Shlomo Berliner

Burnout and risk of cardiovascular disease: evidence, possible causal paths, and promising research directions.

Burnout is characterized by emotional exhaustion, physical fatigue, and cognitive weariness, resulting from prolonged exposure to work-related stress. The authors review the accumulated evidence suggesting that burnout and the related concept of vital exhaustion are associated with increased risk of cardiovascular disease and cardiovascular-related events. The authors present evidence supporting several potential mechanisms linking burnout with ill health, including the metabolic syndrome, dysregulation of the hypothalamic-pituitary-adrenal axis along with sympathetic nervous system activation, sleep disturbances, systemic inflammation, impaired immunity functions, blood coagulation and fibrinolysis, and poor health behaviors. The association of burnout and vital exhaustion with these disease mediators suggests that their impact on health may be more extensive than currently indicated.

Single and Combined Prothrombotic Factors in Patients With Idiopathic Venous Thromboembolism: Prevalence and Risk Assessment

The inherited thrombophilias--deficiencies of protein C, protein S, and antithrombin III--and the prothrombotic polymorphisms factor V G1691A and factor II G20210A predispose patients toward venous thromboembolism (VTE). The aim of this study was to determine the prevalence of single and combined prothrombotic factors in patients with idiopathic VTE and to estimate the associated risks. The study group consisted of 162 patients referred for work-up of thrombophilia after documented VTE. The controls were 336 consecutively admitted patients. In all subjects factor V G1691A, factor II G20210A, and methylenetetrahydrofolate reductase (MTHFR) C677T were analyzed by specific polymerase chain reactions and restriction enzymes. Activities of antithrombin III and protein C, free protein S antigen, and lupus anticoagulant were determined in a subset of 109 patients who were not receiving oral anticoagulants. The prevalences of heterozygotes and homozygotes for factor V G1691A and factor II G20210A among patients and controls were 40.1% versus 3.9% and 18.5% versus 5.4%, respectively (P=0.0001). The prevalence of homozygotes for MTHFR C677T in patients was 22.8% and in controls, 14.3% (P=0.025). Heterozygous and homozygous factor V G1691A, factor II G20210A, and homozygous MTHFR C677T were found to be independent risk factors for VTE, with odds ratios of 16.3, 3.6, and 2.1, respectively. Two or more polymorphisms were detected in 27 of 162 patients (16.7%) and in 3 of 336 controls (0.9%). Logistic regression analysis disclosed odds ratios of 58.6 (confidence interval [CI], 22.1 to 155.2) for joint occurrence of factor V and factor II polymorphisms, of 35.0 (CI, 14.5 to 84.7) for factor V and MTHFR polymorphisms, and of 7.7 (CI, 3.0 to 19.6) for factor II and MTHFR polymorphisms. Among 109 patients in whom a complete thrombophilic work-up was performed, 74% had at least 1 underlying defect. These data indicate that in most patients referred for evaluation of thrombophilia due to idiopathic VTE, 1 or more underlying genetic predispositions were discernible. The presence of >1 of the prothrombotic polymorphisms was associated with a substantial risk of VTE.

The Association Between Burnout, Depression, Anxiety, and Inflammation Biomarkers: C-Reactive Protein and Fibrinogen in Men and Women

Following the demonstrated association of employee burnout or vital exhaustion with several risk factors for cardiovascular disease (CVD) and CVD risk, the authors investigated the possibility that one of the mechanisms linking burnout with CVD morbidity is microinflammation, gauged in this study by high-sensitivity C-reactive protein (hs-CRP) and fibrinogen concentrations. Their sample included 630 women and 933 men, all apparently healthy, who underwent periodic health examinations. The authors controlled for possible confounders including 2 other negative affective states: depression and anxiety. In women, burnout was positively associated with hs-CRP and fibrinogen concentrations, and anxiety was negatively associated with them. In men, depression was positively associated with hs-CRP and fibrinogen concentrations, but not with burnout or anxiety. Thus, burnout, depression, and anxiety are differentially associated with microinflammation biomarkers, dependent on gender.

Neutrophil/lymphocyte ratio is related to the severity of coronary artery disease and clinical outcome in patients undergoing angiography

BACKGROUND White blood cell count is an independent predictor of cardiovascular events and mortality. Neutrophil/lymphocyte ratio (NLR) is a biomarker that can single out individuals at risk for vascular events. OBJECTIVE To evaluate whether NLR adds additional information beyond that provided by conventional risk factors and biomarkers for coronary artery disease (CAD) severity and adverse outcome, in a large cohort of consecutive patients referred for coronary angiography. MATERIALS AND METHODS NLR was computed from the absolute values of neutrophils and lymphocytes from the complete blood count of 3005 consecutive patients undergoing coronary angiography for various indications. CAD severity was determined by an interventional cardiologist unaware of the study aims. The association between NLR and CAD severity was assessed by logistic regression and the association between NLR and 3-years outcome were analyzed using Cox regression models, adjusting for potential clinical, metabolic, and inflammatory confounders. RESULTS The cohort was divided into 3 groups according to the NLR value (<2, 2-3, and >3). NLR was independently associated with CAD severity and it contributed significantly to the regression models. Patients with NLR >3 had more advanced obstructive CAD (OR = 2.45, CI 95% 1.76-3.42, p < 0.001) and worse prognosis, with a higher rate of major CVD events during up to 3 years of follow-up (HR = 1.55, CI 95% 1.09-2.2, p = 0.01). CONCLUSION Neutrophil/lymphocyte ratio is independently associated with CAD severity and 3-years outcome. NLR value appears additive to conventional risk factors and commonly used biomarkers.

Inherited factor XI deficiency confers no protection against acute myocardial infarction

Summary.  Background and purpose: Factor XI (FXI) contributes to thrombin generation thereby affecting fibrin formation and to down regulation of fibrinolysis by activation of thrombin‐activatable fibrinolysis inhibitor (TAFI). The purpose of this study was to evaluate whether patients with severe FXI deficiency are protected against acute myocardial infarction (AMI). Methods: The incidence of AMI in patients with severe FXI deficiency (FXI activity less than 15 U dL−1) whose age was 35 years or more was compared to the incidence of AMI in age and gender matched persons of the general population. Atherosclerotic risk factors were assessed in FXI deficient patients and blood was tested for prothrombotic parameters such as FV Leiden, prothrombin G20210A, lupus anticoagulant, and platelet membrane polymorphisms. The common mutations causing FXI deficiency in Jews were also examined. Results: Of 96 patients with severe FXI deficiency (55 women and 41 men) 16 had a history of AMI (6 women and 10 men). The median age at the time of AMI was 64.5 for women and 58 for men. The calculated annual rate of AMI in men was similar to the expected in the general Israeli population, whereas in women it was almost 2‐fold higher, but this difference did not reach statistical significance. One or more atherosclerotic risk factors were observed in 13 of 16 patients (81.3%) with AMI compared to 44 of 79 patients (55.7%) without AMI (P < 0.001). The frequency distributions of platelet polymorphisms and of prothrombotic polymorphisms were not different between patients with severe FXI deficiency who experienced or not an AMI. None of the patients had lupus anticoagulant. The common genotypes which cause FXI deficiency in Jews were similarly distributed in patients with and without AMI. Conclusions: Severe FXI deficiency does not confer protection against AMI.

Dental surgery in patients with severe factor XI deficiency without plasma replacement.

Bleeding following dental extraction is frequently the first manifestation of severe factor XI deficiency. Safe oral surgery has previously been performed in such patients by using plasma replacement therapy with or without concomitant administration of antifibrinolytic agents. The aim of this study was to determine whether such patients can undergo safe dental extractions using only an antifibrinolytic agent. The study group consisted of 19 patients with severe factor XI deficiency (factor XI:C level less than 14 U/dl) who had previously bled following dental extractions (14 patients) or other trauma (five patients). Tranexamic acid, 1 g q.i.d., was given from 12 h before surgery, until 7 days afterwards. No excessive bleeding was observed following dental extractions. One patient had slight oozing after 3 days which ceased spontaneously. Thus, plasma replacement no longer appears necessary for patients with severe factor XI deficiency requiring dental extractions.

Heart rate and microinflammation in men: a relevant atherothrombotic link

Objective and background: To explore the possibility that increased resting heart rate (HR) is associated with a microinflammatory response. Such an association could explain, at least in part, the recently described worse cardiovascular prognosis in individuals with increased HR. Methods: Concentrations of fibrinogen and high-sensitivity C-reactive protein, as well as the absolute number of polymorphonuclear leucocytes, were analysed in a cohort of 4553 apparently healthy men and in those with atherothrombotic risk factors. Results: Following adjustment for age and body mass index, lipid profile and cardiovascular risk factors, a significant (p<0.001) difference was noted between individuals in the first quintile of HR (⩽58 beats/min) and those in the fifth quintile (⩾79 beats/min) regarding all the above-mentioned inflammatory biomarkers, the respective mean values being 7.38 and 8.11 μmol/l, 1.12 and 1.61 mg/l, and 4.23 and 4.74×109/l. Conclusions: Resting HR is associated with a microinflammatory response in apparently healthy men and in those with atherothrombotic risk factors. Sympathetic activation might be a common factor explaining such an association. If confirmed in additional studies, this association might be a relevant target for therapeutic manipulations.

The Effects of Physical Fitness and Feeling Vigorous on Self-Rated Health

OBJECTIVE We prospectively studied the hypothesized beneficial effects of feeling vigorous and of objective physical fitness (gauged based on functional capacity) on subsequently assessed self-rated health (SRH), controlling for possible confounders known to be precursors of SRH and of our predictors. We also investigated the reverse-causation hypothesis that SRH predicts subsequent vigor and functional capacity. DESIGN Participants were apparently healthy employees (N = 779) who underwent a routine health check at two points of time, Time 1 (T1) and Time 2 (T2), about 18 months apart. We used regression analysis, predicting T2 SRH by T1 SRH, the control variables, and T1vigor and functional capacity. MAIN OUTCOME MEASURES Vigor was assessed using the Shirom-Melamed Vigor Measure; objective physical fitness was indicated by functional capacity following a treadmill exercise, and self-rated health was measured by a single item. RESULTS As hypothesized, we found that the change in T2 SRH was positively predicted by T1 vigor, functional capacity, and their interactive term. Testing the reverse causation paths, we found that T1 SRH did not predict subsequent functional capacity and was a relatively weak predictor of subsequent vigor. CONCLUSION The affective state of vigor and objectively assessed functional capacity interact to predict subsequent changes in self-rated health.

MicroRNA-132 modulates cholinergic signaling and inflammation in human inflammatory bowel disease.

Background:MicroRNA-132 (miR-132) targets acetylcholinesterase (AChE) and potentiates the cholinergic blockade of inflammatory reactions in cultured cells and experimental mice, but the implications of this interaction to human inflammatory disease remained unexplored. This study aimed to test whether miR-132 is causally involved in anti-inflammatory reactions of patients with inflammatory bowel disease (IBD) and modulates vagal tone and consequently inflammation in patients with IBD. Methods:We prospectively measured inflammation readouts and the cholinergic status (total capacity for hydrolyzing acetylcholine in ones circulation), and AChE activity in 2 independent cohorts of patients with IBD and quantified miR-132 levels in intestinal tissue biopsies removed at colonoscopy from inflamed and apparently quiescent tissues of tested volunteers. Results:MiR-132 levels are higher in inflamed compared with apparently quiescent intestinal biopsies from patients with IBD. Correspondingly, the cholinergic status and AChE activity was significantly lower in patients with IBD suffering from moderate–severe disease as compared with healthy controls or patient with IBD presenting low disease severity. Patients with IBD (n = 16) presented lower AChE activity compared with healthy controls (n = 33; 289 ± 128 AU versus 391 ± 102 AU, P = 0.001), and a negative correlation between AChE activity and C-reactive protein levels (r = −0.47, P = 0.01). Corroborating these observations in an additional cohort of participants, C-reactive protein and AChE activity were negatively correlated in patients with moderate–severe disease (n = 16; r = −0.6, P = 0.04) and positively correlated in healthy controls (n = 74, r = 0.24, P = 0.046). Conclusions:Taken together, these findings support an inflammation-dependent homeostatic role for the regulation by miR-132 of AChE in IBD, opening new venues for therapeutic interference.

Prognostic implications of admission inflammatory profile in acute ischemic neurological events

Anuk T, Assayag EB, Rotstein R, Fusman R, Zeltser D, Berliner S, Avitzour D, Shapira I, Arber N, Bornstein NM. Prognostic implications of admission inflammatory profile in acute ischemic neurological events. Acta Neurol Scand 2002: 106: 196–199.