The Application of MEVEC 3D Doppler Ultrasound Technique for a New Classification of Morpho-Functional Phenotypes in Lower Limbs Venous Diseases.

INTRODUCTION: MEVEC 2.1 is a novel 3D mapping software dedicated to the evaluation of the venous vascular three of the lower limbs. It has already proven as a sensitive, specific, and accurate technique able to provide better morphologic and functional details of the lower limb venous system than standard reports. The aim of this study was to identify specific morpho-functional graphic phenotypes in lower limb venous diseases by means of MEVEC 2.1. MATERIALS: Three-hundred eleven consecutive outpatients underwent lower limb Doppler ultrasound examination by means of the MEVEC 2.1 technique. All of them showed at least one among these pathological findings: venous insufficiency, thrombosis, incompressibility, and/or incompetent. RESULTS: We tried to evaluate possible clusters among the different morpho-functional findings from the venous maps in order to outline reproducible phenotypes. Correlation indexes allowed us to provide a classification in morpho-functional phenotypes in order to standardize the data from examinations performed by different physicians. Twelve phenotypes had been proposed. CONCLUSION: The study showed that the MEVEC 2.1 technique provides a standardized classification that allows physicians identifying phenotypes yielded by 3D mapping of the veins of the lower limbs.

Peripheral Arterial Stiffness in Acute Pulmonary Embolism and Pulmonary Hypertension at Short-Term Follow-Up.

Chronic thromboembolic pulmonary hypertension (CTEPH) is a severe and under-recognized complication of acute pulmonary embolism (PE). Forty consecutive patients with acute PE (Group 1), predominantly female (22, 55%) with a mean age of 69 ± 15 years, were matched for demographic data with 40 healthy subjects (Group 2), 40 systemic hypertension patients (Group 3) and 45 prevalent idiopathic pulmonary arterial hypertension (IPAH) patients (Group 4). The baseline evaluation included physical examination, NYHA/WHO functional class, right heart catheterization (RHC) limited to IPAH patients, echocardiographic assessment and systemic arterial stiffness measurement by cardio-ankle vascular index (CAVI). Patients with PE underwent an echocardiographic evaluation within 1 month from hospital discharge (median 27 days; IQR 21-30) to assess the echo-derived probability of PH. The CAVI values were significantly higher in the PE and IPAH groups compared with the others (Group 1 vs. Group 2, p < 0.001; Group 1 vs. Group 3, p < 0.001; Group 1 vs. Group 4, p = ns; Group 4 vs. Group 2, p < 0.001; Group 4 vs. Group 3, p < 0.001; Group 2 vs. Group 3, p = ns). The predicted probability of echocardiography-derived high-risk criteria of PH increases for any unit increase of CAVI (OR 9.0; C.I.3.9-20.5; p = 0.0001). The PE patients with CAVI ≥ 9.0 at the time of hospital discharge presented an increased probability of PH. This study highlights a possible positive predictive role of CAVI as an early marker for the development of CTEPH.

The Growing Role of Echocardiography in Pulmonary Arterial Hypertension Risk Stratification: The Missing Piece.

Pulmonary arterial hypertension (PAH) is a rare, progressive disease with a poor prognosis. The pathophysiologic model is mainly characterized by an afterload mismatch in which an increased right ventricle afterload, driven by increased pulmonary vascular resistance (PVR), leads to right heart failure. International guidelines recommend optimization of treatment based on regular risk assessments to achieve or maintain a low-risk status. Current risk scores are based on a multi-modality approach, including demographic, clinical, functional, exercise, laboratory, and hemodynamic parameters, which lack significant echocardiographic parameters. The originality of echocardiography relies on the opportunity to assess in a non-invasive way a physiologically meaningful combination of easy to measure variables tightly related to right ventricle adaptation/maladaptation to increased afterload, the main determinant of a patient's prognosis. Echo-derived morphological and functional parameters have been investigated in PAH, proving to have prognostic relevance. Different therapeutic strategies proved to have different effects in reducing PVR. An upfront combination of drugs, including a parenteral prostacyclin, has shown to be associated with right heart reverse remodeling in a greater proportion of patients than other treatment strategies as a function of PVR reduction. Adding echocardiographic data to current risk scores would allow better identification of right ventricle (RV) adaptation in PAH patients' follow-up. This additional information would allow better stratification of the patient, leading to optimized and personalized therapeutic management.

Right Ventricular Strain Curve Morphology and Outcome in Idiopathic Pulmonary Arterial Hypertension.

OBJECTIVES: The purpose of this study was to explore speckle tracking echocardiographic right ventricular (RV) post-systolic strain patterns and their clinical relevance in idiopathic pulmonary arterial hypertension (PAH). BACKGROUND: The imaging of RV diastolic function in PAH remains incompletely understood. METHODS: Speckle tracking echocardiography of RV post-systolic strain recordings were examined in 108 consecutive idiopathic patients with PAH. Each of them underwent baseline clinical, hemodynamic, and complete echocardiographic evaluation and follow-up. RESULTS: In total, 3 post-systolic strain patterns derived from the mid-basal RV free wall segments were identified. Pattern 1 was characterized by prompt return of strain-time curves to baseline after peak systolic negativity, like in normal control subjects. Pattern 2 was characterized by persisting negativity of strain-time curves well into diastole, before an end-diastolic returning to baseline. Pattern 3 was characterized by a slow return of strain-time curves to baseline during diastole. The 3 patterns corresponded respectively to mild PH, more advanced PH but with still preserved RV function, and PH with obvious end-stage right heart failure. Patterns were characterized by optimal reproducibility when complementary to quantitative measurement of right ventricular longitudinal early diastolic strain rate (RVLSR-E), and right ventricular longitudinal late diastolic strain rate (RVLSR-A) (Cohen's κ = 0.88; p = 0.0001). Multivariable models for clinical worsening prediction demonstrated that the addition of RV post-systolic patterns to clinical and hemodynamic variables significantly increased their prognostic power (0.78 vs. 0.66; p < 0.001). Freedom from clinical worsening rates at 1 and 2 years from baseline were, respectively, 100% and 93% for Pattern 1; 80% and 55% for Pattern 2; and 60% and 33% for Pattern 3. CONCLUSIONS: Speckle tracking echocardiography allows for the identification of 3 phenotypically distinct, reproducible, and clinically meaningful RV strain-derived post-systolic patterns.

An exploratory cross-sectional study of subclinical vascular damage in patients with polymyalgia rheumatica.

The aim of the study was to investigate the presence of subclinical vascular damage in polymyalgia rheumatica (PMR). We enrolled PMR patients having major cardiovascular risk factors (MCVRF) and, as controls, patients with MCVRF. All underwent: color Doppler ultrasound to evaluate the common carotid intima-media thickness (IMT), the anterior-posterior abdominal aortic diameter (APAD), and the prevalence of carotid artery stenosis; the cardio-ankle vascular index (CAVI) to measure arterial stiffness together with the ankle-brachial index (ABI) to investigate the presence of lower-extremity peripheral arterial disease. Finally, we measured the serum levels of adipocytokines implicated in vascular dysfunction. As a result, 48 PMR and 56 MCVRF patients were included. An increase of IMT (1.07/0.8-1.2 vs 0.8/0.8-1.05; p = 0.0001), CAVI (8.7/7.8-9.3 vs 7.6/6.9-7.8; p < 0.0001) and APAD values (21.15/18.1-25.6 vs 18/16-22; p = 0.0013) was found in PMR patients with respect to controls. No differences were reported in the prevalence of carotid artery stenosis or ABI values between the two groups. A significant correlation between IMT and CAVI in PMR and MCVRF subjects (r2 = 0.845 and r2 = 0.556, respectively; p < 0.01) was found. Leptin levels (pg/mL; median/25th-75th percentile) were higher in PMR than in MCVRF subjects (145.1/67-398.6 vs 59.5/39.3-194.3; p = 0.04). Serum levels of adiponectin (ng/mL) were higher in PMR patients (15.9/10.65-24.1 vs 6.1/2.8-22.7; p = 0.01), while no difference in serum levels of resistin (ng/mL) was found between PMR and MCVRF subjects (0.37/0.16-0.66 vs 0.26/0.14-1.24). Our study shows an increased subclinical vascular damage in PMR patients compared to those with MCVRF, paving the way for further studies aimed at planning primary cardiovascular prevention in this population.

Prognostic relevance of right heart reverse remodeling in idiopathic pulmonary arterial hypertension.

BACKGROUND: Right ventricular (RV) failure is a major determinant of symptoms and shortened survival in pulmonary arterial hypertension (PAH). This study assessed the prognostic relevance of increased right heart (RH) dimensions determined by echocardiography and RH reverse remodeling (RHRR) with targeted therapies in idiopathic PAH (IPAH). METHODS: The study prospectively monitored 102 therapy-naïve IPAH patients for the presence of clinical worsening. Baseline evaluation included RH catheterization and echocardiography. RHRR at the 1-year follow-up was defined by a decrease in RV end-diastolic area, right atrial area, and the left ventricular systolic eccentricity index. RESULTS: At the 1-year follow-up, 18 of 102 patients (17.6%) presented with RHRR. A decrease in pulmonary vascular resistance was the only independent determinant of RHRR. The 94 surviving patients were monitored for 995 ± 529 days. RHRR was an independent prognostic factor and significantly improved the power of the prognostic model based on traditional clinical and hemodynamic parameters. The respective event-free survival rates at 1, 3, and 5 years were 94%, 94%, and 94% in patients with RHRR and 75%, 55%, and 24% in those without RHRR (p = 0.0001). Interestingly, RHRR was able to further stratify patients' risk assessment through the Registry to Evaluate Early And Long-term PAH Disease Management risk score. CONCLUSIONS: RHRR after 1 year of treatment is an independent predictor of prognosis in IPAH. The likelihood of RHRR is proportional to decreased pulmonary vascular resistance.

Association between antibodies to carbamylated proteins and subclinical atherosclerosis in rheumatoid arthritis patients.

BACKGROUND: Rheumatoid arthritis (RA) patients carry a high risk of cardiovascular morbidity and mortality. The excess of cardiovascular disease cannot be entirely explained by traditional risk factors and the immune system contributes to the development of atherosclerosis. Moreover, post-translational modifications such as citrullination and carbamylation have been linked to inflammation and atherosclerosis. Anti-carbamylated proteins antibodies (anti-CarP) are a new subset of autoantibodies identified in RA patients. This study aimed to investigate a possible association between anti-CarP and subclinical atherosclerosis in RA patients. METHODS: We enrolled RA patients and normal healthy controls (NHS) without known cardiovascular risk factors or heart disease. Cardiovascular risk was assessed using the Modified Systemic Coronary Risk Evaluation (mSCORE). Anti-CarP were investigated by a solid phase "home-made" ELISA. Anti-citrullinated protein antibodies (ACPA) and Rheumatoid Factor (RF) were investigated by ELISA assays. Subclinical atherosclerosis was evaluated by brachial artery Flow-Mediated Dilatation (FMD) and Carotid Intima-Media Thickness (c-IMT) while arterial stiffness by Ankle-Brachial Index (ABI) and Cardio-Ankle Vascular Index (CAVI). RESULTS: We enrolled 50 RA patients (34 F and 16 M, mean age 58.4 ± 13.1 years, mean disease duration 127 ± 96.7 months) and 30 age and sex matched NHS. According to the mSCORE, 58% of patients had a low risk, 32% a moderate and 8% a high risk for cardiovascular disease. FMD was significantly lower in RA patients than in NHS (5.6 ± 3.2 vs 10.7 ± 8.1%; p < 0.004) and CAVIs significantly higher in a RA patients compared to NHS (left CAVI 8.9 ± 1.7 vs 8.1 ± 1.5; p < 0.04 for and right CAVI 8.8 ± 1.6 vs 8.0 ± 1.4; p < 0.04 for the). ABI and c-IMT did not differ between the two populations. The multivariate regression analysis showed a significant association of anti-CarP antibodies with FMD, left and right CAVI and both c-IMT (r = 1.6 and p = 0.05; r = 1.7 and p = 0.04; r = 2.9 and p = 0.05; r = 1.5 and p = 0.03; r = 1.1 and p = 0.03 respectively). CONCLUSIONS: This study confirms that RA patients, without evidence of cardiovascular disease or traditional risk factors, have an impaired endothelial function. Moreover, we found an association with anti-CarP antibodies suggesting a possible contribution of these autoantibodies to endothelial dysfunction, the earliest stage of atherosclerosis. Besides ultrasound assessment, anti-CarP should be assessed in RA patients and considered an additional cardiovascular risk factor.

Chronic cerebrospinal venous insufficiency as a cause of inner ear diseases.

CONCLUSION: The present study confirms a correlation between chronic cerebrospinal venous insufficiency (CCSVI) diagnosis and Ménière's disease (MD). CCSVI could be considered a new ultrasound vascular pattern of the cerebrospinal venous system in patients affected by definite MD. Conversely, the present results showed that CCSVI cannot be considered a pathogenic mechanism for idiopathic sudden sensorineural hearing loss (ISSNHL). OBJECTIVES: The aim of this study is to investigate the correlation between CCSVI and MD and to evaluate if CCSVI can be considered a risk factor also for ISSNHL. Moreover, this study seeks to establish if, even with a different timing of onset and natural history, MD and ISSNHL may share a common pathogenic mechanism. METHOD: One hundred and eighty-two patients affected by definite MD, 60 patients affected by ISSNHL, and 100 healthy control patients were enrolled in this study. All subjects underwent an echo-color Doppler (ECD) of the cerebrospinal venous flow. RESULTS: One hundred and fifty-two patients affected by definite MD (83,5%) and 13 patients affected by ISSNHL (21.6%) were positive for CCSVI at the ECD examination of the cerebrospinal venous flow. The healthy control group consisted of 100 subjects and only 21 (21%) showed positivity for CCSVI.

A three-dimensional electronic report of a venous echo color Doppler of the lower limbs: MEVeC®.

BACKGROUND: The reports of ultrasound evaluation of lower limb veins are difficult to understand by general practitioners (GPs) and physicians who are not specialized. We developed software for a three-dimensional (3D) electronic report of venous hemodynamic mapping (MEVeC(®)) in order to represent lower limb venous vasculature in a 3D way. The aim of the study is to compare the novel 3D report with the standard report. METHODS: Thirty subjects (medical students and GPs) evaluated a standard report and a novel 3D report of the lower limb veins of a prespecified patient. The cases were randomly and blindly taken from an archive of 100 cases. GPs and students answered a questionnaire made up of 13 questions that were structured in order to investigate the readability and comprehension of the two reports. A score ranging from 0 to 10 (0= not understandable; 10= full comprehension) was attributed to each report for each question according to the readability of the venous scheme proposed. RESULTS: The scores from each question of the questionnaire were compared. The 3D report (MEVeC(®)) obtained higher scores than those from the evaluation of the standard report (P<0.0001). Each question revealed the superiority of the 3D report (MEVeC(®)) as compared with the standard report of the ultrasound evaluation of lower limbs. When dividing the scores according to percentiles, the 3D report (MEVeC(®)) still continued to show more readability than the standard report in a statistically significant way (P<0.0001). CONCLUSION: The new 3D report (MEVeC(®)) concerning ultrasound evaluation of lower limb veins is more reproducible than the standard report when evaluated by medical physicians not specialized in the evaluation of the vein tree of lower limbs.

Age-related vascular differences among patients suffering from multiple sclerosis.

The aim of our study was to analyze morphological and functional aspects of cerebral veins by means of ecocolor-Doppler in young (i.e., ≤ 30 years old) and older (i.e., >30 years old) patients suffering from multiple sclerosis. 552 multiple sclerosis patients were evaluated by means of a dedicated Echo-Color-Doppler support (MyLab Vinco echocolor Doppler System, Esaote), in both supine and sitting positions. 458 (83%) showed alterations in their morphological and functional structures of cerebral veins and were divided in two different groups: 1) ≤ 30 (110 patients) and 2) >30 years old (348 patients). Young patients showed a statistically significant higher number of both hemodynamically (44% vs. 35%, p<0.01) and non-hemodynamically (51% vs. 45%, p<0.05) significant stenosis in the internal jugular veins as compared to older patients. A lower percentage of young patients showed blocked outflow in the cervical veins (50% vs. 65%, p<0.01) as compared to older ones. Patients >30 years old outlined a significantly higher disability degree (Expanded Disability Status Scale score: 5 vs. 3, p<0.01) as well as higher disease duration (12 vs. 5 months, p<0.01) than younger. No differences could be outlined about multiple sclerosis clinical form of the disease. It was evidenced that young and adult groups are different kind of patients, the former showing much more cerebral veins stenosis and blocked flow in internal jugular veins and vertebral veins than the latter. Duration of disease could explain such differences: the higher the diseases duration, the higher the degree of vascular alterations and, therefore, the disability degree. This could be due to the complex venous hemodynamic impairments induced by alterations in vascular walls: the blocked or difficult blood flow through stenosis could increase the hydrostatic pressure in the skull and this could induce damages to cerebral cells leading to the genesis of more advanced morphological abnormalities. Furthermore, the vessels' alterations could impair venous endothelial functions which could turn in a possible alteration of the controls of cerebral vein return which could worsen the cerebral vascular outflow. It may be possible that early clinical, pharmacological and/or invasive vascular interventions could exert a possible role in the natural history of multiple sclerosis. Nevertheless, further trials are needed in order to confirm such considerations.

Serum levels of asymmetric dimethylarginine and apelin as potential markers of vascular endothelial dysfunction in early rheumatoid arthritis.

OBJECTIVES: Impaired endothelial function represents the early stage of atherosclerosis, which is typically associated with systemic inflammatory diseases like rheumatoid arthritis (RA). As modulators of endothelial nitric oxide synthase expression, asymmetric-dimethylarginine (ADMA) and apelin might be measured in the blood of RA patients to detect early atherosclerotic changes. We conducted a prospective, case-control study to investigate serum ADMA and apelin profiles of patients with early-stage RA (ERA) before and after disease-modifying antirheumatic drug (DMARD) therapy. METHODS: We enrolled 20 consecutively diagnosed, treatment-naïve patients with ERA and 20 matched healthy controls. Serum ADMA and apelin levels and the 28-joint disease activity scores (DAS28) were assessed before and after 12 months of DMARDs treatment. All patients underwent ultrasonographic assessment for intima-media tickness (IMT) evaluation. RESULTS: In the ERA group, ADMA serum levels were significantly higher than controls at baseline (P = 0.007) and significantly decreased after treatment (P = 0.012 versus controls). Baseline serum apelin levels were significantly decreased in this group (P = 0.0001 versus controls), but they were not significantly altered by treatment. IMT did not show significant changes. CONCLUSIONS: ERA is associated with alterations of serum ADMA and apelin levels, which might be used as biomarkers to detect early endothelial dysfunction in these patients.

Doppler ultrasound venous mapping of the lower limbs.

BACKGROUND: The study aim was to test the accuracy (intra and interobserver variability), sensitivity, and specificity of a simplified noninvasive ultrasound methodology for mapping superficial and deep veins of the lower limbs. METHODS: 62 consecutive patients, aged 62 ± 11 years, were enrolled. All underwent US-examinations, performed by two different investigators, of both legs, four anatomical parts, and 17 veins, to assess the interobserver variability of evaluation of superficial and deep veins of the lower limbs. RESULTS: Overall the agreement between the second versus the first operator was very high in detecting reflux (sensitivity 97.9, specificity 99.7, accuracy 99.5; P = 0.80 at McNemar test). The higher CEAP classification stages were significantly associated with reflux (odds ratio: 1.778, 95% confidence interval: 1.552-2.038; P < 0.001) as well as with thrombosis (odds ratio: 2.765, 95% confidence interval: 1.741-4.389; P < 0.001). Thus, our findings show a strict association between the symptoms of venous disorders and ultrasound evaluation results for thrombosis or reflux. CONCLUSION: This study demonstrated that our venous mapping protocol is a reliable method showing a very low interobserver variability, which makes it accurate and reproducible for the assessment of the morphofunctional status of the lower limb veins.

Correlation between coronary artery disease severity, left ventricular mass index and carotid intima media thickness, assessed by radio-frequency.

BACKGROUND: Intima-media thickness of the common carotid artery (CCA-IMT) is a validated marker of systemic atherosclerosis process. The aim of this study was to evaluate the association between coronary artery disease (CAD), left ventricular hypertrophy (LVH) and CCA-IMT, assessed by Radio Frequency-Quality Intima Media Thickness (RFQIMT) method, the next generation of IMT real-time measurement, based on the direct analysis of the radiofrequency signal and endowed with high accuracy and reproducibility in early detection of arterial wall thickness. METHODS: 115 patients (76 men, mean age: 65.1 ± 12 years) referred to our department and shown significant (≥ 70% luminal obstruction) stenosis at least in one major epicardial coronary artery were studied. Coronary angiograms were divided for severity and extent of the disease: 79 patients (69%) had one, 24 patients (21%) two, 12 patients (10%) three major epicardial coronary arteries with ≥ 70% stenosis. All patients underwent echocardiography and carotid ultrasound examination, assessed by RF. RESULTS: Dividing RFQIMT data in tertiles, dyslipidaemia (31 patients with IMT ≥ 1.20 mm vs 16 with IMT = 0.91-1.19 vs 25 with IMT ≤ 0.9, p = 0.004), LVMI (153.5 ± 20.6 g/m² in IMT ≥ 1.20 mm vs 131.2 ± 8.4 g/m² in IMT = 0.91-1.19 mm vs 114.3 ± 11.1 g/m² in IMT ≤ 0.9 mm, P < 0.001) and number of high stenosed coronary arteries (IMT ≥ 1.20 mm population more often showed three vessel diseases than IMT ≤ 0.90 mm one, P < 0.001) seemed to be significantly related to CCA-IMT increases. Furthermore, LVMI is positively related to IMT (r = 0.91; P < 0.001). In a multivariate regression model (R2 = 0.88), RFQIMT remained significantly associated with the dyslipidemia (regression coefficient ± standard error [SE]: 0.057 ± 0.023; p = 0.017), LVMI (regression coefficient ± SE: 0.01 ± 0.001; P < 0.0001) and number of damaged coronaries (regression coefficient ± SE: 0.0174 ± 0.028; P < 0.0001). CONCLUSIONS: RFQIMT is a sophisticated method for carotid ultrasound evaluation. Its evaluation in patients with at least one important major epicardial coronary vessel stenosis would help the accuracy in the general assessment of the number of coronary lesions in these patients.