Alignment Between Heart Rate Variability From Fitness Trackers and Perceived Stress: Perspectives From a Large-Scale In Situ Longitudinal Study of Information Workers.

BACKGROUND: Stress can have adverse effects on health and well-being. Informed by laboratory findings that heart rate variability (HRV) decreases in response to an induced stress response, recent efforts to monitor perceived stress in the wild have focused on HRV measured using wearable devices. However, it is not clear that the well-established association between perceived stress and HRV replicates in naturalistic settings without explicit stress inductions and research-grade sensors. OBJECTIVE: This study aims to quantify the strength of the associations between HRV and perceived daily stress using wearable devices in real-world settings. METHODS: In the main study, 657 participants wore a fitness tracker and completed 14,695 ecological momentary assessments (EMAs) assessing perceived stress, anxiety, positive affect, and negative affect across 8 weeks. In the follow-up study, approximately a year later, 49.8% (327/657) of the same participants wore the same fitness tracker and completed 1373 EMAs assessing perceived stress at the most stressful time of the day over a 1-week period. We used mixed-effects generalized linear models to predict EMA responses from HRV features calculated over varying time windows from 5 minutes to 24 hours. RESULTS: Across all time windows, the models explained an average of 1% (SD 0.5%; marginal R2) of the variance. Models using HRV features computed from an 8 AM to 6 PM time window (namely work hours) outperformed other time windows using HRV features calculated closer to the survey response time but still explained a small amount (2.2%) of the variance. HRV features that were associated with perceived stress were the low frequency to high frequency ratio, very low frequency power, triangular index, and SD of the averages of normal-to-normal intervals. In addition, we found that although HRV was also predictive of other related measures, namely, anxiety, negative affect, and positive affect, it was a significant predictor of stress after controlling for these other constructs. In the follow-up study, calculating HRV when participants reported their most stressful time of the day was less predictive and provided a worse fit (R2=0.022) than the work hours time window (R2=0.032). CONCLUSIONS: A significant but small relationship between perceived stress and HRV was found. Thus, although HRV is associated with perceived stress in laboratory settings, the strength of that association diminishes in real-life settings. HRV might be more reflective of perceived stress in the presence of specific and isolated stressors and research-grade sensing. Relying on wearable-derived HRV alone might not be sufficient to detect stress in naturalistic settings and should not be considered a proxy for perceived stress but rather a component of a complex phenomenon.

Predicting Participant Compliance With Fitness Tracker Wearing and Ecological Momentary Assessment Protocols in Information Workers: Observational Study.

BACKGROUND: Studies that use ecological momentary assessments (EMAs) or wearable sensors to track numerous attributes, such as physical activity, sleep, and heart rate, can benefit from reductions in missing data. Maximizing compliance is one method of reducing missing data to increase the return on the heavy investment of time and money into large-scale studies. OBJECTIVE: This paper aims to identify the extent to which compliance can be prospectively predicted from individual attributes and initial compliance. METHODS: We instrumented 757 information workers with fitness trackers for 1 year and conducted EMAs in the first 56 days of study participation as part of an observational study. Their compliance with the EMA and fitness tracker wearing protocols was analyzed. Overall, 31 individual characteristics (eg, demographics and personalities) and behavioral variables (eg, early compliance and study portal use) were considered, and 14 variables were selected to create beta regression models for predicting compliance with EMAs 56 days out and wearable compliance 1 year out. We surveyed study participation and correlated the results with compliance. RESULTS: Our modeling indicates that 16% and 25% of the variance in EMA compliance and wearable compliance, respectively, could be explained through a survey of demographics and personality in a held-out sample. The likelihood of higher EMA and wearable compliance was associated with being older (EMA: odds ratio [OR] 1.02, 95% CI 1.00-1.03; wearable: OR 1.02, 95% CI 1.01-1.04), speaking English as a first language (EMA: OR 1.38, 95% CI 1.05-1.80; wearable: OR 1.39, 95% CI 1.05-1.85), having had a wearable before joining the study (EMA: OR 1.25, 95% CI 1.04-1.51; wearable: OR 1.50, 95% CI 1.23-1.83), and exhibiting conscientiousness (EMA: OR 1.25, 95% CI 1.04-1.51; wearable: OR 1.34, 95% CI 1.14-1.58). Compliance was negatively associated with exhibiting extraversion (EMA: OR 0.74, 95% CI 0.64-0.85; wearable: OR 0.67, 95% CI 0.57-0.78) and having a supervisory role (EMA: OR 0.65, 95% CI 0.54-0.79; wearable: OR 0.66, 95% CI 0.54-0.81). Furthermore, higher wearable compliance was negatively associated with agreeableness (OR 0.68, 95% CI 0.56-0.83) and neuroticism (OR 0.85, 95% CI 0.73-0.98). Compliance in the second week of the study could help explain more variance; 62% and 66% of the variance in EMA compliance and wearable compliance, respectively, was explained. Finally, compliance correlated with participants' self-reflection on the ease of participation, usefulness of our compliance portal, timely resolution of issues, and compensation adequacy, suggesting that these are avenues for improving compliance. CONCLUSIONS: We recommend conducting an initial 2-week pilot to measure trait-like compliance and identify participants at risk of long-term noncompliance, performing oversampling based on participants' individual characteristics to avoid introducing bias in the sample when excluding data based on noncompliance, using an issue tracking portal, and providing special care in troubleshooting to help participants maintain compliance.

The effects of seasons and weather on sleep patterns measured through longitudinal multimodal sensing.

Previous studies of seasonal effects on sleep have yielded unclear results, likely due to methodological differences and limitations in data size and/or quality. We measured the sleep habits of 216 individuals across the U.S. over four seasons for slightly over a year using objective, continuous, and unobtrusive measures of sleep and local weather. In addition, we controlled for demographics and trait-like constructs previously identified to correlate with sleep behavior. We investigated seasonal and weather effects of sleep duration, bedtime, and wake time. We found several small but statistically significant effects of seasonal and weather effects on sleep patterns. We observe the strongest seasonal effects for wake time and sleep duration, especially during the spring season: wake times are earlier, and sleep duration decreases (compared to the reference season winter). Sleep duration also modestly decreases when day lengths get longer (between the winter and summer solstice). Bedtimes and wake times tend to be slightly later as outdoor temperature increases.

Vascular transcriptome landscape of Trail-/- mice: Implications and therapeutic strategies for diabetic vascular disease.

Circulating plasma TRAIL levels are suppressed in patients with cardiovascular and diabetic diseases. To identify novel targets in vascular metabolic diseases, genome-wide transcriptome of aortic tissue from Trail-/- versus Trail+/+ mice were interrogated. We found 861 genes differentially expressed with TRAIL deletion. Gene enrichment analyses showed many of these genes were related to inflammation, cell-to-cell cytoskeletal interactions, and transcriptional modulation. We identified vascular protective and pathological gene clusters, with Ifi205 as the most significantly reduced vascular protective gene, whereas Glut1, the most significantly increased pathological gene with TRAIL deletion. We hypothesized that therapeutic targets could be devised from such integrated analysis and validated our findings from vascular tissues of diabetic mice. From the differentially expressed gene targets, enriched transcription factor (TF) and microRNA binding motifs were identified. The top two TFs were Elk1 and Sp1, with enrichment to eight gene targets common to both. miR-520d-3p and miR-377-3p were the top enriched microRNAs with TRAIL deletion; with four overlapping genes enriched for both microRNAs. Our findings offer an alternate in silico approach for therapeutic target identification and present a deeper understanding of gene signatures and pathways altered with TRAIL suppression in the vasculature.

TRAIL-Expressing Monocyte/Macrophages Are Critical for Reducing Inflammation and Atherosclerosis.

Circulating tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) levels are reduced in patients with cardiovascular disease, and TRAIL gene deletion in mice exacerbates atherosclerosis and inflammation. How TRAIL protects against atherosclerosis and why levels are reduced in disease is unknown. Here, multiple strategies were used to identify the protective source of TRAIL and its mechanism(s) of action. Samples from patients with coronary artery disease and bone-marrow transplantation experiments in mice lacking TRAIL revealed monocytes/macrophages as the main protective source. Accordingly, deletion of TRAIL caused a more inflammatory macrophage with reduced migration, displaying impaired reverse cholesterol efflux and efferocytosis. Furthermore, interleukin (IL)-18, commonly increased in plasma of patients with cardiovascular disease, negatively regulated TRAIL transcription and gene expression, revealing an IL-18-TRAIL axis. These findings demonstrate that TRAIL is protective of atherosclerosis by modulating monocyte/macrophage phenotype and function. Manipulating TRAIL levels in these cells highlights a different therapeutic avenue in the treatment of cardiovascular disease.

Successful Percutaneous Closure of a Ruptured Saphenous Vein Graft Aneurysm.

A 68-year-old man with previous coronary artery bypass surgery presented with acute onset chest pain. After ruling out an acute coronary syndrome, a computed tomography scan demonstrated a giant aneurysm (10 cm × 8 cm) of the right coronary artery saphenous vein graft (SVG) with signs of rupture into the mediastinum. An Amplatzer Vascular Plug II was successfully deployed at the proximal anastomosis of the SVG, achieving complete exclusion. At 6-month follow-up the patient remained asymptomatic and a computed tomography scan confirmed adequate position of the device. Amplatzer Vascular Plug II is a reasonable alternative for SVG aneurysm closure, providing the vein graft supplies nonviable myocardium.

Transcoronary gradients of HDL-associated MicroRNAs in unstable coronary artery disease.

AIMS: MicroRNAs (miRNAs) are transported on high-density lipoproteins (HDLs) and HDL-associated miRNAs are involved in intercellular communication. We explored HDL-associated miRNAs concentration gradients across the coronary circulation in stable and unstable coronary artery disease patients and whether changes in the transcoronary gradient were associated with changes in HDL composition and size. METHODS: Acute coronary syndrome (ACS, n=17) patients, those with stable coronary artery disease (stable CAD, n=19) and control subjects without CAD (n=6) were studied. HDLs were isolated from plasma obtained from the coronary sinus (CS), aortic root (arterial blood) and right atrium (venous blood). HDL-associated miRNAs (miR-16, miR-20a, miR-92a, miR-126, miR-222 and miR-223) were quantified by TaqMan miRNA assays. HDL particle sizes were determined by non-denaturing polyacrylamide gradient gel electrophoresis. HDL composition was measured immunoturbidometrically or enzymatically. RESULTS: A concentration gradient across the coronary circulation was observed for all the HDL-associated miRNAs. In ACS patients, there was a significant inverse transcoronary gradient for HDL-associated miR-16, miR-92a and miR-223 (p<0.05) compared to patients with stable CAD. Changes in HDL-miRNA transcoronary gradients were not associated with changes in HDL composition or size. CONCLUSION: HDLs are depleted of miR-16, miR-92a and miR-223 during the transcoronary passage in patients with ACS compared to patients with stable CAD.

The NLRP3 inflammasome and the emerging role of colchicine to inhibit atherosclerosis-associated inflammation.

Atherosclerosis is considered a chronic inflammatory disease of the arterial wall. Recently, compelling evidence has arisen for the role of monocytes and neutrophils and a particular protein complex that resides within these cells - the NLRP3 inflammasome - in atherosclerosis-associated inflammation. It is now also known that cholesterol crystals are present through all stages of atherosclerosis and can activate the NLRP3 inflammasome within these inflammatory cells to produce interleukin 1ß and interleukin 18 - key mediators in the inflammatory cascade that drive plaque progression and instability. In this review, we describe the role of monocytes/macrophages and neutrophils in atherosclerosis, outline mechanisms of activation of the NLRP3 inflammasome in the setting of atherosclerosis-associated inflammation and discuss potential therapies that specifically target the NLRP3 inflammasome and/or its downstream mediators in atherosclerosis, with a particular focus on the emerging role of colchicine.

Colchicine Therapy and Plaque Stabilization in Patients With Acute Coronary Syndrome: A CT Coronary Angiography Study.

OBJECTIVES: The authors sought to evaluate the plaque-modifying effects of low-dose colchicine therapy plus optimal medical therapy (OMT) in patients post-acute coronary syndrome (ACS), as assessed by coronary computed tomography angiography (coronary CTA). BACKGROUND: Colchicine therapy has been postulated to have beneficial anti-inflammatory effects in patients with ACS, translating into reduction in future adverse cardiovascular events. However, whether favorable plaque modification underpins this is yet unproven. METHODS: In this prospective nonrandomized observational study of 80 patients with recent ACS (<1 month), patients received either 0.5 mg/day colchicine plus OMT or OMT alone and were followed for 1 year. Our primary outcome was change in low attenuation plaque volume (LAPV), a marker of plaque instability on coronary CTA and robust predictor of adverse cardiovascular events. Secondary outcomes were changes in other coronary CTA measures and in high-sensitivity C-reactive protein (hsCRP). RESULTS: Mean duration of follow-up was 12.6 months; mean age was 57.4 years. Colchicine therapy significantly reduced LAPV (mean 15.9 mm3 [-40.9%] vs. 6.6 mm3 [-17.0%]; p = 0.008) and hsCRP (mean 1.10 mg/l [-37.3%] vs. 0.38 mg/l [-14.6%]; p < 0.001) versus controls. Reductions in total atheroma volume (mean 42.3 mm3 vs. 26.4 mm3; p = 0.28) and low-density lipoprotein levels (mean 0.44 mmol/l vs. 0.49 mmol/l; p = 0.21) were comparable in both groups. With multivariate linear regression, colchicine therapy remained significantly associated with greater reduction in LAPV (p = 0.039) and hsCRP (p = 0.004). There was also a significant linear association (p < 0.001) and strong positive correlation (r = 0.578) between change in LAPV and hsCRP. CONCLUSIONS: Our findings suggest, for the first time, that low-dose colchicine therapy favorably modifies coronary plaque, independent of high-dose statin intensification therapy and substantial low-density lipoprotein reduction. The improvements in plaque morphology are likely driven by the anti-inflammatory properties of colchicine, as demonstrated by reductions in hsCRP, rather than changes in lipoproteins. Colchicine may be beneficial as an additional secondary prevention agent in patients post-ACS if validated in future studies.

Neutrophil-derived microparticles are released into the coronary circulation following percutaneous coronary intervention in acute coronary syndrome patients.

To evaluate (i) local coronary and systemic levels of microparticles (MP) in acute coronary syndrome (ACS) and stable angina pectoris (SAP) patients and (ii) their release after plaque disruption with percutaneous coronary intervention (PCI). MP are small vesicles originating from plasma membranes of cells after activation or apoptosis and are implicated in the pathogenesis of atherosclerosis. Neutrophils play a role in plaque destabilization and shed neutrophil-derived MP that have the potential to drive significant proinflammatory and thrombotic downstream effects. Eight ACS and eight SAP patients were included. Coronary sinus (CS) samples pre-intervention (CS1), 45 s following balloon angioplasty (CS2) and at 45 s intervals following stent deployment (CS3, CS4 and CS5), together with peripheral vein samples, pre- and post-PCI were analysed for neutrophil-derived (CD66b+), endothelial-derived (CD144+), platelet-derived (CD41a+), monocyte-derived (CD14+) and apoptotic (Annexin V+) MP. ELISA for interleukin (IL)-6, myeloperoxidase (MPO) and P-selectin was also performed. CD66b+ MP levels were similar in both groups pre-intervention. Post-PCI, CS levels rose significantly in ACS but not SAP patients (ACS area under the curve (AUC): 549 ± 83, SAP AUC: 24 ± 29, P<0.01). CS CD41a+, CD144+, CD14+ and Annexin V+ MP levels did not differ between groups. Acute neutrophil-derived MP release post-PCI occurs in ACS compared with stable patients, likely to be reflective of plaque MP content in vulnerable lesions.

Basal autophagy protects cardiomyocytes from doxorubicin-induced toxicity.

Doxorubicin (Doxo) is one of the most effective anti-neoplastic agents but its cardiotoxicity has been an important clinical limitation. The major mechanism of Doxo-induced cardiotoxicity is associated to its oxidative capacity. However, other processes are also involved with significant consequences for the cardiomyocyte. In recent years, a number of studies have investigated the role of autophagy on Doxo-induced cardiotoxicity but to date it is not clear how Doxo alters that process and its consequence on cardiomyocytes viability. Here we investigated the effect of Doxo 1uM for 24h of stimulation on cultured neonatal rat cardiomyocytes. We showed that Doxo inhibits basal autophagy. This inhibition is due to both Akt/mTOR signaling pathway activation and Beclin 1 level decrease. To assess the role of autophagy on Doxo-induced cardiomyocyte death, we evaluated the effects 3-methyladenine (3-MA), bafilomycin A1 (BafA), siRNA Beclin 1 (siBeclin 1) and rapamycin (Rapa) on cell viability. Inhibition of autophagy with 3-MA, BafA and siBeclin 1 increased lactate dehydrogenase (LDH) release but, when autophagy was induced by Rapa, Doxo-induced cardiomyocyte death was decreased. These results suggest that Doxo inhibits basal autophagy and contributes to cardiomyocyte death. Activation of autophagy could be used as a strategy to protect the heart against Doxo toxicity.

Colchicine therapy in acute coronary syndrome patients acts on caspase-1 to suppress NLRP3 inflammasome monocyte activation.

Inflammasome activation, with subsequent release of pro-inflammatory cytokines interleukin-1ß (IL-1ß) and IL-18, has recently been implicated in atherosclerosis-associated inflammation. This study aims to assess in acute coronary syndrome (ACS) patients (1) inflammasome activation in circulating monocytes and (2) whether short-term oral colchicine, a recognized anti-inflammatory agent that has been shown to be cardio-protective in clinical studies, might acutely suppress inflammasome-dependent inflammation. ACS patients (n=21) were randomized to oral colchicine (1 mg followed by 0.5 mg 1 h later) or no treatment, and compared with untreated healthy controls (n=9). Peripheral venous blood was sampled pre- (day 1) and 24 h post- (day 2) treatment. Monocytes were cultured and stimulated with ATP. Analysis of key inflammasome markers was performed by ELISA. IL-1ß secretion increased by 580.4% (P<0.01) in ACS patients compared with controls but only with ATP stimulation. Untreated ACS patients secreted significantly higher levels of IL-18 compared with healthy controls independent of ATP stimulation (P<0.05). Colchicine treatment in ACS patients markedly reduced intracellular and secreted levels of IL-1ß compared with pre-treatment levels (P<0.05 for both), as well as significantly reducing pro-caspase-1 mRNA levels by 57.7% and secreted caspase-1 protein levels by 30.2% compared with untreated patients (P<0.05 for both). Monocytes from ACS patients are 'primed' to secrete inflammasome-related cytokines and short-term colchicine acutely and markedly suppresses monocyte caspase-1 activity, thereby reducing monocyte secretion of IL-1ß.

The index of microcirculatory resistance in the physiologic assessment of the coronary microcirculation.

The coronary microcirculation plays a critical role in normal cardiac physiology as well as in many disease states. However, methods to evaluate the function of the coronary microvessels have been limited by technical and theoretical issues. Recently, the index of microcirculatory resistance (IMR) has been proposed and validated as a simple and specific invasive method of assessing the coronary microcirculation. By relying on the thermodilution theory and using a pressure-temperature sensor guidewire, IMR provides a measurement of the minimum achievable microcirculatory resistance in a target coronary artery territory, enabling a quantitative assessment of the microvascular integrity. Unlike indices such as coronary flow reserve, IMR is highly reproducible and independent of hemodynamic changes. In ST-elevation myocardial infarction, IMR predicts myocardial recovery and long-term mortality, whereas in patients with stable coronary artery disease, preintervention IMR predicts the occurrence of periprocedural myocardial infarction. Increasingly, research has focused on IMR-guided interventions of the microcirculation, with the aim of preventing and/or treating the microcirculatory dysfunction that commonly accompanies the epicardial coronary disease. In the present review, we will discuss the theoretical and practical basis for IMR, the clinical studies supporting it, and the future lines of research using this novel tool.

Colchicine Acutely Suppresses Local Cardiac Production of Inflammatory Cytokines in Patients With an Acute Coronary Syndrome.

BACKGROUND: Interleukin (IL)-1ß, IL-18, and downstream IL-6 are key inflammatory cytokines in the pathogenesis of coronary artery disease. Colchicine is believed to block the NLRP3 inflammasome, a cytosolic complex responsible for the production of IL-1ß and IL-18. In vivo effects of colchicine on cardiac cytokine release have not been previously studied. This study aimed to (1) assess the local cardiac production of inflammatory cytokines in patients with acute coronary syndromes (ACS), stable coronary artery disease and in controls; and (2) determine whether acute administration of colchicine inhibits their production. METHODS AND RESULTS: Forty ACS patients, 33 with stable coronary artery disease, and 10 controls, were included. ACS and stable coronary artery disease patients were randomized to oral colchicine treatment (1 mg followed by 0.5 mg 1 hour later) or no colchicine, 6 to 24 hours prior to cardiac catheterization. Blood samples from the coronary sinus, aortic root (arterial), and lower right atrium (venous) were collected and tested for IL-1ß, IL-18, and IL-6 using ELISA. In ACS patients, coronary sinus levels of IL-1ß, IL-18, and IL-6 were significantly higher than arterial and venous levels (P=0.017, <0.001 and <0.001, respectively). Transcoronary (coronary sinus-arterial) gradients for IL-1ß, IL-18, and IL-6 were highest in ACS patients and lowest in controls (P=0.077, 0.033, and 0.014, respectively). Colchicine administration significantly reduced transcoronary gradients of all 3 cytokines in ACS patients by 40% to 88% (P=0.028, 0.032, and 0.032, for IL-1ß, IL-18, and IL-6, respectively). CONCLUSIONS: ACS patients exhibit increased local cardiac production of inflammatory cytokines. Short-term colchicine administration rapidly and significantly reduces levels of these cytokines.