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Background Sigh is a cyclic brief recruitment maneuver: previous physiologic studies showed that its use could be an interesting addition to pressure support ventilation to improve lung elastance, decrease regional heterogeneity, and increase release of surfactant. Research Question Is the clinical application of sigh during pressure support ventilation (PSV) feasible? Study Design and Methods We conducted a multicenter noninferiority randomized clinical trial on adult intubated patients with acute hypoxemic respiratory failure or ARDS undergoing PSV. Patients were randomized to the no-sigh group and treated by PSV alone, or to the sigh group, treated by PSV plus sigh (increase in airway pressure to 30 cm H2O for 3 s once per minute) until day 28 or death or successful spontaneous breathing trial. The primary end point of the study was feasibility, assessed as noninferiority (5% tolerance) in the proportion of patients failing assisted ventilation. Secondary outcomes included safety, physiologic parameters in the first week from randomization, 28-day mortality, and ventilator-free days. Results Two-hundred and fifty-eight patients (31% women; median age, 65 [54-75] years) were enrolled. In the sigh group, 23% of patients failed to remain on assisted ventilation vs 30% in the no-sigh group (absolute difference, –7%; 95% CI, –18% to 4%; P = .015 for noninferiority). Adverse events occurred in 12% vs 13% in the sigh vs no-sigh group (P = .852). Oxygenation was improved whereas tidal volume, respiratory rate, and corrected minute ventilation were lower over the first 7 days from randomization in the sigh vs no-sigh group. There was no significant difference in terms of mortality (16% vs 21%; P = .337) and ventilator-free days (22 [7-26] vs 22 [3-25] days; P = .300) for the sigh vs no-sigh group. Interpretation Among hypoxemic intubated ICU patients, application of sigh was feasible and without increased risk. Trial Registry ClinicalTrials.gov ; No.: NCT03201263 ; URL: www.clinicaltrials.gov

Background Scarce data are available on the long-term outcomes of different regimens of oral anticoagulation in an all comer population of patients undergoing aortic valve replacement with a bileaflet mechanical heart valve. Methods Outcomes of 88 patients discharged with a target INR of 2.0 (LOW-INR) were compared to 147 contemporary patients who have been recommended a target INR of 2.5 (CONV). Primary outcome was the composite of any thromboembolic or haemorrhagic events. Secondary outcomes were the individual components of the primary outcome, cardiovascular mortality and stroke. To reduce selection bias, a propensity weighted analysis was performed. Results After inverse probability of treatment weighting, the primary endpoint occurred in 0.7% of patient in the LOW-INR group and in 7.0% in the CONV group (p = .0255). Linearized event rate were significantly lower in the LOW-INR group (primary endpoint: rate difference − 12.0 per 1000 patient/years, p = .0052; haemorrhage: −5.8 per 1000 patient/years, p = .0330; neurological events: −7.6 per 1000 patient/years, p = .0140). Conventional target INR was associated with an increased hazard of the composite endpoint (HR 11.193, 95% CI 1.424–88.003, p = .0217). Conclusions Lowering the intensity of oral anticoagulation resulted in a relevant clinical benefit of reduced rates of haemorrhagic and neurological adverse events in the mid-term follow-up. This report confirms the safety profile of the low INR regimen in an all comer population undergoing aortic valve replacement with an Abbott mechanical valve.

Type I collagen is the most abundant protein of the human body. Due to its favourable properties, collagen extracted from animal tissues is adopted to manufacture a wide range of devices for biomedical applications. Compared to bovine and porcine collagens, which are the most largely used, equine collagen is free from the risk of zoonosis, has no reported immune reactions, and has not religious constraints. In this work, a recently available type I collagen extracted from horse tendon was evaluated and compared with a commercially available collagen isoform derived from the same species and tissue. Detailed physical, chemical and biological investigations were performed, in agreement with the requirements of the current standard for the characterization of type I collagen to be used for the manufacture of Tissue Engineering Medical Products. To the best of our knowledge, this is the first report on the complete primary structure of the investigated collagen.

The optimization of collagen-based scaffolds for tissue engineering goes through the careful selection of the crosslinking method(s), which should impart the prerequisite mechanical and degradation properties without impairing the cell/tissue response. Here, we investigated the chemically effective (ρxch) and the elastically effective (ρxel) crosslink density of collagen-based scaffolds, induced by various crosslinking methods. The aim was to get a deeper insight into the influence of intramolecular and intermolecular crosslinks on several scaffold properties. Freeze-dried collagen matrices were crosslinked via a dehydrothermal treatment (DHT), and then treated with different chemical agents, including carbodiimide (EDC), glutaraldehyde (GTA), formaldehyde (FA), genipin (GP) and dimethyl suberimidate (DMS). Quantification of primary amines and stress-relaxation compressive tests were performed to evaluate ρxch and ρxel, respectively. Scaffolds were then assessed for their water uptake, thermal stability and in vitro resistance to enzymatic degradation. Interestingly, for the various crosslinking treatments ρxch was found to increase in the order DHT

Background Evaluation of the impact of prosthesis-patient mismatch (PPM) on long-term outcome and quality of life (QOL) in elderly patients who underwent implantation of small size bileaflet prostheses for aortic stenosis. Methods Between September 1988 and September 2006, 377 patients aged greater than 70 years underwent aortic valve replacement with a small size bileaflet prosthesis (17, 19, and 21 mm) in one Institution. The study population's survivors (345 patients) were divided into three groups according to the indexed effective orifice area (EOAI): Group A included patients with EOAI less than 0.60 cm 2 /m 2 ; group B included patients with EOAI ranging between 0.61 and 0.84 cm 2 /m 2 ; and group C included patients with EOAI 0.85 cm 2 /m 2 or greater. Cumulative and comparative analyses of long-term outcomes and of left ventricular mass regression were performed. The QOL was evaluated with the 36-Item Short Form Health Survey (SF-36) questionnaire. Results Overall hospital mortality was 8.5% (32 patients). Group A included 33 patients (9.6%), group B 175 (50.7%), and group C 137 (39.7%). Actuarial survival was 88.8% ± 0.016 at 1 year, 82.1% ± 0.022 at 5 years, and 76.7% ± 0.032 at 10 years. No difference emerged among the three groups. A significant reduction in left ventricular mass was observed in all groups and in all patient subsets of prosthetic size. The scores obtained in the SF-36 test were similar in the three groups and significantly higher than those of the general population ( p Conclusions Incidence of severe PPM is low after aortic valve replacement. Presence of severe or moderate PPM, did not influence long-term outcome, left ventricular mass regression and QOL in a population of septuagenarians.

Objectives Peak oxygen uptake (Vo 2 ) and ventilatory efficiency have prognostic implications in the population with congestive heart failure. This study evaluated quality-of-life functional capacity after the 2 treatment strategies of surgical ventricular restoration and transplantation for severe left ventricular dysfunction of ischemic cause. Methods The 75-patient study population (between 2004 and 2006) with severe heart failure included 35 patients undergoing surgical ventricular restoration (mean age, 62.6 ± 8.7 years), sometimes together with coronary artery bypass grafting or mitral surgery, and 40 cardiac transplant recipients (mean age, 55.6 ± 7.7 years). Preoperative and 6-month postoperative function (peak Vo 2 , the anaerobic threshold, and the slope of minute ventilation/carbon dioxide uptake), cardiac catheterization parameters (left and right), and hospital and early outcomes were evaluated. Results The 2 groups had comparable baseline functional impairment and experienced similar hospital stay and early outcomes. They also showed similar improvements in left ventricular volume indexes and hemodynamic parameters and sustained significant improvements of median Vo 2 , anaerobic threshold, and minute ventilation/carbon dioxide uptake values. Conclusions Both surgical strategies resulted in a significant and comparable improvement of functional capacity at the 6-month evaluation. These early studies must be repeated to determine the long-term benefits of surgical ventricular restoration because maximal Vo 2 and ventilatory efficiency lose their prognostic survival role after transplantation.

The aim of this study was to determine whether changes in prognosis and quality of life (QOL) after aortic valve replacement (AVR) in octogenarians differ depending on the choice of mechanical (MP) or tissue (BP) valves.Between July 1992 and September 2006, 160 consecutive octogenarians underwent AVR with (18.8%) or without concomitant coronary artery bypass grafting. At follow-up (mean 3.4 +/- 2.8 years, 552 patient-years, 98.3% complete), 121 were still alive and answered the Medical Outcomes Study Short-Form 36 Health Survey (SF-36) QOL questionnaire.Group BP had 62 patients. Group MP had 98 patients. Preoperative risk factors were comparable except group BP was older. Global hospital mortality was 8.8%. There were 21 late deaths, 61.9% of which were not valve- or anticoagulation-related. A significant difference emerged in 1-, 3-, 5- and 8-year actuarial survival rates (BP: 86.4% +/- 0.04%, 76.9% +/- 0.06%, 58.1% +/- 0.1%, 46.5% +/- 0.14%, respectively, vs MP: 91.3% +/- 0.03%, 88.6% +/- 0.03%, 81.6% +/- 0.05%, 70% +/- 0.67%; p = 0.025) but not in terms of 8-year freedom from valve-related complications (82.6% +/- 0.1% vs 87% +/- 0.053%, p = 0.55). One anticoagulant-related hemorrhage occurred in group MP; one stroke occurred in group BP. Survivors had significant improvement in New York Heart Association functional class compared with preoperatively (1.1 vs 2.8, p0.001) Mean QOL scores were satisfactory and substantially comparable between the two groups; in seven domains, scores were higher than those of the age- and sex-matched general Italian population.Long-term survival after AVR in selected octogenarians was similar to that of the general elderly population. The device type exerted no influence on QOL.

Background Although surgical management with early debridement and closed mediastinal irrigation has proved successful in reducing early mortality following poststernotomy deep sternal wound infection, recurrence rates are still up to 20%. This study compared the effectiveness and safety of wound dressing with granulated sugar versus early muscle flap surgery in the management of recurrent postoperative Staphylococcal mediastinitis. Methods Between January 1995 and January 2002, 25 patients with severe recurrent staphylococcal mediastinitis were treated with granulated sugar wound dressing (group A) or with wound debridement, v-shape sternectomy and associated muscle flap surgery (group B). Clinical outcomes and perioperative data were analyzed. Outcomes were compared between the groups evaluating the length of time for normalization of white blood cell (WBC) count and of body temperature and length of hospital stay. Patient characteristics determining best treatment option were identified. Survival and incidence of recurrence at follow-up were also analyzed. Results Study groups proved homogenous as to preoperative characteristics. Complete cure was achieved earlier in group A than in group B (defervescence: p = 0.0005; WBC normalization: p = 0.0001, respectively). Hospital stay was shorter in group A. A statistically significant difference was found in hospital mortality (16% overall) between the two groups with better outcomes in group A ( p = 0.039). In the patient subset with the most severe preoperative profile (hemodialysis, tracheostomy, inotropic support) surgical treatment produced worse results than the sugar dressing method ( p = 0.048). No case of recurrence was observed. Conclusions Both treatments proved effective in recurrent type IV A Staphylococcal mediastinitis. Granulated sugar proved a safer option in severely compromised patients.

Objectives This pilot prospective observational study aimed to evaluate the maternal and fetal outcomes of pregnancies under low-dose oral anticoagulation therapy after aortic mechanical replacement. Background Need for valve replacement is still an issue for young women with native valve disease who are planning on future pregnancy. Choice of replacement device is a challenging clinical task. Methods A comprehensive pre-operative counseling protocol to guide choice of replacement device was developed. The pre-operative anticoagulation trial to determine the warfarin daily dosage needed to reach target international normalized ratio (INR) represented the main stem of such protocol. Pregnancies on low-dose anticoagulation therapy (target INR: 1.5 to 2.5) were allowed in a highly selected subset of mechanical aortic valve recipients. Results Twenty-two patients of 40 originally referred for native valve disease surgery requiring valve replacement, safely underwent the pre-operative anticoagulation challenge. No maternal or fetal complications were detected in 16 pregnancies under low oral anticoagulation. Patterns of warfarin daily dosage and induced INRs were characterized during pregnancy. Conclusions In this small sample observational study, a pre-operative anticoagulation therapy trial helped young women scheduled for valve replacement to acquire complete information as to the choice of prosthetic device. In selected third-generation mechanical aortic prosthesis recipients, low-dose anticoagulation therapy seems safe and feasible for both mother and fetus. Further studies are needed to validate this approach.

OBJECTIVESThe purpose of this study was to assess the incidence of warfarin fetal complications and whether they are dose-dependent.BACKGROUNDGravid patients with mechanical heart valves require long-term anticoagulant therapy. Controversy exists concerning the appropriate treatment of these patients.METHODSForty-three women on warfarin carrying out 58 pregnancies were studied. For each patient with full-term pregnancy a caesarian section was scheduled for the 38th week during brief warfarin discontinuation. Maternal and fetal complications were evaluated. Fetal complications were divided according to the warfarin dosage ≤5 mg and >5 mg necessary to keep an international normalized ratio (INR) of 2.5 to 3.5, and analyzed subsequently.RESULTSA total of 58 pregnancies were observed: 31 healthy babies (30 full term, 1 premature) and 27 fetal complications (22 spontaneous abortions, 2 warfarin embryopathies, 1 stillbirth, 1 ventricular septal defect, 1 growth retardation) were recorded. Two maternal valve thromboses occurred. No fetal or maternal bleeding was observed during caesarian sections or premature vaginal delivery. Patients whose warfarin doses during pregnancy were >5 mg had 22 fetal complications, whereas those taking a dose ≤5 mg had only five fetal complications (p = 0.0001). For an increase of the warfarin dose there was a substantially increased probability of fetal complications (p < 0.0001; ρ < 0.7316).CONCLUSIONSThere is a close dependency between warfarin dosage and fetal complications. Patients on warfarin anticoagulation may be delivered by planned caesarian section at the 38th week while briefly interrupting anticoagulation.

Backgrou nd Moderate anticoagulation after mechanical heart valve replacement has been proposed to reduce the risk of bleeding related to lifelong anticoagulation. However, the efficacy of such reduced antithrombotic regimens is still unknown. The present prospective open-label, single-center, randomized controlled trial aimed to evaluate the safety and feasibility of reduced oral anticoagulation after isolated mechanical aortic valve replacement. Metho ds Low-risk patients undergoing bileaflet mechanical aortic valve replacement were randomized to a low International normalized ratio (INR) target (1.5-2.5; LOW-INR group) or to the standard currently recommended INR (2.0-3.0; CONVENTIONAL-INR group) through daily coumarine oral therapy. No aspirin was added. Median follow-up was 5.6 years. Th e pr imar y out co me was a sse ss me nt of no ni nfe ri ori ty of t he lo w ov er the s tan dar d an t ico agu l ati on reg imen on thromboembolic events. Secondary end point was the superiority of the reduced INR target strategy on bleeding events. Results We analyzed 396 patients (197 in the LOW-INR group and 199 in the CONVENTIONAL-INR group). The mean of INR was 1.94 ± 0.21 and 2.61 ± 0.25 in the LOW-INR and CONVENTIONAL-INR groups, respectively (P b .001). One versus three thromboembolic events occurred in the LOW-INR and CONVENTIONAL-INR, respectively, meeting the noninferiority criterion ( P = .62). Total hemorrhagic events occurred in 6 patients in the LOW-INR group and in 16 patients in the CONVENTIONAL-INR group (P = .04). Conclusio ns LOWERING-IT trial established that the proposed LOW-INR target is safe and feasible in low-risk patients after bileaflet aortic mechanical valve replacement. It results in similar thrombotic events and in a significant reduction of bleeding occurrence when compared to the conventional anticoagulation regimen.

Postischemic cardiomyopathy remains one of the disorders in urgent need of effective noninvasive therapy. It is currently accepted that the isolation, expansion and application of resident cardiac stem cells may hold therapeutic promise for the future. Recently, it has been demonstrated that shock waves (SW) could enhance the expression of vascular endothelial growth factor (VEGF) and its receptor, Flt-1. As the development of angiogenic noninvasive therapy is very important for future therapeutic strategies in cardiovascular diseases, we examined in vitro, the effects of SW treatment on adult resident cardiac primitive cells isolated from bioptic fragments of normal human hearts and from explanted pathologic hearts with postischemic cardiomyopathy. This study demonstrates that SW have positive influence on both the proliferation and the differentiation of cardiomyocytes, smooth muscle and endothelial cells precursors, with a more obvious effect being evident in the cells from normal heart than in those taken from pathologic hearts. Our results suggest that SW treatment could inhibit or retard the pathologic remodeling and functional degradation of the heart if applied during the early stages of heart failure.

Objective Congenital bicuspid aortic valves frequently cause aortic stenosis or regurgitation. Improved understanding of valve and root biomechanics is needed to achieve advancements in surgical repair techniques. By using imaging-derived data, finite element models were developed to quantify aortic valve and root biomechanical alterations associated with bicuspid geometry. Methods A dynamic 3-dimensional finite element model of the aortic root with a bicuspid aortic valve (type 1 right/left) was developed. The model's geometry was based on measurements from 2-dimensional magnetic resonance images acquired in 8 normotensive and otherwise healthy subjects with echocardiographically normal function of their bicuspid aortic valves. Numeric results were compared with those obtained from our previous model representing the normal root with a tricuspid aortic valve. The effects of raphe thickening on valve kinematics and stresses were also evaluated. Results During systole, the bicuspid valve opened asymmetrically compared with the normal valve, resulting in an elliptic shape of its orifice. During diastole, the conjoint cusp occluded a larger proportion of the valve orifice and leaflet bending was altered, although competence was preserved. The bicuspid model presented higher stresses compared with the tricuspid model, particularly in the central basal region of the conjoint cusp (+800%). The presence of a raphe partially reduced stress in this region but increased stress in the other cusp. Conclusions Aortic valve function is altered in clinically normally functioning bicuspid aortic valves. Bicuspid geometry per se entails abnormal leaflet stress. The stress location suggests that leaflet stress may play a role in tissue remodeling at the raphe region and in early leaflet degeneration.

OBJECTIVE: The present study examined temporal and spatial patterns of extracellular matrix and smooth muscle cell changes in the ascending aorta with bicuspid and tricuspid aortic valve stenosis. METHODS: Wall specimens were retrieved from both the greater and the lesser curvature ("convexity" and "concavity") of 14 nonaneurysmal and 12 aneurysmal aortas (aortic ratios 1.2 and 1.5, respectively) and from 3 heart donors (normal). Immunochemistry was performed for detection of apoptotic (terminal deoxynucleotidyl transferase-mediated dUTP nick end labelling [TUNEL]-positive) and proliferating (Ki-67-positive) smooth muscle cells and for semiquantification of matrix proteins (collagens, fibronectin, tenascin, laminin). Co-immunoprecipitation assessed the extent of Bcl-2-modifying factor binding to Bcl-2, indicating a matrix-derived cytoskeleton-mediated proapoptotic signaling. Polymerase chain reaction allowed for quantification of messenger RNA expression for Bcl-2. RESULTS: In both bicuspid and tricuspid aneurysms, fibrillar collagens were reduced, whereas fibronectin and tenascin were increased compared with those in normal conditions. These matrix alterations were already evident in bicuspid nonaneurysmal aortas at the convexity, with significant elevation of apoptotic indexes (P = .02 bicuspid vs normal; P = .48 tricuspid vs normal). Apoptotic indexes correlated with aortic dimensions only in tricuspid aortas (P = .01). No significant increase in Ki-67 was found. Higher levels of Bcl-2-modifying factor-Bcl-2 binding were found in bicuspid nonaneurysmal aorta versus tricuspid (P = .03) and normal aortas (P = .01). Bcl-2 messenger RNA expression was reduced in the bicuspid aorta versus normal (P = .08). CONCLUSIONS: Smooth muscle cell apoptosis with bicuspid aortic valve stenosis occurred before overt aortic dilation, mainly at the convexity, where wall stress is expectedly higher. In this setting, a matrix-dependent proapoptotic signaling was evidenced by increased Bcl-2-modifying factor-Bcl-2 binding. Stress-dependent bicuspid aortic valve matrix changes may trigger early apoptosis by inducing cytoskeletal rearrangement.

OBJECTIVE: This study aimed to assess extracellular matrix protein expression patterns at the convexity (right anterolateral wall) and the concavity of the dilated ascending aorta in patients with bicuspid aortic valve disease. METHODS: Aortic wall specimens were retrieved from the convexity and the concavity in 27 bicuspid aortic valve patients (12 with stenosis and 15 with regurgitation) and 6 heart donors (controls). Morphometry, immunohistochemistry, Western blot, and polymerase chain reaction were performed, focusing on matrix proteins involved in vascular remodeling. RESULTS: Type I and III collagens were significantly decreased in bicuspid-associated dilated aortas versus controls (P < .001), particularly at the convexity (P < .05 vs concavity). Expression of messenger RNA for collagens was lower than normal only in the regurgitant subgroup. At immunohistochemistry, proteins whose overproduction has been demonstrated in response to abnormal wall stress, such as tenascin and fibronectin, were more expressed in the convexity than in the concavity, especially in the stenosis subgroup. Tenascin, which is produced by smooth muscle cells in the synthetic phenotype, was nearly undetectable in controls. Fewer smooth muscle cells (stenosis, P = .017; regurgitation, P = .008) and more severe elastic fiber fragmentation (P = .029 and P < .001) were observed in the convexity versus the concavity. CONCLUSIONS: In bicuspid-associated aortic dilations, an asymmetric pattern of matrix protein expression was found that was consistent with the asymmetry in wall-stress distribution reported previously. Differences exist between patients with stenosis and those with regurgitation in terms of protein expression and content in the aortic wall. Further studies could clarify the relations between these findings and the pathogenesis of aortic dilatation in bicuspid aortic valve patients.

Surgical approaches to postoperative mediastinitis that imply wire removal achieve earlier infection recovery but leave the patient with sternal instability. In 10 patients after wound surgical debridement, my colleagues and I achieved sternal synthesis by using Achilles tendons retrieved from multiorgan donors and stored in glutaraldehyde. Three tendons were used in each patient; they were passed through the bone at the manubrium and parasternally at the midsternum and the lower sternum. Thirty-day computed tomographic scan results, infection recovery, and quality of life were satisfactory.

Background. Superimposed acute right ventricular dysfunction in the setting of preexisting pulmonary hypertension is a nearly fatal complication after heart transplantation. The optimal treatment modality remains a matter of debate. Recently, sildenafil citrate, a nonselective pulmonary vasodilator, has gained popularity in the treatment of pulmonary hypertension in transplant candidates. Methods. Herein we have presented a series of 13 patients in whom sildenafil was used to treat right ventricular dysfunction and pulmonary hypertension as detected by transesophageal echocardiography and Swan-Ganz right heart catheterization after heart transplant. Their characteristics were mean age 49 11.4 years; 38.4% with previous cardiac procedures, 30.8% status I, basal pulmonary vascular resistance index 10.4 4.6 WoodU, mean transpulmonary gradient 18.7 5.4 mmHg. In addition to conventional inodilator support, we administered 1 to 3 mg per kilogram of sildenafil. Complete hemodynamic measurements were obtained before and after the institution of the therapy and at 1-month follow-up. Results. Within the first 72 hours, acute right ventricular dysfunction resolved in all cases without untoward side effects or significant systemic impact. Sildenafil significantly decreased the transpulmonary gradient and pulmonary vascular resistance index relative to baseline values; 5.6 1.82 versus 10.4 4.6 WU, (P .05), 13.5 3.4 mm Hg versus 18.7 5.4 mm Hg (P .05), respectively. Improved indices of right ventricular function were observed on echocardiographic monitoring. After 1 month, sildenafil treatment was discontinued. Conclusion. Management of acute right ventricular dysfunction in heart transplant recipients with pulmonary hypertension using sildenafil proved safe and effective.

The objectives of this study were to perform bioelectrical impedance analysis before and after heart transplantation with comparison to healthy subjects. Eight patients (7 men, 1 woman) before (day 0) and after transplantation (day 3, 7, 12, 15, and 180) and 24 healthy controls, matched for sex, age, and body mass were studied. Data collection included bioelectrical impedance analysis (resistance, reactance, and estimates of body water), clinical, and laboratory measurements. Compared with controls, patients had at baseline significantly higher reactance, not significantly different resistance, body weight, total body water, and intra- to extracellular water ratio. After surgery, for reactance, there was an acute decrease followed by a slow, progressive increase up to normal level by day 15. Resistance and body weight did not significantly change; the intra- to extracellular water ratio significantly decreased with stable total body water. Changes in reactance are the main effects induced on bioelectrical impedance by heart transplantation. Acutely, there is a large decrease which likely reflects changes both in water distribution and in cell membrane function. The late changes more likely reflect the shift of body water from the extra- to the intracellular space with stable total body water.