Flow dynamic assessment of native mitral valve, mitral valve repair and mitral valve replacement using vector flow mapping intracardiac flow dynamic in mitral valve regurgitation.

Objectives: The present study aims to assess and describe the intracardiac blood flow dynamic in patients with mitral regurgitation (MR), repaired mitral valves (MV) and mitral valve prostheses using vector flow mapping (VFM). Methods: Patients with different MV pathologies and MV disease treatments were analysed. All patients underwent 2D transthoracic echocardiography, and images for flow visualization were acquired in VFM mode in an apical three-chamber view and four-chamber view. Vectors and vortices were qualitatively analyzed. Results: thirty-two (32) patients underwent 2D transthoracic echocardiography (TTE) with VFM analysis. We evaluated intracardiac flow dynamics in 3 healthy subjects, 10 patients with MR (5 degenerative, 5 functional), 4 patients who underwent MV repair, 5 who underwent MV replacement (3 biological, 2 mechanical), 2 surgically implanted transcatheter heart valve (THV), 2 transcatheter edge-to-edge MV repair with MitraClip (TEER), 3 transcatheter MV replacement (TMVR) and 3 transapical off-pump MV repair with NeoChord implantation. Blood flow patterns are significantly altered in patients with MV disease and MV repair compared to control patients. MV repair is superior to replacement in restoring more physiologicalpatterns, while TMVR reproducesan intraventricular flowcloser to normal than surgical MVR and TEER. Conclusions: Intracardiac flow patterns can be clearly defined using VFM. Restoration of a physiological blood flow pattern inside the LV directly depends on the procedure used to address MV disease.

The incremental value of multi-organ assessment of congestion using ultrasound in outpatients with heart failure.

AIMS: We investigated the prevalence and clinical value of assessing multi-organ congestion by ultrasound in heart failure (HF) outpatients. METHODS AND RESULTS: Ultrasound congestion was defined as inferior vena cava of ≥21 mm, highest tertile of lung B-lines, or discontinuous renal venous flow. Associations with clinical characteristics and prognosis were explored. We enrolled 310 HF patients [median age: 77 years, median NT-proBNP: 1037 ng/L, 51% with a left ventricular ejection fraction (LVEF) <50%], and 101 patients without HF. There were no clinical signs of congestion in 224 (72%) patients with HF, of whom 95 (42%) had at least one sign of congestion by ultrasound (P < 0.0001). HF patients with ≥2 ultrasound signs were older, and had greater neurohormonal activation, lower urinary sodium concentration, and larger left atria despite similar LVEF. During a median follow-up of 13 (interquartile range: 6-15) months, 77 patients (19%) died or were hospitalized for HF. HF patients without ultrasound evidence of congestion had a similar outcome to patients without HF [reference; hazard ratio (HR) 1.02, 95% confidence interval (CI) 0.86-1.35], while those with ≥2 ultrasound signs had the worst outcome (HR 26.7, 95% CI 12.4-63.6), even after adjusting for multiple clinical variables and NT-proBNP. Adding multi-organ assessment of congestion by ultrasound to a clinical model, including NT-proBNP, provided a net reclassification improvement of 28% (P = 0.03). CONCLUSION: Simultaneous assessment of pulmonary, venous, and kidney congestion by ultrasound is feasible, fast, and identifies a high prevalence of sub-clinical congestion associated with poor outcomes.

Validation and Feasibility of an Automated System for the Assessment of Vascular Structure and Mechanical Properties in the Digital Arteries: An Ultrahigh-Frequency Ultrasound Study.

Ultrahigh-frequency ultrasound (UHFUS) allows sharp visualization of human small muscular arteries. This may help in elucidating some aspects of the pathophysiology of arterial aging, such as the stiffness gradient between large and small conduit arteries and its consequences on the microcirculation, as well as vascular diseases affecting medium-sized arteries. However, UHFUS use is still limited, partly because of the lack of validated tools to quantify vascular structure and mechanical properties of small muscular arteries. In this validation study, scans of digital arteries were obtained with UHFUS (VevoMD, Visualsonics-Fujifilm, Toronto, ON, Canada), analyzed using Carotid Studio software (Quipu, Pisa, Italy) and compared with the manual measurement. Agreement between the two techniques on measures of diameter, distension and intima-media thickness (IMT) was evaluated using Bland-Altman analyses; inter- and intra-operator reproducibility was evaluated using coefficients of variation (CVs). Overall, no trend or significant bias was observed between Carotid Studio and manual analysis. All limits of agreement were acceptable. The intra-observer CV of diastolic diameter and IMT were 4.1% and 4.2%, respectively. The inter-observer CV for diastolic diameter and IMT were 7.3% and 5.4%, respectively. Intra- and inter-observer CVs for distension were higher (25.7% and 26.7%, respectively). These results suggest that the Carotid Studio software is a valid and reproducible tool to study UHFUS scans of digital arteries, with potential utility both in rare vascular diseases of medium-sized arteries and in the study of the pathophysiology of arterial aging in general.

Assessment and pathophysiology of microvascular disease: recent progress and clinical implications.

The development of novel, non-invasive techniques and standardization of protocols to assess microvascular dysfunction have elucidated the key role of microvascular changes in the evolution of cardiovascular (CV) damage, and their capacity to predict an increased risk of adverse events. These technical advances parallel with the development of novel biological assays that enabled the ex vivo identification of pathways promoting microvascular dysfunction, providing novel potential treatment targets for preventing cerebral-CV disease. In this article, we provide an update of diagnostic testing strategies to detect and characterize microvascular dysfunction and suggestions on how to standardize and maximize the information obtained from each microvascular assay. We examine emerging data highlighting the significance of microvascular dysfunction in the development CV disease manifestations. Finally, we summarize the pathophysiology of microvascular dysfunction emphasizing the role of oxidative stress and its regulation by epigenetic mechanisms, which might represent potential targets for novel interventions beyond conventional approaches, representing a new frontier in CV disease reduction.

Expert consensus and evidence-based recommendations for the assessment of flow-mediated dilation in humans.

Endothelial dysfunction is involved in the development of atherosclerosis, which precedes asymptomatic structural vascular alterations as well as clinical manifestations of cardiovascular disease (CVD). Endothelial function can be assessed non-invasively using the flow-mediated dilation (FMD) technique. Flow-mediated dilation represents an endothelium-dependent, largely nitric oxide (NO)-mediated dilatation of conduit arteries in response to an imposed increase in blood flow and shear stress. Flow-mediated dilation is affected by cardiovascular (CV) risk factors, relates to coronary artery endothelial function, and independently predicts CVD outcome. Accordingly, FMD is a tool for examining the pathophysiology of CVD and possibly identifying subjects at increased risk for future CV events. Moreover, it has merit in examining the acute and long-term impact of physiological and pharmacological interventions in humans. Despite concerns about its reproducibility, the available evidence shows that highly reliable FMD measurements can be achieved when specialized laboratories follow standardized protocols. For this purpose, updated expert consensus guidelines for the performance of FMD are presented, which are based on critical appraisal of novel technical approaches, development of analysis software, and studies exploring the physiological principles underlying the technique. Uniformity in FMD performance will (i) improve comparability between studies, (ii) contribute to construction of reference values, and (iii) offer an easy accessible and early marker of atherosclerosis that could complement clinical symptoms of structural arterial disease and facilitate early diagnosis and prediction of CVD outcomes.

Blood pressure control and treatment adherence in hypertensive patients with metabolic syndrome: protocol of a randomized controlled study based on home blood pressure telemonitoring vs. conventional management and assessment of psychological determinants of adherence (TELEBPMET Study).

BACKGROUND: Inadequate blood pressure control and poor adherence to treatment remain among the major limitations in the management of hypertensive patients, particularly of those at high risk of cardiovascular events. Preliminary evidence suggests that home blood pressure telemonitoring (HBPT) might help increasing the chance of achieving blood pressure targets and improve patient's therapeutic adherence. However, all these potential advantages of HBPT have not yet been fully investigated. METHODS/DESIGN: The purpose of this open label, parallel group, randomized, controlled study is to assess whether, in patients with high cardiovascular risk (treated or untreated essential arterial hypertension--both in the office and in ambulatory conditions over 24 h--and metabolic syndrome), long-term (48 weeks) blood pressure control is more effective when based on HBPT and on the feedback to patients by their doctor between visits, or when based exclusively on blood pressure determination during quarterly office visits (conventional management (CM)). A total of 252 patients will be enrolled and randomized to usual care (n = 84) or HBPT (n = 168). The primary study endpoint will be the rate of subjects achieving normal daytime ambulatory blood pressure targets (< 135/85 mmHg) 24 weeks and 48 weeks after randomization. In addition, the study will assess the psychological determinants of adherence and persistence to drug therapy, through specific psychological tests administered during the course of the study. Other secondary study endpoints will be related to the impact of HBPT on additional clinical and economic outcomes (number of additional medical visits, direct costs of patient management, number of antihypertensive drugs prescribed, level of cardiovascular risk, degree of target organ damage and rate of cardiovascular events, regression of the metabolic syndrome). DISCUSSION: The TELEBPMET Study will show whether HBPT is effective in improving blood pressure control and related medical and economic outcomes in hypertensive patients with metabolic syndrome. It will also provide a comprehensive understanding of the psychological determinants of medication adherence and blood pressure control of these patients. TRIAL REGISTRATION: Clinical Trials.gov: NCT01541566.

Multigroup confirmatory factor analysis of U.S. and Italian children's performance on the PASS theory of intelligence as measured by the Cognitive Assessment System.

This study examined Italian and U.S. children's performance on the English and Italian versions, respectively, of the Cognitive Assessment System (CAS; Naglieri & Conway, 2009; Naglieri & Das, 1997), a test based on a neurocognitive theory of intelligence entitled PASS (Planning, Attention, Simultaneous, and Successive; Naglieri & Das, 1997; Naglieri & Otero, 2011). CAS subtest, PASS scales, and Full Scale scores for Italian (N=809) and U.S. (N=1,174) samples, matched by age and gender, were examined. Multigroup confirmatory factor analysis results supported the configural invariance of the CAS factor structure between Italians and Americans for the 5- to 7-year-old (root-mean-square error of approximation [RMSEA]=.038; 90% confidence interval [CI]=.033, .043; comparative fit index [CFI]=.96) and 8- to 18-year-old (RMSEA=.036; 90% CI=.028, .043; CFI=.97) age groups. The Full Scale standard scores (using the U.S. norms) for the Italian (100.9) and U.S. (100.5) samples were nearly identical. The scores between the samples for the PASS scales were very similar, except for the Attention Scale (d=0.26), where the Italian sample's mean score was slightly higher. Negligible mean differences were found for 9 of the 13 subtest scores, 3 showed small d-ratios (2 in favor of the Italian sample), and 1 was large (in favor of the U.S. sample), but some differences in subtest variances were found. These findings suggest that the PASS theory, as measured by CAS, yields similar mean scores and showed factorial invariance for these samples of Italian and American children, who differ on cultural and linguistic characteristics.

Local carotid stiffness and intima-media thickness assessment by a novel ultrasound-based system in essential hypertension.

OBJECTIVE: To evaluate local carotid stiffness (CS) and intima-medial thickness (C-IMT) in hypertensive patients with different cardiovascular risk profile, using a new user-friendly ultrasound-based system, previously validated vs. RF-based echotracking device. METHODS: We investigated a population with different cardiovascular risk: 45 healthy normotensives (NT), 90 non-diabetic hypertensives (HT), and 48 patients with hypertension and type-2 diabetes (DM). Framingham risk factor score (FRS) was calculated. PWV was assessed by applanation tonometry. The relative stroke change in diameter (ΔD) and C-IMT were measured on carotid scans. Distensibility coefficient (DC) was calculated as ΔA/(A*ΔP), where A = diastolic lumen area, ΔA = stroke change in lumen area, and ΔP = carotid pulse pressure. CS (m/s) was calculated as (ρ*DC) - 1/2 (ρ = blood density). RESULTS: CS, C-IMT, PWV were significantly increased in HT and DM vs. NT. C-IMT and PWV were significantly higher in DM than HT. ΔD and DC were significantly lower in HT and DM vs. NT. FRS ≥10% group showed increased carotid diameter, C-IMT and CS than the FRS <10%. FRS was (p < 0.001) correlated with CS (r = 0.35); ΔD (r = -0.36), DC (r = 0.35), C-IMT (r = 0.48), PWV (r = 0.38). CS correlated (p < 0.05) with PWV in the entire population (r = 0.37), in the NT (r = 0.35), in the HT and DM (r = 0.20). PWV (r = 0.50) and CS (r = 0.33) were correlated with age. Determinants of aortic and carotid stiffness were identified by multivariate stepwise analysis. CONCLUSIONS: The proposed B-mode ultrasound-based system is a reliable and user-friendly method that could serve to investigate the predictive value of CS for cardiovascular events in future large clinical studies.

Assessment of flow-mediated dilation reproducibility: a nationwide multicenter study.

OBJECTIVE: Impaired flow-mediated dilation (FMD) is associated with cardiovascular risk factors and provides prognostic information. Despite the noninvasive nature of this technique, a major limitation to its widespread use is low reproducibility. The aim of this study was to evaluate impact of methodological standardization among different investigation sites on brachial artery FMD reproducibility. METHODS: Seven Italian centers recruited 135 healthy volunteers, aged 20-60 years. FMD was assessed by high-resolution ultrasound equipped with a stereotactic probe-holding device. Certified sonographers recorded brachial artery scans at baseline (day 1a), 1 h after (day 1b), and 1 month later (day 30). Endothelium-independent vasodilation (EIVD) to sublingual glyceril-trinitrate was recorded at day 1 and day 30. FMD and EIVD were blindly evaluated at the coordinating center by an automated edge detection system. The intra-session (day 1a versus 1b) and inter-session (day 1a versus 30) coefficients of variation were calculated. RESULTS: FMD was not significantly (P = 0.91) different at day 1a, day 1b and day 30 (6.52 ± 2.9, 6.42 ± 3.1, 6.57 ± 2.8%, respectively). The FMD intra-session coefficient of variation was 9.9 ± 8.4% (from 7.6 to 11.9% across centers). The FMD inter-session coefficient of variation was 12.9 ± 11.6% (from 11.6 to 16.1% across centers). Inter-session coefficient of variation for EIDV was 19.7 ± 16.8%. CONCLUSIONS: This study shows a homogeneous coefficient of variation for FMD among different centers. The inter-session coefficient of variation was similar to the intra-session coefficient of variation, representing the intrinsic FMD variability. We demonstrate for the first time that rigorous and standardized procedure may provide reproducible FMD assessment to study endothelial function in multicenter clinical trials.

How to evaluate microvascular organ damage in hypertension: assessment of endothelial function.

Patients with essential hypertension are characterized by endothelial dysfunction and impaired nitric oxide availability secondary to oxidative stress production. A dysfunctioning endothelium is an early marker of the development of atherosclerotic changes and can also contribute to cardiovascular events. The autocrine/paracrine activity of endothelial cells makes it very difficult to investigate endothelial function in clinical research. Vascular reactivity tests represent the most widely used methods of clinical assessment of endothelial function. The aim of these tests is to activate or block endothelial cell function while measuring consequent changes in vascular tone in selected vascular districts. Many studies have evaluated the endothelium in hypertensive patients, using different techniques. Several methodologies were developed to study microcirculation (resistance arteries and arterioles), both in coronary and peripheral vascular districts. In particular, peripheral microcirculation can be evaluated in functionally isolated vascular districts such as the peripheral muscle (usually forearm), the subcutaneous tissue, or the skin. This article focuses on the most relevant available techniques in the research on endothelial dysfunction in essential hypertension, in particular their advantages and major limitations. The coronary microcirculation can be evaluated by measuring coronary blood flow with Doppler flow wire and quantitative angiography during the intracoronary infusion of endothelial agonists. The isolated and perfused forearm technique is the most often used approach in the assessment of endothelial function in peripheral muscle microcirculation. The subcutaneous small resistance arteries can be studied using the Mulvany myograph device, an in vitro, ex vivo technique. Finally, the use of the laser digital Doppler technique provides a non-invasive approach to the evaluation of the skin microcirculation. Each technique employed to assess endothelial function has specific limitations that hinder its applicability in large-scale screening. In addition, studies assessing the degree of correlation among measures of endothelial function, as evaluated in different vascular beds, have demonstrated a poor relationship and, while statistically significant, the findings are of no clinical relevance. Therefore, no one technique can be considered a surrogate for another. At the present time, the optimal methodology for investigating the multifaceted aspects of endothelial dysfunction is still under debate. Only the growing concordant results from different reproducible and reliable methods exploring endothelial function with different stimuli will support and strengthen experimental findings, thus providing conclusive answers in this area of research.

Endothelial function and dysfunction. Part I: Methodological issues for assessment in the different vascular beds: a statement by the Working Group on Endothelin and Endothelial Factors of the European Society of Hypertension.

An enormous number of studies in the last two decades have been devoted to investigating the role of the endothelium in cardiovascular diseases. Nonetheless, the optimal methodology for investigating the multifaceted aspects of endothelial dysfunction is still under debate. Biochemical markers, molecular genetic tests and invasive and non-invasive tools with and without pharmacological and physiological stimuli have been introduced. Furthermore newer pharmacological tools have been proposed. However, the application of these methodologies should fulfil a number of requirements in order to provide conclusive answers in this area of research. Thus, the most relevant methodological issues in the research on endothelial function and dysfunction are summarized in this paper.

[Clinical significance of the assessment of endothelial function]. / Significato clinico della valutazione della funzione endoteliale.

Endothelium-derived nitric oxide is not only a potent vasodilator but also inhibits platelet aggregation, vascular smooth muscle cell migration and proliferation, monocyte adhesion and adhesion molecule expression, thus protecting the vessel wall from the development of atherosclerosis and thrombosis. Major cardiovascular risk factors are associated with endothelial dysfunction, which involves enhanced production of oxygen free radicals, that can destroy nitric oxide and reduce its availability, and release of endothelium-derived contracting factors including prostanoids and endothelin-1. Endothelial dysfunction is a promoter of atherosclerotic and thrombotic damage and in prospective studies on patients with high cardiovascular risk impaired endothelium-dependent vasodilation is associated with an increased incidence of cardiovascular events. However, endothelial function cannot yet be included among the surrogate endpoints which need to be measured for cardiovascular risk stratification. This limitation springs from the fact that available tests to assess endothelium-dependent vasodilation are invasive or, if noninvasive, they have no sufficient sensitivity and specificity to be proposed for clinical practice. Moreover, no study is available demonstrating that reversal of endothelial dysfunction, which can be obtained by appropriate treatment, is independently associated with a better clinical outcome. However it is conceivable that in the future, by the utilization of a non-invasive method such as the determination of brachial artery flow-mediated dilation, large-scale multicenter trials might provide a definitive answer to the real prognostic value of endothelial dysfunction, in terms of cardiovascular risk and therapeutic approach.