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Carfilzomib (CFZ) is a proteasome inhibitor associated with cardiovascular (CV) adverse events (AEs) mainly hypertension (HTN) and cardiac dysfunction. Endothelial dysfunction is a major mediating mechanism in cardiovascular diseases and endothelial function may be adversely affected by proteasome inhibition. However, CFZ effects on endothelial and vascular function and associations with inhibition of proteasome activity have not been explored in humans. We prospectively evaluated CFZ effects on endothelial function and underlying mechanisms as well as baseline vascular function and its response to treatment as potential predictors of CFZ-associated CV toxicity. In this prospective study (NCT03543579), 48 relapsed/refractory myeloma patients (median 1 (1-3) lines of therapy, median age: 67.5, 67% men) received Kd [CFZ 20/56 mg/m2 and dexamethasone] in routine practice. A detailed medical history and evaluation of risk factors for cardiotoxicity [age≥65 years, obesity, smoking, HTN, hypercholesterolemia, diabetes mellitus, previous anthracyclin use, chest or mediastinum radiotherapy and current myocardial disease] were recorded. Before CFZ start and at prespecified timepoints cardiac echo, hemodynamic parameters and vascular function that reflect pivotal mechanisms involved in development of HTN and CV events were non-invasively assessed [aortic blood pressure and arterial wave reflections, aortic stiffness and endothelial function using flow-mediated dilatation of the brachial artery (FMD)] along with 24h ambulatory blood pressure monitoring. Proteasome activity (PrA) was measured in peripheral blood mononuclear cells (PBMC) before and 2 hours post CFZ infusion on days 1 (FMDbaseD1 and FMDpostCFZD1) and 2 (FMDbaseD2 and FMDpostCFZD2) of cycle 1 and at prespecified time points concurrently with vascular function assessment. CV AEs were recorded and rated according to CTCAE v4.03. The prevalence of risk factors for cardiotoxicity was high (median 3 factors, IQR 2-4). After first CFZ dose, FMD decreased acutely at 2 hours (FMDbaseD1: 5.2%, IQR: 3.2-7.4 vs FMDpostCFZD1: 3.6%, IQR: 1.5-4.7, p=0.008), which partially recovered before and after second CFZ infusion (FMDbaseD2: 4.1% and FMDpostCFZD2: 4%, as compared to FMDbaseD1) (Figure1A). However, FMD decrease was more pronounced among patients who subsequently had lower recovery rate of PBMC PrA 24 hours after first CFZ administration (FMDbaseD1: 5.1%, vs FMDpostCFZD1: 3%, p=0.002) while FMD was not decreased significantly in those who had higher recovery rates of PrA (FMDbaseD1: 5.3%, vs FMDpost CFZD1: 4.5%, p=0.197, Figure 1B), suggesting that the ability to recover PrA is implicated in CFZ induced endothelial dysfunction. At the time of analysis, enrolment has completed; 35 patients are still receiving therapy, 13 have discontinued Kd and median follow up is 4.73 months. CV AEs were recorded in 17 (35.4%) patients [HTN(Gr3): 20.8%, Gr3 Left Ventricular dysfunction : 8.3%, Gr3 acute coronary syndrome: 4.2%, Gr3 pulmonary embolism: 2.1%] and generally occurred early (median time to CV event 2.9 months). Kd was discontinued in 2 patients (4.2%) due to cardiotoxicity and in 2 patients (4.2%) CFZ dose was reduced due to cardiotoxicity; no CFZ dose reduction or discontinuation was needed for HTN. Among clinical and hemodynamic parameters assessed at baseline, patients with higher aortic SBP (i.e at higher quartile) had a higher risk of HTN even after adjustment for age, gender and baseline HTN (HR=8, 95%CI 2.4-26, p=0.001 and HR=4.9, 95%CI 1.5-15, p=0.007 respectively). Lower PrA recovery rate was associated with increased risk of developing Gr3 HTN (log-rank test p=0.01). Higher post-CFZ reduction of FMD was associated with HTN in patients not receiving statins but not in those receiving statins (a drug class strongly affecting FMD), indicating that statin treatment may exert protective effects against CFZ-related CV toxicity. In conclusion, CFZ causes acute endothelial dysfunction; however, higher recovery of proteasome activity is associated with ameliorated depression of endothelial function. Given that poor proteasome recovery rate and acute deterioration of endothelial function are both associated with development of HTN, these findings may improve our understanding of CFZ-related CV toxicity and its prevention. The study is ongoing and more data will be presented at the meeting. Disclosures Kastritis: Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Prothena: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees. Terpos:Amgen Inc.: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: travel grant, steering committee member, Research Funding; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: member of DMC, Research Funding; Genesis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: travel grant, Research Funding; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: member of steering committee, Research Funding; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: travel grant, Research Funding; BMS: Consultancy; Novartis: Consultancy. Dimopoulos:Bristol-Myers Squibb: Honoraria; Amgen: Honoraria; Takeda: Honoraria; Celgene: Honoraria; Janssen: Honoraria.

The menopausal transition is related to cardiometabolic risk factors, but its direct impact on the incidence of cardiovascular events is controversial. In this respect, the study by Zhao et al. [(1)][1] provides important new evidence that increased androgenicity, as shown by the ratio of total

The menopausal status is closely related with cardiovascular disease (CVD). Nevertheless, it is still not included in risk stratification by total cardiovascular risk estimation systems. The present study aimed to evaluate the extent of subclinical vascular disorders in young healthy postmenopausal women.This cross-sectional study consecutively recruited 120 healthy postmenopausal women without clinically overt CVD or diabetes, aged 41-60 years and classified as not high-risk by the Heartscore (5%). In addition to risk factors used for Heartscore calculations, years since menopause and associated risk factors (triglycerides (range 37-278 mg/dl), waist circumference (62-114 cm), fasting blood glucose (69-114 mg/dl) and HOMA-IR (0.44-5)) were also assessed. Carotid-femoral pulse wave velocity, carotid and femoral intima-media thickness in the abnormal range as well as atheromatous plaques both in carotid and femoral arteries were used to define the presence of subclinical atherosclerosis.Subclinical atherosclerosis and the presence of at least one plaque were identified in 55% and 28% of women, respectively. Subjects with subclinical atherosclerosis had higher age, years since menopause, HOMA-IR and blood pressure. By multivariate analysis years since menopause and systolic blood pressure independently determined subclinical atherosclerosis while 79% of intermediate-risk women (Heartscore 2-4.9%) being in menopause for at least 4 years would be reclassified to a higher risk for the presence of atherosclerosis.Subclinical atherosclerosis was highly prevalent in postmenopausal women with low to medium Heartscore. Thus our data suggest that menopausal status and associated risk factors should be additionally weighted in risk calculations, regarding primary prevention strategies in this population.

BACKGROUND: Hypertension related cardiovascular (CV) complications could be amplified by the presence of metabolic co-morbidities. Azilsartan medoxomil (AZL-M) is the eighth approved member of angiotensin II receptor blockers (ARBs), a drug class of high priority in the management of hypertensive subjects with diabetes mellitus type II (DMII). METHODS: Under this prism, we performed a systematic review of the literature for all relevant articles in order to evaluate the efficacy, safety, and possible clinical role of AZL-M in hypertensive diabetic patients. RESULTS: AZL-M was found to be more effective in terms of reducing indices of blood pressure over alternative ARBs or angiotensin-converting enzyme (ACE) inhibitors with minimal side effects. Preclinical studies have established pleiotropic effects for AZL-M beyond its primary antihypertensive role through differential gene expression, up-regulation of membrane receptors and favorable effect on selective intracellular biochemical and pro-atherosclerotic pathways. CONCLUSION: Indirect but accumulating evidence from recent literature supports the efficacy and safety of AZL-M among diabetic patients. However, no clinical data exist to date that evince a beneficial role of AZL-M in patients with metabolic disorders on top of its antihypertensive effect. Further clinical studies are warranted to assess the pleiotropic cardiometabolic benefits of AZL-M that are derived from preclinical research.

Background and aims Inhibition of proprotein convertase subtilisin/kexin type 9 (PCSK9) reduces atherogenic lipoproteins and could lead to reduction of cardiovascular (CV) events. However, it is unclear whether blood PCSK9 levels predict future CV events. We performed a meta-analysis of all longitudinal studies to determine the ability of PCSK9 levels to predict risk of future CV events. Methods A comprehensive search of electronic databases was conducted up to February 2016. Longitudinal studies that reported events or relative risk (RR) estimates with 95% confidence intervals (CI) were included. Results All 9 studies included (12,081 participants, mean follow-up 6.62 years) reported results on total CV events. The pooled RR of total CV events for an increase in baseline PCSK9 by 1 standard deviation (SD) was 1.098 (95% CI, 1.02–1.18), corresponding to a risk increase of 10% (Z = 2.43, p = 0.015). The pooled RR of total CV events for subjects categorized in the highest tertile of baseline PCSK9 was 1.228 (95% CI, 1.035–1.457), corresponding to a risk increase of 23% (Z = 2.35, p = 0.019). When pooled estimates were derived independently for low- and high-CV risk populations, baseline PCSK9 levels predicted total CV events only in apparently healthy subjects (RR = 1.13, 95% CI: 1.050–1.222, Z = 3.21, p = 0.001) and not in populations with established CV or renal disease (RR = 1.09, 95% CI: 0.961–1.23, Z = 1.33, p = 0.182). Conclusions PCSK9 levels are modestly but significantly associated with increased risk of total CV events. These results suggest a predictive role of PCSK9 levels on CV health and support the possible clinical role of PCSK9 inhibitors.

BACKGROUND Cross-sectional evidence indicates that eating frequency correlates with blood pressure, hypertension, and related target organ damage. The aim of the present study was to prospectively assess eating frequency as a predictor of arteriosclerosis progression and new onset hypertension over a follow-up period of 5 years in adults without cardiovascular disease. METHODS Eating frequency among other dietary parameters was evaluated in 115 nondiabetic study participants from a general population sample (54 ± 9.1 years, 45 women) at a baseline visit. Metabolic parameters known to be associated with eating frequency, markers of arteriosclerosis, including augmentation index, pulse wave velocity, SBP, and DBP were evaluated in all volunteers at baseline and after a 5-year follow-up. RESULTS By applying linear mixed models analysis, it was found that a high eating frequency at baseline significantly correlated with the rate of progression of pulse wave velocity (β = 0.521, P = 0.004), augmentation index (β = 0.503, P = 0.01), SBP (β = 0.694, P

SummaryThe genomic control (GC) approach is extensively used to effectively control false positive signals due to population stratification in genome-wide association studies (GWAS). However, GC affects the statistical power of GWAS. The loss of power depends on the magnitude of the inflation factor (λ) that is used for GC. We simulated meta-analyses of different GWAS. Minor allele frequency (MAF) ranged from 0·001 to 0·5 and λ was sampled from two scenarios: (i) random scenario (empirically-derived distribution of real λ values) and (ii) selected scenario from simulation parameter modification. Adjustment for λ was considered under single correction (within study corrected standard errors) and double correction (additional λ corrected summary estimate). MAF was a pivotal determinant of observed power. In random λ scenario, double correction induced a symmetric power reduction in comparison to single correction. For MAF λ adjustment. Moderate λ approach yielded more conservative results for population stratification adjustment, especially for MAF λ approach yielded an approximate two fold decrease in power when compared to moderate λ approach and almost four fold when the original random λ scenario was considered. Meta-analysis power can be adequate to detect significant variants even for double GC correction when effect size exceeds >1·2 and MAF >5%. Our results provide a quick but detailed index for power considerations of future meta-analyses of GWAS that enables a more flexible design from early steps based on the number of studies accumulated in different groups and the λ values observed in the single studies.

Obstructive sleep apnea-hypopnea syndrome (OSAHS) is an independent risk factor for hypertension, coronary artery disease, and diabetes mellitus. Epicardial fat has been recently recognized as a new risk factor and active participant on cardiometabolic risk. The aim of this study was to assess an independent relationship between sleep apnea severity, metabolic and vascular markers, and epicardial fat, at baseline and after 3 months of continuous positive airway pressure (CPAP) therapy.Our study group consisted of 48 patients with suspected OSAHS and no prior history of cardiovascular disease or diabetes mellitus. All patients underwent full overnight polysomnography. Thickness of epicardial and visceral adipose tissue, brachial artery flow-mediated dilation (FMD), carotid intima media thickness (cIMT), pulse wave velocity (PWV), plasma C-reactive protein (CRP) levels, fasting glucose levels, HbA1c, homeostatic model assessment of insulin resistance index (HOMA), and lipid profile were measured at baseline and after 3 months of CPAP use in patients with moderate to severe OSAHS.In OSAHS patients (Apnea-hypopnea index (AHI) ≥15/h, N = 28), epicardial fat correlated with fasting glucose (rho = 0.406, p = 0.04) and HOMA (rho = 0.525, p = 0.049) but was not associated with visceral fat (rho = 0.126, p = 0.595). Epicardial adipose tissue (EAT) (p = 0.022) increased across AHI severity along with PWV (p = 0.045) and carotid intima media thickness (IMT) (p = 0.034) while FMD (p = 0.017) decreased. Therapy with CPAP reduced both epicardial (p 0.001) and visceral fat (p = 0.001). Alterations in epicardial fat across the follow-up were associated with changes in PWV (p = 0.026) and HOMA (p = 0.037) independently of major confounders.Epicardial fat thickness was associated with OSA severity and may be an additional marker of cardiovascular risk as well as of future diabetes in these patients. CPAP therapy reduced epicardial fat, suggesting its potentially beneficial role in reducing cardiometabolic risk in OSA patients.

Aging causes deterioration in kidney function leading to chronic kidney disease. Chronic kidney disease has been associated with oxidative stress, increased circulating levels of inflammatory markers, phosphate retention with medial vascular calcification, increased parathyroid hormone concentrations causing valvular calcification and dysfunction, anemia, and left ventricular hypertrophy, all of which can increase cardiovascular risk. Among lifestyle factors, diet plays an important role in the prevention of renal failure. Although, there is no specific dietary pattern for preventing renal failure, excessive intake of protein, sodium, potassium and alcohol have shown to be related with the progression of renal failure even among elderly individuals; while the well-balanced Mediterranean diet has been related with preserved renal function. Fish and polyunsaturated fatty acids (PUFA) consumption has been favorably related to the prognosis of kidney function, mainly due to the anti-inflammatory properties of PUFA, as well as to its negative correlation with blood pressure levels.

Apart from the effects of a dysfunctional thyroid gland on the cardiovascular system, thyroid function within the reference range may have an impact on the vasculature. The present study aimed to evaluate the association between thyroid function and markers of arterial structure and function in euthyroid postmenopausal women.The present cross-sectional study recruited 106 healthy postmenopausal women with a mean age of 55.0 years and thyroid-stimulating hormone (TSH) levels within the laboratory reference range (0.4-4.5 μIU/ml). Anthropometric and biochemical measures as well as blood pressure were determined in each individual. Vascular structure and function were assessed by intima-media thickness, pulse wave velocity (PWV), augmentation index and flow-mediated dilation, respectively. We evaluated the associations between arterial markers and serum TSH, free triiodothyronine, free thyroxin, as well as serum thyroid peroxidase and thyroglobulin autoantibodies.Mean levels of PWV increased linearly across increasing TSH quartiles (P value = 0.014). Individuals with serum TSH greater than 2.5 μIU/ml had significantly higher values of PWV when compared with individuals with TSH levels below 2.5 μIU/ml (9.68 ± 1.97 vs. 8.54 ± 1.83 m/s; P = 0.030). In multivariate analysis, age, insulin resistance and TSH above 2.5 μIU/ml were the only significant predictors of PWV (TSH, β-coefficient = 0.222; P = 0.014). No associations were found between the remaining markers and levels of thyroid hormones, whereas thyroid antibodies were not associated with any of the arterial markers.Women with TSH levels in the upper reference range have increased arterial stiffness compared to women with lower TSH. The upper limit of normal TSH in postmenopausal women may need re-evaluation with respect to the effects on the vasculature.

ObjectiveThe association between hypothyroidism and breast cancer has been described from very early on. Breast and thyroid tissue are interconnected on a molecular level mainly through activation of thyroid hormone receptors expressed on cells of the mammary gland as well as on the plasma membrane of breast cancer cells. Despite the experimental evidence the true value of hypothyroidism as a risk factor for breast cancer remains controversial.MethodsWe searched the PubMed database through February 2011 to identify studies that evaluated the association between hypothyroidism and risk for breast cancer as well as the effect of thyroid hormone replacement therapy on breast cancer incidence.ResultsA meta-analysis performed in 12 studies showed that hypothyroidism was not associated with risk for breast cancer (pooled risk ratio (RR)=1.06, 95% confidence intervals (CIs) 0.82–1.35, P=0.672). The effect of treatment was assessed in seven studies and no evidence for an association between thyroid hormone replacement and breast cancer was observed with an overall RR of 0.99 (95% CI 0.73–1.35, P=0.965).ConclusionsOur meta-analysis showed that hypothyroidism is not associated with increased risk for breast cancer and thyroid hormone replacement therapy does not reduce breast cancer prevalence; however, the heterogeneity of the studies analyzed precludes firm conclusions.

We aimed to assess the prognostic value of free androgen index (FAI) and its change over time in arterial stiffness progression, endothelial function and hypertension in postmenopausal women.Postmenopausal women (n = 180) without clinically overt cardiovascular disease or diabetes were consecutively recruited and followed for a median of 29 months. The main outcome measures were changes over time in endothelial function (FMD), reflected waves, localized and systemic (PWV) arterial stiffness and hypertension.Increased baseline FAI was significantly associated with new onset hypertension (OR for each SD, 2.71, 95% CI 1.14-6.41, p = 0.024), deterioration of pulse wave velocity (PWV) (0.414 m/s per SD), flow-mediated dilation (FMD) (-0.42% per SD), systolic (2.5 mmHg per SD) and pulse pressure progression (2.3 mmHg per SD, p0.05 for all). Baseline FAI remained an independent predictor of changes in PWV (p = 0.006), FMD (p = 0.02), peripheral pulse pressure (p = 0.028), transition to new onset hypertension (p = 0.001) and higher BP category (p = 0.012), after adjustment for age, changes in systolic blood pressure, traditional risk factors, vasoactive medication or total testosterone. Baseline FAI improved reclassification for the risk of transition into higher BP category (NRI = 47.5 ± 20.3%, p = 0.02) and abnormal PWV (NRI = 53.4 ± 23.2%, p = 0.021). Similarly, in a subgroup of patients with measured FAI at follow-up, its changes over time predicted changes in PWV, peripheral pulse pressure and hypertension status (p0.05 for all).In apparently healthy postmenopausal women, FAI could be a novel biomarker superior to total testosterone for accelerated vascular aging and hypertension status.

Smoking is associated with increased inflammatory process and impairment of fibrinolytic status. Concord grape juice (CGJ), a rich source of flavonoids, can modify cardiovascular risk factors. We aimed to evaluate the impact of CGJ on smoking-induced impairment of inflammatory and fibrinolytic status in healthy smokers.We studied the effect of a 2-week oral treatment with CGJ in 26 healthy smokers on three occasions (day 0: baseline, day 7 and day 14) in a randomized, placebo-controlled, double-blind, cross-over design. Measurements were carried out before (pSm) and 20 min after (Sm20) cigarette smoking. Serum levels of intercellular adhesion molecule-1 (sICAM-1) and plasminogen activator inhibitor 1 (PAI-1) were measured as markers of inflammatory and fibrinolytic status, respectively.Treatment with CGJ reduced pSm sICAM-1 levels (p 0.001), while placebo had no impact on ICAM-1 levels (p = 0.31). Moreover, treatment with CGJ decreased pSm values of PAI-1 (p 0.001) while placebo had no impact on PAI-1 levels (p = 0.89). Smoking induced an elevation in PAI-1 levels after smoking compared to pro-smoking levels in all study days and in both arms (CGJ and placebo) of the study (p 0.001 for all). Interestingly, CGJ compared to placebo, attenuated the acute smoking increase in sICAM-1 and PAI-1 levels (p 0.001 and p = 0.005 respectively).CGJ consumption improved inflammatory and fibrinolytic status in healthy smokers and attenuated acute smoking induced increase in ICAM-1 and PAI-1 levels. These findings shed further light on the favorable effects of flavonoids in cardiovascular health.

To determine whether menopausal symptoms are associated with changes in arterial structure and function in healthy, recently postmenopausal women.One hundred and ten postmenopausal women aged 45-55 years were included in the present cross-sectional study. Menopausal symptoms were recorded by the Greene Climacteric Scale. Anthropometric measures, blood pressure, serum lipids, glucose, insulin, sex and thyroid hormones were determined in each individual. Arterial structure, function and stiffness were assessed by intima-media thickness (IMT), flow-mediated dilation and pulse-wave velocity, respectively.Women with moderate to severe hot flushes had increased IMT compared to women with no or mild hot flushes (IMT in women with no hot flushes 0.61±0.08 mm, IMT in women with mild hot flushes 0.62±0.11 mm, IMT in women with moderate to severe hot flushes 0.67±0.11 mm; p = 0.034). This difference was independent of cardiovascular risk factors like age, menopausal age, smoking, blood pressure, adiposity, lipid levels, insulin resistance or hormone levels. No association was detected between psychological or psychosomatic symptoms and arterial indices. Furthermore, menopausal symptoms were not associated with serum sex steroids or thyroid hormone levels.Carotid IMT, a surrogate marker of subclinical atherosclerosis and cardiovascular risk, was found to be increased in women with vasomotor symptoms as compared to asymptomatic women. This association was independent of cardiovascular risk factors or endogenous hormone levels. It remains to be elucidated whether the presence of menopausal symptoms is an additional cardiovascular risk factor requiring preventive intervention.

BACKGROUND Hyperprolactinemia has been recently associated with hypertension and endothelial dysfunction in humans, confirming animal studies performed in the 1970s that showed high prolactin levels to exert positive chronotropic and vasoconstrictive effects. Whether prolactin affects endothelial function, in the absence of hyperprolactinemia, remains unknown. Considering that secretion of prolactin presents circadian rhythmicity, we tested the hypothesis that in patients with hypertension, who present diurnal variation in their endothelial function as well, prolactin levels correlate with endothelial function and/or blood pressure. METHODS Endothelial function, assessed by flow-mediated dilatation (FMD) and serum prolactin were examined successively at 12 PM, 9 PM, and 7 AM in 27 nonhyperprolactinemic men with newly diagnosed, untreated essential hypertension. RESULTS Both FMD and prolactin presented 24-h variation (P < 0.01). FMD reached its lowest values at 7 AM (2.1 ± 1.8%, mean ± s.d.); concurrently prolactin levels peaked (7.18 ng/ml, median). Across the three time points, prolactin changes inversely interacted with FMD changes (P = 0.002). Systolic and diastolic blood pressure also varied significantly but no interaction with prolactin changes was evident. CONCLUSIONS Diurnal fluctuations of prolactin levels are associated with decreased endothelial function that occurs early in the morning in men with hypertension, although this study did not assess causality. Additional studies are required to determine whether these responses differ from normotensive individuals.

Background Amyloid-β (1-40) (Aβ40) is implicated in mechanisms related to plaque destabilization and correlates with adverse outcomes in stable coronary artery disease. Objective To determine the prognostic and reclassification value of baseline circulating levels of Aβ40 after adjustment for the Global Registry of Acute Coronary Events (GRACE) score, which is widely recommended for risk stratification in non-ST-segment elevation acute coronary syndrome (NSTE-ACS). Design Retrospective cohort study using data from 2 independent prospective cohorts, the Heidelberg study (n = 1145) and the validation multicenter international APACE (Advantageous Predictors of Acute Coronary Syndrome Evaluation) study (n = 734). Setting Academic hospitals in 7 European countries. Participants Patients with adjudicated NSTE-ACS followed for a median of 21.9 and 24.9 months in the Heidelberg and APACE studies, respectively. Measurements All-cause mortality was the primary end point. Results Amyloid-β (1-40) was associated with mortality after multivariate adjustment for age, sex, diabetes mellitus, high-sensitivity cardiac troponin T and C-reactive protein, revascularization, and ACS type (Heidelberg cohort hazard ratio [HR] for 80th vs. 20th percentiles, 1.66 [95% CI, 1.06 to 2.61; P = 0.026]; APACE cohort HR, 1.50 [CI, 1.15 to 1.96; P = 0.003]). It was also associated with mortality after adjustment for the GRACE score (Heidelberg cohort HR for 80th vs. 20th percentiles, 1.11 [CI, 1.04 to 1.18; P = 0.001]; APACE cohort HR, 1.39 [CI, 1.02 to 1.88; P = 0.036]). Amyloid-β (1-40) correctly reclassified risk for death over the GRACE score (net reclassification index, 33.4% and 47.1% for the Heidelberg and APACE cohorts, respectively) (P Limitation At low concentrations of Aβ40, dose-response associations with mortality differed between cohorts, possibly because of varying blood preparations used to measure Aβ40. Conclusion Circulating Aβ40 is a predictor of mortality and improves risk stratification of patients with NSTE-ACS over the GRACE score recommended by clinical guidelines. The clinical application of Aβ40 as a novel biomarker in NSTE-ACS should be further explored and validated. Primary funding source German Cardiac Society.

Emotion and depression may affect atherosclerosis progression. We examined the association between depression, arterial stiffness and atheromatic burden in carotid arteries. Corinthia study is a cross sectional epidemiological study based on 2043 inhabitants (age 40-99years) of Corinthia region in

Arterial stiffness and vascular calcification significantly contribute to coronary atherosclerosis progression. We study the prognostic impact of arterial stiffness and serum osteoprotegerin (OPG) levels in patients with stable coronary artery disease (CAD) after composite primary percutaneous

Hashimoto's thyroiditis (HT) is an autoimmune disorder associated with increased cardiovascular risk, mainly as a result of accelerated atherosclerosis. The aim of this study was to determine the effect of HT on carotid atherosclerosis and arterial stiffness, as possible mediators of this vascular impairment. Menopausal status was also considered in this setting since HT is mainly prevalent in women.Fifty-four women with HT and normal thyroid function (thyrotropin [TSH]4.5 mU/L) and 72 healthy controls with comparable age and risk factor prevalence were examined in this cross-sectional study. Intima-media thickness (IMT) in the carotid arteries averaged from six sites and carotid-femoral pulse wave velocity (PWV) were measured.Although both groups had TSH levels within normal limits, TSH was higher in HT patients (2.1 +/- 1.16 vs. 1.5 +/- 0.8 mU/L, p = 0.001). PWV (7.95 +/- 2.02 vs. 7.21 +/- 1.24 m/s, p = 0.021), but not IMT (0.644 +/- 0.144 vs. 0.651 +/- 0.169 mm, p = 0.798), was significantly higher in HT patients compared to controls. When the women were divided according to menopausal status, only premenopausal women without HT had significantly lower PWV when compared with the three other subgroups (6.51 +/- 1.09 m/s premenopausal controls vs. 7.64 +/- 2.05 m/s premenopausal HT vs. 7.69 +/- 1.11 m/s postmenopausal controls vs. 8.3 +/- 1.97 m/s postmenopausal HT, p0.001). By multivariate analysis PWV independently correlated with age (p = 0.042), the presence of HT (p = 0.002), TSH (p = 0.003), and menopause (p0.001) in the whole population while HT was an independent determinant of PWV only in premenopausal women.HT is associated with increased PWV independent of arterial atheromatosis, indicating a direct impact of this disorder on arterial stiffening. This effect may be masked in postmenopausal women possibly due to their heavier cardiovascular risk profile.

ObjectiveWe aimed to evaluate the association between thyroid hormones and indices of obesity in a sample of euthyroid postmenopausal women.DesignCross-sectional study.MethodsSerum levels of TSH, free triiodothyronine (FT3), and free thyroxine (FT4) as well as BMI and waist:hip ratio (WHR) were evaluated in 194 healthy euthyroid postmenopausal women. Ultrasonography was used to assess abdominal fat layers (subcutaneous fat (SF), preperitoneal fat (PF), and SF:PF ratio). Indices of adiposity were defined as high vs low depending on the median value of the assessed parameters.ResultsAfter multivariate adjustment for traditional risk factors, lower FT4levels and a higher FT3:FT4ratio predicted higher SF mass (FT4, Exp(β)=0.035,P=0.020 and FT3:FT4, Exp(β)=2.374,P=0.018), whereas higher FT3predicted higher PF mass (Exp(β)=2.815,P=0.032). Women with FT3:FT4above the highest quartile had a significantly higher SF mass as compared to women in the lowest quartile (1.81±0.62 cm vs 1.54±0.46 cm,P=0.027). BMI had a positive independent association with TSH (Exp(β)=1.829,P=0.018). Finally, FT3was significantly associated with SF mass among women with higher BMI (FT3,β=0.259,P=0.040) and women with higher WHR (β=0.309,P=0.020) but not among women with lower BMI or WHR values.ConclusionThyroid hormone levels, and in particular FT3, were independently associated with SF and PF in euthyroid postmenopausal women, and this association was mainly evident in women with higher BMIs. On the other hand, among traditional indices of adiposity, only TSH was positively associated with BMI. Larger prospective studies are needed to evaluate the significance of the present findings.

Background: Uncontrolled as well as apparent resistant hypertension (aRHT) are clinical conditions that deserve a thorough evaluation of heart function to assess the relevant risk profile. The purpose was to investigate echocardiographic characteristics of patients without symptoms of heart failure

Introduction: Omega-3 polyunsaturated fatty acids (PUFAs) exert anti-inflammatory properties and have been tested in patients with systolic heart failure (HF). Soluble suppression of tumorigenicity2, is a member of the interleukin 1 (IL1) receptor family and is released from cardiomyocytes and

Recent evidence suggests that primary hyperparathyroidism (pHPT) is linked with hypertension and subclinical atherosclerosis. These associations have not been examined in postmenopausal women, in whom cardiovascular risk steeply rises after menopausal transition.The objective of the study was to assess whether pHPT is associated with hemodynamic markers and subclinical atherosclerosis in postmenopausal women under a cross-sectional case-control design.One hundred two postmenopausal women with pHPT and 102 women matched 1:1 for age and menopausal status were consecutively recruited. In all patients, flow-mediated dilatation, carotid-femoral pulse wave velocity, reflected waves, aortic blood pressures (BP), intima-media thickness, and the presence of plaques in the carotid and common femoral arteries were measured.Women with pHPT had higher aortic and peripheral BP (P.05 for all), but no correlation was observed with subclinical atherosclerosis. After adjusting for possible confounders, pHPT was an independent determinant of peripheral and aortic diastolic BP (P.05 for all). The association with systolic BP was lost after adjusting for C-reactive protein. Further adjustment for PTH and 25-hydroxyvitamin D levels revealed that PTH but not 25-hydroxyvitamin D was an independent determinant of all BP parameters. Both peripheral and aortic BP increased across PTH tertiles as compared with the control group, but this association lost significance after adjustment for C-reactive protein.These results suggest that pHPT may increase peripheral and aortic BP through PTH and inflammatory-mediated mechanisms. A direct impact of the disease on the arterial wall cannot be implicated despite the large number of markers of subclinical atherosclerosis measured in this study.

To determine the rate of tuberculosis (TB) screening test conversion during anti-tumour necrosis factor (TNF) therapy in rheumatic patients with negative baseline screening.This was a prospective study of rheumatic patients with negative baseline TB screening (tuberculin skin test (TST):5 mm, and negative T-SPOT.TB, QuantiFERON-TB Gold In Tube (QFT-GIT) and chest X-ray) treated with anti-TNF agents. All patients underwent re-screening for TB with all assays 1 year later. Factors associated with TB test conversion were analysed and compared between 'converters' and 'non-converters'.Seventy patients (mean age 50.6±15.5 years) with rheumatic disease (33 with rheumatoid arthritis, 33 with spondyloarthropathies and 4 with other conditions) were enrolled. Patients were treated with different anti-TNFs (27 with adalimumab, 14 etanercept, 16 infliximab, 8 golimumab, 5 certolizumab pegol) for 1 year. Twenty patients (29%) displayed conversion of at least one screening assay 12 months after anti-TNF therapy: conversion of TST occurred in 9 (13%), T-SPOT.TB in 7 (10%) and QFT-GIT in 5 (7%). Only one patient had concomitant conversion of more than one screening test. Univariate and multivariate analysis revealed that only infliximab was associated with a decreased rate of TB screening assay conversion (OR 0.048, 95% CI 0.004 to 0.606, p=0.017). No patient (40% received isoniazid therapy) developed active TB during follow-up (27±12 months).Approximately one third of patients with negative baseline TB screening develop conversion of at least one screening test during anti-TNF treatment. These findings should be considered when designing re-screening strategies and contemplating latent TB therapy.

Objective We tested the hypotheses that monthly fluctuations in markers of arterial stiffness and blood pressure hemodynamics differ between women with and without premenstrual syndrome. We also assessed hypertension prevalence and arterial stiffening in postmenopausal women with or without history of premenstrual symptoms. Methods Twenty one pre-menopausal women with premenstrual syndrome and 15 women without were prospectively examined in three distinct phases of their menstrual cycle (menses, late follicular and luteal phase). Pulse-wave velocity and analysis were used to assess arterial stiffness and wave reflection indices, respectively. Endothelial function was evaluated by flow-mediated vasodilation. In a cross-sectional substudy, 156 postmenopausal women were assessed for possible associations between retrospectively reported PMS symptoms and hypertension. Results In women with premenstrual syndrome, arterial stiffness significantly increased during the luteal and menses phase (late follicular: 6.48 ± 1.07, luteal: 7.1 ± 1.26, menstruation: 7.12 ± 1.19 m/s, p = 0.003), while blood pressure peaked at the menses phase. Significant interactions between PMS and changes in arterial stiffness and blood pressure but not endothelial function, were observed. Changes in PWV were significantly associated with concomitant changes in blood pressure, C-reactive protein and the severity of PMS symptoms. The prevalence of hypertension (20.9% vs. 40.9%, p = 0.041) and pulse-wave velocity values (8.64 ± 1.52 vs. 9.37 ± 1.1, p = 0.046) were higher in postmenopausal women with 7 or more reported PMS symptoms. Arterial stiffness differences remained significant after adjustment for confounding factors. Conclusion These results imply that PMS may affect arterial stiffness and BP monthly variability. Whether PMS is associated with new onset hypertension later in life needs further evaluation.

Objective To compare the prevalence of subclinical atherosclerosis between postmenopausal women and men of similar age early after the onset of menopause. Methods In the first part of this cross-sectional study 186 non-diabetic young postmenopausal women ( n =101, menopausal age ≤10 years) and men ( n =85) aged 40–60 years without overt CVD were consecutively recruited from the outpatients clinics of an academic hospital. Subclinical carotid atherosclerosis was assessed by high-resolution ultrasonography. The presence of carotid atherosclerosis was defined as either increased carotid intima-media thickness (IMT>0.9mm) and/or the presence of plaques. In the second part, 1:1 matching for age and traditional risk factors (hyperlipidemia, smoking, hypertension and BMI) was performed between men and women of this cohort resulting in a matched sub-sample of 76 subjects. Results By multivariate analysis, gender was not an independent determinant of any measure of carotid atherosclerosis. In the matched sub-sample, carotid IMT and the number of segments with atherosclerosis did not significantly differ between women and men (0.734±0.119mm and 1.47±1.6 versus 0.717±0.138mm and 1.47±1.5, p =0.575 and p =0.999, respectively). Also, the prevalence of increased IMT (60.5% in both genders), carotid plaques and subclinical atherosclerosis (31.6% and 63.2% versus 28.9% and 65.8%, p =0.803 and p =0.811, respectively) was similar between men and women. Conclusions The prevalence and severity of carotid atherosclerosis was similar between men and young postmenopausal women matched for traditional risk factors. Whether these women may be better risk stratified irrespective of gender should be further assessed in prospective studies.

Although increasing evidence supports an association between endogenous sex hormones and cardiovascular disease, the results still remain controversial. This study aims to examine the association between endogenous sex hormones and indices of vascular function and structure. Serum follicle-stimulating hormone, luteinizing hormone, estradiol, testosterone, sex hormone-binding globulin, dehydroepiandrosterone sulfate (DHEAS), and Δ4-androstenedione were measured in 120 healthy postmenopausal women aged 41 to 60 years. Possible associations with surrogate markers of subclinical atherosclerosis, arterial stiffness, and endothelial function were investigated. Indices of arterial structure included carotid and femoral intima-media thickness and atheromatous plaques presence. Indices of arterial function included flow-mediated dilation of the brachial artery, carotid-femoral pulse wave velocity (PWV), and augmentation index. Total testosterone and free androgen index (FAI) were the most important predictors of common carotid artery intima-media thickness (β = 0.376 and β = 0.236, P < .001 and P = .014, respectively). Similarly, FAI was the only significant independent predictor of PWV (β = 0.254, P = .027) after adjusting for age, smoking, body mass index, homeostasis model assessment of insulin resistance, and blood lipids. Free estrogen index showed a positive association with PWV, independently of age, smoking, and body mass index, but not of homeostasis model assessment of insulin resistance and blood lipids. Age-adjusted levels of DHEAS exhibited a significant independent negative association with measures of augmentation index. Follicle-stimulating hormone, luteinizing hormone, estradiol, sex hormone-binding globulin, and Δ4-androstenedione were not associated with any of the vascular parameters independently of traditional cardiovascular risk factors. Higher serum testosterone and FAI are associated with subclinical atherosclerosis in healthy recently menopausal women. This association is independent of traditional cardiovascular risk factors or insulin resistance. On the contrary, serum DHEAS exhibits a negative association with arterial stiffness.

According to a recently published editorial article in the Open Hypertension Journal written by Anagnostis et al., [1] adherence to a Mediterranean type diet was associated with reduced cardiovascular disease (CVD) risk, by modulating arterial blood pressure levels. Hypertension consist, both a traditional risk factor with increasing prevalence among older subjects [2] and specific subpopulations (i.e., metabolic syndrome) as well as a high-yield target in means of primary and secondary prevention. The common CVD risk scores (e.g., Framingham score sheet, ESC SCORE) [3,4] that are implicated in individual CVD risk assessment through easily measured characteristics constantly incorporate arterial blood pressure indices in underlying estimation models [3,4]. Accumulating evidence [5] suggests that adherence to healthier dietary patterns is associated with favorable CVD profile; i.e., in 2008 the INTERHEART study with approximately 16,500 participants concluded that 30% of CVD deaths in Europe could have been prevented through adoption of healthier dietary habits [6]. Despite emerging associations between dietary patterns and CVD risk, diet’s assessment has never been, directly, incorporated into existing CVD risk scores [5]. Researchers who added diet’s assessment into CVD risk estimation models, reported incremental value of the dietary component over traditional risk factors in terms of overall model performance and improved reclassification of the true events [7,8]. In addition, updating CVD risk estimation scores with dietary information could improve the correct classification rate of people at high risk. This suggestion is further reinforced by the aforementioned editorial, which identifies unhealthy dietary patterns as a risk factor for adverse CVD events, independently of blood pressure status and lipid profile. The individual CVD risk estimation is highly recommended by the European guidelines for the majority of middle- aged people, even without known CVD history [9]. Under this context, classification rate improvement of the existing CVD risk estimation scores should be addressed as a cardinal issue in terms of public health policies. Dietary patterns assessment should be examined as the most promising candidate parameter for incorporation into the existing CVD risk estimation scores in order to upgrade current prevention strategies.

Objective: Vascular closure devices (VCDs), such as the Angio-Seal, a three-component hemostatic plug, have greatly facilitated the routine clinical practice in the catheterization laboratory. The manufacturer recommends a local angiogram before Angio-Seal deployment. However, from the outset, we employed a simplified routine of deploying this VCD, i.e. without use of local angiography. Methods: The Angio-Seal was employed without a preceding femoral arteriogram over 8 years in 2074 consecutive patients, 72% presenting with acute coronary syndromes and subjected to coronary angiography (n = 1032) or PCI n = 1042) via a transfemoral approach with use of heparin and dual antiplatelet therapy. Results: Deployment of the VCD was successful in 99.4%. Complete hemostasis was obtained in 98% of cases. In 14 patients, Angio-Seal deployment failed. Mean time for placement of Angio-Seal was

BackgroundThe amyloid beta peptide is the major protein constituent of neuritic plaques in Alzheimer disease and appears to play a central role in vascular inflammation pathophysiology.ObjectivesThis study sought to determine the clinical value of amyloid-beta 1-40 (Abeta40) measurement in predicting cardiovascular (CV) mortality in patients with coronary heart disease (CHD) and arterial stiffness progression in young healthy subjects.MethodsAbeta40 was retrospectively measured in blood samples collected from 3 independent prospective cohorts and 2 case-control cohorts (total N = 1,464). Major adverse cardiac events (MACE) were assessed in the 2 prospective cohorts (n = 877) followed for a median of 4.4 years. To look at effects on subclinical disease, arterial stiffness was evaluated at baseline and after 5-year follow-up (n = 107) in young healthy subjects. The primary endpoint was the predictive value of Abeta40 for CV mortality and outcomes in patients with CHD.ResultsIn Cox proportional hazards models adjusted for age, sex, estimated glomerular filtration rate, left ventricular ejection fraction, high-sensitivity C-reactive protein, and high-sensitivity troponin T, Abeta40 independently predicted CV death and MACE in patients with CHD (p < 0.05 for all). After multivariate adjustment, Abeta40 levels conferred a substantial enhancement of net reclassification index and integrated discrimination improvement of individuals at risk in the total combined CHD cohort over the best predictive model. Further cohort-based analysis revealed that Abeta40 levels were significantly and independently associated with arterial stiffness progression, incident subclinical atherosclerosis, and incident CHD.ConclusionsMeasuring blood levels of Abeta40 identified patients at high risk for CV death.