Chronic Stress-Related Neural Activity Associates With Subclinical Cardiovascular Disease in a Community-Based Cohort: Data From the Washington, D.C. Cardiovascular Health and Needs Assessment.

Background: Psychosocial stress correlates with cardiovascular (CV) events; however, associations between physiologic measures of stressors and CVD remain incompletely understood, especially in racial/ethnic minority populations in resource-limited neighborhoods. We examined associations between chronic stress-related neural activity, measured by amygdalar 18Fluorodeoxyglucose (18FDG) uptake, and aortic vascular FDG uptake (arterial inflammation measure) in a community-based cohort. Methods: Forty participants from the Washington, DC CV Health and Needs Assessment (DC-CHNA), a study of a predominantly African-American population in resource-limited urban areas and 25 healthy volunteers underwent detailed phenotyping, including 18FDG PET/CT for assessing amygdalar activity (AmygA), vascular FDG uptake, and hematopoietic (leukopoietic) tissue activity. Mediation analysis was used to test whether the link between AmygA and vascular FDG uptake was mediated by hematopoietic activity. Results: AmygA (1.11 ± 0.09 vs. 1.05 ± 0.09, p = 0.004) and vascular FDG uptake (1.63 ± 0.22 vs. 1.55 ± 0.17, p = 0.05) were greater in the DC-CHNA cohort compared to volunteers. Within the DC-CHNA cohort, AmygA associated with vascular FDG uptake after adjustment for Framingham score and body mass index (ß = 0.41, p = 0.015). The AmygA and aortic vascular FDG uptake relationship was in part mediated by splenic (20.2%) and bone marrow (11.8%) activity. Conclusions: AmygA, or chronic stress-related neural activity, associates with subclinical CVD risk in a community-based cohort. This may in part be mediated by the hematopoietic system. Our findings of this hypothesis-generating study are suggestive of a potential relationship between chronic stress-related neural activity and subclinical CVD in an African American community-based population. Taken together, these findings suggest a potential mechanism by which chronic psychosocial stress, such as stressors that can be experienced in adverse social conditions, promotes greater cardiovascular risk amongst resource-limited, community-based populations most impacted by cardiovascular health disparities. However, larger prospective studies examining these findings in other racially and ethnically diverse populations are necessary to confirm and extend these findings.

Chronic Stress-Related Neural Activity Associates With Subclinical Cardiovascular Disease in Psoriasis: A Prospective Cohort Study.

OBJECTIVES: This study hypothesized that there is an association between chronic stress (as indexed by resting amygdalar activity [AmygA]), hematopoietic system activity (HMPA), and subclinical cardiovascular indexes (aortic vascular inflammation [VI] and noncalcified coronary plaque burden [NCB]) in psoriasis (PSO). The study also hypothesized that treatment of PSO would improve these parameters. BACKGROUND: PSO is a stress-related chronic inflammatory condition that is associated with increased prevalence of subclinical cardiovascular disease (CVD). In individuals without PSO, stress has been linked to CVD through a serial biological pathway that involves the amygdala, hematopoietic tissues, and atherosclerotic plaques. METHODS: A total of 164 consecutive patients with PSO and 47 healthy volunteers underwent 18-fluorodeoxyglucose positron emission tomography/computed tomography scans for assessment of AmygA, HMPA, and VI, as well as coronary computed tomography angiography scans for quantifying NCB. Furthermore, a consecutive subset of 30 patients with severe PSO (Psoriasis Area Severity Index Score >10) were followed at 1 year to assess the relationship between skin disease improvement and AmygA, HMPA, VI, and NCB. RESULTS: The PSO cohort was middle-aged (mean age: 50 years), had low cardiovascular risk (Framingham risk score: median: 3) and had mild to moderate PSO activity (median Psoriasis Area Severity Index Score: 5.6). AmygA was higher in patients with PSO compared to volunteer participants. AmygA was associated with HMPA (bone marrow activity: ß = 0.20, p = 0.01) and subclinical CVD (VI: ß = 0.31, p < 0.001; NCB: ß = 0.27, p < 0.001) The AmygA-CVD association was in part mediated by HMPA (VI: 20.9%, NCB: 36.7%). Following 1 year of PSO treatment in those with severe disease, improvement in skin disease was accompanied by a reduction in AmygA, bone marrow activity, and VI, with no progression of NCB. CONCLUSIONS: In PSO, a chronic inflammatory disease state, AmygA, which is a manifestation of chronic stress, substantially contributes to the risk of subclinical CVD. Additional studies that use psychometric measures of stress are required to explore therapeutic impact.

Association Between Soluble Lectinlike Oxidized Low-Density Lipoprotein Receptor-1 and Coronary Artery Disease in Psoriasis.

Importance: Psoriasis, a chronic inflammatory skin disease associated with accelerated noncalcified coronary burden (NCB) by coronary computed tomography angiography (CCTA), accelerates lipoprotein oxidation in the form of oxidized modified lipoproteins. A transmembrane scavenger receptor for these oxidized modified lipoproteins is lectinlike oxidized low-density lipoprotein receptor-1 (LOX-1), which has been reported to be associated with coronary artery disease. It is unknown whether this receptor is associated with coronary artery disease in psoriasis. Objective: To assess the association between soluble LOX-1 (sLOX-1) and NCB in psoriasis over time. Design, Setting, and Participants: In a cohort study at the National Institutes of Health, 175 consecutive patients with psoriasis were referred from outpatient dermatology practices between January 1, 2013, and October 1, 2017. A total of 138 consecutively recruited patients with psoriasis were followed up at 1 year. Exposures: Circulating soluble lectinlike oxidized low-density lipoprotein receptor-1 levels were measured blindly by field scientists running undiluted serum using an enzyme-linked immunosorbent assay. Main Outcomes and Measures: Coronary computed tomography angiography scans were performed to quantify NCB in all 3 major epicardial coronary arteries by a reader blinded to patient demographics, visit, and treatment status. Results: Among the 175 patients with psoriasis, the mean (SD) age was 49.7 (12.6) years and 91 were men (55%). The cohort had relatively low median cardiovascular risk by Framingham risk score (median, 2.0 [interquartile range (IQR), 1.0-6.0]) and had a mean (SD) body mass index (calculated as weight in kilograms divided by height in meters squared) suggestive of overweight profiles (29.6 [6.0]). Elevated sLOX-1 levels were found in patients with psoriasis compared with age- and sex-matched controls (median, 210.3 [IQR, 110.9-336.2] vs 83.7 [IQR, 40.1-151.0]; P < .001), and were associated with Psoriasis Area Severity Index (PASI) score (ß = 0.23; 95% CI, 0.082-0.374; P = .003). Moreover, sLOX-1 was associated with NCB independent of hyperlipidemia status (ß = 0.11; 95% CI, 0.016-0.200; P = .023), an association which persisted after adjusting for traditional cardiovascular risk factors, statin use, and biologic psoriasis treatment (ß = 0.10; 95% CI, 0.014-0.193; P = .03). At 1 year, in those who had clinical improvement in PASI (eg, >50% improvement), a reduction in sLOX-1 (median, 311.1 [IQR, 160.0-648.8] vs median, 224.2 [IQR, 149.1 - 427.4]; P = .01) was associated with a reduction in NCB (ß = 0.14; 95% CI, 0.028-0.246; P = .02). Conclusions and Relevance: Soluble lectinlike oxidized low-density lipoprotein receptor-1 levels were elevated in patients with psoriasis and were associated with severity of skin disease. Moreover, sLOX-1 associated with NCB independent of hyperlipidemia status, suggesting that inflammatory sLOX-1 induction may modulate lipid-rich NCB in psoriasis. Improvement of skin disease was associated with a reduction of sLOX-1 at 1 year, demonstrating the potential role of sLOX-1 in inflammatory atherogenesis in psoriasis.

Serum active 1,25(OH)2D, but not inactive 25(OH)D vitamin D levels are associated with cardiometabolic and cardiovascular disease risk in psoriasis.

BACKGROUND AND AIMS: Vitamin D exists as an inactive 25-hydroxyvitamin D (25(OH)D) in the bloodstream, which is converted to active 1,25-dihydroxyvitaminD (1,25(OH)2D) in target tissues. Cohort studies reporting cardiovascular disease among individuals with low vitamin D are inconsistent and solely measure 25(OH)D. Psoriasis, a chronic inflammatory disease, is a vitamin D deficient state and is associated with increased cardiovascular disease risk. While serum 25(OH)D is routinely measured, we hypothesized that measurement of 1,25(OH)2D in psoriasis may perform better than 25(OH)D in capturing cardiovascular risk. METHODS: Consecutive psoriasis patients (N = 122) at baseline underwent FDG PET/CT and CCTA scans to measure visceral adipose volume, aortic vascular uptake of FDG, and coronary plaque burden respectively. Blood levels of both 1,25(OH)2D and 25(OH)D were measured by chemiluminescence (LIAISON XL DIaSorin, Stillwater, MN). RESULTS: The psoriasis cohort was middle-aged (mean ±â€¯SD: 49.6 ±â€¯13.0), predominantly male (n = 71, 58%), in majority Caucasians (n = 98, 80%), and had moderate-to-severe skin disease [psoriasis area severity index score, PASI score, med. (IQR): 5.5 (3.2-10.7)], with almost one-fourth of the cohort on biologic psoriasis therapy for skin disease management (n = 32, 27%) at baseline. Interestingly, serum levels of 1,25(OH)2D but not 25(OH)D were found to be inversely associated with visceral adipose, a marker of cardiometabolic risk in fully adjusted models (ß = - 0.43, p = 0.026 and ß = -0.26 p = 0.13). Similarly, we found an inverse relationship between 1,25(OH)2D, but not 25(OH)D, and aortic vascular uptake of FDG independent of traditional risk factors (ß = -0.19, p = 0.01). Finally, we found that serum 1,25(OH)2D, but not 25(OH)D, was inversely associated with non-calcified coronary plaque burden, as measured by CCTA independent of traditional risk factors (ß = -0.18, p = 0.03). CONCLUSIONS: In conclusion, we demonstrate that low 1,25(OH)2D levels were associated with visceral adipose volume, vascular uptake of FDG and coronary plaque burden independent of traditional risk factors, suggesting that 1,25(OH)2D may better capture the cardiometabolic risk associated with vitamin D deficient states.

Association Between Aortic Vascular Inflammation and Coronary Artery Plaque Characteristics in Psoriasis.

Importance: Inflammation is critical to atherosclerosis. Psoriasis, a chronic inflammatory disease associated with early cardiovascular events and increased aortic vascular inflammation (VI), provides a model to study the process of early atherogenesis. Fludeoxyglucose F 18 positron emission tomography/computed tomography (18F-FDG PET/CT) helps quantify aortic VI, and coronary computed tomography angiography provides coronary artery disease (CAD) assessment through evaluation of total plaque burden (TB) and noncalcified coronary plaque burden (NCB), luminal stenosis, and high-risk plaques (HRP). To our knowledge, association between aortic VI and broad CAD indices has not yet been assessed in a chronic inflammatory disease state. Such a study may provide information regarding the utility of aortic VI in capturing early CAD. Objective: To assess the association between aortic VI and CAD indices, including TB, NCB, luminal stenosis, and HRP prevalence, in psoriasis. Design, Setting, and Participants: In a cross-sectional cohort study at the National Institutes of Health, 215 consecutive patients with psoriasis were recruited from surrounding outpatient dermatology practices. All patients underwent 18F-FDG PET/CT for aortic VI assessment, and 190 of 215 patients underwent coronary computed tomography angiography to characterize CAD. The study was conducted between January 1, 2013, and May 31, 2017. Data were analyzed in March 2018. Exposures: Aortic VI assessed by 18F-FDG PET/CT. Main Outcomes and Measures: Primary outcome: TB and NCB. Secondary outcomes: luminal stenosis and HRP. Results: Among 215 patients with psoriasis (mean [SD] age, 50.4 [12.6] years; 126 men [59%]), patients with increased aortic VI had increased TB (standardized ß = 0.48; P < .001), and higher prevalence of luminal stenosis (OR, 3.63; 95% CI, 1.71-7.70; P = .001) and HRP (OR, 3.05; 95% CI, 1.42-6.47; P = .004). The aortic VI and TB association was primarily driven by NCB (ß = 0.49; P < .001), whereas the aortic VI and HRP association was driven by low-attenuation plaque (OR, 5.63; 95% CI, 1.96-16.19; P = .001). All associations of aortic VI remained significant after adjustment for cardiovascular risk factors: aortic VI and TB (ß = 0.23; P < .001), NCB (ß = 0.24; P < .001), luminal stenosis (OR, 3.40; 95% CI, 1.40-8.24; P = .007), and HRP (OR, 2.72; 95% CI, 1.08-6.83; P = .03). No association was found between aortic VI and dense-calcified coronary plaque burden. Conclusions and Relevance: Aortic VI is associated with broad CAD indices, suggesting that aortic VI may be a surrogate for early CAD. Larger prospective studies need to assess these associations longitudinally and examine treatment effects on these outcomes.

Association between neighborhood-level socioeconomic deprivation and incident hypertension: A longitudinal analysis of data from the Dallas heart study.

BACKGROUND: Cardiovascular disease is a leading economic and medical burden in the United States (US). As an important risk factor for cardiovascular disease, hypertension represents a critical point of intervention. Less is known about longitudinal effects of neighborhood deprivation on blood pressure outcomes, especially in light of new hypertension guidelines. METHODS: Longitudinal data from the Dallas Heart Study facilitated multilevel regression analysis of the relationship between neighborhood deprivation, blood pressure change, and incident hypertension over a 9-year period. Factor analysis explored neighborhood perception, which was controlled for in all analyses. Neighborhood deprivation was derived from US Census data and divided into tertiles for analysis. Hypertension status was compared using pre-2017 and 2017 hypertension guidelines. RESULTS: After adjusting for covariates, including moving status and residential self-selection, we observed significant associations between residing in the more deprived neighborhoods and 1) increasing blood pressure over time and 2) incident hypertension. In the fully adjusted model of continuous blood pressure change, significant relationships were seen for both medium (SBP: ß = 4.81, SE = 1.39, P = .0005; DBP: ß = 2.61, SE = 0.71, P = .0003) and high deprivation (SBP: ß = 7.64, SE = 1.55, P < .0001; DBP: ß = 4.64, SE = 0.78, P < .0001). In the fully adjusted model of incident hypertension, participants in areas of high deprivation had 1.69 higher odds of developing HTN (OR 1.69; 95% CI 1.02, 2.82), as defined by 2017 hypertension guidelines. Results varied based on definition of hypertension used (pre-2017 vs. 2017 guidelines). CONCLUSION: These findings highlight the potential impact of adverse neighborhood conditions on cardiometabolic outcomes, such as hypertension.

A single electrical pulse within the protective zone of each cardiac cycle prevented reperfusion-induced ventricular tachycardia in conscious mice.

Early pioneering investigators discovered, in anesthetized dogs, a protective period within the cardiac cycle. The protective period was a time within the cardiac cycle when a precisely timed stimulus prevented the initiation of ventricular fibrillation caused by an earlier stimulus. Thus, in addition to the susceptible period of repolarization discussed by Wiggers and Wegria (Am. J. Physiol. 131:296, 1940; Am. J. Physiol. 128:500, 1940), there is also a nearby protective period. This report describes a protective period within the cardiac cycle of conscious mice when a precisely timed stimulus prevented the initiation of ventricular tachycardia caused by an earlier stimulus. In addition, we tested the hypothesis that this precisely timed pulse within the protective period prevents reperfusion-induced ventricular tachyarrhythmias in conscious mice. Mice (n = 6) were prepared to record arterial blood pressure and the electrocardiogram. In addition, a vascular occluder was placed around the left main coronary artery, and stimulating electrodes were secured onto the left ventricle. A single precisely timed electrical pulse (5 msec pulse width and 2.5 V) to the left ventricle arriving 13.9 ± 1.1 msec after the R-wave, caused ventricular tachycardia occurring 24.9 ± 0.9 msec after the R-wave. Importantly, a second precisely timed electrical pulse arriving 18.8 ± 0.5 msec after the first stimulus blocked the induction of ventricular tachycardia caused by the earlier stimulus. On an alternate day, the susceptibility to sustained ventricular tachycardia produced by 3.5 min of occlusion and reperfusion of the coronary artery was determined in conscious mice by use of the vascular occluder. Reperfusion resulted in ventricular tachycardia in all six mice. A precisely timed pulse within the protective period prevented ventricular tachycardia in all mice.

Visceral Adiposity in Psoriasis is Associated With Vascular Inflammation by 18F-Fluorodeoxyglucose Positron-Emission Tomography/Computed Tomography Beyond Cardiometabolic Disease Risk Factors in an Observational Cohort Study.

OBJECTIVES: The authors sought to examine the relationship between visceral adipose tissue (VAT) and vascular inflammation (VI) by 18F-Fluorodeoxyglucose (18F-FDG) positron-emission tomography (PET)/computed tomography (CT) in psoriasis (PSO). Furthermore, we evaluated whether treatment of PSO modulated VAT and VI. BACKGROUND: PSO, a chronic inflammatory skin disease, is associated with VI by 18F-FDG PET/CT and increased cardiometabolic risk including adipose tissue dysregulation. Recently, VI was associated with future cardiovascular events; however, the relationship of visceral and subcutaneous adiposity with VI in PSO has yet to be evaluated. METHODS: Consecutive PSO patients (N = 77) underwent 18F-FDG PET/CT scans to measure VI and abdominal adiposity. A subset of PSO patients with severe skin disease was scanned at 1 year following PSO treatment (N = 13). RESULTS: The cohort was middle aged (51.8 ± 12.6 years), predominantly male (n = 44, 57%), had low cardiovascular risk by Framingham 10-year risk (median 4 years [interquartile range (IQR): 2 to 7 years]), and mild-to-moderate skin disease (5.2 [IQR: 3.0 to 8.5]). PSO disease severity associated with VAT (ß = 0.33; p = 0.004) beyond SAT (ß = 0.30; p = 0.005). VAT (ß = 0.55; p < 0.001), but not SAT (ß = 0.15; p = 0.11), associated with VI beyond cardiovascular risk factors. We followed a subset of severe PSO patients treated aggressively for PSO and observed improvement in PSO severity and VAT, which was associated with an improvement in VI at 1 year beyond cardiovascular risk factors (ß = 0.53; p = 0.049). CONCLUSIONS: Volume-based CT measurement of VAT may capture metabolic risk associated with VI compared to subcutaneous adipose tissue in PSO. PSO treatment associated with a decrease in VAT as well as decrease in VI suggesting VAT as a relevant biomarker related to VI in PSO.

Association Between Skin and Aortic Vascular Inflammation in Patients With Psoriasis: A Case-Cohort Study Using Positron Emission Tomography/Computed Tomography.

Importance: Inflammation is critical in the development of atherosclerosis. Psoriasis is a chronic inflammatory skin disease that is associated with increased vascular inflammation by 18fluorodeoxyglucose positron emission tomography/computed tomography in vivo and future cardiovascular events. It provides a human model to understand the effect of treating inflammation in a target organ (eg, the skin) on vascular diseases. Objective: To investigate the association between change in skin disease severity and change in vascular inflammation at 1 year and to characterize the impact of 1 year of anti-tumor necrosis factor therapy on vascular inflammation. Design, Setting, and Participants: In this prospective cohort study, 220 participants from outpatient practices were recruited at the US National Institutes of Health. A total of 115 consecutively recruited patients with psoriasis were followed up at 1 year. The study was conducted from January 1, 2013, through October 31, 2016, with data analyzed in November 2016. Exposure: Skin inflammation measured as Psoriasis Area and Severity Index (PASI) score. Main Outcomes and Measures: Vascular inflammation assessed as target-to-background ratio by 18fluorodeoxyglucose positron emission tomography/computed tomography. Results: Among the 115 patients, the mean (SD) age at 1-year follow-up was 50.8 (12.8) years and 68 were men (59%). The cohort had a low cardiovascular risk by Framingham risk score and mild-to-moderate psoriasis, with a median PASI score of 5.2 (interquartile range, 3.0-8.9). At follow-up, the total cohort had a median improvement in PASI score of 33%, with use of topical therapy (60%), biological therapy (66%, mostly anti-tumor necrosis factor) and phototherapy (15%) (P < .001). Moreover, improvement in PASI score was associated with improvement in target-to-background ratio of 6%, mainly driven by those with higher responses in PASI score (P < .001). This association persisted beyond traditional risk factors (ß = 0.19; 95% CI, 0.012-0.375; P = .03) and was the strongest in those initiated with anti-tumor necrosis factor therapy (ß = 0.79; 95% CI, 0.269-1.311; P = .03). Conclusions and Relevance: Improvement in psoriasis skin disease severity was associated with improvement in aortic vascular inflammation by 18fluorodeoxyglucose positron emission tomography/computed tomography, with greater improvement in aortic vascular inflammation observed in those who had higher than 75% reduction in skin disease severity. These findings suggest that controlling remote target organ inflammation (eg, in the skin) may improve vascular diseases; however, randomized clinical trials are needed to confirm these findings.

Complex and interacting influences of the autonomic nervous system on cardiac electrophysiology in conscious mice.

Mice may now be the preferred animal model for biomedical research due to its anatomical, physiological, and genetic similarity to humans. However, little is known about accentuated antagonism of chronotropic and dromotropic properties in conscious mice. Accordingly, we describe the complex and interacting influence of the autonomic nervous system on cardiac electrophysiology in conscious mice. Specifically, we report the effects of single and combined cardiac autonomic blockade on measurements of pulse interval (heart rate), atrio-ventricular interval, sinus node recovery time (SNRT), SNRT corrected for spontaneous sinus cycle, and Wenckebach cycle length in conscious mice free of the confounding influences of anesthetics and surgical trauma. Autonomic influences were quantified as the change in parameter induced by its selective blocker (Sympathetic or Parasympathetic Effect) or as the difference between the intrinsic value and the value after a selective blocker (Sympathetic or Parasympathetic Tonus). Sympatho-Vagal Balance (SVB) was assessed as the ratio of control interval to intrinsic interval. SVB suggests slight parasympathetic dominance in the control of cardiac electrophysiology intervals. Furthermore, results documents a complex interaction between the sympathetic and parasympathetic divisions of the autonomic nervous system in the control of cardiac electrophysiology parameters. Specifically, the parasympathetic effect was greater than the parasympathetic tonus in the control of cardiac electrophysiology parameters. In contrast, the sympathetic effect was smaller than the sympathetic tonus in the control of cardiac electrophysiology parameters. Results have important implications because actions of pharmacological agents that alter the autonomic control of cardiac electrophysiology are transformed by these interacting mechanisms.