Lucia Mannini

Role of hemodynamic shear stress in cardiovascular disease

Atherosclerosis is the main cause of morbidity and mortality in the Western world. Inflammation and blood flow alterations are new markers emerging as possible determinants for the development of atherosclerotic lesions. In particular, blood flow exerts a shear stress on vessel walls that alters cell physiology. Shear stress arises from the friction between two virtual layers of a fluid and is induced by the difference in motion and viscosity between these layers. Regions of the arterial tree with uniform geometry are exposed to a unidirectional and constant flow, which determines a physiologic shear stress, while arches and bifurcations are exposed to an oscillatory and disturbed flow, which determines a low shear stress. Atherosclerotic lesions develop mainly in areas of low shear stress, while those exposed to a physiologic shear stress are protected. The presence of areas of the arterial tree with different wall shear stress may explain, in part, the different localization of atherosclerotic lesions in both coronary and extracoronary arteries. The measurement of this parameter may help in identifying atherosclerotic plaques at higher risk as well as in evaluating the efficacy of different pharmacological interventions. Moreover, an altered shear stress is associated with the occurrence of both aortic and intracranial aneurysms, possibly leading to their growth and rupture. Finally, the evaluation of shear stress may be useful for predicting the risk of developing restenosis after coronary and peripheral angioplasty and for devising a coronary stent with a strut design less thrombogenic and more conducive to endothelization.

Cardiovascular and thrombophilic risk factors in patients with retinal artery occlusion.

This article evaluates the prevalence of cardiovascular and thrombophilic risk factors in patients with retinal artery occlusion. Forty-one patients with a first episode of a retinal artery occlusion underwent complete ophthalmic examination, routine blood testing and specific laboratory tests for thrombophilia, such as fasting and postmethionine homocysteine, lipoprotein(a), plasminogen activator inhibitor-1, factor VIII, factor V Leiden, factor II G20210A polymorphism, lupus anticoagulant and anticardiolipin antibodies. The control population consisted of 100 healthy individuals comparable as regards age and sex. At univariate analysis, hypertension, smoking, dyslipidaemia (both high cholesterol and triglyceride levels), antiphospholipid antibodies, hyperhomocysteinaemia, elevated factor VIII and lipoprotein(a) levels were significantly associated with retinal artery occlusion; at multivariate analysis, adjusted for age, sex, traditional and thrombophilic risk factors, smoking, hypercholesterolaemia, elevated homocysteine and lipoprotein(a) levels confirmed their independent role as risk factors for retinal artery occlusion. In conclusion, the results of the present pilot study demonstrate that the prevalence of hypercholesterolaemia and smoking and the ‘thrombophilic burden’ are increased in patients with retinal artery occlusion. Our findings may have implications for the management of these patients, suggesting the need for an intensive and tailored secondary prevention and new therapeutic approaches.

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.

Effects of Short-Term Consumption of Bread Obtained by an Old Italian Grain Variety on Lipid, Inflammatory, and Hemorheological Variables: An Intervention Study

The aim of this study was to evaluate the influence of short-term dietary intake of bread obtained by a selected variety of old grain grown in Tuscany, Italy on some parameters related to the atherosclerotic process. Twenty healthy subjects (median age, 39.5 years) followed for 10 weeks a diet containing bread (150 g/day) made from the test grain (test period) and for the same period a diet containing commercially available bread of the same quantity (control period). Lipid, inflammatory, and hemorheological profiles before and after dietary intervention were evaluated. The test period showed a significant (P < .05) improvement of total cholesterol (pre-intervention, 211.2 +/- 10.8 mg/dL; post-intervention, 196.5 +/- 9.8 mg/dL) and low-density lipoprotein-cholesterol levels (pre-intervention, 137.5 +/- 8.1 mg/dL; post-intervention, 119.5 +/- 7.5 mg/dL), whereas no significant changes during the control period were observed. With regard to inflammatory and hemorheological parameters, the test period showed a significant decrease in some of the parameters investigated (interleukin-8 [pre-intervention vs. post-intervention, 67.4 +/- 10.7 vs. 43.9 +/- 4.1 pg/mL], whole blood viscosity at high [4.36 +/- 0.03 vs. 4.32 +/- 0.03 mPa x s, respectively] and low [26.1 +/- 0.4 vs. 24.8 +/- 0.5 mPa x s, respectively] shear rates, and erythrocyte filtration [8.4 +/- 0.7% vs. 9.1 +/- 0.6%, respectively]) relative to the control period, which showed no significant changes. Short-term dietary intake of whole grain bread obtained from an old grain variety seems to impose a favorable status with regard to lower circulating levels of markers of atherosclerosis.

Relationship between blood viscosity and infarct size in patients with ST-segment elevation myocardial infarction undergoing primary percutaneous coronary intervention

BACKGROUND Previous studies explored the association between hemorheological alterations and acute myocardial infarction, pointing out the role of hematological components on microvascular flow. The aim of this study was to evaluate the association between blood viscosity and infarct size, estimated by creatine kinase (CK) peak activity and cardiac Troponin I (cTnI) peak concentration in ST-segment elevation myocardial infarction (STEMI) patients after primary percutaneous coronary intervention (PCI). METHODS The study population included 197 patients with diagnosis of STEMI undergoing PCI. Hemorheological studies were performed by assessing whole blood viscosity (measured at shear rates of 0.512 s(-1) and 94.5 s(-1)) and plasma viscosity using the Rotational Viscosimeter LS 30 and erythrocyte deformability index by Myrenne filtrometer. RESULTS Significant correlations between CK peak activity, cTnI peak concentration, left ventricular ejection fraction and hemorheological variables were observed. At linear regression analysis (adjusted for age, gender, traditional cardiovascular risk factors, renal dysfunction, timeliness of reperfusion, pre-PCI TIMI flow, infarct location, multivessel disease and previous coronary artery disease) leukocytes and whole blood viscosity at 0.512 s(-1) and 94.5 s(-1) were independently and positively associated with infarct size. CONCLUSIONS These results demonstrate a significant and independent association between hemorheology and infarct size in STEMI patients after PCI suggesting that blood viscosity, in a condition of low flow, might worsen myocardial perfusion leading to an increased infarct size. The measurement of whole blood viscosity in STEMI patients could help to identify those who may benefit from new therapeutic strategies.

Role of haemorheological factors in patients with retinal vein occlusion

Retinal vein occlusion (RVO) is an important cause of permanent visual loss. Hyperviscosity, due to alterations of blood cells and plasma components, may play a role in the pathogenesis of RVO. Aim of this case-control study was to evaluate the possible association between haemorheology and RVO. In 180 RVO patients and in 180 healthy subjects comparable for age and gender we analysed the whole haemorheological profile: [whole blood viscosity (WBV), erythrocyte deformability index (DI), plasma viscosity (PLV), and fibrinogen]. WBV and PLV were measured using a rotational viscosimeter, whereas DI was measured by a microcomputer-assisted filtrometer. WBV at 0.512 sec(-1) and 94.5 sec(-1) shear rates as well as DI, but not PLV, were found to be significantly different in patients as compared to healthy subjects. At the logistic univariate analysis, a significant association between the highest tertiles of WBV at 94.5 sec(-1) shear rate (OR: 4.91, 95% CI 2.95-8.17; p < 0.0001), WBV at 0.512 sec(-1) shear rate (OR: 2.31, 95% CI 1.42-3.77; p < 0.0001), and the lowest tertile of DI (OR: 0.18, 95% CI 0.10-0.32; p < 0.0001) and RVO was found. After adjustment for potential confounders, the highest tertiles of WBV at 0.512 sec(-1) shear rate (OR: 3.23, 95% CI 1.39-7.48; p = 0.006), WBV at 94.5 sec(-1) shear rate (OR: 6.74, 95% CI 3.06-14.86; p < 0.0001) and the lowest tertile of DI (OR: 0.20,95% CI 0.09-0.44, p < 0.0001) remained significantly associated with the disease. In conclusion, our data indicate that an alteration of haemorheological parameters may modulate the susceptibility to the RVO, by possibly helping to identify patients who may benefit from haemodilution.

eNOS gene affects red cell deformability : Role of T-786c, G894T, and 4a/4b polymorphisms

Plasma viscosity and erythrocyte deformability play a key role in maintaining and regulating microcirculation. In vitro and in vivo studies suggested a role for nitric oxide (NO) in modulating flow-mediated vasodilatation and red blood cell deformability. Impaired NO availability due to mutations in eNOS gene might contribute to the altered haemorheologic state. The aim of this study was to investigate the role of eNOS T-786C, G894T, and 4a/4b polymorphisms in modulating the haemorheologic state in a clinical condition characterized by a microcirculatory disorder. Eighty patients with idiopathic sudden sensorineural hearing loss (ISSHL) and 80 healthy subjects were studied. By using a dominant model of inheritance, we found a significant association between eNOS 894T rare variant and ISSHL (odds ratio [OR] 894TT+GT = 2.08, p = 0.03) after adjustment with traditional vascular risk factors. A higher percentage of altered red cell deformability both in patients and in controls carrying the eNOS rare variants was found in comparison to subjects carrying the wild type. Apart from the disease, eNOS T-786C and G894T polymorphisms independently affected the deformability index (OR,-786CC+TC = 2.81, p = 0.01 and OR, 894TT+GT = 2.5, p = 0.02, respectively), in particular in subjects in whom the contemporary presence of the two rare alleles was observed (OR,-786CC+TC and 894TT+GT combined genotype = 6.9, p<0.0001). Our study documented that eNOS gene affects the red blood cell deformability, so possibly contributing to ISSHL, which may represent a suitable model of microcirculatory disorder.

The thrombophilic pattern of different clinical manifestations of venous thromboembolism: a survey of 443 cases of venous thromboembolism.

Although pulmonary embolism (PE) and deep vein thrombosis (DVT) share many risk factors, it is uncertain whether thrombophilic abnormalities may impact differently on the development of these two clinical manifestations of venous thromboembolism (VTE). To give further insight into this issue, we estimated the association of PE with different types of thrombophilia and evaluated whether these abnormalities have a different prevalence in patients presenting with PE, alone or associated with DVT, as compared with those with isolated DVT. In this study 443 consecutive patients with a first episode of VTE and 304 matched healthy controls underwent laboratory screening for thrombophilia, including natural anticoagulants, factor V Leiden and prothrombin G20210A polymorphisms, antiphospholipid antibodies, homocysteine, factor VIII, and lipoprotein(a). Of the 443 patients, 224 patients had isolated DVT, 144 had combined DVT/PE, and 75 had isolated PE. At least one thrombophilic abnormality was detected in 72.8% of DVT, 66% of DVT/EP, and 60% of isolated PE patients. A high prevalence of hyperhomocysteinemia and elevated lipoprotein(a) levels was found in all patients with no significant differences among the three groups. The prevalence of prothrombin G20210A polymorphism and of elevated factor VIII levels was significantly higher in patients with DVT and DVT/PE than in controls, but not in those with isolated PE, whereas factor V Leiden polymorphism was associated with isolated DVT but not with DVT/PE or isolated PE. In conclusion, the thrombophilic burden seems different in isolated PE versus DVT with or without PE, suggesting that PE may encompass a different pathophysiological process of thrombosis to DVT.

Comparison of Hemorheological Variables in ST-Elevation Myocardial Infarction Versus Those in Non-ST-Elevation Myocardial Infarction or Unstable Angina Pectoris

The aim of this study was to evaluate hemorheologic variables in patients with acute coronary syndromes in relation to the occurrence of ST-segment elevation myocardial infarction (STEMI). In 370 consecutive patients with acute coronary syndromes, 215 with STEMIs and 155 with non-ST-segment elevation myocardial infarctions or unstable angina pectoris, who underwent percutaneous coronary intervention, hemorheologic studies were performed by assessing whole-blood viscosity (at shear rates of 0.512 and 94.5 s(-1)), plasma viscosity, and erythrocyte deformability index. A significant difference in hematocrit and in whole-blood viscosity at 0.512 s(-1) was found between the 2 groups of patients. Hematocrit at admission in the highest tertile compared with the lowest tertile remained independently associated with the occurrence of STEMI on multivariate analysis adjusted for traditional cardiovascular risk factors, previous coronary artery disease, multivessel disease, bleeding complications, and leukocyte count. In conclusion, erythrocyte concentration seems to play a role per se in the occurrence of STEMI and complete coronary artery occlusion and might be considered in stratifying high-risk cardiovascular patients and as a possible therapeutic target in patients presenting with acute coronary syndromes.

A hypercoagulable and hypofibrinolytic state is detectable by global methods in patients with retinal vein occlusion

The pathogenesis of retinal vein occlusion (RVO), has not been well understood. Recent data have shown the efficacy of an anticoagulant therapy with LMWHs in the treatment of acute RVO suggesting the presence of a hypercoagulable state in these patients. New global tests for detection of hypercoagulability and hypofibrinolysis have become available and their application might improve the knowledge of the pathophysiology of RVO and, potentially, its treatment. The aim of our study was to evaluate coagulation and fibrinolytic alterations by two global tests in RVO patients: Endogenous Thrombin Potential (ETP) and Clot Lysis Time (CLT), respectively. We studied 81 RVO patients (40 males; median age 61 years) and a control group matched for age and sex. The ETP was measured by functional chromogenic assay and expressed as the time until thrombin burst (LagTime), Time to peak (T(max)), Peak amount of thrombin generation (C(max)) and ETP. CLT was determined by a plasma-based, tissue factor-induced clot lysis assay. C(max), ETP and CLT values were significantly higher in RVO patients than in controls (C(max)p = 0.010; ETP p < 0.001; CLT p < 0.001) and remained significantly associated with the disease at the multivariate analysis adjusted for cardiovascular risk factors. Our results indicate that -beyond the assay of different parameters associated with clotting activation and lysis- global methods might allow us to easily detect the presence of hypercoagulability and hypofibrinolysis in RVO patients. Further studies should assess the possible clinical value of our data in the management of RVO patients.