales (depression, posttraumatic stress, anxiety, anger, hostility, and perceived stress) as a predictor of an adjudicated composite end point of adverse events (cardiovascular death, myocardial infarction, stroke, heart failure, or unstable angina). During a mean follow-up of 2.8 years, 120 (18%) subjects developed CVD events. In the overall population, there was no association between the psychological distress measure and CVD events, but there was a sex-based interaction ( P=0.004). In women, higher psychological distress was associated with a higher incidence of CVD events; each SD increase in the composite score of psychological distress was associated with 1.44 times adjusted hazard of CVD events (95% CI, 1.09-1.92). No such association was found in men. Conclusions Among patients with coronary artery disease, higher psychological distress is associated with future cardiovascular events in women only.

The Relation of Psychosocial Distress With Myocardial Perfusion and Stress-Induced Myocardial Ischemia.

OBJECTIVE: Mental stress-induced myocardial ischemia is a frequent phenomenon in patients with coronary artery disease (CAD). The link between an integrated measure of chronic psychosocial distress and mental stress-induced myocardial ischemia, and whether it differs by sex, has not been examined before. METHODS: We used latent class analysis to derive a composite measure of psychosocial distress integrating scales of depression, posttraumatic stress, anxiety, anger, hostility, and perceived stress in 665 individuals with stable CAD. Participants underwent myocardial perfusion imaging with mental stress and perfusion defects were quantified at rest (summed rest score), with mental stress (summed stress score), and their difference (summed difference score), the latter being an index of inducible ischemia. RESULTS: The M (SD) age was 63 (9) years, and 185 (28%) were women. Latent class analysis characterized the study sample into four distinct classes of incremental psychosocial distress. In women, class 4 (highest distress) had an adjusted 4.0-point higher summed rest score (95% confidence interval = 0.2-7.7) as compared with class 1 (lowest distress), whereas no difference was observed in men (-0.87 points, 95% confidence interval = -3.74 to 1.99, p = .04 for interaction). There was no association between the psychosocial distress latent variable and summed difference score in either women or men. CONCLUSIONS: Among patients with CAD, a higher level of psychosocial distress is not associated with mental stress ischemia, but it is associated with more resting (fixed) perfusion abnormalities in women only, as well as with blunted hemodynamic response to mental stress in both men and women.

Brain correlates of stress-induced peripheral vasoconstriction in patients with cardiovascular disease.

The influence of acute psychological stress on cardiovascular disease is an emerging public health concern. Identification of brain mechanisms underlying this may aid in the discovery of possible treatments. Acute psychological stress may induce arteriolar vasoconstriction and reduce blood flow to vital organs. We hypothesized that functional changes in brain regions involved with memory and autonomic/emotional regulation are implicated in the vasoconstrictive stress response, including the medial prefrontal cortex (anterior cingulate), insula, and dorsolateral prefrontal cortex. Subjects with a history of coronary artery disease (N = 59) underwent measurement of microvascular vasomotor tone with the EndoPAT device and O-15 positron emission tomography (PET) imaging of the brain during exposure to mental stress and control conditions. The peripheral arterial tonometry (PAT) ratio was calculated as the mean peripheral vasomotor tone during stress divided by the mean tone during rest. Whole brain contrasts were performed between groups above and below the median PAT ratio, and significant contrasts were defined with cutoff p < 0.005. Stress-induced peripheral vasoconstriction (below median PAT ratio) was associated with increased stress activation in insula and parietal cortex, and decreased activation in the medial prefrontal cortex with stress tasks compared to control tasks. These findings demonstrate that stress-induced vasoreactivity is associated with changes in brain responses to stress in areas involved in emotion and autonomic regulation. These findings have important implications on possible treatments for mental stress-induced vascular toxicity.

Longitudinal association of inflammation with depressive symptoms: A 7-year cross-lagged twin difference study.

BACKGROUND: The direction of the association between inflammation and depressive symptoms remains inconsistent. The objective of this study was to evaluate the temporal relationship between inflammation and depressive symptoms, and to assess the role of genetic factors on this association. METHODS: In this longitudinal cross-lagged twin difference study, we examined 166 (83 pairs) middle-aged male twins recruited from the Vietnam Era Twin Registry, who were assessed at baseline and after 7 years of follow-up. We assayed plasma levels of two inflammatory biomarkers, interleukin-6 (IL-6) and high sensitivity C-reactive protein (CRP) and measured depressive symptoms using the Beck Depression Inventory-II (BDI). To evaluate the direction of the association, we constructed multivariable mixed-effects regression models and calculated standardized beta-coefficients to compare the strength of the within-pair association for both pathways. We then conducted a stratified analysis by zygosity and assessed the associations in monozygotic and dizygotic twin pairs separately. RESULTS: The 166 twins were 95% white and had a mean (SD) age of 54 (3) years at baseline. The cross-lagged analysis showed significant and positive associations from visit 1 IL-6 to visit 2 BDI across all models (beta-coefficients ranging from 0.18 to 0.22). However, the opposite pathway (visit 1 BDI to visit 2 IL-6) was not significant after adjusting for confounding factors. In contrast, visit 1 BDI was significantly associated with visit 2 CRP in all models (beta-coefficients ranging from 0.23 to 0.33), while the opposite pathway (visit 1 CRP to visit 2 BDI) showed no significant association. When stratifying by zygosity, significant associations from IL-6 to depression were only seen in monozygotic twins, but associations from depression to CRP were more robust in dizygotic twins, which implies that genetic factors may play a role in this association. CONCLUSIONS: The association between inflammation and depression may be bidirectional. Elevated IL-6 levels are more likely to be a risk factor of depression rather than a consequence, while the opposite may be true for elevated CRP. The biological underpinnings of these bidirectional pathways need further evaluation.

Use of High-Sensitivity Cardiac Troponin for the Exclusion of Inducible Myocardial Ischemia: A Cohort Study.

Background: Many patients with coronary artery disease (CAD) are routinely referred for surveillance stress testing despite recommendations against it. Objective: To determine whether low levels of resting high-sensitivity cardiac troponin I (hs-cTnI) can identify persons without inducible myocardial ischemia. Design: Observational study. Setting: A university-affiliated hospital network. Patients: Persons with stable CAD: 589 in the derivation group and 118 in the validation cohort. Measurements: Presence of inducible myocardial ischemia was determined by myocardial perfusion imaging with technetium-99m single-photon emission computed tomography during either treadmill or pharmacologic stress testing. Resting plasma hs-cTnI was measured within 1 week of the stress test, and the negative predictive value (NPV) for inducible ischemia was calculated. The derivation cohort was followed for 3 years for incident cardiovascular death and myocardial infarction. Results: In the derivation cohort, 10 of 101 patients with an hs-cTnI level below 2.5 pg/mL had inducible myocardial ischemia (NPV, 90% [95% CI, 83% to 95%]) and 3 of 101 had inducible ischemia involving at least 10% of the myocardium (NPV, 97% [CI, 92% to 99%]). In the validation cohort, 4 of 32 patients with an hs-cTnI level below 2.5 pg/mL had inducible ischemia (NPV, 88% [CI, 71% to 96%]) and 2 of 32 had ischemia of 10% or greater (NPV, 94% [CI, 79% to 99%]). After a median follow-up of 3 years in the derivation cohort, no adverse events occurred in patients with an hs-cTnI level below 2.5 pg/mL, compared with 33 (7%) cardiovascular deaths or incident myocardial infarctions among those with an hs-cTnI level of 2.5 pg/mL or greater. Limitation: The data may not be applicable to a population without known CAD or to persons with unstable angina, and the modest sample sizes warrant further validation in a larger cohort. Conclusion: Very low hs-cTnI levels may be useful in excluding inducible myocardial ischemia in patients with stable CAD. Primary Funding Source: National Institutes of Health.

Association of Depressive Symptoms and Heart Rate Variability in Vietnam War-Era Twins: A Longitudinal Twin Difference Study.

Importance: Depressive symptoms are associated with lower heart rate variability (HRV), an index of autonomic dysregulation, but the direction of the association remains unclear. Objective: To investigate the temporal association between depression and HRV. Design, Settings, and Participants: A longitudinal, cross-lagged twin difference study, with baseline assessments from March 2002 to March 2006 (visit 1) and a 7-year follow-up (visit 2) at an academic research center with participants recruited from a national twin registry. Twins (n = 166) from the Vietnam Era Twin Registry, who served in the US military during the Vietnam War, and were discordant for depression at baseline were recruited. Main Outcomes and Measures: At both visits, depressive symptoms were measured using the Beck Depression Inventory-II (BDI-II), and HRV was measured through 24-hour electrocardiogram monitoring. To assess the direction of the association, within-pair differences in multivariable mixed-effects regression models were examined, and standardized ß coefficients for both pathways were calculated. The associations were evaluated separately in monozygotic and dizygotic twins. Results: In the final analytic sample (N = 146), all participants were men, 138 (95%) were white, and the mean (SD) age was 54 (3) years at baseline. Results showed consistent associations between visit 1 HRV and visit 2 BDI score across all HRV domains and models (ß coefficients ranging from -0.14 to -0.29), which were not explained by antidepressants or other participant characteristics. The magnitude of the association was similar in the opposite pathway linking visit 1 BDI score to visit 2 HRV, with ß coefficients ranging from 0.05 to -0.30, but it was largely explained by antidepressant use. In stratified analysis by zygosity, significant associations were observed in monozygotic and dizygotic twins for the path linking visit 1 HRV to visit 2 BDI score, although the associations were slightly stronger in dizygotic twins. Conclusions and Relevance: The association between depression and autonomic dysregulation, indexed by HRV, is bidirectional, with stronger evidence suggesting that autonomic function affects depression risk rather than vice versa. The opposite causal pathway from depression to lower HRV is mostly driven by antidepressant use. These findings highlight an important role of autonomic nervous system in the risk of depression and contribute new understanding of the mechanisms underlying the comorbidity of depression and cardiovascular disease.

Mental Stress-Induced-Myocardial Ischemia in Young Patients With Recent Myocardial Infarction: Sex Differences and Mechanisms.

BACKGROUND: Mental stress-induced myocardial ischemia (MSIMI) is frequent in patients with coronary artery disease and is associated with worse prognosis. Young women with a previous myocardial infarction (MI), a group with unexplained higher mortality than men of comparable age, have shown elevated rates of MSIMI, but the mechanisms are unknown. METHODS: We studied 306 patients (150 women and 156 men) ≤61 years of age who were hospitalized for MI in the previous 8 months and 112 community controls (58 women and 54 men) frequency matched for sex and age to the patients with MI. Endothelium-dependent flow-mediated dilation and microvascular reactivity (reactive hyperemia index) were measured at rest and 30 minutes after mental stress. The digital vasomotor response to mental stress was assessed using peripheral arterial tonometry. Patients received 99mTc-sestamibi myocardial perfusion imaging at rest, with mental (speech task) and conventional (exercise/pharmacological) stress. RESULTS: The mean age of the sample was 50 years (range, 22-61). In the MI group but not among controls, women had a more adverse socioeconomic and psychosocial profile than men. There were no sex differences in cardiovascular risk factors, and among patients with MI, clinical severity tended to be lower in women. Women in both groups showed a higher peripheral arterial tonometry ratio during mental stress but a lower reactive hyperemia index after mental stress, indicating enhanced microvascular dysfunction after stress. There were no sex differences in flow-mediated dilation changes with mental stress. The rate of MSIMI was twice as high in women as in men (22% versus 11%, P=0.009), and ischemia with conventional stress was similarly elevated (31% versus 16%, P=0.002). Psychosocial and clinical risk factors did not explain sex differences in inducible ischemia. Although vascular responses to mental stress (peripheral arterial tonometry ratio and reactive hyperemia index) also did not explain sex differences in MSIMI, they were predictive of MSIMI in women only. CONCLUSIONS: Young women after MI have a 2-fold likelihood of developing MSIMI compared with men and a similar increase in conventional stress ischemia. Microvascular dysfunction and peripheral vasoconstriction with mental stress are implicated in MSIMI among women but not among men, perhaps reflecting women's proclivity toward ischemia because of microcirculatory abnormalities.

Myocardial Ischemia and Mobilization of Circulating Progenitor Cells.

BackgroundThe response of progenitor cells (PCs) to transient myocardial ischemia in patients with coronary artery disease remains unknown. We aimed to investigate the PC response to exercise-induced myocardial ischemia (ExMI) and compare it to flow mismatch during pharmacological stress testing. Methods and ResultsA total of 356 patients with stable coronary artery disease underwent 99mTc-sestamibi myocardial perfusion imaging during exercise (69%) or pharmacological stress (31%). CD34+ and CD34+/chemokine (C-X-C motif) receptor 4 PCs were enumerated by flow cytometry. Change in PC count was compared between patients with and without myocardial ischemia using linear regression models. Vascular endothelial growth factor and stromal-derived factor-1α were quantified. Mean age was 63±9 years; 76% were men. The incidence of ExMI was 31% and 41% during exercise and pharmacological stress testing, respectively. Patients with ExMI had a significant decrease in CD34+/chemokine (C-X-C motif) receptor 4 (-18%, P=0.01) after stress that was inversely correlated with the magnitude of ischemia (r=-0.19, P=0.003). In contrast, patients without ExMI had an increase in CD34+/chemokine (C-X-C motif) receptor 4 (14.7%, P=0.02), and those undergoing pharmacological stress had no change. Plasma vascular endothelial growth factor levels increased (15%, P<0.001) in all patients undergoing exercise stress testing regardless of ischemia. However, the change in stromal-derived factor-1α level correlated inversely with the change in PC counts in those with ExMI (P=0.03), suggesting a greater decrease in PCs in those with a greater change in stromal-derived factor-1α level with exercise. ConclusionsExMI is associated with a significant decrease in circulating levels of CD34+/chemokine (C-X-C motif) receptor 4 PCs, likely attributable, at least in part, to stromal-derived factor-1α-mediated homing of PCs to the ischemic myocardium. The physiologic consequences of this uptake of PCs and their therapeutic implications need further investigation.

Association Between High-Sensitivity Cardiac Troponin Levels and Myocardial Ischemia During Mental Stress and Conventional Stress.

OBJECTIVES: This study sought to investigate whether patients with mental stress-induced myocardial ischemia will have high resting and post-mental stress high-sensitivity cardiac troponin I (hs-cTnI). BACKGROUND: Hs-cTnI is a marker of myocardial necrosis, and its elevated levels are associated with adverse outcomes. Hs-cTnI levels may increase with exercise in patients with coronary artery disease. Mental stress-induced myocardial ischemia is also linked to adverse outcomes. METHODS: In this study, 587 patients with stable coronary artery disease underwent technetium Tc 99m sestamibi-single-photon emission tomography myocardial perfusion imaging during mental stress testing using a public speaking task and during conventional (pharmacological/exercise) stress testing as a control condition. Ischemia was defined as new/worsening impairment in myocardial perfusion using a 17-segment model. RESULTS: The median hs-cTnI resting level was 4.3 (interquartile range [IQR]: 2.9 to 7.3) pg/ml. Overall, 16% and 34.8% of patients developed myocardial ischemia during mental and conventional stress, respectively. Compared with those without ischemia, median resting hs-cTnI levels were higher in patients who developed ischemia either during mental stress (5.9 [IQR: 3.9 to 8.3] pg/ml vs. 4.1 [IQR: 2.7 to 7.0] pg/ml; p < 0.001) or during conventional stress (5.4 [IQR: 3.9 to 9.3] pg/ml vs. 3.9 [IQR: 2.5 to 6.5] pg/ml; p < 0.001). Patients with high hs-cTnI (cutoff of 4.6 pg/ml for men and 3.9 pg/ml for women) had greater odds of developing mental (odds ratio [OR]: 2.4; 95% confidence interval [CI]: 1.5 to 3.9; p < 0.001) and conventional (OR: 2.4; 95% CI: 1.7 to 3.4; p < 0.001) stress-induced ischemia. Although there was a significant increase in 45-min post-treadmill exercise hs-cTnI levels in those who developed ischemia, there was no significant increase after mental or pharmacological stress test. CONCLUSIONS: In patients with coronary artery disease, myocardial ischemia during either mental stress or conventional stress is associated with higher resting levels of hs-cTnI. This suggests that hs-cTnI elevation is an indicator of chronic ischemic burden experienced during everyday life. Whether elevated hs-cTnI levels are an indicator of adverse prognosis beyond inducible ischemia or whether it is amenable to intervention requires further investigation.

Sex Differences in Hemodynamic and Microvascular Mechanisms of Myocardial Ischemia Induced by Mental Stress.

OBJECTIVE: To investigate sex-specific vascular mechanisms for mental stress-induced myocardial ischemia (MSIMI). APPROACH AND RESULTS: Baseline data from a prospective cohort study of 678 patients with coronary artery disease underwent myocardial perfusion imaging before and during a public speaking stressor. The rate-pressure product response was calculated as the difference between the maximum value during the speech minus the minimum value during rest. Peripheral vasoconstriction by peripheral arterial tonometry was calculated as the ratio of pulse wave amplitude during the speech over the resting baseline; ratios <1 indicate a vasoconstrictive response. MSIMI was defined as percent of left ventricle that was ischemic and as a dichotomous variable. Men (but not women) with MSIMI had a higher rate-pressure product response than those without MSIMI (6500 versus 4800 mm Hg bpm), whereas women (but not men) with MSIMI had a significantly lower peripheral arterial tonometry ratio than those without MSIMI (0.5 versus 0.8). In adjusted linear regression, each 1000-U increase in rate-pressure product response was associated with 0.32% (95% confidence interval, 0.22-0.42) increase in inducible ischemia among men, whereas each 0.10-U decrease in peripheral arterial tonometry ratio was associated with 0.23% (95% confidence interval, 0.11-0.35) increase in inducible myocardial ischemia among women. Results were independent of conventional stress-induced myocardial ischemia. CONCLUSIONS: Women and men have distinct cardiovascular reactivity mechanisms for MSIMI. For women, stress-induced peripheral vasoconstriction with mental stress, and not increased hemodynamic workload, is associated with MSIMI, whereas for men, it is the opposite. Future studies should examine these pathways on long-term outcomes.

Chest Pain and Mental Stress-Induced Myocardial Ischemia: Sex Differences.

BACKGROUND: Mental stress-induced myocardial ischemia is a frequent phenomenon in patients with coronary artery disease. Women with coronary artery disease tend to have more mental stress-induced myocardial ischemia and more chest pain/anginal symptoms than men, but whether the association between mental stress-induced myocardial ischemia and angina burden differs in women and men is unknown. METHODS: This was a cross-sectional study with experimental manipulation of 950 individuals with stable coronary artery disease. Chest pain/angina frequency in the previous 4 weeks was assessed with the Seattle Angina Questionnaire's angina-frequency subscale. Mental stress-induced myocardial ischemia was assessed with myocardial perfusion imaging during mental stress (standardized public speaking task). Presence of mental stress-induced myocardial ischemia was based on expert readers and established criteria. A conventional (exercise or pharmacologic) stress test was used as a control condition. RESULTS: Overall, 338 individuals (37%) reported angina; 112 (12%) developed mental stress-induced myocardial ischemia, and 256 (29%) developed conventional stress ischemia. Women who reported angina had almost double the probability to develop mental stress-induced myocardial ischemia (19% vs 10%, adjusted prevalence rate ratio, 1.90; 95% confidence interval, 1.04-3.46), whereas there was no such difference in men (11% vs 11%, adjusted prevalence rate ratio, 1.09; 95% confidence interval, 0.66-1.82). No association was found between angina symptoms and conventional stress ischemia for women or men. Results for ischemia as a continuous variable were similar. CONCLUSIONS: In women, but not in men, anginal symptoms may be a marker of vulnerability toward ischemia induced by psychologic stress. These results highlight the psychosocial origins of angina in women and may have important implications for the management and prognosis of women with angina.

Inflammatory response to mental stress and mental stress induced myocardial ischemia.

BACKGROUND: Mental stress-induced myocardial ischemia (MSIMI) is associated with increased risk of adverse cardiovascular outcomes, yet the underlying mechanisms are not well understood. We measured the inflammatory response to acute laboratory mental stress in patients with coronary artery disease (CAD) and its association with MSIMI. We hypothesized that patients with MSIMI would have a higher inflammatory response to mental stress in comparison to those without ischemia. METHODS: Patients with stable CAD underwent 99mTc sestamibi myocardial perfusion imaging during mental stress testing using a public speaking stressor. MSIMI was determined as impaired myocardial perfusion using a 17-segment model. Inflammatory markers including interleukin-6 (IL-6), monocyte chemoattractant protein-1 (MCP-1), matrix metallopeptidase 9 (MMP-9) and high-sensitivity C reactive protein (hsCRP) were measured at rest and 90 min after mental stress. Results were validated in an independent sample of 228 post-myocardial infarction patients. RESULTS: Of 607 patients analyzed in this study, (mean age 63 ±â€¯9 years, 76% male), 99 (16.3%) developed MSIMI. Mental stress resulted in a significant increase in IL-6, MCP-1, and MMP-9 (all p <0.0001), but not hsCRP. However, the changes in these markers were similar in those with and without MSIMI. Neither resting levels of these biomarkers, nor their changes with mental stress were significantly associated with MSIMI. Results in the replication sample were similar. CONCLUSION: Mental stress is associated with acute increases in several inflammatory markers. However, neither the baseline inflammatory status nor the magnitude of the inflammatory response to mental stress over 90 min were significantly associated with MSIMI.