Increased homocysteine and lipoprotein(a) levels highlight systemic atherosclerotic burden in patients with a history of acute coronary syndromes.

BACKGROUND: Strong evidence supports an association between high levels of homocysteine (Hcy) and lipoprotein(a) [Lp(a)] and an increased rate of ischemic vascular events. METHODS: The study population comprised 162 patients (50 women [30.9%]; age, 66.71 ± 12.76 years) having a history of acute coronary syndrome within 1 year who underwent fasting blood sampling, measurement of intima-media thickness and pulse wave velocity at the common carotid and femoral arteries by Doppler ultrasound, and ankle-brachial index measurement. Cutoff values were considered 0.9 mm and 1.2 mm for carotid and femoral intima-media thickness, respectively; 12 m/s for pulse wave velocity; and <0.9 for ankle-brachial index. We included hypertension, dyslipidemia, diabetes, overweight/obesity, smoking, and family history of cardiovascular disease in the count of traditional risk factors (CRFs). Adding Hcy ≥15 µmol/L and Lp(a) ≥500 mg/L to CRFs, we obtained a new score, named TOTAL. RESULTS: On univariate analysis, Hcy and Lp(a) were significantly associated with presence of atherosclerotic extracoronary lesions (for Hcy: ß = .934; standard error = 0.178; P < .0001; for Lp(a): ß = .961; standard error = 0.177; P < .0001) and compliance alterations (for Hcy: odds ratio, 13.3; 95% confidence interval, 3.9-45.3; P < .0001; for Lp(a): odds ratio, 14.6; 95% confidence interval, 5.69-37.62; P < .0001). On multivariate analysis, Lp(a) and Hcy were significantly associated with extracoronary atherosclerosis, even after correction for CRFs. The area under the curve of the TOTAL score for both atherosclerosis and vascular compliance alterations was significantly higher than the area under the curve of traditional CRFs plus only Hcy ≥15 µmol/L or plus Lp(a) ≥500 mg/L, separately added. CONCLUSIONS: The addition of evaluation of Hcy ≥15 µmol/L and Lp(a) ≥500 mg/L to the traditional CRF count does improve detection of systemic atherosclerotic burden of patients with acute coronary syndrome and can offer a new opportunity to optimize secondary prevention.

Detrimental effects of niacin/laropiprant on microvascular reactivity and red cell deformability in patients with elevated lipoprotein(a) levels.

Several studies have found a beneficial effect of nicotinic acid on lipid profile, but there remains a limitation in the clinical use of nicotinic acid due to its side effects. In this study, 46 (F/M = 22/24, age = 58.74 ± 10.02 years) patients with Lp(a) ≥500 mg/L and with a previous arterial thrombotic event were treated with nicotinic acid/laropiprant (Tredaptive®). We found a significant reduction in the Lp(a) values at T1 (after 12 months), with a decrease of 32.3 % from baseline levels. At T1, 11 patients (23.9 %) showed Lp(a) levels to be <500 mg/L. PAT values were significantly decreased after treatment (2.13 ± 0.81 vs 1.74 ± 0.42, p = 0.001), showing a worsening of endothelial function in 27 (58.6 %) patients. A significantly higher number of patients had RHI <1.5 after the treatment [18 (39.1 %) vs 8 (17.4 %)]. Blood rheology worsened as ED was impaired (p < 0.0001) after 12 months, whereas WHV, plasma viscosity, and red cell aggregation did not show any significant differences in comparison to baseline. Patients with a worsening in microvascular reactivity in comparison to baseline showed a marked impairment in ED (0.3327 ± 0.037 vs 0.3091 ± 0.0351; p < 0.0001), while others showed only a mild, even though significant, reduction (0.3347 ± 0.0299 vs 0.3272 ± 0.0235; p = 0.044). In the light of the results of HPS2-THRIVE study, we may hypothesize that the addition of laropiprant to niacin might be responsible for these negative effects. In turn, these effects might explain, at least in part, the lack of a clinical net benefit of niacin/laropiprant in the trial.

Platelet function and long-term antiplatelet therapy in women: is there a gender-specificity? A 'state-of-the-art' paper.

Although the female gender is generally less represented in cardiovascular studies, observational and randomized investigations suggest that-compared with men-women may obtain different benefits from antiplatelet therapy. Multiple factors, including hormonal mechanisms and differences in platelet biology, might contribute to such apparent gender peculiarities. The thrombotic and bleeding risks, as well as outcomes after a cardiovascular event, appear to differ between genders, partly in relation to differences in age, comorbidities and body size. Equally, the benefits of antiplatelet therapy may differ in women compared with men in different vascular beds, during primary or secondary prevention and according to the type of an antiplatelet agent used. This document is an attempt to bring together current evidence, clinical practices and gaps of knowledge on gender-specific platelet function and antiplatelet therapy. On the basis of the available data, we provide suggestions on current indications of antiplatelet therapy for cardiovascular prevention in women with different clinical features; no strong recommendation may be given because the available data derive from observational studies or post hoc/subgroup analyses of randomized studies without systematic adjustments for baseline risk profiles.

Searching for a common mechanism for placenta-mediated pregnancy complications and cardiovascular disease: role of lipoprotein(a).

OBJECTIVE: To investigate lipoprotein(a) [Lp(a)], a well known cardiovascular risk factor, in women with history of placenta-mediated pregnancy complications (PMPC) compared with healthy uneventful-pregnancy women (HW), and the role of LPA gene functional polymorphisms in modulating both Lp(a) levels and PMPC risk. DESIGN: Retrospective observational study. SETTING: University hospital. PATIENT(S): A total of 360 women with history of PMPC (154 preeclampsia [PE], 121 stillbirth [SB], and 85 small for gestational age [SGA]) and 270 HW. INTERVENTION(S): Not applicable. MAIN OUTCOME MEASURE(S): Lp(a) levels measurement and LPA +93C >T and +121G>A polymorphisms genotyping. RESULT(S): In PMPCs we observed higher Lp(a) levels than those found in HW and an association with PMPC risk, also after adjustment for age, familial history of cardiovascular disease, and traditional risk factors. By analyzing Lp(a) concentrations according to each pregnancy complication, we observed significantly higher Lp(a) levels in women with history of SB and PE, conferring 2.5-fold and 2-fold increased risks, respectively; no association with SGA was observed. Lp(a) concentrations progressively and significantly increased as LPA unfavorable allelic burden increased; unfavorable allelic burden influenced SB and PE risk. CONCLUSION(S): We evidenced, for the first time, an association between high Lp(a) concentrations and history of SB, and we confirmed the role of Lp(a) in PE risk; this well known atherothrombotic marker might represent one of the possible mechanisms shared by PMPC and cardiovascular disease.

Impaired Femoral Vascular Compliance and Endothelial Dysfunction in 30 Healthy Male Soccer Players: Competitive Sports and Local Detrimental Effects.

BACKGROUND: Despite beneficial effects of physical activity on cardiovascular risk, discordant data on elite athletes (high atherosclerotic damage in activity comprising strenuous exertion) and retired sportsmen are reported in the literature. HYPOTHESIS: We hypothesize that long-lasting daily physical activity could affect the morphology and function of the carotid and femoral vessel walls differently, as assessed in elite male athletes aged 20 to 30 years compared with age- and sex-matched healthy controls. STUDY DESIGN: Retrospective case-control study. LEVEL OF EVIDENCE: Level 3. METHODS: Sixty male subjects (30 athletes and 30 controls) underwent medical examination for ankle brachial index, augmentation index (AIX) and AIX corrected for heart rate (AIXr), peripheral arterial tonometry (PAT), and intima media thickness and pulse wave velocity assay at common carotid (carotid-intima media thickness [c-IMT], carotid-pulse wave velocity [c-PWv]) and femoral arteries (femoral-intima media thickness [f-IMT], femoral-pulse wave velocity [f-PWv]) assessed by ultrasonography using Doppler ultrasound. RESULTS: Athletes showed a significantly lower heart rate (HR) at rest and a better lipid profile than controls. In athletes, c-PWv (5.87 ± 0.80 vs 6.62 ± 1.02 m/s, P = 0.001) and f-PWv (8.96 ± 1.29 vs 7.89 ± 1.39, P = 0.002) were, respectively, significantly lower and higher than values found in controls; accordingly, carotid AIX (4.03 ± 6.21 vs 7.81 ± 5.21, P = 0.003) and femoral AIX (8.56 ± 10.21 vs 6.09 ± 7.95, P = 0.042) were lower and higher than control values, even after correction for heart rate (P = 0.03). On the other hand, IMT values were significantly higher in controls than in athletes (c-IMT, P < 0.0001; f-IMT, P < 0.0001). A positive significant correlation between HR and c-IMT and f-IMT (r = 0.527, P < 0.001 and r = 0.539, P < 0.0001, respectively) and between HR and c-PWv (r = 0.410, P = 0.01) was found when controls and athletes were considered as a whole group. Soccer players showed lower PAT values in comparison with controls (P = 0.002). CONCLUSION: Elite sports positively affect c-IMT, f-IMT, and carotid PWv and AIX but not femoral PWv, AIX, AIXr, or PAT. CLINICAL RELEVANCE: Physical activity affects vascular beds in elite athletes differentially, depending on the rate of superior or inferior limb involvement in different sports. In soccer players, physical activity has a protective effect on carotid and femoral vessel walls but worsens femoral arterial and endothelial function. These findings highlight how different results can be shown on carotid and femoral districts, when these vascular districts are differently stressed during sport activity.

Gender and anti-thrombotic therapy: from biology to clinical implications.

Cardiovascular diseases actually remain the leading cause of death and morbidity in Western countries, and it is the most common cause of death in American women accounting for about one third of all deaths. Women remain underrepresented in published trial literature relative to their disease prevalence. Strong evidence do exists demonstrating gender differences in efficacy (ischemic risk) and safety (bleeding risk) associated with antithrombotic treatment, mostly related to different values of body mass, and renal function in women than men. Several data show a higher platelet reactivity in females and a higher prevalence of high platelet reactivity on aspirin and clopidogrel therapy. In primary prevention, the use of aspirin is associated with a higher reduction of risk for ischemic stroke in females and for myocardial infarction in males. In the setting of ACS, female gender is associated with a significantly higher risk of bleeding. In summary, there are some gender-related aspects of guidance in the complex spectrum of the net clinical benefit related to antithrombotic treatment.

Is tissue factor pathway inhibitor a marker of procoagulable status in healthy infertile women undergoing ovarian stimulation for assisted reproduction?

Increased serum estradiol levels occurred during ovarian stimulation for assisted reproduction. Tissue factor pathway inhibitor (TFPI) plays a relevant role in regulating haemostatic equilibrium, and its decrease has been documented in conditions in which blood coagulation occurs. We investigated TFPI concentrations and coagulative pathway in healthy infertile women undergoing ovarian stimulation. We investigated 27 healthy infertile women, median age 37 (25-41) years, undergoing ovarian stimulation, observed during the mid-luteal phase of cycle (T0) and on day 5 (T1), and between day 7 and 9 (T2) of ovarian stimulation. Coagulative pathway was assessed by a global test [endogenous thrombin potential, (ETP)] and TFPI concentrations. TFPI values progressively and significantly decreased throughout the ovarian stimulation procedure (P = 0.03), contemporarily estradiol levels progressively and significantly increased from baseline to T2 (P < 0.0001). A significant negative correlation between changes in estradiol and TFPI levels was observed (P = 0.03). As concerns ETP parameters a significant increase of ETP (mA) and Cmax (mA/min) throughout the ovarian stimulation cycle was found (P = 0.003 and P = 0.002, respectively). TFPI values progressively and significantly decreased throughout the ovarian stimulation, and negatively correlated with estradiol, thus suggesting that TFPI may represent one of the main 'actors' involved in the hypercoagulable status, occurring during assisted reproduction. The relationship between TFPI and estradiol levels might contribute to the knowledge of mechanisms able to modify a quite milieu into a prothrombotic status. Nevertheless, the small number of individuals investigated might influence the relevance of our results.

Peripheral-arterial tonometry for assessing endothelial function in relation to dietary habits.

BACKGROUND: Peripheral-arterial tonometry (PAT) provides, with good reproducibility, measures of nitric oxide-mediated endothelial response, which correlate with flow-mediated dilation (FMD) findings obtained by brachial artery ultrasound. Few data about the ability of exploring endothelial function by PAT in relation to dietary habits are available. The aim of this study was to evaluate natural logarithm of reactive hyperemia index (lnRHI) in subjects referred for primary prevention, in relation to classic risk factors, in particular to adherence to Mediterranean diet and red wine consumption. METHODS: The study population was composed of 95 consecutive clinically stable subjects in primary prevention for cardiovascular diseases. All subjects underwent medical questionnaire, clinical examination, and PAT for endothelial function evaluation. RESULTS: A significant inverse correlation between lnRHI values and body mass index (r = -0.284; P = 0.022) was found. We described a gradual reduction in lnRHI values, corresponding to the increase in the number of risk factors (0.75 [0.31-1.26], 0.66 [0.25-0.97], 0.63 [0.37-1.19], 0.48 [0.32-0.71], 0.43 [0.31-0.91], respectively, for none, 1, 2, 3, and 4 cardiovascular risk factors; P = 0.004). A significant positive correlation between score of adherence to Mediterranean diet and lnRHI values was found (r = 0.307; P = 0.002). Higher adherence to Mediterranean diet was found in subjects with lnRHI values greater than 0.40 in comparison to others (39 [27-50] vs 33 [28-45], respectively; P = 0.064). The lnRHI values were significantly higher in regular drinkers in comparison to nonregular drinkers (0.46 [0.25-0.83] vs 0.70 [0.32-1.26], respectively; P < 0.0001).Relationship between reactive hyperemia index and red wine consumption remained statistically significant even after adjustment for age, sex, body mass index, smoking habit, hypertension, and adherence to Mediterranean diet. CONCLUSIONS: Our findings strengthen the ability of PAT to evaluate alterations of endothelium response to ischemia, in relation to physiological and clinical conditions, so indicating possible usefulness to optimize and personalize risk stratification.

Stress-induced hyperviscosity in the pathophysiology of takotsubo cardiomyopathy.

Takotsubo cardiomyopathy (TC) is characterized by transient hypokinesis of the left ventricular apex or midventricular segments with coronary arteries without significant stenosis. It is often associated with emotional or physical stress; however, its pathophysiology is still unclear. In the present study, we analyzed the alterations in blood viscosity and markers of endothelial damage induced by sympathetic stimulation in patients with previous TC. Seventeen women (mean age 71 years) with previous TC, included and investigated in the TC Tuscany Registry, were compared to a control group of 8 age- and risk factor-matched women with chest pain and coronary arteries free of stenosis. All subjects underwent the cold pressor test (CPT). Before and after the CPT, the hemorheologic parameters (whole blood viscosity at 0.512 s(-1) and 94.5 s(-1), plasma viscosity, erythrocyte deformability index, and erythrocyte aggregation), catecholamines, plasminogen activator inhibitor-1 (PAI-1), and von Willebrand factor levels were assessed. The patients with TC had significantly greater baseline PAI-1 levels (p <0.01) and lower erythrocyte deformability index values (p <0.01). After CPT, both the patients with TC and the controls had a significant increase in several hemorheologic parameters, catecholamines, and von Willebrand factor levels and a decrease in erythrocyte deformability index. However, the PAI-1 levels were significantly increased only in the patients with TC. Compared to the controls, the patients with TC had significantly greater values of whole blood viscosity at 94.5 s(-1) (p <0.05), PAI-1 (p <0.01), von Willebrand factor (p <0.05) and lower erythrocyte deformability index values (p <0.01) after CPT. In conclusion, the results of the present study suggest that in patients with TC, the alterations in erythrocyte membranes and endothelial integrity induced by catecholaminergic storm could determine microvascular hypoperfusion, possibly favoring the occurrence of left ventricular ballooning.

Diabetes and sex: from pathophysiology to personalized medicine.

The prevalence and incidence of diabetes is similar in the two sexes but the long-term impact of diabetes on vascular and non-vascular complications is more gender specific. Men, in comparison with women, seem to be at higher risk for micro-vascular complications, such as severe retinopathy and nephropathy. On the other hand, the impact of diabetes on the risk of major cardiovascular events is different in women in comparison with men. Both type 1 and type 2 diabetes are associated with a significant increase in the incidence of bone fractures. Although this phenomenon is present in both sexes, its impact is greater in women, due to the higher baseline incidence of fractures. Diabetes negatively affects mood, leading to an increased risk of depressive disorders, due to the burden and side effects of therapy, together with the fear of complications. This phenomenon can be more evident in women, who are at greater risk of depressive disorders. Non-pharmacological treatments (i.e. diet and exercise), which are the backbone of therapy for type 2 diabetes, do not differ across genders. On the other hand, some drugs could have diverse profiles of action in women and in men. In relation to diabetes, the sex-related difference in platelet activity and platelet inhibitory response to anti-aggregating therapy, reported in the general population, was observed also in diabetic women.

Antiplatelets in acute coronary syndrome: personal perspectives.

High platelet reactivity (HPR) during dual-antiplatelet therapy is a marker of vascular risk, in particular stent thrombosis, in patients with acute coronary syndromes. Genetic determinants (CYP2C19*2 polymorphism), advanced age, female gender, diabetes and reduced ventricular function are related to a higher risk to develop HPR. In addition, inflammation and increased platelet turnover, as revealed by the elevated percentage of reticulate platelets in patients' blood, that characterize the acute phase of acute coronary syndrome are associated with HPR. To overcome the limitation of clopidogrel, new antiplatelet agents (prasugrel and ticagrelor) were developed and the demonstration of their superiority over clopidogrel was obtained in the two randomized trials, TRITON TIMI 38 and PLATO. Due to the current possibility not a choice between multiple antiplatelet strategies, the future prospect is to include, in addition to clinical data and classical risk factors, the definition of platelet function during treatment in order to set a tailored therapy.

Thrombosis and acute coronary syndrome.

Acute coronary syndromes (ACS) represent the main clinical manifestation of atherosclerotic progression in the coronary district. Thrombosis plays a critical role in the patho-anatomical of ACS, as disruption of an atherosclerotic plaque exposes flowing blood to subendothelial collagen, tissue factor, and other procoagulant molecules that trigger activation of platelets and formation of fibrin within the vessel lumen. Endothelial damage/dysfunction, inflammation and coagulation are closely related to the pathophysiology of ACS and may be inter-related. Platelets play key roles in both the formation of the atheromatous plaque and clinical presentation of acute atherothrombotic events following plaque rupture. In the pathogenesis of the ACS, blood clotting activation has a crucial role and thrombin generation and TF may represent useful markers for the identification of patients at high risk of vascular events. Lipoprotein-associated phospholipase A2 (Lp-PLA2) represents the crossroads between lipid metabolism and inflammatory response.

[Antithrombotic drugs in women: should we worry more about bleeding?]. / I farmaci antitrombotici nella donna: dobbiamo avere più paura delle emorragie?

Since the mid '90s, the concept of evidence-based medicine has grown exponentially, contributing to the advancement of personalized medicine, which considers the "female gender" as an extremely important area of customization, but orphan of targeted research. Strong evidence do exists demonstrating gender differences in bleeding risk associated with antithrombotic treatment, mostly related to lower values of body mass, organ size and renal function in women than men. Across clinical studies, the search for the specific risk of bleeding in the female vs male gender has gained attention only recently; therefore, data from different studies and relatively limited meta-analyses should be assessed carefully. As for antiplatelet therapy for primary prevention, the risk of major bleeding events, such as cerebral hemorrhage, is lower for women than for men. Conversely, in acute situations in which antithrombotic drugs are given in association, the risk of bleeding is greater for women, in particular for combination therapies with heparin or low molecular weight heparin or thrombolytic agents. Numerous studies in the literature evaluated the incidence of minor and major bleeding during oral anticoagulant therapy in relation to gender, but the results are not entirely consistent and appear to vary over the years. In summary, there are some aspects of guidance in the complex spectrum of the bleeding risk related to antithrombotic treatment, with indications of a lower bleeding risk in women than men related to long-term preventive single antithrombotic drug treatments. In addition, hormonal effects and use of outprescribed drugs may also play a significant role in modulating hemostasis.

Relationship among endothelial response to hyperemia, bone marrow-derived progenitor cells, and parathyroid hormone in renal transplantation.

BACKGROUND: Endothelial dysfunction may contribute to modulate cardiovascular complications in renal transplant recipients (RTRs), and a relationship between endothelial dysfunction and parathyroid hormone (PTH) levels in RTRs has been demonstrated. We evaluated the relationship between endothelial response to hyperemia and circulating progenitor cells (CPCs) and endothelial progenitor cells (EPCs) PTH, and genetic parameters in RTRs. METHODS: In 120 RTRs and in healthy subjects without (n=107, group A) and with cardiovascular risk factors (n=109, group B), we evaluated endothelial response to hyperemia through digital tonometry (peripheral arterial tonometry) detected by reactive hyperemia index (RHI) and EPCs and CPCs by flow cytometry. RESULTS: In RTRs, RHI median value was lower than in group A (P=0.05). EPC number was significantly lower in RTRs than in groups A and B (P<0.0001), whereas PTH median value was significantly higher (P<0.0001). In RTRs, RHI values were significantly lower according to the presence of three or more risk factors (P=0.04) and positively correlated with EPCs (P=0.04) but not with PTH (P=0.2). In patients who underwent dialysis for more than 5 years, lower RHI values (P=0.08), EPC number (P=0.5), and higher PTH concentrations (P=0.09) than in patients with less than 1 year dialysis time were observed. No relationship between eNOS gene -786T>C, 894G>T, and 4a/4b polymorphisms and RHI, EPC, and CPC number was found. CONCLUSIONS: This study shows an altered endothelial response, associated with reduced EPCs, and increased PTH in RTRs; the evaluation of endothelial status in RTRs may contribute to better assess the risk profile of these patients.

Hemorheologic profile in healthy women undergoing controlled ovarian stimulation.

We investigated the hemorheologic profile in 110 women undergoing controlled ovarian stimulation and provide evidence that smokers and women with body mass index>25 kg/m2 exhibit alterations of rheologic profile. A progressive increase of whole-blood viscosity throughout the ovarian stimulation cycle was observed; deformability and aggregation of erythrocytes decreased from baseline to the beginning of recombinant FSH administration, then remained unchanged throughout the next days; hematocrit mildly decreased during the last days of recombinant FSH administration; and fibrinogen and cholesterol levels decreased and increased, respectively, throughout the stimulation cycle.