A novel passive left heart platform for device testing and research.

Integration of biological samples into in vitro mock loops is fundamental to simulate real device's operating conditions. We developed an in vitro platform capable of simulating the pumping function of the heart through the external pressurization of the ventricle. The system consists of a fluid-filled chamber, in which the ventricles are housed and sealed to exclude the atria from external loads. The chamber is connected to a pump that drives the motion of the ventricular walls. The aorta is connected to a systemic impedance simulator, and the left atrium to an adjustable preload. The platform reproduced physiologic hemodynamics, i.e. aortic pressures of 120/80 mmHg with 5 L/min of cardiac output, and allowed for intracardiac endoscopy. A pilot study with a left ventricular assist device (LVAD) was also performed. The LVAD was connected to the heart to investigate aortic valve functioning at different levels of support. Results were consistent with the literature, and high speed video recordings of the aortic valve allowed for the visualization of the transition between a fully opening valve and a permanently closed configuration. In conclusion, the system showed to be an effective tool for the hemodynamic assessment of devices, the simulation of surgical or transcatheter procedures and for visualization studies.

In vitro study of the aortic interleaflet triangle reshaping.

Aortic interleaflet triangle reshaping (AITR) is a surgical approach to aortic valve incontinence that involves placing three stitches at half of the interleaflet triangles height. In this work, the relationship between the actual stitch height and valve functioning, and the safety margin that the surgeon can rely on in applying the stitches were systematically investigated in vitro. AITR surgery was applied to six swine aortic roots placing the stitches empirically at 50%, 60% and 75% of the triangle heights. Then the actual stitch heights were measured and the hydrodynamic performances were evaluated with a pulsatile hydrodynamic mock loop. Actual stitch heights were 45±2%, 61±4% and 79±6%. As compared to untreated conditions, the 50% configuration induced a significant variation in the effective orifice area. With stitches placed at 60%, the mean systolic pressure drop increased significantly with respect to the untreated case, but no significant changes were recorded with respect to the 50% configuration. At 75%, all the hydrodynamic parameters of systolic valve functioning worsened significantly. Summarizing, the AITR technique, when performed in a conservative manner did not induce significant alterations in the hydrodynamics of the aortic root in vitro, while more aggressive configurations did. The absence of a statistically significant difference between the 50% and 60% configurations suggests that there is a reasonably limited risk of inducing valve stenosis in the post-op scenario due to stitch misplacement.

In vitro hemodynamics and valve imaging in passive beating hearts.

Due to their high complexity, surgical approaches to valve repair may benefit from the use of in vitro simulators both for training and for the investigation of those measures which can lead to better clinical results. In vitro tests are intrinsically more effective when all the anatomical substructures of the valvular complexes are preserved. In this work, a mock apparatus able to house an entire explanted porcine heart and subject it to pulsatile fluid-dynamic conditions was developed, in order to enable the hemodynamic analysis of simulated surgical procedures and the imaging of the valvular structures. The mock loop's hydrodynamic design was based on an ad-hoc defined lumped-parameter model. The left ventricle of an entire swine heart was dynamically pressurized by an external computer-controlled pulse duplicator. The ascending aorta was connected to a hydraulic circuit which simulated the input impedance of the systemic circulation; a reservoir passively filled the left atrium. Accesses for endoscopic imaging were located in the apex of the left ventricle and in the aortic root. The experimental pressure and flow tracings were comparable with the typical in vivo curves; a mean flow of 3.5±0.1l pm and a mean arterial pressure of 101±2 mmHg was obtained. High-quality echographic and endoscopic video recordings demonstrated the system's excellent potential in the observation of the cardiac structures dynamics. The proposed mock loop represents a suitable in vitro system for the testing of minimally-invasive cardiovascular devices and surgical procedures for heart valve repair.

Gaucher disease and bone: laboratory and skeletal mineral density variations during a long period of enzyme replacement therapy.

The usefulness of bone turnover markers in Gaucher disease is still unclear and their utility in monitoring the effects of enzyme replacement therapy (ERT) on bone metabolism has not yet been investigated exhaustively. Skeletal involvement seems to improve slowly during ERT, but only a few studies evaluating bone mineral density (BMD) changes during a long follow-up period have been reported. The aim of this study was to assess the efficacy of ERT on bone involvement in a group of 12 type I Gaucher disease (GD I) patients by monitoring biochemical indices of bone resorption/formation and BMD measured by dual energy x-ray absorptiometry (DEXA). Serum (calcium, phosphorus, bone alkaline phosphatase isoenzyme, carboxyterminal propeptide of type I procollagen (PICP), carboxyterminal telopeptide of type I collagen (ICTP), osteocalcin, intact parathyroid hormone) and urinary (calcium, phosphorus, hydroxyproline and free deoxypyridinoline) markers of bone metabolism and lumbar BMD were measured at baseline, after 6 and 12 months, and then every year for a mean ERT follow-up period of 4.5 years (range 4.4-6 years). Twelve healthy adult subjects matched for age and sex were tested as negative controls. A significant decrease of PICP was detected in the patient group at baseline (mean value 100.52 ng/ml vs 142.45 ng/ml, p = 0.017), while ICTP was remarkably higher: mean value 3.93 ng/ml vs 2.72 ng/ml, p = 0.004 (two-sided Student's t-test). No changes in bone formation indices were observed during the follow-up period, while urinary calcium excretion increased significantly from 0.065 to 0.191 mg/mg creatinine (p = 0.0014) (repeated measures ANOVA). A significant BMD improvement was also detected after an average ERT period of 4.5 years: Z-score increased from -0.81 to -0.56 (p = 0.005) (two-sided Student's t-test). These data evidenced the ineffectiveness of the biochemical markers used in monitoring ERT efficacy in GD I skeletal involvement, whereas DEXA was demonstrated to be a reliable method with which to follow up BMD improvement.

Bone marker alterations in patients with type 1 Gaucher disease.

Bone involvement is one of the most disabling aspects of type I Gaucher disease and its pathophysiology is still not well understood. As an invasive procedure, bone biopsies are not appropriate in a large population study. The development of sensitive bone resorption and formation tests have allowed the authors to study bone metabolism in a noninvasive manner in a group of type 1 Gaucher patients. Ten type I Gaucher adult patients with mild-to-severe bone disease were evaluated. Bone mineral density and markers of bone formation (total alkaline phosphatase and isoenzymes, carboxyterminal propeptide of type I procollagen, osteocalcin) and resorption (carboxyterminal telopeptide of type I collagen, urinary hydroxyproline, free-deoxypyridinoline and calcium) were measured in patients and in a control group, matched for sex and age. In Gaucher patients, carboxyterminal propeptide of type I procollagen (PICP), a bone formation index, was significantly lower compared with normal subjects (mean 101.17 ng/ml vs 140.75 ng/ml, P = 0.038), and analysis of bone resorption indexes showed a significant increase (mean 4.24 ng/ml vs 2.87 ng/ml, P = 0.012) of serum carboxyterminal telopeptide of type I collagen (ICTP). No significant differences were observed in osteocalcin, alkaline phosphatase, and urinary hydroxyproline. Bone mineral density revealed osteopenia in six patients, with a mean Z-score of ?1.04. It was not possible to show a relationship between sex, splenectomy status, age, weight, spleen, and liver volume and bone density, expressed as a Z-score nor a correlation between Z score and severity of skeletal disease. Results have shown a predominance of the resorption phase in the bone metabolism of Gaucher patients. These markers could be useful in monitoring the effect of enzyme replacement therapy on Gaucher disease skeletal involvement.

Gluten-dependent diabetes-related and thyroid-related autoantibodies in patients with celiac disease.

Patients with celiac disease are at high risk of having autoimmune disorders. Moreover, untreated patients with celiac disease have been found to have a higher than expected prevalence of organ-specific autoantibodies. In a prospective study of 90 patients with celiac disease, we found that the prevalence of diabetes and thyroid-related serum antibodies was 11.1% and 14.4%, respectively. Like antiendomysium autoantibodies, these organ-specific antibodies seem to be gluten-dependent and tend to disappear during a gluten-free diet.