Association of vital exhaustion and depressive symptoms with changes in fibrin D-dimer to acute psychosocial stress

OBJECTIVE: Vital exhaustion and depression are psychosocial risk factors of coronary artery disease. A hypercoagulable state in response to acute psychosocial stress contributes to atherothrombotic events. We aimed to investigate the hypothesis that vital exhaustion and depression correlate with stress-induced changes in the hypercoagulability marker D-dimer. METHODS: Thirty-eight healthy and nonsmoking school teachers (mean age 50+/-8 years, 55% women) completed the nine-item Maastricht Vital Exhaustion Questionnaire and the seven-item depression subscale of the Hospital Anxiety and Depression Scale. Within 1 week, subjects twice underwent the Trier Social Stress Test (i.e., preparation phase, mock job interview, and mental arithmetic that totaled 13 min). Plasma D-dimer levels were determined at five time points during the protocol. RESULTS: Vital exhaustion (P=.022; eta(2)=.080) and depressive symptoms (P=.011; eta(2)=.090) were associated with stress-induced changes in D-dimer levels over time controlling for sex and age. Elevated levels of vital exhaustion (r=-.46, P=.005) and of depression (r=-.51, P=.002) correlated with reduced D-dimer increase from pre-stress to immediately post-stress. Also, elevated vital exhaustion (r=.34, P=.044) and depression (r=.41, P=.013) were associated with increase (i.e., attenuated recovery) of D-dimer levels between 20 and 45 min post-stress. Controlling for stress hormone and blood pressure reactivity did not substantially alter these results. CONCLUSION: The findings suggest an attenuated immediate D-dimer stress response and delayed recovery of D-dimer levels post-stress with elevated vital exhaustion and depressive symptoms. In particular, the prolonged hypercoagulability after stress cessation might contribute to the atherothrombotic risk previously observed with vital exhaustion and depression, even at subclinical levels.

Nighttime vagal cardiac control and plasma fibrinogen levels in a population of working men and women

BACKGROUND: Elevated plasma fibrinogen levels have prospectively been associated with an increased risk of coronary artery disease in different populations. Plasma fibrinogen is a measure of systemic inflammation crucially involved in atherosclerosis. The vagus nerve curtails inflammation via a cholinergic antiinflammatory pathway. We hypothesized that lower vagal control of the heart relates to higher plasma fibrinogen levels. METHODS: Study participants were 559 employees (age 17-63 years; 89% men) of an airplane manufacturing plant in southern Germany. All subjects underwent medical examination, blood sampling, and 24-hour ambulatory heart rate recording while kept on their work routine. The root mean square of successive differences in RR intervals during the night period (nighttime RMSSD) was computed as the heart rate variability index of vagal function. RESULTS: After controlling for demographic, lifestyle, and medical factors, nighttime RMSSD explained 1.7% (P = 0.001), 0.8% (P = 0.033), and 7.8% (P = 0.007), respectively, of the variance in fibrinogen levels in all subjects, men, and women. Nighttime RMSSD and fibrinogen levels were stronger correlated in women than in men. In all workers, men, and women, respectively, there was a mean +/- SEM increase of 0.41 +/- 0.13 mg/dL, 0.28 +/- 0.13 mg/dL, and 1.16 +/- 0.41 mg/dL fibrinogen for each millisecond decrease in nighttime RMSSD. CONCLUSIONS: Reduced vagal outflow to the heart correlated with elevated plasma fibrinogen levels independent of the established cardiovascular risk factors. This relationship seemed comparably stronger in women than men. Such an autonomic mechanism might contribute to the atherosclerotic process and its thrombotic complications.

Association between longitudinal changes in depressive symptoms and plasma fibrinogen levels in school teachers

Depression and anxiety previously predicted coronary artery disease (CAD) risk. Inflammation contributes to CAD and shows an association with depression. We followed 57 teachers (mean 49+/-8 years) over 21 months and investigated whether changes in depressive and anxiety symptoms relate to those in the CAD risk and inflammation marker fibrinogen and vice versa. Increase in depressive symptoms and in fibrinogen levels were significantly correlated. While controlling for baseline depression rendered the association between changes in depression and fibrinogen nonsignificant, taking into account baseline fibrinogen levels maintained the predictive value of fibrinogen change for depression change. Anxiety and fibrinogen changes were not significantly correlated. This dynamic relationship between depression and the inflammatory biomarker fibrinogen might advance our knowledge about psychobiological mechanisms underlying both CAD and sickness behavior.

Long-term outcomes of biodegradable polymer versus durable polymer drug-eluting stents in patients with diabetes a pooled analysis of individual patient data from 3 randomized trials

BACKGROUND There is ongoing debate on the optimal drug-eluting stent (DES) in diabetic patients with coronary artery disease. Biodegradable polymer drug-eluting stents (BP-DES) may potentially improve clinical outcomes in these high-risk patients. We sought to compare long-term outcomes in patients with diabetes treated with biodegradable polymer DES vs. durable polymer sirolimus-eluting stents (SES). METHODS We pooled individual patient-level data from 3 randomized clinical trials (ISAR-TEST 3, ISAR-TEST 4 and LEADERS) comparing biodegradable polymer DES with durable polymer SES. Clinical outcomes out to 4years were assessed. The primary end point was the composite of cardiac death, myocardial infarction and target-lesion revascularization. Secondary end points were target lesion revascularization and definite or probable stent thrombosis. RESULTS Of 1094 patients with diabetes included in the present analysis, 657 received biodegradable polymer DES and 437 durable polymer SES. At 4years, the incidence of the primary end point was similar with BP-DES versus SES (hazard ratio=0.95, 95% CI=0.74-1.21, P=0.67). Target lesion revascularization was also comparable between the groups (hazard ratio=0.89, 95% CI=0.65-1.22, P=0.47). Definite or probable stent thrombosis was significantly reduced among patients treated with BP-DES (hazard ratio=0.52, 95% CI=0.28-0.96, P=0.04), a difference driven by significantly lower stent thrombosis rates with BP-DES between 1 and 4years (hazard ratio=0.15, 95% CI=0.03-0.70, P=0.02). CONCLUSIONS In patients with diabetes, biodegradable polymer DES, compared to durable polymer SES, were associated with comparable overall clinical outcomes during follow-up to 4years. Rates of stent thrombosis were significantly lower with BP-DES.

Type A aortic dissection after nonaortic cardiac surgery

BACKGROUND Cardiac surgery with cardiopulmonary bypass is associated with mechanical manipulation of the ascending aorta that occasionally leads to type A aortic dissection (AAD). METHODS AND RESULTS One hundred three patients with surgical repair for AAD following nonaortic cardiac surgery were identified. With the use of logistic regression modeling, coronary artery bypass surgery (CABG), either isolated or combined with another procedure in the initial operation, was associated with significantly higher operative mortality in comparison with patients with non-CABG procedures at the time of AAD repair both for all patients (odds ratio, 2.90; 95% confidence interval, 1.09-7.72; P=0.033) and for patients with acute and chronic AAD≥30 days after the initial operation (odds ratio, 3.62; 95% confidence interval, 1.13-11.54; P=0.03). In patients who developed AAD late after the initial operation, operative mortality was highest in patients without preoperative coronary angiography and appropriate management of their native coronary artery disease and graft disease (odds ratio, 5.36; 95% confidence interval, 1.68-17.0; P=0.002). Nearly all the intimal dissection tears were located at sites of previous surgical trauma. Most of the ascending aortas that had dissected initially had a diameter≥40 mm with histological evidence of medial degeneration in resected tissue samples. CONCLUSIONS In patients who have undergone previous cardiac surgery, preexisting aortic wall pathology contributes to AAD with typical intimal damage at sites of mechanical trauma. The operative mortality was the highest in patients with previous CABG in comparison with patients with non-CABG procedures. Preoperative coronary angiography and operative management of native coronary and graft disease were significantly associated with outcome in patients with previous CABG.

Safety and efficacy of drug-eluting stents in women: a patient-level pooled analysis of randomised trials

BACKGROUND The safety and efficacy of drug-eluting stents (DES) in the treatment of coronary artery disease have been assessed in several randomised trials. However, none of these trials were powered to assess the safety and efficacy of DES in women because only a small proportion of recruited participants were women. We therefore investigated the safety and efficacy of DES in female patients during long-term follow-up. METHODS We pooled patient-level data for female participants from 26 randomised trials of DES and analysed outcomes according to stent type (bare-metal stents, early-generation DES, and newer-generation DES). The primary safety endpoint was a composite of death or myocardial infarction. The secondary safety endpoint was definite or probable stent thrombosis. The primary efficacy endpoint was target-lesion revascularisation. Analysis was by intention to treat. FINDINGS Of 43,904 patients recruited in 26 trials of DES, 11,557 (26·3%) were women (mean age 67·1 years [SD 10·6]). 1108 (9·6%) women received bare-metal stents, 4171 (36·1%) early-generation DES, and 6278 (54·3%) newer-generation DES. At 3 years, estimated cumulative incidence of the composite of death or myocardial infarction occurred in 132 (12·8%) women in the bare-metal stent group, 421 (10·9%) in the early-generation DES group, and 496 (9·2%) in the newer-generation DES group (p=0·001). Definite or probable stent thrombosis occurred in 13 (1·3%), 79 (2·1%), and 66 (1·1%) women in the bare-metal stent, early-generation DES, and newer-generation DES groups, respectively (p=0·01). The use of DES was associated with a significant reduction in the 3 year rates of target-lesion revascularisation (197 [18·6%] women in the bare-metal stent group, 294 [7·8%] in the early-generation DES group, and 330 [6·3%] in the newer-generation DES group, p<0·0001). Results did not change after adjustment for baseline characteristics in the multivariable analysis. INTERPRETATION The use of DES in women is more effective and safe than is use of bare-metal stents during long-term follow-up. Newer-generation DES are associated with an improved safety profile compared with early-generation DES, and should therefore be thought of as the standard of care for percutaneous coronary revascularisation in women. FUNDING Women in Innovation Initiative of the Society of Cardiovascular Angiography and Interventions.

Plasma levels of mannan-binding lectin (MBL)-associated serine proteases (MASPs) and MBL-associated protein in cardio- and cerebrovascular diseases

Growing evidence suggests a prominent role of the complement system in the pathogenesis of cardio- and cerebrovascular diseases (CVD). Mannan-binding lectin-associated serine proteases (MASPs) MASP-1 and MASP-2 of the complement lectin pathway contribute to clot formation and may represent an important link between inflammation and thrombosis. MBL-associated protein MAp44 has shown cardioprotective effects in murine models. However, MAp44 has never been measured in patients with CVD and data on MASP levels in CVD are scarce. Our aim was to investigate for the first time plasma levels of MAp44 and MASP-1, -2, -3 concomitantly in patients with CVD. We performed a pilot study in 50 healthy volunteers, in stable coronary artery disease (CAD) patients with one-vessel (n = 51) or three-vessel disease (n = 53) and age-matched controls with normal coronary arteries (n = 53), 49 patients after myocardial infarction (MI) and 66 patients with acute ischaemic stroke. We measured MAp44 and MASP-1 levels by in-house time-resolved immunofluorometric assays. MASP-2 and MASP-3 levels were measured using commercial enzyme-linked immunosorbent assay kits. MASP-1 levels were highest in subacute MI patients and lowest in acute stroke patients. MASP-2 levels were lower in MI and stroke patients compared with controls and CAD patients. MASP-3 and MAp44 levels did not differ between groups. MASP or MAp44 levels were not associated with severity of disease. MASP and MAp44 levels were associated with cardiovascular risk factors including dyslipidaemia, obesity and hypertension. Our results suggest that MASP levels may be altered in vascular diseases. Larger studies are needed to confirm our results and elucidate the underlying mechanisms.

Oral contraceptives and the risk of thrombosis and atherosclerosis.

Oral contraceptives containing synthetic oestrogens have been used successfully as birth control for > 40 years and are currently prescribed to > 100 million women worldwide. Several new progestins have been introduced and the third generation of progestins has now been available for two decades. Oral contraceptives are prescribed over a prolonged period of time and therefore substantially impact on hormonal, metabolic and plasmatic functions. Oral contraceptives increase the risk for venous thrombosis and pulmonary embolism, particularly if associated with confounding factors, such as genetic predisposition, smoking, hypertension or obesity. The risk of developing coronary artery disease is also increased in users with cardiovascular risk factors. This article discusses mechanistic and clinical issues and reviews the need for novel approaches targeting the considerable side effects in order to reduce cardiovascular morbidity in women using oral contraceptives.

Testosterone and acute stress are associated with fibrinogen and von Willebrand factor in African men: the SABPA study.

BACKGROUND Low testosterone, acute and chronic stress and hypercoagulation are all associated with hypertension and hypertension-related diseases. The interaction between these factors and future risk for coronary artery disease in Africans has not been fully elucidated. In this study, associations of testosterone, acute cardiovascular and coagulation stress responses with fibrinogen and von Willebrand factor in African and Caucasian men in a South African cohort were investigated. METHODS Cardiovascular variables were studied by means of beat-to-beat and ambulatory blood pressure monitoring. Fasting serum-, salivary testosterone and citrate coagulation markers were obtained from venous blood samples. Acute mental stress responses were evoked with the Stroop test. RESULTS The African group demonstrated a higher cardiovascular risk compared to Caucasian men with elevated blood pressure, low-grade inflammation, chronic hyperglycemia (HbA1c), lower testosterone levels, and elevated von Willebrand factor (VWF) and fibrinogen levels. Blunted testosterone acute mental stress responses were demonstrated in African males. In multiple regression analyses, higher circulating levels of fibrinogen and VWF in Africans were associated with a low T environment (R(2) 0.24-0.28; p≤0.01), but only circulating fibrinogen in Caucasians. Regarding endothelial function, a low testosterone environment and a profile of augmented α-adrenergic acute mental stress responses (diastolic BP, D-dimer and testosterone) were associated with circulating VWF levels in Africans (Adj R(2) 0.24; p<0.05). CONCLUSIONS An interdependence between acute mental stress, salivary testosterone, D-dimer and vascular responses existed in African males in their association with circulating VWF but no interdependence of the independent variables occurred with fibrinogen levels.

Smooth Muscle Hyperplasia due to ACTA2/MYH11 Mutations: Identification of Novel Pathology and Pathways Leading to Aneurysms and Diverse Vascular Occlusive Diseases

Missense mutations in smooth muscle cell (SMC) specific ACTA2 (á-actin) and MYH11 (â-myosin heavy chain) cause diffuse and diverse vascular diseases, including thoracic aortic aneurysms and dissections (TAAD) and early onset coronary artery disease and stroke. The mechanism by which these mutations lead to dilatation of some arteries but occlusion of others is unknown. We hypothesized that the mutations act through two distinct mechanisms to cause varied vascular diseases: a loss of function, leading to decreased SMC contraction and aneurysms, and a gain of function, leading to increased SMC proliferation and occlusive disease. To test this hypothesis, ACTA2 mutant SMCs and myofibroblasts were assessed and found to not form á-actin filaments whereas control cells did, suggesting a dominant negative effect of ACTA2 mutations on filament formation. A loss of á-actin filaments would be predicted to cause decreased SMC contractility. Histological examination of vascular tissues from patients revealed SMC hyperplasia leading to arterial stenosis and occlusion, supporting a gain of function associated with the mutant gene. Furthermore, ACTA2 mutant SMCs and myofibroblasts proliferated more rapidly in static culture than control cells (p<0.05). We also determined that Acta2-/- mice have ascending aortic aneurysms. Histological examination revealed aortic medial SMC hyperplasia, but minimal features of medial degeneration. Acta2-/- SMCs proliferated more rapidly in culture than wildtype (p<0.05), and microarray analysis of Acta2-/- SMCs revealed increased expression of Actg2, 15 collagen genes, and multiple focal adhesion genes. Acta2-/- SMCs showed altered localization of vinculin and zyxin and increased phosphorylated focal adhesion kinase (FAK) in focal adhesions. A specific FAK inhibitor decreased Acta2-/- SMC proliferation to levels equal to wildtype SMCs (p<0.05), suggesting that FAK activation leads to the increased proliferation. We have described a unique pathology associated with ACTA2 and MYH11 mutations, as well as an aneurysm phenotype in Acta2-/- mice. Additionally, we identified a novel pathogenic pathway for vascular occlusive disease due to loss of SMC contractile filaments, alterations in focal adhesions, and activation of FAK signaling in SMCs with ACTA2 mutations.

Smoking, apolipoprotein E genotypes, and mortality (the Ludwigshafen RIsk and Cardiovascular Health study).

AIMS The genetic polymorphism of apolipoprotein E (APOE) has been suggested to modify the effect of smoking on the development of coronary artery disease (CAD) in apparently healthy persons. The interaction of these factors in persons undergoing coronary angiography is not known. METHODS AND RESULTS We analysed the association between the APOE-genotype, smoking, angiographic CAD, and mortality in 3263 participants of the LUdwigshafen RIsk and Cardiovascular Health study. APOE-genotypes were associated with CAD [ε22 or ε23: odds ratio (OR) 0.56, 95% confidence interval (CI) 0.43-0.71; ε24 or ε34 or ε44: OR 1.10, 95% CI 0.89-1.37 compared with ε33] and moderately with cardiovascular mortality [ε22 or ε23: hazard ratio (HR) 0.71, 95% CI 0.51-0.99; ε33: HR 0.92, 95% CI 0.75-1.14 compared with ε24 or ε34 or ε44]. HRs for total mortality were 1.39 (95% CI 0.39-0.1.67), 2.29 (95% CI 1.85-2.83), 2.07 (95% CI 1.64-2.62), and 2.95 (95% CI 2.10-4.17) in ex-smokers, current smokers, current smokers without, or current smokers with one ε4 allele, respectively, compared with never-smokers. Carrying ε4 increased mortality in current, but not in ex-smokers (HR 1.66, 95% CI 1.04-2.64 for interaction). These findings applied to cardiovascular mortality, were robust against adjustment for cardiovascular risk factors, and consistent across subgroups. No interaction of smoking and ε4 was seen regarding non-cardiovascular mortality. Smokers with ε4 had reduced average low-density lipoprotein (LDL) diameters, elevated oxidized LDL, and lipoprotein-associated phospholipase A2. CONCLUSION In persons undergoing coronary angiography, there is a significant interaction between APOE-genotype and smoking. The presence of the ε4 allele in current smokers increases cardiovascular and all-cause mortality.

Copper, ceruloplasmin, and long-term cardiovascular and total mortality (the Ludwigshafen Risk and Cardiovascular Health Study)

BACKGROUND Copper and its main transport protein ceruloplasmin have been suggested to promote the development of atherosclerosis. Most of the data come from experimental and animal model studies. Copper and mortality have not been simultaneously evaluated in patients undergoing coronary angiography. METHODS AND RESULTS We examined whether serum copper and ceruloplasmin concentrations are associated with angiographic coronary artery disease (CAD) and mortality from all causes and cardiovascular causes in 3253 participants of the Ludwigshafen Risk and Cardiovascular Health Study. Age and sex-adjusted hazard ratios (HR) for death from any cause were 2.23 (95% CI, 1.85-2.68) for copper and 2.63 (95% CI, 2.17-3.20) for ceruloplasmin when we compared the highest with the lowest quartiles. Corresponding hazard ratios (HR) for death from cardiovascular causes were 2.58 (95% CI, 2.05-3.25) and 3.02 (95% CI, 2.36-3.86), respectively. Further adjustments for various risk factors and clinical variables considerably attenuated these associations, which, however, were still statistically significant and the results remained consistent across subgroups. CONCLUSIONS The elevated concentrations of both copper and ceruloplasmin are independently associated with increased risk of mortality from all causes and from cardiovascular causes.

HDL Cholesterol Is Not Associated with Lower Mortality in Patients with Kidney Dysfunction

In the general population, HDL cholesterol (HDL-C) is associated with reduced cardiovascular events. However, recent experimental data suggest that the vascular effects of HDL can be heterogeneous. We examined the association of HDL-C with all-cause and cardiovascular mortality in the Ludwigshafen Risk and Cardiovascular Health study comprising 3307 patients undergoing coronary angiography. Patients were followed for a median of 9.9 years. Estimated GFR (eGFR) was calculated using the Chronic Kidney Disease Epidemiology Collaboration eGFR creatinine-cystatin C (eGFRcreat-cys) equation. The effect of increasing HDL-C serum levels was assessed using Cox proportional hazard models. In participants with normal kidney function (eGFR>90 ml/min per 1.73 m(2)), higher HDL-C was associated with reduced risk of all-cause and cardiovascular mortality and coronary artery disease severity (hazard ratio [HR], 0.51, 95% confidence interval [95% CI], 0.26-0.92 [P=0.03]; HR, 0.30, 95% CI, 0.13-0.73 [P=0.01]). Conversely, in patients with mild (eGFR=60-89 ml/min per 1.73 m(2)) and more advanced reduced kidney function (eGFR<60 ml/min per 1.73 m(2)), higher HDL-C did not associate with lower risk for mortality (eGFR=60-89 ml/min per 1.73 m(2): HR, 0.68, 95% CI, 0.45-1.04 [P=0.07]; HR, 0.84, 95% CI, 0.50-1.40 [P=0.50]; eGFR<60 ml/min per 1.73 m(2): HR, 1.18, 95% CI, 0.60-1.81 [P=0.88]; HR, 0.82, 95% CI, 0.40-1.69 [P=0.60]). Moreover, Cox regression analyses revealed interaction between HDL-C and eGFR in predicting all-cause and cardiovascular mortality (P=0.04 and P=0.02, respectively). We confirmed a lack of association between higher HDL-C and lower mortality in an independent cohort of patients with definite CKD (P=0.63). In summary, higher HDL-C levels did not associate with reduced mortality risk and coronary artery disease severity in patients with reduced kidney function. Indeed, abnormal HDL function might confound the outcome of HDL-targeted therapies in these patients.

The Impact of Renal Impairment on Long-Term Safety and Effectiveness of Drug-Eluting Stents

BACKGROUND Renal impairment (RI) is associated with impaired prognosis in patients with coronary artery disease. Clinical and angiographic outcomes of patients undergoing percutaneous coronary intervention (PCI) with the use of drug-eluting stents (DES) in this patient population are not well established. METHODS We pooled individual data for 5,011 patients from 3 trials with the exclusive and unrestricted use of DES (SIRTAX - N = 1,012, LEADERS - N = 1,707, RESOLUTE AC - N = 2,292). Angiographic follow-up was available for 1,544 lesions. Outcomes through 2 years were stratified according to glomerular filtration rate (normal renal function: GFR≥90 ml/min; mild RI: 90

Ten year clinical follow-up after Sirolimus-eluting stent implantation

BACKGROUND: Little is known on the "very" long-term incidence of major adverse cardiac events (MACE), target-lesion revascularization (TLR), target-vessel revascularization and stent thrombosis after sirolimus-eluting stent (SES) implantation. We present the first study to provide a 10-year clinical follow-up in an unselected patient population who underwent SES implantation. METHODS AND RESULTS: We ran a systematic 10-year clinical follow-up in a series of 200 consecutive patients treated with unrestricted SES implantation between April 2002 and April 2003 in two Swiss hospitals. Outcomes and follow-up were obtained in all 200 patients. The cumulative 10-year MACE rate was 47% with all-cause death of 20%, cardiac death of 9%, myocardial infarction of 7%, TLR and target-vessel revascularization of 8% and 11% respectively. Academic Research Consortium-defined "definite and probable" stent thrombosis-rate was 2.5%. TLR risk was maximal between 3 to 6 years. New lesion revascularization increased throughout the study period. CONCLUSION: Incidence of TLR was maximal 3 to 6 years after SES implantation and decreased thereafter. MACE and non-TLR revascularization rates steadily increased during the complete follow-up underlining the progression of coronary artery disease.