Mast cell-mediated immune regulation in health and disease.

Mast cells are important components of the immune system, and they perform pro-inflammatory as well as anti-inflammatory roles in the complex process of immune regulation in health and disease. Because of their strategic perivascular localization, sensitivity and adaptability to the microenvironment, and ability to release a variety of preformed and newly synthesized effector molecules, mast cells perform unique functions in almost all organs. Additionally, Mast cells express a wide range of surface and cytoplasmic receptors which enable them to respond to a variety of cytokines, chemicals, and pathogens. The mast cell's role as a cellular interface between external and internal environments as well as between vasculature and tissues is critical for protection and repair. Mast cell interactions with different immune and nonimmune cells through secreted inflammatory mediators may also turn in favor of disease promoting agents. First and forefront, mast cells are well recognized for their multifaceted functions in allergic diseases. Reciprocal communication between mast cells and endothelial cells in the presence of bacterial toxins in chronic/sub-clinical infections induce persistent vascular inflammation. We have shown that mast cell proteases and histamine induce endothelial inflammatory responses that are synergistically amplified by bacterial toxins. Mast cells have been shown to exacerbate vascular changes in normal states as well as in chronic or subclinical infections, particularly among cigarette smokers. Furthermore, a potential role of mast cells in SARS-CoV-2-induced dysfunction of the capillary-alveolar interface adds to the growing understanding of mast cells in viral infections. The interaction between mast cells and microglial cells in the brain further highlights their significance in neuroinflammation. This review highlights the significant role of mast cells as the interface that acts as sensor and early responder through interactions with cells in systemic organs and the nervous system.

Effects of Vitamin D Supplementation and 25-Hydroxyvitamin D Levels on the Risk of Atrial Fibrillation.

The effects of vitamin D (Vit-D) deficiency and Vit-D treatment (VDT) on atrial fibrillation (AF) remain inconclusive. This study sought to determine the effects of VDT and nontreatment on AF risk in Vit-D-deficient patients without a previous history of AF. In this nested case-control study, 39,845 individuals with low 25-hydroxy-Vit-D ([25-OH]D) levels (<20 ng/ml) were divided into group-A (untreated, levels ≤20 ng/ml), group-B (treated, levels 21 to 29 ng/ml), and group-C (treated, levels ≥30 ng/ml). The risk of AF was compared utilizing propensity score-weighted Cox proportional hazard models. Among the individuals receiving VDT for ≥6 months, the risk of AF was significantly lower in group-B (hazard ratio [HR] 0.89, 95% confidence interval [CI] 0.80 to 0.98, p = 0.03] and group-C (HR 0.84, 95% CI 0.73 to 0.0.95, p = 0.007] than in group-A. A subgroup analysis of men >65 years showed individuals with hypertension had a significantly lower risk of AF in group-C than in group-B (HR 0.79, CI 0.65 to 0.94, p = 0.02) and group-A (HR 0.78, CI 0.64 to 0.96, p = 0.012). A similar result was found in men >65 years with diabetes mellitus in group-C compared with group-B (HR 0.69, CI 0.51 to 0.93, p = 0.012) and group-A (HR 0.63, CI 0.47 to 0.84, p = 0.002). In what is, to best of our knowledge, the largest observational study to date of patients with Vit-D deficiency and no previous history of AF, (25-OH)D level of >20 ng/ml with VDT for ≥6 months was associated with a significantly lower risk of AF. Additionally, men >65 years with hypertension or diabetes mellitus had a further decrease in AF risk when the (25-OH)D levels were ≥30 ng/ml.

Recognizing the True Value of Testosterone Therapy in Health Care.

There has been little recognition within the medical community of the health impact of testosterone (T) deficiency (TD), also known as hypogonadism, and the substantial benefits of testosterone therapy (TTh) on health and quality of life despite high-level clinical evidence. In a roundtable symposium, investigators summarized the contemporary evidence in several key clinical areas. TD negatively impacts human health and quality of life and is associated with increased mortality. Several studies have demonstrated that TTh in men with TD reduced all-cause and cardiovascular mortality. The longstanding belief that TTh is associated with increased prostate cancer (PCa) risk is contradicted by recent evidence, including multiple studies showing that TTh is associated with reduced PCa risk. Similarly, the weight of current evidence indicates the purported concern that TTh is associated with increased cardiovascular risk is incorrect. Normalization of physiological T reduces myocardial infarction, stroke, and deaths compared with men whose testosterone levels failed to normalize. In diabetic men TTh improves insulin resistance, and a large 2-year controlled study in men with abnormal glucose tolerance showed a substantially reduced rate of diabetes among men treated with TTh compared with untreated controls. Long-term TTh in diabetic men resulted in progressive improvements in obesity and insulin requirements, including a substantial number who experienced complete remission of diabetes. Finally, TTh has been shown to reduce severe outcomes with Covid-19 infection. These lines of evidence argue strongly for the need for greater awareness in the medical community of the impact of TD on health, and of the health benefits of TTh.

The Effects of Vitamin D Supplementation and 25-Hydroxyvitamin D Levels on the Risk of Myocardial Infarction and Mortality.

OBJECTIVE: The aim of the study was to examine the effects of the vitamin D (Vit-D) treatment and nontreatment on Vit-D-deficient patients without a prior history of myocardial infarction (MI). MATERIALS AND METHODS: This was a retrospective, observational, nested case-control study of patients (N = 20 025) with low 25-hydroxyvitamin D ([25-OH]D) levels (<20 ng/mL) who received care at the Veterans Health Administration from 1999 to 2018. Patients were divided into 3 groups: Group A (untreated, levels ≤20 ng/mL), Group B (treated, levels 21-29 ng/mL), and Group C (treated, levels ≥30 ng/mL). The risk of MI and all-cause mortality were compared utilizing propensity score-weighted Cox proportional hazard models. RESULTS: Among the cohort of 20 025 patients, the risk of MI was significantly lower in Group C than in Group B (hazard ratio [HR] 0.65, 95% CI 0.49-0.85, P = .002) and Group A (HR 0.73, 95% CI 0.55-0.96), P = .02). There was no difference in the risk of MI between Group B and Group A (HR 1.14, 95% CI 0.91-1.42, P = 0.24). Compared with Group A, both Group B (HR 0.59, 95% CI 0.54-0.63, P < .001) and Group C (HR 0.61, 95% CI 0.56-0.67, P < .001) had significantly lower all-cause mortality. There was no difference in all-cause mortality between Group B and Group C (HR 0.99, 95% CI 0.89-1.09, P = .78). CONCLUSIONS: In patients with Vit-D deficiency and no prior history of MI, treatment to the (25-OH)D level of >20 ng/mL and >30 ng/mL was associated with a significantly lower risk of all-cause mortality. The lower risk of MI was observed only in individuals maintaining (25-OH)D levels ≥30 ng/mL.

Reducing Tobacco-Related Disability in Chronic Smokers.

Tobacco consumption (predominantly cigarettes) is the leading preventable cause of mortality worldwide. Although the major focus of strategies to reduce mortality from tobacco must include prevention of future generations from initially gaining access, some smokers are unwilling or unable to quit. Can the higher risk chronic smoker be identified and can their risk be reduced? The risk of adverse events in cigarette smokers is influenced by the intensity and duration of cigarette smoking or secondhand exposure, associated conventional risk factors, environmental stressors, and certain genetic variants and epigenetic modifiers. Recent data suggest that inflammatory markers such as high-sensitivity C-reactive protein (hs CRP) and targeted imaging can identify some smokers at higher risk. As smoking is prothrombotic, aspirin initiation and expanded statin use might reduce cardiovascular risk in those who do not presently meet criteria for these therapies, but further study is required. Thus, although advocacy for smoking cessation should always be the primary approach, increased efforts are needed to identify and potentially treat those who are unable or unwilling to quit.

Relation of Testosterone Normalization to Mortality and Myocardial Infarction in Men With Previous Myocardial Infarction.

The effect of normalization of serum testosterone levels with testosterone replacement therapy (TRT) in patients with a history of myocardial infarction (MI) is unknown. The objective of this study was to determine the incidence of recurrent MI and all-cause mortality in subjects with a history of MI and low total testosterone (TT) with and without TRT. We retrospectively examined 1,470 men with documented low TT levels and previous MI, categorized into Gp1: TRT with normalization of TT levels (n = 755) Gp2: TRT without normalization of TT levels (n = 542), and Gp3: no TRT (n = 173). The association of TRT with all-cause mortality and recurrent MI was compared using propensity score-weighted Cox proportional hazard models. All-cause mortality was lower in Gp1 versus Gp2 (hazard ratio [HR] 0.76, confidence interval [CI] 0.64 to 0.90, p = 0.002), and Gp1 versus Gp3 (HR 0.76, CI 0.60 to 0.98, p = 0.031). There was no significant difference in the risk of death between Gp2 versus Gp3 (HR 0.97, CI 0.76 to 1.24, p = 0.81). Adjusted regression analyses showed no significant differences in the risk of recurrent MI between groups (Gp1 vs Gp3, HR 0.79, CI 0.12 to 5.27, p = 0.8; Gp1 vs Gp2 HR 1.10, CI 0.25 to 4.77, p = 0.90; Gp2 vs Gp3 HR 0.58, CI 0.08 to 4.06, p = 0.58). In conclusion, in a large observational cohort of male veterans with previous MI, normalization of TT levels with TRT was associated with decreased all-cause mortality compared with those with non-normalized TT levels and the untreated group. Furthermore, in this high-risk population, TRT was not associated with an increased risk of recurrent MI.

Prognostic significance, angiographic characteristics and impact of antithrombotic and anticoagulant therapy on outcomes in high versus low grade coronary artery ectasia: A long-term follow-up study.

OBJECTIVES: To assess the prognostic significance of high vs. low grade coronary artery ectasia (CAE) and the impact of antithrombotic or anticoagulant therapy on adverse cardiac outcomes. BACKGROUND: There is paucity of knowledge on the impact of angiographic characteristics in CAE or that of antithrombotic or anticoagulant therapy on outcomes. METHODS AND RESULTS: In this retrospective study, we reviewed angiograms and medical records of all cases of confirmed CAE (2001-2011). Extent of CAE was categorized using the Markis classification. Types 1 and 2 were categorized as high-grade and types 3 and 4 as low-grade CAE. Angiographic flow was recorded as normal or sluggish (

Environmental Tobacco Smoke and Cardiovascular Disease.

Environmental tobacco smoke (ETS) and its sequelae are among the largest economic and healthcare burdens in the United States and worldwide. The relationship between active smoking and atherosclerosis is well-described in the literature. However, the specific mechanisms by which ETS influences atherosclerosis are incompletely understood. In this paper, we highlight the definition and chemical constituents of ETS, review the existing literature outlining the effects of ETS on atherogenesis and thrombosis in both animal and human models, and briefly outline the public health implications of ETS based on these data.

Normalization of Testosterone Levels After Testosterone Replacement Therapy Is Associated With Decreased Incidence of Atrial Fibrillation.

BACKGROUND: Atrial fibrillation (AF) is the most common cardiac dysrhythmia associated with significant morbidity and mortality. Several small studies have reported that low serum total testosterone (TT) levels were associated with a higher incidence of AF. In contrast, it is also reported that anabolic steroid use is associated with an increase in the risk of AF. To date, no study has explored the effect of testosterone normalization on new incidence of AF after testosterone replacement therapy (TRT) in patients with low testosterone. METHODS AND RESULTS: Using data from the Veterans Administrations Corporate Data Warehouse, we identified a national cohort of 76 639 veterans with low TT levels and divided them into 3 groups. Group 1 had TRT resulting in normalization of TT levels (normalized TRT), group 2 had TRT without normalization of TT levels (nonnormalized TRT), and group 3 did not receive TRT (no TRT). Propensity score-weighted stabilized inverse probability of treatment weighting Cox proportional hazard methods were used for analysis of the data from these groups to determine the association between post-TRT levels of TT and the incidence of AF. Group 1 (40 856 patients, median age 66 years) had significantly lower risk of AF than group 2 (23 939 patients, median age 65 years; hazard ratio 0.90, 95% CI 0.81-0.99, P=0.0255) and group 3 (11 853 patients, median age 67 years; hazard ratio 0.79, 95% CI 0.70-0.89, P=0.0001). There was no statistical difference between groups 2 and 3 (hazard ratio 0.89, 95% CI 0.78- 1.0009, P=0.0675) in incidence of AF. CONCLUSIONS: These novel results suggest that normalization of TT levels after TRT is associated with a significant decrease in the incidence of AF.

Normalization of Testosterone Levels After Testosterone Replacement Therapy Is Not Associated With Reduced Myocardial Infarction in Smokers.

OBJECTIVE: To examine the effect of cigarette smoking (CS) status and total testosterone (TT) levels after testosterone replacement therapy (TRT) on all-cause mortality, myocardial infarction (MI), and stroke in male smokers and nonsmokers without history of MI and stroke. PARTICIPANTS AND METHODS: Data from 18,055 males with known CS status and low TT levels who received TRT at the Veterans Health Administration between December 1, 1999, and May 31, 2014, were grouped into (1) current smokers with normalized TT, (2) current smokers with nonnormalized TT, (3) nonsmokers with normalized TT, and (4) nonsmokers with nonnormalized TT. Combined effect of CS status and TT level normalization after TRT on all-cause mortality, MI, and stroke was compared using propensity score-weighted Cox proportional hazard models. RESULTS: Normalization of serum TT levels in nonsmokers was associated with a significant decrease in all-cause mortality (hazard ratio [HR]=0.526; 95% CI, 0.477-0.581; P<.001) and MI (HR=0.717; 95% CI, 0.522-0.986; P<.001). Among current smokers, normalization of serum TT levels was associated with a significant decrease in only all-cause mortality (HR=0.563; 95% CI, 0.488-0.649; P<.001) without benefit in MI (HR=1.096; 95% CI, 0.698-1.720; P=.69). Importantly, compared with nonsmokers with normalized TT, all-cause mortality (HR=1.242; 95% CI, 1.104-1.396; P<.001), MI (HR=1.706; 95% CI, 1.242-2.342; P=.001), and stroke (HR=1.590; 95% CI, 1.013-2.495; P=.04) were significantly higher in current smokers with normalized TT. CONCLUSION: We conclude that active CS may negate the protective effect of testosterone level normalization on all-cause mortality and MI after TRT.

Association Between Testosterone Replacement Therapy and the Incidence of DVT and Pulmonary Embolism: A Retrospective Cohort Study of the Veterans Administration Database.

BACKGROUND: Testosterone replacement therapy (TRT) prescriptions have increased several-fold in the last decade. There have been concerns regarding a possible increased incidence of DVT and pulmonary embolism (PE) with TRT. Few data support the association between TRT and DVT/PE. We evaluated the incidence of DVT and PE in men who were prescribed TRT for low serum total testosterone (sTT) levels. METHODS: This is a retrospective cohort study, conducted using data obtained from the Veterans Affairs Informatics and Computing Infrastructure. We compared the incidence of DVT/PE between those who received TRT and subsequently had normal on-treatment sTT levels (Gp1), those who received TRT but continued to have low on-treatment sTT (Gp2), and those who did not receive TRT (Gp3). Those with prior history of DVT/PE, cancer, hypercoagulable state, and chronic anticoagulation were excluded. RESULTS: The final cohort consisted of 71,407 subjects with low baseline sTT. Of these, 10,854 did not receive TRT (Gp3) and 60,553 received TRT. Of those who received TRT, 38,362 achieved normal sTT (Gp1) while 22,191 continued to have low sTT (Gp2). The incidence of DVT/PE was 0.5%, 0.4%, and 0.4% in Gp1, Gp2, and Gp3, respectively. Univariate, multivariate, and stabilized inverse probability of treatment weights analyses showed no statistically significant difference in DVT/PE-free survival between the various groups. CONCLUSIONS: This study did not detect a significant association between testosterone replacement therapy and risk of DVT/PE in adult men with low sTT who were at low to moderate baseline risk of DVT/PE.

Epinephrine-Induced Takotsubo Cardiomyopathy.

Treatment of an allergic reaction led to stress-induced transient cardiomyopathy and provided evidence to support the role of epinephrine in the pathogenesis of this disease.

Cigarette Smoke Amplifies Inflammatory Response and Atherosclerosis Progression Through Activation of the H1R-TLR2/4-COX2 Axis.

Emerging evidence suggests that infection and persistent inflammation are key players in the pathogenesis of atherosclerotic cardiovascular disease (CVD). Although it is well established that cigarette smoke (CS) promotes atherosclerotic CVD, very little is known about the potential impact of the collective effects of CS and intermittent or chronic subclinical infection on atherosclerosis. Our previous studies demonstrated that mast cell-derived histamine and lipopolysaccharide (LPS) synergistically enhance endothelial cell inflammatory response. We further noted that the synergy between histamine and LPS was due to reciprocal upregulation of histamine receptor and Toll-like receptor 4 (TLR4) expression and functions. These results suggest that the combined and persistent effects of mast cell mediators and bacterial agents on the vasculature are risk factors of CVD. Our recent data demonstrated that CS extract enhances histamine- and LPS-induced expression of cyclooxygenase-2 (COX-2) in endothelial cells, suggesting that CS and mast cell mediators may collectively amplify inflammatory response in the vessel wall. We hypothesize that CS enhances histamine-mediated upregulation of TLR2/TLR4 signaling in the endothelium and promotes progression of atherosclerosis. This article presents our perspective on the modulatory effects of CS and nicotine on the "histamine-TLR-COX-2 axis."

Normalization of testosterone level is associated with reduced incidence of myocardial infarction and mortality in men.

AIMS: There is a significant uncertainty regarding the effect of testosterone replacement therapy (TRT) on cardiovascular (CV) outcomes including myocardial infarction (MI) and stroke. The aim of this study was to examine the relationship between normalization of total testosterone (TT) after TRT and CV events as well as all-cause mortality in patients without previous history of MI and stroke. METHODS AND RESULTS: We retrospectively examined 83 010 male veterans with documented low TT levels. The subjects were categorized into (Gp1: TRT with resulting normalization of TT levels), (Gp2: TRT without normalization of TT levels) and (Gp3: Did not receive TRT). By utilizing propensity score-weighted Cox proportional hazard models, the association of TRT with all-cause mortality, MI, stroke, and a composite endpoint was compared between these groups. The all-cause mortality [hazard ratio (HR): 0.44, confidence interval (CI) 0.42-0.46], risk of MI (HR: 0.76, CI 0.63-0.93), and stroke (HR: 0.64, CI 0.43-0.96) were significantly lower in Gp1 (n = 43 931, median age = 66 years, mean follow-up = 6.2 years) vs. Gp3 (n = 13 378, median age = 66 years, mean follow-up = 4.7 years) in propensity-matched cohort. Similarly, the all-cause mortality (HR: 0.53, CI 0.50-0.55), risk of MI (HR: 0.82, CI 0.71-0.95), and stroke (HR: 0.70, CI 0.51-0.96) were significantly lower in Gp1 vs. Gp2 (n = 25 701, median age = 66 years, mean follow-up = 4.6 years). There was no difference in MI or stroke risk between Gp2 and Gp3. CONCLUSION: In this large observational cohort with extended follow-up, normalization of TT levels after TRT was associated with a significant reduction in all-cause mortality, MI, and stroke.

Mechanisms of coronary thrombosis in cigarette smoke exposure.

Acute rupture or erosion of a coronary atheromatous plaque and subsequent coronary artery thrombosis cause the majority of sudden cardiac deaths and myocardial infarctions. Cigarette smoking is a major risk factor for acute coronary thrombosis. Indeed, a majority of sudden cardiac deaths attributable to acute thrombosis are in cigarette smokers. Both active and passive cigarette smoke exposure seem to increase the risk of coronary thrombosis and myocardial infarctions. Cigarette smoke exposure seems to alter the hemostatic process via multiple mechanisms, which include alteration of the function of endothelial cells, platelets, fibrinogen, and coagulation factors. This creates an imbalance of antithrombotic/prothrombotic factors and profibrinolytic/antifibrinolytic factors that support the initiation and propagation of thrombosis.

Acute cigarette smoke exposure reduces clot lysis--association between altered fibrin architecture and the response to t-PA.

BACKGROUND: Enhanced thrombolysis is a proposed mechanism for reduced mortality in cigarette smokers with STEMI ("smoker's paradox"). The mechanisms remain unclear but studies suggest fibrin architecture (FA) may affect thrombolysis. Our group has previously shown that acute cigarette smoke exposure (CSE) alters FA. This study was done to evaluate the association between FA, thrombolysis and CSE. METHODS AND RESULTS: Otherwise healthy smokers (n=22) were studied before and after smoking two cigarettes. Non-smokers (n=22) served as controls. Two ex-vivo models were used to evaluate clot lysis of venous blood and these data were compared to FA as determined by SEM. In the first model, clot lysis in a glass tube at 60minutes after addition of t-PA was measured. The second model quantified lysis utilizing thromboelastography. With the latter, after a clot reached maximum strength, t-PA was added and clot lysis at 60min was noted. SEM studies were performed on platelet poor plasma mixed with thrombin and FA was examined at 20K. Clot lysis was similar in both groups except that post-smoking, TEG showed a significantly lower lysis compared to pre- and non-smoking clots. SEM analysis showed significantly thinner fibers and denser clots post-smoking. CONCLUSIONS: Venous clots from smokers failed to show an enhanced lysis when exposed to t-PA. In fact, acute CSE was associated with changes in FA and increased resistance to thrombolysis. These findings in part may explain enhanced thrombogenicity but suggest that mechanisms other than enhanced fibrinolysis are likely to be responsible for "smoker's paradox."

Effects of cigarette smoke exposure on clot dynamics and fibrin structure: an ex vivo investigation.

OBJECTIVE: The purpose of this study was to examine the effect of cigarette smoke exposure (CSE) on clot dynamics and fibrin architecture and to isolate the relative contribution of platelets and fibrinogen to clot dynamics. METHODS AND RESULTS: From young healthy males smokers (n=34) and nonsmokers (n=34) a baseline blood was drawn, and smokers had another blood draw after smoking 2 regular cigarettes. Using thromboelastography (TEG) the degree of platelet-fibrin interaction was measured. In additional experiments, abciximab (20 microg/mL) was added to the smokers samples (n=27) to reduce the effects of platelet function from the TEG parameters. The maximum clot strength (G) obtained with abciximab measured mainly the contribution of fibrinogen to clot strength (GF). By subtracting GF from G, the contribution of platelets to clot strength (GP) was presumed. A significant difference was found for all TEG parameters between nonsmokers versus postsmoking and pre- versus postsmoking samples. Postsmoking both GF and GP were significantly higher as compared to presmoking. On electron microscopy and turbidity analysis, postsmoking fibrin clots were significantly different compared to presmoking and nonsmoking samples. CONCLUSIONS: Acute CSE changes clot dynamics and alters fibrin architecture. Both functional changes in fibrinogen and platelets appear to contribute to heightened thrombogenicity after acute CSE.