Emanuele Cecchi

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.

Effects of ULTRAfiltration vs. DIureticS on clinical, biohumoral and haemodynamic variables in patients with deCOmpensated heart failure: the ULTRADISCO study

To evaluate the clinical, biohumoral, and haemodynamic effects of ultrafiltration vs. intravenous diuretics in patients with decompensated heart failure (HF). Signs and symptoms of volume overload are often present in these patients and standard therapy consists primarily of intravenous diuretics. Increasing evidence suggests that ultrafiltration can be an effective alternative treatment.

Culprit Factors for the Failure of Well-Conducted Warfarin Therapy to Prevent Ischemic Events in Patients With Atrial Fibrillation The Role of Homocysteine

Background and Purpose— In patients with atrial fibrillation (AF), oral anticoagulant therapy (OAT) is effective in reducing stroke and embolism. However, despite OAT, ischemic events do occur in some patients. Studies specifically addressing the identification of risk factors for ischemic events during well-conducted OAT are not available. In this study, we prospectively investigated the role of classic risk factors and homocysteine levels in the occurrence of ischemic complications in 364 AF patients on OAT. Methods— The quality of anticoagulation levels and the occurrence of bleeding and thrombotic events were recorded. Results— During follow-up (859 patient years) 21 patients had ischemic complications (rate 2.4×100 patient-years). Homocysteine plasma levels were higher in these patients than in patients without ischemic complications during OAT (P<0.01), whereas no difference was observed in relation to the quality of OAT. The presence of a history of previous ischemic events, hypertension, and homocysteine plasma levels over the 90th percentile were all associated with an increased risk of ischemic events during OAT (odds ratio [OR]=7, 4.5, and 4.7, respectively). The coexistence of these risk factors markedly increased the risk (OR=13.1; 95% CI, 3.7 to 45.7; P=0.001). Conclusion— In conclusion, our results indicate that AF patients with multiple risk factors may not be sufficiently protected by OAT, even when this is well conducted.

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.

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.

Cardiac Efficiency Improvement after Slow Continuous Ultrafiltration Is Assessed by Beat-to-Beat Minimally Invasive Monitoring in Congestive Heart Failure Patients: A Preliminary Report

Background: We have evaluate the effect of slow continuous ultrafiltration (SCUF) on cardiac output (CO) and other hemodynamic parameters related to the overall performance of the cardiovascular system in patients with congestive heart failure (CHF). Minimally invasive hemodynamic monitoring was performed via the radial artery using a pressure recording analytical method (PRAM) during SCUF treatment. Patients and Methods: Using PRAM, hemodynamic changes were assessed in 15 CHF patients (New York Heart Association (NYHA) class III–IV) treated with fluid overload removal by ultrafiltration. We analyzed the clinical and hemodynamic data recorded from 6 h before to 36 h after SCUF treatment. Results: Fluid removal was associated with clinical improvements, reductions in weight (7.4%, p < 0.01), edema and dyspnea, increased response to diuretics, and reductions in NYHA class (3.5 ± 0.52 to 2.4 ± 0.63, p < 0.01) and plasma pro-B-type natriuretic peptide (BNP) levels (21,810 ± 13,016 to 8,581 ± 5,549 pg/ml, p < 0.05). Clinical improvement was associated with significant variations in stroke volume (+17%, p < 0.05), CO (+19%, p < 0.05), cardiac power output (+19%, p < 0.05), dP/dtmax (+49%, p < 0.01), cardiac cycle efficiency (CCE; +0.44 units, p < 0.01), systemic vascular resistances (SVR; –12%, p < 0.05) and dicrotic pressure (–10%, p < 0.05) with respect to their baseline values. No significant variations in heart rate, and systolic and mean blood pressure were observed. Pro-BNP levels were found to correlate positively with both SVR (r = 0.96, p = 0.002) and NYHA class (r = 0.96, p = 0.037) and negatively with dP/dtmax (r = –0.83, p = 0.039), CCE (r = –0.93, p = 0.011) and CO (r = –0.94, p = 0.014). Conclusions: In CHF patients, ultrafiltration improves not only CO, as previously reported, but also contractile cardiac efficiency and performance. The PRAM system, a minimally invasive method, was able to record hemodynamic changes during SCUF treatment.

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.

Thrombophilic mutations in high-risk atrial fibrillation patients: high prevalence of prothrombin gene G20210A polymorphism and lack of correlation with thromboembolism

Atrial fibrillation (AF) is a common arrhythmia that results in a high risk of cerebral and peripheral embolism. Factor V Leiden and factor II G20210A variant are two leading conditions for venous thrombosis. The aim of our study was to find out whether these two common prothrombotic mutations play a role in the occurrence of embolic events in AF patients. We investigated 336 non-valvular AF patients and 336 healthy control subjects. Factor II G20210A variant was found in 24/336 patients (7.14%) and in 11/336 of control subjects (3.3%). At a multivariate analysis, factor II G20210A variant was independently associated to AF (OR 2.4 95% CI 1.1-5.2; p<0.05). No significant difference was observed in the prevalence of factor V Leiden in the two groups investigated [6/304 (2.0%) in patients vs 13/336 (3.9%) in controls (p=0.24)]. AF patients were separately analyzed in relation to the occurrence or absence of a cerebral or peripheral embolic event (200 with and 136 without embolic event). The prevalence of the two mutations among AF patients with and without an embolic event was similar [factor II G20210A polymorphism (7% and 7.3% respectively) and factor V Leiden (1.2% and 2.9%, respectively)]. No differences were found in relation to the type of embolic event. Our results suggest a possible relationship between the presence of prothrombin gene variant and AF per se.

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.

Clotting activation after oral anticoagulant therapy discontinuation: a risk factor for recurrent venous thromboembolism.

A hypercoagulable state has been reported in some patients treated for venous thromboembolism (VTE) after oral anticoagulant treatment (OAT) discontinuation. It is unclear whether this is a risk factor for thrombosis recurrence. We investigated 139 patients with VTE and followed them up for a median of 20.5 months (6–90 months) to evaluate whether fragment 1 + 2 (F1 + 2) plasma levels are prognostic for VTE recurrence and to confirm clotting activation after OAT withdrawal. Fourteen patients had recurrences during the follow-up. F1 + 2 was measured the day before OAT withdrawal (T0) and 4 weeks later (T1) and its levels were similar in patients with spontaneous VTE versus those with transient risk factors for VTE. F1 + 2 levels increased from T0 to T1 (P < 0.0005). At T1, F1 + 2 values were significantly higher in patients with recurrence than in those without (P < 0.005). The negative predictive value of normal levels of F1 + 2 at T1 was 95%. In carriers of thrombophilic conditions no correlation was found between F1 + 2 levels and VTE recurrence. The results of this study confirm clotting activation after OAT discontinuation and suggest that higher F1 + 2 plasma levels are an independent risk factor for VTE recurrence.