Giacomo Zoppellaro

Comprehensive analysis of left ventricular geometry and function by three-dimensional echocardiography in healthy adults

BACKGROUND Recent European Association of Echocardiography and American Society of Echocardiography guidelines on three-dimensional echocardiography state that normal values of left ventricular (LV) parameters for age and body size remain to be established. METHODS In 226 consecutive healthy subjects (125 women; age range, 18-76 years), comprehensive three-dimensional echocardiographic analyses of LV parameters were performed, and values were compared with those obtained by conventional echocardiography. RESULTS Upper reference values (mean+ 2 SDs) for three-dimensional LV end-diastolic and end-systolic volumes were 85 and 34 mL/m(2) in men and 72 and 28 mL/m(2) in women, respectively. Indexing LV volumes to body surface area did not eliminate gender differences. Lower reference values (mean - 2 SDs) for ejection fraction were 54% in men and 57% in women and for stroke volume were 25 and 24 mL/m(2), respectively. Upper reference values for LV mass were 97 g/m(2) in men and 90 g/m(2) in women and for end-diastolic sphericity index were 0.49 and 0.48, respectively. Significant age dependency of LV parameters was identified and reported across age groups. Three-dimensional echocardiographic LV volumes were larger, ejection fraction was similar, and LV stroke volume and mass were significantly smaller in comparison with the corresponding values obtained by conventional echocardiography. CONCLUSIONS The investigators report a comprehensive analysis of LV geometry and function using three-dimensional echocardiography in a relatively large cohort of healthy Caucasian subjects with a wide age range. These may serve to establish age-specific and gender-specific reference ranges, which are crucial for the routine implementation of three-dimensional echocardiography to detect LV remodeling and dysfunction in clinical practice.

Current Clinical Applications of Transthoracic Three-Dimensional Echocardiography

The advent of three-dimensional echocardiography (3DE) has significantly improved the impact of non-invasive imaging on our understanding and management of cardiac diseases in clinical practice. Transthoracic 3DE enables an easier, more accurate and reproducible interpretation of the complex cardiac anatomy, overcoming the intrinsic limitations of conventional echocardiography. The availability of unprecedented views of cardiac structures from any perspective in the beating heart provides valuable clinical information and new levels of confidence in diagnosing heart disease. One major advantage of the third dimension is the improvement in the accuracy and reproducibility of chamber volume measurement by eliminating geometric assumptions and errors caused by foreshortened views. Another benefit of 3DE is the realistic en face views of heart valves, enabling a better appreciation of the severity and mechanisms of valve diseases in a unique, noninvasive manner. The purpose of this review is to provide readers with an update on the current clinical applications of transthoracic 3DE, emphasizing the incremental benefits of 3DE over conventional two-dimensional echocardiography.

Efficacy and safety of rivaroxaban vs warfarin in high-risk patients with antiphospholipid syndrome: Rationale and design of the Trial on Rivaroxaban in AntiPhospholipid Syndrome (TRAPS) trial:

Background New oral anticoagulants may simplify long-term therapy in conditions requiring anticoagulation. Rivaroxaban is a direct factor Xa inhibitor that has been extensively studied and is now approved for the prevention and therapy of a number of thromboembolic conditions. Objective and methods This is a multicentre, randomized, open-label, study that will evaluate if Rivaroxaban 20 mg od (or 15 mg od in patients with moderate renal insufficiency) is non-inferior to warfarin (INR target 2.5), for the prevention of thromboembolic events, major bleeding and death in high risk (triple positive) patients with antiphospholipid syndrome. Secondary endpoints will assess the incidence of any individual component of the composite end point. An external adjudication committee will evaluate all suspected outcome events. This will be a unique trial, as it will enrol the biggest homogenous cohort of high risk APS individuals. Conclusion The methods and the study design should be appropriate to achieve study results that are both scientifically valid and relevant to clinical practice.

Antiphospholipid syndrome and the heart: A case series and literature review

Antiphospholipid syndrome is a rare autoimmune disease characterized by a high tendency of developing thrombotic events. It is diagnosed in the presence of specific laboratory criteria (positivity for lupus anticoagulant, and the presence of anticardiolipin and aβ2GPI antibodies) and clinical criteria such as thrombosis in any district (arterial or venous) and pregnancy morbidity. Being a multisystem disease, the heart is commonly affected by direct (autoimmune mediated action) or indirect (thrombosis) pathological mechanisms. Heart valve lesions are the most frequent manifestations; however, the haemodynamic significance is quite uncommon but when it occurs it may require surgery that further complicates the picture due to the high risk of thrombosis. Coronary arteries and myocardium are also affected leading to ischaemic heart disease and left ventricular dysfunction. Other findings include chronic thromboembolic pulmonary hypertension and accelerated atherosclerosis. The consequences of heart involvement may be significant in overt disease. The treatment of cardiac complications is challenging and requires an in-depth knowledge of the disease.

Clones of Interstitial Cells From Bovine Aortic Valve Exhibit Different Calcifying Potential When Exposed to Endotoxin and Phosphate

Objective—Our purpose was to study in vitro whether phenotypically-distinct interstitial cell clones from bovine aortic valve (BVIC) possess different calcifying potential in response to endotoxin (lipopolysaccharide [LPS]) and phosphate (Pi). Methods and Results—Among various clones of BVIC obtained by limited dilution technique we selected 4 clones displaying different growth patterns and immunophenotypes. Uncloned and cloned cells were treated with combinations of LPS (100 ng/mL) and Pi (2.4 mmol/L). Uncloned BVIC showed increased alkaline phosphatase activity (ALP) after treatment with LPS, which resulted in calcification after addition of Pi. Among BVIC clones, only Clone 1 (fibroblast-like phenotype) showed a relevant increase in ALP after LPS treatment in parallel with prevention of smooth muscle (SM) α-actin accumulation. No effect was observed in clonal cells harboring a more stable SM cell-like profile (Clone 4). None of the isolated clones calcified but mineralization was induced in the presence of LPS plus Pi when Clone 1 was cocultured with Clone 4 or after seeding on type I collagen sponges. Conclusion—Endotoxin and phosphate can act as valve calcification promoters by targeting specific fibroblast-like interstitial valve cells that possess a unique procalcific potential.

Critical Role of Macrophages in Glucocorticoid Driven Vascular Calcification in a Mouse-Model of Atherosclerosis

Objective—Macrophage-derived products are known to play a crucial role during atherogenesis and vascular calcification. Glucocorticoids (GC) are important modulators of immune cell functions, but their specific effects on macrophages behavior during plaque formation are not defined. The present study was therefore designed to investigate the effects of macrophage-specific deletion of the glucocorticoid receptor (GRLysMCre) on atherogenesis and vascular calcification in a hyperlipidemic mouse-model. Methods and Results—Bone marrow was isolated from GRLysMCre mice and wild-type controls (GRflox) and subsequently transplanted into lethally irradiated LDL-receptor–deficient mice. Animals were fed a Western-type diet for 15 or 24 weeks, and atherosclerotic lesions within the aortic sinus were evaluated. At both time points, no significant difference in serum lipid and corticosterone concentrations, atherosclerotic lesion size and macrophage-content within the lesions could be observed. However, GRLysMCre mice showed less calcification as well as a significant reduction of RANKL, BMP2, and Msx2 expression within the vasculature. In vitro studies using conditioned media from macrophages which had been stimulated with dexamethasone demonstrated a dose-dependent increase in calcium deposition by vascular smooth muscle cells. Conclusion—This study demonstrates that macrophage-specific glucocorticoid receptor inactivation reduces vascular calcification without affecting atherosclerotic lesion size in LDL receptor–deficient mice.

Antibodies to Domain 4/5 (Dm4/5) of β2-Glycoprotein 1 (β2GP1) in different antiphospholipid (aPL) antibody profiles

BACKGROUND Determination of the three recommended tests for the diagnosis of antiphospholipid syndrome [Lupus Anticoagulant (LA), anticardiolipin (aCL) and anti β2-Glycoprotein 1 (aβ2GP1) antibodies] allow physicians to allocate patients into classification (risk) categories. OBJECTIVES To measure antibodies of IgG isotype directed towards Domain 4/5 (Dm4/5) of β2GP1. PATIENTS/METHODS In this cross-sectional study we measured IgG aβ2GP1-Dm4/5 in a group of individuals positive for IgG aβ2GP1 and classified as triple (LAC+, IgG aCL+, IgG aβ2GP1+, n=32), double (LAC-, IgG aCL+, IgG aβ2GP1+, n=23) or single positive (LA-, IgG aCL-, IgG aβ2GP1+, n=10). RESULTS Geometric mean and standard deviation of IgG aβ2GP1 values expressed as Chemiluminescent Units (CU) in triple, double, single positive groups and in 40 healthy individuals were 1795±783, 321±181, 29±8 and 5.0±1.0, respectively (ANOVA p<0.0001). Geometric mean and standard deviation of IgG aβ2GP1-Dm4/5 expressed as Optical Density (OD) in triple, double and single positive groups and in 40 healthy individuals were 0.16±0.13, 0.16±0.15 and 0.26±0.15, 0.13±0,11, respectively (ANOVA p<0.002). Individuals in the single positive group, expressed significantly higher values with respect to triple (p=0.04) and double (p=0.03) positive groups. Approximate OD cut-off value (99° percentile) calculated in 40 normal control subjects is 0.404. Positivity to IgG aβ2GP1-Dm4/5 according to this cutoff was found in only 5 individuals, 3 in triple positive and 2 in single positive groups and was not associated with thromboembolism. CONCLUSION Mean level of IgG aβ2GP1-Dm4/5 is higher in single positive group. There is no association between positivity to IgG aβ2GP1-Dm4/5 and thromboembolic events.

Fibroblast Growth Factor 23 and the Bone-Vascular Axis: Lessons Learned From Animal Studies

Calcification of arteries and cardiac valves is observed commonly in dialysis patients and represents a major determinant of the heightened cardiovascular risk observed during chronic kidney disease (CKD) progression. Recent advances from clinical and basic science studies suggest that vascular calcification should be considered a systemic disease in which pathologic processes occurring in the bone and kidney contribute to calcium deposition in the vasculature. Among the factors potentially involved in the vascular-bone axis dysregulation associated with CKD, there now is increasing interest in the role of the phosphaturic hormone fibroblast growth factor 23 (FGF-23). Increased FGF-23 plasma levels are observed with a decrease in kidney function and predict the risk of future cardiovascular mortality. However, clinical data are still unclear about whether a direct pathogenetic effect of FGF-23 on vascular/kidney/bone health exists. In the last few years, a series of basic science studies, performed using engineered mice, have contributed important pathophysiologic information about FGF-23 activities. This review summarizes findings from these studies and discusses the potential role of FGF-23 during the pathologic interplay between kidney, vessels, and bone in CKD.

APS - Diagnostics and challenges for the future.

Diagnosis of antiphospholipid syndrome (APS) is essentially based on the detection of circulating antiphospholipid (aPL) antibodies. Progress have been made on the standardization of tests exploring the presence of aPL as guidelines on coagulation and immunological tests were recently published in the literature. Clinical relevance of aPL profile has come from prospective cohort studies in populations with a homogeneous antibody profile supporting the view that triple positivity is a high risk pattern in patients and carriers. In addition to the classic ones, several other tests have been proposed for the diagnosis of APS. The detection of antibodies directed to domain 1 and 4/5 of β2-Glycoprotein I (β2GP1) were found to be particularly sound. Several issues remain to be addressed. We do not yet know what is the physiological function of β2GP1 and the pathophysiology of thrombosis and pregnancy loss in these patients. Moreover, treatment is poorly defined especially in the case of feared catastrophic APS.

The left atrial appendage: from embryology to prevention of thromboembolism

The left atrial appendage (LAA) is the main source of thromboembolism in patients with non-valvular atrial fibrillation (AF). As such, the LAA can be the target of specific occluding device therapies. Optimal management of patients with AF includes a comprehensive knowledge of the many aspects related to LAA structure and thrombosis. Here we provide baseline notions on the anatomy and function of the LAA, and then focus on current imaging tools for the identification of anatomical varieties. We also describe pathogenetic mechanisms of LAA thrombosis in AF patients, and examine the available evidence on treatment strategies for LAA thrombosis, including the use of non-vitamin K antagonist oral anticoagulants and interventional approaches.