Transient stress-related hyperviscosity and endothelial dysfunction in Takotsubo syndrome: a time course study.

Takotsubo syndrome (TTS) is an acute and usually reversible heart failure syndrome, frequently associated with emotional or physical stress. Its pathophysiology remains largely unclear, although several mechanisms related to catecholaminergic storm have been proposed. In this study we analyzed during the acute phase of TTS and at follow-up both hemorheological parameters and biomarkers of endothelial damage, whose time course has never been fully explored. In 50 TTS women, we analyzed several hemorheological parameters [whole blood viscosity (WBV) at 0.512 s-1 and at 94.5 s-1, plasma viscosity (PLV), erythrocyte deformability and aggregation index] as well as biomarkers of endothelial dysfunction [von Willebrand Factor (vWF), Plasminogen activator inhibitor-1 and factor VIII levels] during the acute phase and after a median 6 months follow-up. These variables were also assessed in 50 age-matched healthy women. Respect to follow-up, in the acute phase of TTS we observed higher values of white blood cell count, fibrinogen, WBV at low and high shear rates, PLV, erythrocyte aggregation index and lower values of erythrocyte elongation index. Moreover, all biomarkers of endothelial dysfunction resulted significantly higher in the acute phase. During follow-up WBV at 94.5 s-1, erythrocyte elongation index and vWF resulted significantly altered with respect to controls. The results of this study confirm the role of hyperviscosity and endothelial dysfunction in TTS pathophysiology. Moreover, they suggest the persistence of alterations of erythrocyte deformability and endothelial dysfunction even beyond the acute phase that could be the target of therapeutic strategies also during follow-up.

Stratifying Parkinson's Patients With STN-DBS Into High-Frequency or 60 Hz-Frequency Modulation Using a Computational Model.

OBJECTIVE: High frequency stimulation (HFS) of the subthalamic nucleus (STN) is a well-established therapy for Parkinson's disease (PD), particularly the cardinal motor symptoms and levodopa induced motor complications. Recent studies have suggested the possible role of 60 Hz stimulation in STN-deep brain stimulation (DBS) for patients with gait disorder. The objective of this study was to develop a computational model, which stratifies patients a priori based on symptomatology into different frequency settings (i.e., high frequency or 60 Hz). METHODS: We retrospectively analyzed preoperative MDS-Unified Parkinson's Disease Rating Scale III scores (32 indicators) collected from 20 PD patients implanted with STN-DBS at Mount Sinai Medical Center on either 60 Hz stimulation (ten patients) or HFS (130-185 Hz) (ten patients) for an average of 12 months. Predictive models using the Random Forest classification algorithm were built to associate patient/disease characteristics at surgery to the stimulation frequency. These models were evaluated objectively using leave-one-out cross-validation approach. RESULTS: The computational models produced, stratified patients into 60 Hz or HFS (130-185 Hz) with 95% accuracy. The best models relied on two or three predictors out of the 32 analyzed for classification. Across all predictors, gait and rest tremor of the right hand were consistently the most important. CONCLUSIONS: Computational models were developed using preoperative clinical indicators in PD patients treated with STN-DBS. These models were able to accurately stratify PD patients into 60 Hz stimulation or HFS (130-185 Hz) groups a priori, offering a unique potential to enhance the utilization of this therapy based on clinical subtypes.

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.

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.

Anti-SARS-CoV-2 vaccination does not influence anticoagulation levels in stable long-term warfarin treatment.

BACKGROUND: Since the outbreak of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic, administration of the currently available vaccines has mostly been recommended for subjects at high risk, including elderly populations on long-term oral anticoagulation therapy (OAT) with warfarin. However, there is no clear evidence of the stability of the International Normalised Ratio (INR) after vaccine administration in those subjects on long-term OAT. The present study aimed to investigate the effects of COVID-19 vaccination on anticoagulation levels in patients on long-term OAT. MATERIALS AND METHODS: INR values of patients on long-term OAT who had undergone anti-SARS-CoV-2 vaccination from January to June 2021 were monitored for a total of 90 days follow-up after the first vaccination dose. These were then compared with INR values before vaccination. The second dose, when required, was administered during follow-up. Inclusion criterion was stable long-term INR for at least 6 months before vaccination. Exclusion criteria were recent surgery, intercurrent diseases, or treatment with medication that could compromise findings in the 3 months before vaccination and during follow-up. RESULTS: No differences were observed in the anticoagulation levels before and after COVID-19 vaccination in any of the patients studied: mean INR values were 2.39 (range 2.20-2.63) before vaccination and 2.40 (range 2.16-2.76) after vaccination (p=0.5). There was no difference in anticoagulation levels in relation to age, sex, indication for OAT, or type of vaccine (p>0.5). No bleeding or thrombotic complications were documented during follow-up. DISCUSSION: These are the first data to be reported on anticoagulation levels in patients on stable OAT after COVID-19 vaccination. No influence on the quality of OAT was detected after the vaccination; no bleeding or thrombotic complications were recorded in the follow-up. No difference between the four available COVID vaccines was found. Dose adjustment was only required in a few cases, thus confirming the stability of anticoagulation levels.

Effects of de-alcoholised wines with different polyphenol content on DNA oxidative damage, gene expression of peripheral lymphocytes, and haemorheology: an intervention study in post-menopausal women.

PURPOSE: Epidemiological studies suggest that a moderate consumption of wine is associated with a reduced risk of cardiovascular diseases and with a reduced mortality for all causes, possibly due to increased antioxidant defences. The present intervention study was undertaken to evaluate the in vivo effects of wine polyphenols on gene expression in humans, along with their supposed antioxidant activity. METHODS: Blood haemorheology and platelet function were also evaluated. In order to avoid interferences from alcohol, we used de-alcoholised wine (DAW) with different polyphenol content. A randomised cross-over trial of high-proanthocyanidin (PA) red DAW (500 mL/die, PA dose = 7 mg/kg b.w.) vs. low-PA rosé DAW (500 mL/die, PA dose = 0.45 mg/kg) was conducted in 21 post-menopausal women in Florence, Italy. Oxidative DNA damage by the comet assay and gene expression by microarray was measured in peripheral blood lymphocytes, collected during the study period. Blood samples were also collected for the evaluation of haematological, haemostatic, haemorheological, and inflammatory parameters. RESULTS: The results of the present study provide evidence that consumption of substantial amounts of de-alcoholised wine for 1 month does not exert a protective activity towards oxidative DNA damage, nor modifies significantly the gene expression profile of peripheral lymphocytes, whereas it shows blood-fluidifying actions, expressed as a significant decrease in blood viscosity. However, this effect does not correlate with the dosage of polyphenols of the de-alcoholised wine. CONCLUSIONS: More intervention studies are needed to provide further evidence of the health-protective effects of wine proanthocyanidins.

Lipid, inflammatory and haemorheological profiles are significantly affected by farmed fish eating: an intervention study.

AIM: The objective of the present study was to evaluate the influence of short-term dietary intake of farmed fish on biomarkers related to the atherosclerotic process. METHODS AND RESULTS: Lipid, inflammatory, and haemorheological variables before (T0) and after a dietary intervention with about 800 g Orbetello farmed sea bass per week for 10 weeks (T1) were evaluated in nine dyslipidemic subjects. Fish intake significantly decreased triacylglycerols (T1, 140.2+/-20.3 mg/dl versus T0, 183.3+/-29.2 mg/dl; P =0.04), whereas no significant changes for the other lipid variables have been observed. Moreover, dietary intervention significantly (P <0.05) decreased all of the inflammatory parameters investigated; namely, high-sensitivity C-reactive protein, interleukin-6, and interleukin-8. Furthermore, a significant (P =0.04) improvement in erythrocytes' deformability index was reported after 10 weeks of fish dietary intake (9.0+/-0.7% versus 5.4+/-1.0% for T1 and T0, respectively). CONCLUSION: Dietary short-term intake of farmed fish seems to impose favourable biochemical changes in dyslipidemic subjects.

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.

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.

Risk of bleeding in very old atrial fibrillation patients on warfarin: relationship with ageing and CHADS2 score.

AIMS: In atrial fibrillation (AF) patients, age >or=75 years is one of the major risk factors for stroke. However, it is not clear if an upper limit for the indication to OAT exists. METHODS AND RESULTS: For this reason, we performed a prospective study on 290 AF patients on OAT aged >or=75 years (median age 82 years, total follow-up period 814 pt/years) followed by our Anticoagulation Clinic. Seventeen major bleeding events were recorded (rate 2.1 x 100 pt/years), 11 of which cerebral (1.35 x 100 pt/years). The occurrence of major bleedings was associated with history of previous TIA or stroke [OR 3.4 (1.1-12.5), p=0.01] and with diabetes [OR 4.4 (1.3-14.7) p=0.01]. We found a trend to a progressive increase in the rate of bleeding risk with the increase of the CHADS2 score: patients with score 4-6 showed a rate of 3.4 x 100 pt/years with respect to 1.5 x 100 pt/years of patients with lower score. Number Needed to Harm (NNH) was calculated in relation to different classes of age (75-89, 80-84, >or=85 years) and to CHADS2 score. For patients in CHADS2 score 1-3 NNH remained stable across the different age classes. Instead for patients in CHADS2 score 4-6, NNH varied among the 3 groups of ages, reaching a value of 10 in patients >or=85 years. CONCLUSION: Our data suggest that: 1) in AF patients older than 75 years with CHADS2 score 1-3 the risk of bleeding is low, 2) in AF patients >85 years with CHADS2 4-6 the risk of bleeding is high so that the use of OAT should be highly individualised.

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.

Clinical haemorheology and microcirculation.

Hyperviscosity, due to alterations of blood cells and plasma components, can induce microvascular damage. Nitric oxide (NO) is released by endothelium and plays a crucial role in flow-mediated vasodilation. An impaired availability of NO, due to polymorphisms of endothelial NO synthase (eNOS), may influence erythrocyte deformability thus increasing blood viscosity. We investigated haemorheological variables in patients with idiopathic sudden sensorineural hearing loss (ISSHL), retinal vein occlusion (RVO) and systemic sclerosis (SSc), as possible models of microvascular damage, and their relationship with eNOS gene T-786C, G894T and 4a/4b polymorphisms. Whole blood viscosity and plasma viscosity were assessed with a rotational viscosimeter and erythrocyte deformability index (DI) with Myrenne filtrometer. eNOS polymorphisms were analyzed in ISSHL and SSc patients. At multivariate analysis alterations of some haemorheological variables resulted significantly associated with ISSHL, RVO and SSc. A significantly higher prevalence of eNOS -786C and 894T was found in both ISSHL and SSc patients than in controls; at multivariate analysis these two polymorphisms significantly affected DI in both groups of patients. These results suggest that hyperviscosity, either determined by genetic susceptibility or not, can be involved in the pathophysiology of these clinical disorders and can be the target of new therapeutic strategies.

Erythrocyte Membrane Fluidity Alterations in Sudden Sensorineural Hearing Loss Patients: The Role of Oxidative Stress.

Introduction Sudden sensorineural hearing loss (SSNHL) involves an acute unexplained hearing loss, nearly always unilateral, that occurs over less than a 72-hour period. SSNHL pathogenesis is not yet fully understood. Cochlear vascular occlusion has been proposed as a potential mechanism of hearing damage and cochlear ischaemia has been related to alterations of cochlear microvessels. In addition, some researchers have focused their attention on the rheological alterations and blood hyperviscosity. Erythrocyte deformability plays a key role in determining blood viscosity, and it is critical to cochlear perfusion. It has been shown that oxidative stress-induced erythrocyte membrane fluidity alterations are linked to the progression of cardiovascular diseases. Methods To determine whether erythrocytes from SSNHL patients show signs of oxidative stress, and whether this condition can modify the haemorheologic profile in these patients, we analysed haemorheologic profile and erythrocyte oxidative stress in 35 SSNHL patients and 35 healthy subjects, matched for age and sex. Fluorescence anisotropy was used to evaluate the fluidity of erythrocyte membranes. Results Our results show a significant structural and functional involvement of erythrocyte membrane alterations in SSNHL, as well as elevated levels of membrane lipid peroxidation and intracellular reactive oxygen species (ROS) production. In addition, erythrocyte-derived ROS and erythrocyte lipid peroxidation positively correlated with whole blood viscosity and erythrocyte deformability. Moreover, in vitro experiments demonstrated that ROS display a key role in erythrocyte membrane fluidity. Conclusion These findings indicate that erythrocyte oxidative stress plays a key role in the pathogenesis of SSNHL and pave the way to new therapeutic interventions.

Hyperviscosity as a possible risk factor for cerebral ischemic complications in atrial fibrillation patients.

Recent studies have suggested that hyperviscosity is frequent in patients with atrial fibrillation (AF). The aims of this study were to evaluate if hemorheologic alterations play a role in the occurrence of cerebral ischemic events in patients with AF and to explore a possible association between inflammation and hyperviscosity in these patients. Sixty-two patients with AF with a history of >or=1 cerebral ischemic event and 94 patients with AF without cerebral ischemic events were studied. A control population included 130 age- and gender-matched healthy volunteers. Hemorheologic variables (whole-blood viscosity, plasma viscosity, the erythrocyte deformability index, and hematocrit), fibrinogen, and high-sensitivity C-reactive protein levels were assayed. An alteration in whole blood viscosity at 94.5 seconds(-1) and the erythrocyte deformability index were found more frequently in patients with previous ischemic events on univariate and multivariate analyses (odds ratio 3.19, p=0.023 and odds ratio 4.26, p=0.002, respectively) adjusted for age, gender, hypertension, diabetes, history of coronary artery disease, left ventricular dysfunction, smoking habit, dyslipidemia, hematocrit, fibrinogen, high-sensitivity C-reactive protein, and hemorheologic parameters. These results should stimulate prospective studies on the role of hemorheologic alterations in the occurrence of cerebral ischemic complications in patients with AF.

Erythrocyte deformability and white blood cell count are associated with aspirin resistance in high-risk vascular patients.

Recently the phenomenon of aspirin resistance has been object of several studies, but no data are available on the possible role of the haemorheologic parameters in affecting platelet function and resistance to antiplatelet agents. Aim of our study was to evaluate platelet function and haemorheology in patients with acute coronary syndromes (ACS), receiving double antiplatelet therapy with aspirin and clopidogrel. The study population included 301 (231M/70F; age: 66 +/- 13 yrs) consecutive adult patients admitted to the Coronary Care Unit of the Azienda Ospedaliero-Universitaria Careggi, with diagnosis of acute myocardial infarction or unstable angina. We assessed: whole blood viscosity (WBV) at shear rates of 0.512 s(-1) and 94.5 s(-1), plasma viscosity (PLV) at 94.5 s(-1) shear rate, erythrocyte deformability index (DI) and PFA-100 closure times with ADP (PFA/ADP) and epinephrine (PFA/EPI). We considered any PFA-100-EPI result < 203 sec (95th percentile of control distribution) to be indicative of aspirin resistance. 104/301 patients (34.5%) had PFA/EPI CTs in the reference range (group 1) whereas the remaining had values higher than 203 sec (group 2). WBV at 94.5 sec (-1) s.r. was similar in group 1 and 2 (WBV: 4.43 +/- 0.25 vs 4.45 +/- 0.61 mPa.sec, respectively). PLV and WBV at 0.512 sec (-1) s.r. were slightly higher, but not significantly, in group 1 than in group 2 (PLV: 1.47+/-0.13 vs 1.44 +/- 0.15 mPa.sec; p = 0.08 and WBV: 23.37 +/- 4.6 vs 22.54 +/- 3.90 mPa.sec; p = 0.07). DI was significantly lower in group 1 with respect to group 2 (4.05 +/- 2.93 vs 5.71 +/- 3.30, p < 0.0001). White blood count (WBC) was significantly higher in group 1 than in group 2 (11464 +/- 3504 vs 7867 +/- 2162, p < 0.0001). In conclusion, these results demonstrate that in patients with acute coronary syndromes the antiaggregant effect of aspirin is modulated not only by the direct action on platelets, but also by erythrocyte deformability and white blood cell count.

Prevalence of thrombophilic disorders in takotsubo patients: the (ThROmbophylia in TAkotsubo cardiomyopathy) TROTA study.

Takotsubo cardiomyopathy (TTC) pathophysiology is still unclear. A transient intracoronary thrombosis dissolved at the time of angiography has been hypothesized. We aimed to evaluate the prevalence of thrombophilic disorders in TTC patients. In 75 TTC women, 75 age- and sex-matched acute coronary syndrome (ACS) patients, both enrolled during the acute phase, and in 75 control subjects, we compared the prevalence of congenital and acquired thrombophilic alterations and the values of clotting and endothelial activation biomarkers. Some parameters were re-assessed 1 month after the acute phase in TTC patients. No significant difference between the three groups was observed in factor II (G20210A) and V (G1691A) polymorphisms prevalence. Homocysteine levels were significantly higher in ACS patients vs. TTC and control subjects. Lipoprotein(a) values trended to be higher in TTC patients vs. control subjects, though not significantly. Other thrombophilic alterations in TTC patients were similar to that previously reported in healthy women. Von Willebrand factor and plasminogen activator inhibitor-1 were significantly higher in TTC and in ACS patients than controls. Clotting activation biomarkers were not statistically different between TTC patients and controls. During follow-up, in TTC patients, endothelial damage indices significantly decreased while clotting activation biomarkers remained unchanged. In conclusion, our results, showing a rate of thrombophilic alterations in TTC patients similar to control subjects, do not support the transient intracoronary thrombus hypothesis. However, several endothelial damage markers and lipoprotein(a) were higher in TTC patients vs. controls suggesting a role of endothelial dysfunction and of other factors concurring to hyperviscosity, as recently hypothesized.

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.

Reduced erythrocyte deformability and hypercoagulability in idiopathic sudden sensorineural hearing loss.

OBJECTIVE: Sudden sensorineural hearing loss is a frequent disease whose aetiology is still unknown in about 80% of patients. Aim of this study was to evaluate if haemorheological changes and some indexes of hypercoagulability and hypofibrinolysis are associated with idiopathic sudden sensorineural hearing loss (ISSHL). METHODS: We studied 63 patients with ISSHL and 67 healthy control subjects, matched for age, sex and traditional cardiovascular risk factors. Haemorheological studies were performed by assessing whole blood viscosity (WBV) at 0.512 s(-1) and 94.5 s(-1), plasma viscosity (PLV) and erythrocyte deformability index (DI). To assess whole blood coagulation Sonoclot analysis was performed. Sonoclot variables studied were Sonoclot activated clotting time (SonACT), clot rate and time to peak. Fibrinogen, PAI-1 antigen (ag) and factor VIII:C plasma levels were also measured. RESULTS: WBV, PLV, SonACT, clot rate, time to peak, PAI-1ag and factor VIII:C were significantly altered in patients in comparison with controls (p<0.05). A multivariate analysis (adjusted for traditional cardiovascular risk factors, hematocrit, fibrinogen, haemostatic and haemorheological variables) indicated that WBV at 94.5 s(-1), DI, SonACT, clot rate, PAI-1ag plasma levels and factor VIII:C activity were independently associated with ISSHL (p<0.05). CONCLUSIONS: The observed changes in viscosity, blood clotting and fibrinolysis may contribute, at least in part, to the pathophysiological mechanism of ISSHL.