Laser Doppler Fluximetry in Cutaneous Vasculature: Methods for Data Analyses.

INTRODUCTION: Acquisition of a deeper understanding of microvascular function across physiological and pathological conditions can be complicated by poor accessibility of the vascular networks and the necessary sophistication or intrusiveness of the equipment needed to acquire meaningful data. Laser Doppler fluximetry (LDF) provides a mechanism wherein investigators can readily acquire large amounts of data with minor inconvenience for the subject. However, beyond fairly basic analyses of erythrocyte perfusion (fluximetry) data within the cutaneous microcirculation (i.e., perfusion at rest and following imposed challenges), a deeper understanding of microvascular perfusion requires a more sophisticated approach that can be challenging for many investigators. METHODS: This manuscript provides investigators with clear guidance for data acquisition from human subjects for full analysis of fluximetry data, including levels of perfusion, single- and multiscale Lempel-Ziv complexity (LZC) and sample entropy (SampEn), and wavelet-based analyses for the major physiological components of the signal. Representative data and responses are presented from a recruited cohort of healthy volunteers, and computer codes for full data analysis (MATLAB) are provided to facilitate efforts by interested investigators. CONCLUSION: It is anticipated that these materials can reduce the challenge to investigators integrating these approaches into their research programs and facilitate translational research in cardiovascular science.

Cerebrovascular dysfunction and depressive symptoms in preclinical models: insights from a scoping review.

Although existing literature supports associations between cerebrovascular dysfunction and the emergence of depression and depressive symptoms, relatively little is known about underlying mechanistic pathways that may explain potential relationships. As such, an integrated understanding of these relationships in preclinical models could provide insight into the nature of the relationship, basic mechanistic linkages, and areas in which additional investment should be targeted. This scoping review was conducted in MEDLINE, EMBASE, and Scopus to outline the relationship between depressive symptoms and cerebrovascular dysfunction in preclinical animal models with an additional focus on the areas above. From 3,438 articles initially identified, 15 studies met the inclusion criteria and were included in the review. All studies reported a positive association between the severity of markers for cerebrovascular dysfunction and that for depressive symptoms in rodent models and this spanned all models for either pathology. Specific mechanistic links between the two such as chronic inflammation, elevated vascular oxidant stress, and altered serotonergic signaling were highlighted. Notably, almost all studies addressed outcomes in male animals, with a near complete lack of data from females, and there was little consistency in terms of how cerebrovascular dysfunction was assessed. Across nearly all studies was a lack of clarity for any "cause and effect" relationship between depressive symptoms and cerebrovascular dysfunction. At this time, it is reasonable to conclude that a correlative relationship clearly exists between the two, and future investigation will be required to parse out more specific aspects of this relationship.NEW & NOTEWORTHY This scoping review presents a structured evaluation of all relevant existing literature linking cerebral vasculopathy to depressive symptom emergence in preclinical models. Results support a definite connection between vascular dysfunction and depressive symptoms, highlighting the importance of chronic elevations in inflammation and oxidant stress, and impaired serotonergic signaling. The review also identified significant knowledge gaps addressing male versus female differences and limited clear mechanistic links between cerebral vasculopathy and depressive symptoms.

Corrigendum: Prioritizing determinants of cognitive function in healthy middle-aged and older adults: insights from a machine learning regression approach in the Canadian longitudinal study on aging.

[This corrects the article DOI: 10.3389/fpubh.2023.1290064.].

Thromboxane-induced cerebral microvascular rarefaction predicts depressive symptom emergence in metabolic disease.

Previous studies have suggested that the loss of microvessel density in the peripheral circulation with evolving metabolic disease severity represents a significant contributor to impaired skeletal muscle oxygenation and fatigue-resistance. Based on this and our recent work, we hypothesized that cerebral microvascular rarefaction was initiated from the increased prooxidant and proinflammatory environment with metabolic disease and is predictive of the severity of the emergence of depressive symptoms in obese Zucker rats (OZRs). In male OZR, cerebrovascular rarefaction followed the emergence of elevated oxidant and inflammatory environments characterized by increased vascular production of thromboxane A2 (TxA2). The subsequent emergence of depressive symptoms in OZR was associated with the timing and severity of the rarefaction. Chronic intervention with antioxidant (TEMPOL) or anti-inflammation (pentoxifylline) therapy blunted the severity of rarefaction and depressive symptoms, although the effectiveness was limited. Blockade of TxA2 production (dazmegrel) or action (SQ-29548) resulted in a stronger therapeutic effect, suggesting that vascular production and action represent a significant contributor to rarefaction and the emergence of depressive symptoms with chronic metabolic disease (although other pathways clearly contribute as well). A de novo biosimulation of cerebrovascular oxygenation in the face of progressive rarefaction demonstrates the increased probability of generating hypoxic regions within the microvascular networks, which could contribute to impaired neuronal metabolism and the emergence of depressive symptoms. The results of the present study also implicate the potential importance of aggressive prodromic intervention in reducing the severity of chronic complications arising from metabolic disease.NEW & NOTEWORTHY With clinical studies linking vascular disease risk to depressive symptom emergence, we used obese Zucker rats, a model of chronic metabolic disease, to identify potential mechanistic links between these two negative outcomes. Depressive symptom severity correlated with the extent of cerebrovascular rarefaction, after increased vascular oxidant stress/inflammation and TxA2 production. Anti-TxA2 interventions prevasculopathy blunted rarefaction and depressive symptoms, while biosimulation indicated that cerebrovascular rarefaction increased hypoxia within capillary networks as a potential contributing mechanism.

Prevalence of dementia, heart disease and stroke in community-dwelling adults in Canada, 2016-2021: opportunities for joint prevention.

INTRODUCTION: This aim of this study is to provide updated estimates on the prevalence of dementia, heart disease, and stroke in Canadian communities. Targeting all three conditions together, at the community level, may be key to disease prevention and health aging in the Canadian population. METHODS: Using nationwide health survey data, we calculated the age-standardized prevalence of self-reported dementia, heart disease and stroke in adults aged 18 years and over residing in Canadian communities from 2016 to 2021. Poisson regression models were used to detect statistically significant changes in the prevalence of all three conditions from 2016 to 2021. RESULTS: Less than 1% (~ 175,000 individuals) of adults residing in Canadian communities reported dementia, 5% (~ 1.5 million individuals) reported heart disease, and more than 1% (~ 370,000 individuals) reported stroke annually from 2016 to 2021. Overall, the age-standardized prevalence for stroke decreased minimally from 2016 to 2021 (p = 0.0004). Although the age-standardized prevalence of heart disease and dementia decreased from 2016 to 2018, subsequent increases in prevalence from 2018 to 2021 led to a lack of overall statistically significant changes from 2016 to 2021 (p = 0.10 for heart disease and p = 0.37 for dementia). CONCLUSION: Recent increases in the prevalence of dementia, heart disease and stroke in Canadian communities threaten to reverse any gains in vascular disease prevention over the past six years. Findings reveal the urgent need for intensified prevention efforts that are community-based with a focus on joint reduction in the shared risk factors contributing to all three diseases.

Assessments of Perfusion, Blood Flow, and Vascular Structure in Ambulatory Subjects: Guidance for Translational Research Scientists.

Research involving human subjects in ambulatory settings is a critical link in the chain comprising translational research, spanning preclinical research to human subject and patient cohort studies. There are presently a wide array of techniques and approaches available to investigators wishing to study blood flow, perfusion, and vascular structure and function in human subjects. In this multi-sectioned review, we discuss capillaroscopy, carotid intima-media thickness, flow-mediated dilation, laser Doppler flowmetry, near-infrared spectroscopy, peripheral arterial tonometry, pulse wave velocity, retinal fundus imaging, and vascular plethysmography. Each section contains a general overview and the physical basis of the technique followed by a discussion of the procedures involved and the necessary equipment, with attention paid to specific requirements or limitations. Subsequently, we detail which aspects of vascular function can be studied with a given technique, the analytical approach to the collected data, and the appropriate application and limitation(s) to the interpretation of the data collected. Finally, a modified scoping review provides a summary of how each assessment technique has been applied in previous studies. It is anticipated that this review will provide an efficient source of information and insight for preclinical investigators seeking to add translational aspects to their research programs.

Influence of the Social Environment on Ideal Cardiovascular Health.

Background The environment plays a large role in the health of individuals; however, more research is needed to better understand aspects of the environment that most influence health. Specifically, our study examines how the social environment influences cardiovascular health (CVH). Methods and Results The social environment was characterized using measures of belonging and life and work stress in individuals, as well as nationally derived measures of marginalization, deprivation, economic status, and community well-being in neighborhoods. CVH was defined by the American Heart Association's Cardiovascular Health Index-a summed score of 7 clinical and behavioral components known to have the greatest impact on CVH. Data were obtained from the Canadian Community Health Survey 2015 to 2016 and multiple national data sources. Multilevel regression models were used to analyze the associations between CVH and the social environment. Overall, 27% of Canadians reported ideal CVH (6-7 score points), 68% reported intermediate CVH (3-5 score points), and 5% reported poor CVH (0-2 score points). The neighborhood environment contributed up to 7% of the differences in CVH between individuals. Findings indicated that residing in a neighborhood with greater community well-being (odds ratio [OR], 1.33 [95% CI, 1.26-1.41]) was associated with achieving higher odds of ideal CVH, while weaker community belonging (OR, 0.67 [95% CI, 0.62-0.72]) and residing in a neighborhood with greater marginalization (OR, 0.87 [95% CI, 0.82-0.91]) and deprivation (OR, 0.67 [95% CI, 0.64-0.69]) were associated with achieving lower odds of ideal CVH. Conclusions Aspects of individual-level social environment and residing in a neighborhood with a more favorable social environment were both independently and significantly associated with achieving ideal CVH.

Application of a novel index for understanding vascular health following pharmacological intervention in a pre-clinical model of metabolic disease.

While a thorough understanding of microvascular function in health and how it becomes compromised with progression of disease risk is critical for developing effective therapeutic interventions, our ability to accurately assess the beneficial impact of pharmacological interventions to improve outcomes is vital. Here we introduce a novel Vascular Health Index (VHI) that allows for simultaneous assessment of changes to vascular reactivity/endothelial function, vascular wall mechanics and microvessel density within cerebral and skeletal muscle vascular networks with progression of metabolic disease in obese Zucker rats (OZR); under control conditions and following pharmacological interventions of clinical relevance. Outcomes are compared to "healthy" conditions in lean Zucker rats. We detail the calculation of vascular health index, full assessments of validity, and describe progressive changes to vascular health index over the development of metabolic disease in obese Zucker rats. Further, we detail the improvement to cerebral and skeletal muscle vascular health index following chronic treatment of obese Zucker rats with anti-hypertensive (15%-52% for skeletal muscle vascular health index; 12%-48% for cerebral vascular health index; p < 0.05 for both), anti-dyslipidemic (13%-48% for skeletal muscle vascular health index; p < 0.05), anti-diabetic (12%-32% for cerebral vascular health index; p < 0.05) and anti-oxidant/inflammation (41%-64% for skeletal muscle vascular health index; 29%-42% for cerebral vascular health index; p < 0.05 for both) drugs. The results present the effectiveness of mechanistically diverse interventions to improve cerebral or skeletal muscle vascular health index in obese Zucker rats and provide insight into the superiority of some pharmacological agents despite similar effectiveness in terms of impact on intended targets. In addition, we demonstrate the utility of including a wider, more integrative approach to the study of microvasculopathy under settings of elevated disease risk and following pharmacological intervention. A major benefit of integrating vascular health index is an increased understanding of the development, timing and efficacy of interventions through greater insight into integrated microvascular function in combination with individual, higher resolution metrics.

Prioritizing determinants of cognitive function in healthy middle-aged and older adults: insights from a machine learning regression approach in the Canadian longitudinal study on aging.

Introduction: The preservation of healthy cognitive function is a crucial step toward reducing the growing burden of cognitive decline and impairment. Our study aims to identify the characteristics of an individual that play the greatest roles in determining healthy cognitive function in mid to late life. Methods: Data on the characteristics of an individual that influence their health, also known as determinants of health, were extracted from the baseline cohort of the Canadian Longitudinal Study of Aging (2015). Cognitive function was a normalized latent construct score summarizing eight cognitive tests administered as a neuropsychological battery by CLSA staff. A higher cognitive function score indicated better functioning. A penalized regression model was used to select and order determinants based on their strength of association with cognitive function. Forty determinants (40) were entered into the model including demographic and socioeconomic factors, lifestyle and health behaviors, clinical measures, chronic diseases, mental health status, social support and the living environment. Results: The study sample consisted mainly of White, married, men and women aged 45-64 years residing in urban Canada. Mean overall cognitive function score for the study sample was 99.5, with scores ranging from 36.6 to 169.2 (lowest to highest cognitive function). Thirty-five (35) determinants were retained in the final model as significantly associated with healthy cognitive functioning. The determinants demonstrating the strongest associations with healthy cognitive function, were race, immigrant status, nutritional risk, community belongingness, and satisfaction with life. The determinants demonstrating the weakest associations with healthy cognitive function, were physical activity, greenness and neighborhood deprivation. Conclusion: Greater prioritization and integration of demographic and socioeconomic factors and lifestyle and health behaviors, such greater access to healthy foods and enhancing aid programs for low-income and immigrant families, into future health interventions and policies can produce the greatest gains in preserving healthy cognitive function in mid to late life.

A novel vascular health index: Using data analytics and population health to facilitate mechanistic modeling of microvascular status.

The study of vascular function across conditions has been an intensive area of investigation for many years. While these efforts have revealed many factors contributing to vascular health, challenges remain for integrating results across research groups, animal models, and experimental conditions to understand integrated vascular function. As such, the insights attained in clinical/population research from linking datasets, have not been fully realized in the basic sciences, thus frustrating advanced analytics and complex modeling. To achieve comparable advances, we must address the conceptual challenge of defining/measuring integrated vascular function and the technical challenge of combining data across conditions, models, and groups. Here, we describe an approach to establish and validate a composite metric of vascular function by comparing parameters of vascular function in metabolic disease (the obese Zucker rat) to the same parameters in age-matched, "healthy" conditions, resulting in a common outcome measure which we term the vascular health index (VHI). VHI allows for the integration of datasets, thus expanding sample size and permitting advanced modeling to gain insight into the development of peripheral and cerebral vascular dysfunction. Markers of vascular reactivity, vascular wall mechanics, and microvascular network density are integrated in the VHI. We provide a detailed presentation of the development of the VHI and provide multiple measures to assess face, content, criterion, and discriminant validity of the metric. Our results demonstrate how the VHI captures multiple indices of dysfunction in the skeletal muscle and cerebral vasculature with metabolic disease and provide context for an integrated understanding of vascular health under challenged conditions.

Highlighting the Mechanistic Relationship Between Perinatal Depression and Preeclampsia: A Scoping Review.

Background: Although there is scientific literature supporting an association between depression and preeclampsia (PE), little is known about the underlying mechanistic pathways that may explain these observed associations. Thus, this study aimed to outline the relationship between depression and PE, and to highlight the underlying cardiovascular and metabolic risk factors that are common to both. Methods: A scoping review of the literature was conducted in Medline, Scopus, and Web of Science. Results: From 706 articles initially identified, 23 articles met the inclusion criteria and were included in this review. Although some studies reported a positive association between PE and postpartum depressive symptoms, challenges comparing different methodologies, measurement instruments and when measurements were administered, and patient populations do not permit a decisive conclusion. In addition, very few studies addressed potential underlying mechanisms that may be contributing to observed associations; thus, a secondary search was conducted to identify cardiovascular and metabolic risk factors that are common to both depression and PE. Conclusion: The cardiovascular and metabolic risk factors (i.e., increased inflammation and oxidative stress and decreased vascular and endothelial function) common to both depression and PE suggest that these factors may contribute as underlying mechanisms in both conditions. These similarities underscore the importance to better understand these mechanisms so preventative and therapeutic strategies could be developed to improve maternal health.

The relationship between anxiety sensitivity and clinical outcomes in cardiac rehabilitation: A scoping review.

Background: Despite well-established efficacy for patients with a cardiovascular diagnosis or event, exercise-based cardiac rehabilitation program participation and completion has remained alarmingly low due to both system-level barriers and patient-level factors. Patient mental health, particularly depression, is now recognized as significantly associated with reduced enrollment, participation, attendance, and completion of a cardiac rehabilitation program. More recently, anxiety sensitivity has emerged as an independent construct, related to but distinct from both depression and anxiety. Anxiety sensitivity has been reported to be adversely associated with participation in exercise and, thus, may be important for patients in cardiac rehabilitation. Accordingly, the objective of this study was to conduct a scoping review to summarize the evidence for associations between anxiety sensitivity and cardiovascular disease risk factors, exercise, and clinical outcomes in cardiac rehabilitation. Methods: A formal scoping review, following PRISMA-ScR guidelines, was undertaken. Searches of MEDLINE, Web of Science, CINAHL, PSYCINFO, and Scopus databases were conducted, supplemented by hand searches; studies published through December of 2020 were included. The initial screening was based on titles and abstracts and the second stage of screening was based on full text examination. Results: The final search results included 28 studies. Studies reported statistically significant associations between anxiety sensitivity and exercise, cardiovascular disease, and participation in cardiac rehabilitation. Many studies, however, were conducted in non-clinical, community-based populations; there were few studies conducted in cardiovascular disease and cardiac rehabilitation clinical patient populations. Additionally, significant gaps remain in our understanding of the sex-based differences in the complex relationships between anxiety sensitivity, exercise and cardiac rehabilitation. Conclusion: More research is needed to understand specific associations between anxiety sensitivity and clinical outcomes among clinical cardiovascular disease patients and participants in cardiac rehabilitation programs. Treatment of anxiety sensitivity to optimize clinical outcomes in cardiac rehabilitation programs should be investigated in future studies.

The development of peripheral microvasculopathy with chronic metabolic disease in obese Zucker rats: a retrograde emergence?

The study of peripheral vasculopathy with chronic metabolic disease is challenged by divergent contributions from spatial (the level of resolution or specific tissue being studied) and temporal origins (evolution of the developing impairments in time). Over many years of studying the development of skeletal muscle vasculopathy and its functional implications, we may be at the point of presenting an integrated conceptual model that addresses these challenges within the obese Zucker rat (OZR) model. At the early stages of metabolic disease, where systemic markers of elevated cardiovascular disease risk are present, the only evidence of vascular dysfunction is at postcapillary and collecting venules, where leukocyte adhesion/rolling is elevated with impaired venular endothelial function. As metabolic disease severity and duration increases, reduced microvessel density becomes evident as well as increased variability in microvascular hematocrit. Subsequently, hemodynamic impairments to distal arteriolar networks emerge, manifesting as increasing perfusion heterogeneity and impaired arteriolar reactivity. This retrograde "wave of dysfunction" continues, creating a condition wherein deficiencies to the distal arteriolar, capillary, and venular microcirculation stabilize and impairments to proximal arteriolar reactivity, wall mechanics, and perfusion distribution evolve. This proximal arteriolar dysfunction parallels increasing failure in fatigue resistance, hyperemic responses, and O2 uptake within self-perfused skeletal muscle. Taken together, these results present a conceptual model for the retrograde development of peripheral vasculopathy with chronic metabolic disease and provide insight into the timing and targeting of interventional strategies to improve health outcomes.NEW & NOTEWORTHY Working from an established database spanning multiple scales and times, we studied progression of peripheral microvascular dysfunction in chronic metabolic disease. The data implicate the postcapillary venular endothelium as the initiating site for vasculopathy. Indicators of dysfunction, spanning network structures, hemodynamics, vascular reactivity, and perfusion progress in an insidious retrograde manner to present as functional impairments to muscle blood flow and performance much later. The silent vasculopathy progression may provide insight into clinical treatment challenges.

Variability in Reassessment of Left Ventricular Ejection Fraction After Myocardial Infarction in the Acute Myocardial Infarction Quality Assurance Canada Study.

Importance: Persistently depressed left ventricular ejection fraction (LVEF) after myocardial infarction (MI) is associated with adverse prognosis and directs the use of evidence-based treatments to prevent sudden cardiac death and/or progressive heart failure. Objective: To assess adherence with guideline-recommended LVEF reassessment and to study the evolution of LVEF over 6 months of follow-up. Design, Setting, and Participants: This was a multicenter cohort study at Canadian academic and community hospitals with on-site cardiac catheterization services. Patients with type 1 acute MI and LVEF less than or equal to 45% during the index hospitalization were enrolled between January 2018 and August 2019 and were followed-up for 6 months. Data analysis was performed from May 2020 to September 2021. Exposures: Baseline clinical factors, in-hospital care and LVEF, and site-specific features. Main Outcomes and Measures: The main outcomes were receipt of repeat LVEF assessment by 6 months and the presence of a persistent LVEF reduction at 2 thresholds: LVEF less than or equal to 40%, prompting consideration of additional medical therapy for heart failure, or LVEF less than or equal to 35%, prompting referral for implanted cardioverter defibrillator in addition to medical therapy. Results: This study included 501 patients (mean [SD] age, 63.3 [13.0] years; 113 women [22.6%]). Overall, 370 patients (73.4%) presented with STEMI, and 454 (90.6%) had in-hospital revascularization. The median (IQR) baseline LVEF was 40% (34%-43%). Of 458 patients (91.4%) who completed the 6-month follow-up, 303 (66.2%; 95% CI, 61.7%-70.5%) had LVEF reassessment, with a range of 46.7% to 90.0% across sites (χ213 = 19.6; P = .11). Participants from community hospitals were more likely than those from academic hospitals to undergo LVEF reassessment (73.6% vs 63.2%; χ21 = 4.50; P = .03), as were those with worse LVEF at baseline. Follow-up LVEF improved by an absolute median (IQR) of 8% (3%-15%). However, 103 patients (34.1%) met the definitions of clinically relevant LVEF reduction, including 52 patients (17.2%) with LVEF less than or equal to 35% and 51 patients (16.9%) with LVEF of 35.1% to 40.0%. Conclusions and Relevance: In this cohort study, approximately 1 in 3 patients with at least mild LVEF reduction after acute MI did not undergo indicated LVEF reassessment within 6 months, suggesting that programs to improve the quality of post-MI care should include measures to ensure that indicated repeat cardiac imaging is performed. In those with follow-up imaging, clinically relevant persistent LVEF reduction was identified in more than one-third of patients.

Geographic variation in preventable hospitalisations across Canada: a cross-sectional study.

OBJECTIVE: The objective of this study is to examine the magnitude and pattern of small-area geographic variation in rates of preventable hospitalisations for ambulatory care-sensitive conditions (ACSC) across Canada (excluding Québec). DESIGN AND SETTING: A cross-sectional study conducted in Canada (excluding Québec) using data from the 2006 Canadian Census Health and Environment Cohort (CanCHEC) linked prospectively to hospitalisation records from the Discharge Abstract Database (DAD) for the three fiscal years: 2006-2007, 2007-2008 and 2008-2009. PRIMARY OUTCOME MEASURE: Preventable hospitalisations (ACSC). PARTICIPANTS: The 2006 CanCHEC represents a population of 22 562 120 individuals in Canada (excluding Québec). Of this number, 2 940 150 (13.03%) individuals were estimated to be hospitalised at least once during the 2006-2009 fiscal years. METHODS: Age-standardised annualised ACSC hospitalisation rates per 100 000 population were computed for each of the 190 Census Divisions. To assess the magnitude of Census Division-level geographic variation in rates of preventable hospitalisations, the global Moran's I statistic was computed. 'Hot spot' analysis was used to identify the pattern of geographic variation. RESULTS: Of all the hospitalisation events reported in Canada during the 2006-2009 fiscal years, 337 995 (7.10%) events were ACSC-related hospitalisations. The Moran's I statistic (Moran's I=0.355) suggests non-randomness in the spatial distribution of preventable hospitalisations. The findings from the 'hot spot' analysis indicate a cluster of Census Divisions located in predominantly rural and remote parts of Ontario, Manitoba and Saskatchewan and in eastern and northern parts of Nunavut with significantly higher than average rates of preventable hospitalisation. CONCLUSION: The knowledge generated on the small-area geographic variation in preventable hospitalisations can inform regional, provincial and national decision makers on planning, allocation of resources and monitoring performance of health service providers.

Chronic atorvastatin and exercise can partially reverse established skeletal muscle microvasculopathy in metabolic syndrome.

It has long been known that chronic metabolic disease is associated with a parallel increase in the risk for developing peripheral vascular disease. Although more clinically relevant, our understanding about reversing established vasculopathy is limited compared with our understanding of the mechanisms and development of impaired vascular structure/function under these conditions. Using the 13-wk-old obese Zucker rat (OZR) model of metabolic syndrome, where microvascular dysfunction is sufficiently established to contribute to impaired skeletal muscle function, we imposed a 7-wk intervention of chronic atorvastatin treatment, chronic treadmill exercise, or both. By 20 wk of age, untreated OZRs manifested a diverse vasculopathy that was a central contributor to poor muscle performance, perfusion, and impaired O2 exchange. Atorvastatin or exercise, with the combination being most effective, improved skeletal muscle vascular metabolite profiles (i.e., nitric oxide, PGI2, and thromboxane A2 bioavailability), reactivity, and perfusion distribution at both individual bifurcations and within the entire microvascular network versus responses in untreated OZRs. However, improvements to microvascular structure (i.e., wall mechanics and microvascular density) were less robust. The combination of the above improvements to vascular function with interventions resulted in an improved muscle performance and O2 transport and exchange versus untreated OZRs, especially at moderate metabolic rates (3-Hz twitch contraction). These results suggest that specific interventions can improve specific indexes of function from established vasculopathy, but either this process was incomplete after 7-wk duration or measures of vascular structure are either resistant to reversal or require better-targeted interventions. NEW & NOTEWORTHY We used atorvastatin and/or chronic exercise to reverse established microvasculopathy in skeletal muscle of rats with metabolic syndrome. With established vasculopathy, atorvastatin and exercise had moderate abilities to reverse dysfunction, and the combined application of both was more effective at restoring function. However, increased vascular wall stiffness and reduced microvessel density were more resistant to reversal. Listen to this article's corresponding podcast at https://ajpheart.podbean.com/e/reversal-of-microvascular-dysfunction/ .

Subclinical atherosclerosis, cardiovascular health, and disease risk: is there a case for the Cardiovascular Health Index in the primary prevention population?

BACKGROUND: Current primary prevention guidelines for cardiovascular disease (CVD) prioritize risk identification, risk stratification using clinical and risk scores, and risk reduction with lifestyle interventions and pharmacotherapy. Subclinical atherosclerosis is an early indicator of atherosclerotic burden and its timely recognition can slow or prevent progression to CVD. Thus, individuals with subclinical atherosclerosis are a priority for primary prevention. This study takes a practical approach to answering a challenge commonly faced by primary care practitioners: in patients with no known CVD, how can individuals likely to have subclinical atherosclerosis be easily identified using existing clinical data and/or information provided by the patient? METHODS: Using NHANES (1999-2004), 6091 men and women aged ≥40 years without any CVD comprised the primary prevention population for this study. Subclinical atherosclerosis was determined via ankle-brachial index (ABI) using established cutoffs (subclinical atherosclerosis defined as ABI (0.91-0.99); normal defined as ABI (1.00-1.30)). Three common scores were calculated: the Framingham Risk Score (FRS), the Metabolic Syndrome (MetS), and the Cardiovascular Health Index (CVHI). Logistic regression analysis assessed the association between these scores and subclinical atherosclerosis. The sensitively and specificity of these scores in identifying subclinical atherosclerosis was determined. RESULTS: In eligible participants, 3.8% had subclinical atherosclerosis. Optimum and average CVHI was associated with decreased odds for subclinical atherosclerosis. High, but not intermediate-risk, FRS was associated with increased odds for subclinical atherosclerosis. MetS was not associated with subclinical atherosclerosis. Of the 3 scores, CVHI was the most sensitive in identifying subclinical atherosclerosis and had the lowest number of missed cases. The FRS was the most specific but least sensitive of the 3 scores, and had almost 10-fold more missed cases vs. the CVHI. The MetS had "middle" sensitivity and specificity, and 10-fold more missed cases vs. the CVHI. CONCLUSIONS: Results from this study suggest that routine administration of the CVHI in a primary prevention population would yield the benefits of identifying patients with existing subclinical CVD not identified through traditional CVD risk factors or scores, and bring physical activity and nutrition to the forefront of provider-patient discussions about lifestyle factors critical to maintaining and prolonging cardiovascular health.

Beneficial Pleiotropic Antidepressive Effects of Cardiovascular Disease Risk Factor Interventions in the Metabolic Syndrome.

BACKGROUND: Although the increased prevalence and severity of clinical depression and elevated cardiovascular disease risk represent 2 vexing public health issues, the growing awareness of their combined presentation compounds the challenge. The obese Zucker rat, a model of the metabolic syndrome, spontaneously develops significant depressive symptoms in parallel with the progression of the metabolic syndrome and, thus, represents a compelling model for study. The primary objective was to assess the impact on both cardiovascular outcomes, specifically vascular structure and function, and depressive symptoms in obese Zucker rats after aggressive treatment for cardiovascular disease risk factors with long-term exercise or targeted pharmacological interventions. METHODS AND RESULTS: We chronically treated obese Zucker rats with clinically relevant interventions against cardiovascular disease risk factors to determine impacts on vascular outcomes and depressive symptom severity. While most of the interventions (chronic exercise, anti-hypertensive, the interventions (long-term exercise, antihypertensive, antidyslipidemia, and antidiabetic) were differentially effective at improving vascular outcomes, only those that also resulted in a significant improvement to oxidant stress, inflammation, arachidonic acid metabolism (prostacyclin versus thromboxane A2), and their associated sequelae were effective at also blunting depressive symptom severity. Using multivariable analyses, discrimination between the effectiveness of treatment groups to maintain behavioral outcomes appeared to be dependent on breaking the cycle of inflammation and oxidant stress, with the associated outcomes of improving endothelial metabolism and both cerebral and peripheral vascular structure and function. CONCLUSIONS: This initial study provides a compelling framework from which to further interrogate the links between cardiovascular disease risk factors and depressive symptoms and suggests mechanistic links and potentially effective avenues for intervention.

Protection from chronic stress- and depressive symptom-induced vascular endothelial dysfunction in female rats is abolished by preexisting metabolic disease.

While it is known that chronic stress and clinical depression are powerful predictors of poor cardiovascular outcomes, recent clinical evidence has identified correlations between the development of metabolic disease and depressive symptoms, creating a combined condition of severely elevated cardiovascular disease risk. In this study, we used the obese Zucker rat (OZRs) and the unpredictable chronic mild stress (UCMS) model to determine the impact of preexisting metabolic disease on the relationship between chronic stress/depressive symptoms and vascular function. Additionally, we determined the impact of metabolic syndrome on sex-based protection from chronic stress/depressive effects on vascular function in female lean Zucker rats (LZRs). In general, vasodilator reactivity was attenuated under control conditions in OZRs compared with LZRs. Although still impaired, conduit arterial and resistance arteriolar dilator reactivity under control conditions in female OZRs was superior to that in male or ovariectomized (OVX) female OZRs, largely because of better maintenance of vascular nitric oxide and prostacyclin levels. However, imposition of metabolic syndrome in combination with UCMS in OZRs further impaired dilator reactivity in both vessel subtypes to a similarly severe extent and abolished any protective effect in female rats compared with male or OVX female rats. The loss of vascular protection in female OZRs with UCMS was reflected in vasodilator metabolite levels, which closely matched those in male and OVX female OZRs subjected to UCMS. These results suggest that presentation of metabolic disease in combination with depressive symptoms can overwhelm the vasoprotection identified in female rats and, thereby, may reflect a severe impairment to normal endothelial function. NEW & NOTEWORTHY This study addresses the protection from chronic stress- and depression-induced vascular dysfunction identified in female compared with male or ovariectomized female rats. We determined the impact of preexisting metabolic disease, a frequent comorbidity of clinical depression in humans, on that vascular protection. With preexisting metabolic syndrome, female rats lost all protection from chronic stress/depressive symptoms and became phenotypically similar to male and ovariectomized female rats, with comparably poor vasoactive dilator metabolite profiles.

Protection from vascular dysfunction in female rats with chronic stress and depressive symptoms.

The increasing prevalence and severity of clinical depression are strongly correlated with vascular disease risk, creating a comorbid condition with poor outcomes but demonstrating a sexual disparity whereby female subjects are at lower risk than male subjects for subsequent cardiovascular events. To determine the potential mechanisms responsible for this protection against stress/depression-induced vasculopathy in female subjects, we exposed male, intact female, and ovariectomized (OVX) female lean Zucker rats to the unpredictable chronic mild stress (UCMS) model for 8 wk and determined depressive symptom severity, vascular reactivity in ex vivo aortic rings and middle cerebral arteries (MCA), and the profile of major metabolites regulating vascular tone. While all groups exhibited severe depressive behaviors from UCMS, severity was significantly greater in female rats than male or OVX female rats. In all groups, endothelium-dependent dilation was depressed in aortic rings and MCAs, although myogenic activation and vascular (MCA) stiffness were not impacted. Higher-resolution results from pharmacological and biochemical assays suggested that vasoactive metabolite profiles were better maintained in female rats with normal gonadal sex steroids than male or OVX female rats, despite increased depressive symptom severity (i.e., higher nitric oxide and prostacyclin and lower H2O2 and thromboxane A2 levels). These results suggest that female rats exhibit more severe depressive behaviors with UCMS but are partially protected from the vasculopathy that afflicts male rats and female rats lacking normal sex hormone profiles. Determining how female sex hormones afford partial vascular protection from chronic stress and depression is a necessary step for addressing the burden of these conditions on cardiovascular health. NEW & NOTEWORTHY This study used a translationally relevant model for chronic stress and elevated depressive symptoms to determine how these factors impact conduit and resistance arteriolar function in otherwise healthy rats. While chronic stress leads to an impaired vascular reactivity associated with elevated oxidant stress, inflammation, and reduced metabolite levels, we demonstrated partial protection from vascular dysfunction in female rats with normal sex hormone profiles compared with male or ovariectomized female rats.