Gabriele Cioni

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.

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.

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.

Reticulated Platelets and Platelet Reactivity in Renal Transplant Recipients Receiving Antiplatelet Therapy

INTRODUCTION Renal transplant recipients are at increased risk of cardiovascular morbidity and mortality. We assessed platelet reactivity and reticulated platelets (RPs) in 90 recipients, 51 (56.6%) of whom were not receiving acetylsalicylic acid (ASA) therapy (group A) and 39 (43.3%) who were receiving ASA therapy, 100 mg (group B), and in 60 healthy controls (group C). METHODS Reticulated platelets were measured using a hematology automated analyzer (XE-2100; Sysmex Corp, Kobe, Japan) and were expressed as the percentage of RPs in the total optical platelet count (immature platelet fraction [IPF]), as the percentage of highly fluorescent RPs, and as the absolute number of RPs (IPF#). Platelet function was assessed using optical aggregometry (platelet aggregation) induced using 1 mmol/L of arachidonic acid, 2 or 10 micromol/L of adenosine diphosphate, or 2 microg/mL of collagen. RESULTS Group A demonstrated significantly higher values of RP compared with group B or group C. Group B demonstrated a substantially higher percentage of RPs compared with group C, which was significant only for the IPF parameter. Multiple regression analysis demonstrated that IPF and IPF# were significantly and positively related to collagen-induced platelet aggregation. CONCLUSION We documented the presence of higher concentrations of RPs in transplant recipients compared with a control population, and a significant association between RPs and platelet function.

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.

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.

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.

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.