Ca2+ dysregulation in cardiac stromal cells sustains fibro-adipose remodeling in Arrhythmogenic Cardiomyopathy and can be modulated by flecainide.

BACKGROUND: Cardiac mesenchymal stromal cells (C-MSC) were recently shown to differentiate into adipocytes and myofibroblasts to promote the aberrant remodeling of cardiac tissue that characterizes arrhythmogenic cardiomyopathy (ACM). A calcium (Ca2+) signaling dysfunction, mainly demonstrated in mouse models, is recognized as a mechanism impacting arrhythmic risk in ACM cardiomyocytes. Whether similar mechanisms influence ACM C-MSC fate is still unknown. Thus, we aim to ascertain whether intracellular Ca2+ oscillations and the Ca2+ toolkit are altered in human C-MSC obtained from ACM patients, and to assess their link with C-MSC-specific ACM phenotypes. METHODS AND RESULTS: ACM C-MSC show enhanced spontaneous Ca2+ oscillations and concomitant increased Ca2+/Calmodulin dependent kinase II (CaMKII) activation compared to control cells. This is manly linked to a constitutive activation of Store-Operated Ca2+ Entry (SOCE), which leads to enhanced Ca2+ release from the endoplasmic reticulum through inositol-1,4,5-trisphosphate receptors. By targeting the Ca2+ handling machinery or CaMKII activity, we demonstrated a causative link between Ca2+ oscillations and fibro-adipogenic differentiation of ACM C-MSC. Genetic silencing of the desmosomal gene PKP2 mimics the remodelling of the Ca2+ signalling machinery occurring in ACM C-MSC. The anti-arrhythmic drug flecainide inhibits intracellular Ca2+ oscillations and fibro-adipogenic differentiation by selectively targeting SOCE. CONCLUSIONS: Altogether, our results extend the knowledge of Ca2+ dysregulation in ACM to the stromal compartment, as an etiologic mechanism of C-MSC-related ACM phenotypes. A new mode of action of flecainide on a novel mechanistic target is unveiled against the fibro-adipose accumulation in ACM.

Right Ventricular Function After Minimally Invasive Mitral Valve Surgery.

OBJECTIVES: Right ventricular (RV) dysfunction is a significant cause of morbidity and mortality after cardiac surgery. Minimally invasive mitral valve surgery (MIMVS) increasingly is being performed. The authors aim was to evaluate postoperative RV function in patients who underwent MIMVS versus traditional mitral valve surgery. DESIGN: Six hundred seventy-five patients who underwent elective isolated mitral valve surgery at Centro Cardiologico Monzino from January 2016 to December 2019 were analyzed. After 1:1 propensity score matching, 60 patients were identified in the MIMVS (study group A) and 58 patients in the median sternotomy (control group B) and compared. SETTING: A university-affiliated scientific institute, monocentric. PARTICIPANTS: Patients. INTERVENTIONS: Mitral valve surgery. MEASUREMENTS AND MAIN RESULTS: No in-hospital deaths occurred. Aortic cross-clamp time (102 [87.5-119] v 83 [61-109] minutes, p = 0.0001), cardiopulmonary bypass duration (161.5 [142.5-181] v 105.5 [74-134] minutes, p < 0.0001) and intensive care unit stay (47 [44-72] v 45 [40-47] hours, p = 0.0015) were significantly longer in group A. The tricuspid annular plane systolic excursion was not different between group A and group B neither postoperatively (15 ± 3 v 14 ± 4 mm, p = 0.1) nor at three-month follow-up (18 ± 4 v 15 ± 3 mm, p = 0.3). No differences in peak postoperative lactates, inotropic score, central venous pressure, and pulmonary artery pulsatility index were observed. The length of hospital stay was significantly shorter in the minimally invasive group (ten [eight-13] v 12 [ten-17], p = 0.006). CONCLUSION: The authors study showed that the surgical strategy had no significant impact on postoperative RV function after mitral valve surgery.

The "P-stitch": A simplified strategy to achieve valvular symmetry during Ozaki procedure.

During Ozaki procedure, relocating a valvular commissure could be technically demanding. This novel technique provides an easy tool to achieve valvular symmetry avoiding commissure shifting.

The prognostic value of left ventricular dimensions at the time of transcatheter aortic valve replacement: A propensity-matched analysis.

AIMS: In the clinical practice a noteworthy proportion of severe symptomatic aortic stenosis patients presents with low-flow low-gradients features, these having reported a less favorable prognosis even when surgically or transcatheter treated. METHODS AND RESULTS: We retrospectively analyzed the prospectively collected data on 1051 consecutive patients undergone balloon-expandable transcatheter aortic valve replacement at our Institution from January 2008 to January 2020. We divided the population according with a mean aortic gradient (MAG) < or ≥40 mmHg and we performed a propensity-matched analysis based on the Society of Thoracic Surgery Score and age, obtaining two homogeneous groups of 314 patients each (Groups A and B, respectively). We then analyzed the outcomes of the two groups by implementing adjusted Cox models adjusted for significant clinical differences between the two groups, such as sex, ejection fraction, comorbidities and other variables not included in the propensity-matched analysis. The only variable associated with both cardiovascular and all-cause events was an ejection fraction ≤35%. Finally, a sensitivity analysis found that an ejection fraction ≤35% was associated with an increase cardiovascular and all-cause mortality only in patients with an indexed end-diastolic volume >97 ml/m2 (p = .0438 and .3363, respectively). CONCLUSIONS: In our series a MAG <40 mmHg was not found to be per se an independent risk factor for cardiac and all-cause mortality after transcatheter aortic valve replacement. The ejection fraction was found to be an independent risk factor only in the context of enlarged left ventricular dimensions.

Percutaneous closure of femoral pseudaneurysm after TAVR.

Fully percutaneous transfemoral transcatheter aortic valve replacement (TF-TAVR) is currently the standard of the catheter-based treatment of severe aortic stenosis patients. Even though experience, lower delivery catheters profile and improved vascular closure devices performances have resulted in an overall reduction of both vascular and bleeding complications after TAVR, femoral pseudoaneurysm due to incomplete local hemostasis may occur, prolonging the in-hospital length of stay, causing discomfort to the patient and potentially evolving in serious consequences affecting the outcome. We report two successful percutaneous ultrasound-guided closure of both the main and secondary femoral access pseudoaneurysm.

Cardiovascular tissue banking activity during SARS-CoV-2 pandemic: evolution of national protocols and Lombardy experience.

The worldwide pandemic outbreak due to severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2) has created unprecedented challenges for public health services. Lombardy, region of the Northern Italy, has been the first area in the Western world whose organs and tissues procurement programs have had to face the virus pandemic emergency. We retrospectively collected and analyzed data about cardiovascular tissues (CT) in 2019 and in 2020. We aimed to describe the rapid evolution of SARS-CoV-2 regulation laws for tissue donor's selection and harvesting from February 2020 until January 2021. As expected the number of CT donors in 2020 was significantly lower than those of 2019 (66 vs. 99, p value 0.02). The total number of CT collected from donors have been 254 in 2019 and 206 in 2020 (p 0.28). Femoral arteries were the most required vascular tissues (55.5% in 2019 and 40% in 2020). Fifty-five and forty-eight pulmonary valves were implanted in 2019 and 2020, respectively. No differences were found for the types of CT requests between the 2 years. The median age of receivers of vascular tissues was 69.6 ± 14.6 years in the 2019 and 63.3 ± 14.9 years in 2020 (p < 0.01). The median age of receivers of pulmonary and aortic valves did not differ between the 2 years (9.32 ± 11.49 vs. 8.36 ± 10.66 and 48.67 ± 27.19 vs. 37.14 ± 31.97 respectively). Despite the dramatically reduction of donors, the number of CT collected has not decreased significantly and so far the CT distribution rate is comparable to those of 2019.

Excess TGF-ß1 Drives Cardiac Mesenchymal Stromal Cells to a Pro-Fibrotic Commitment in Arrhythmogenic Cardiomyopathy.

Arrhythmogenic Cardiomyopathy (ACM) is characterized by the replacement of the myocardium with fibrotic or fibro-fatty tissue and inflammatory infiltrates in the heart. To date, while ACM adipogenesis is a well-investigated differentiation program, ACM-related fibrosis remains a scientific gap of knowledge. In this study, we analyze the fibrotic process occurring during ACM pathogenesis focusing on the role of cardiac mesenchymal stromal cells (C-MSC) as a source of myofibroblasts. We performed the ex vivo studies on plasma and right ventricular endomyocardial bioptic samples collected from ACM patients and healthy control donors (HC). In vitro studies were performed on C-MSC isolated from endomyocardial biopsies of both groups. Our results revealed that circulating TGF-ß1 levels are significantly higher in the ACM cohort than in HC. Accordingly, fibrotic markers are increased in ACM patient-derived cardiac biopsies compared to HC ones. This difference is not evident in isolated C-MSC. Nevertheless, ACM C-MSC are more responsive than HC ones to TGF-ß1 treatment, in terms of pro-fibrotic differentiation and higher activation of the SMAD2/3 signaling pathway. These results provide the novel evidence that C-MSC are a source of myofibroblasts and participate in ACM fibrotic remodeling, being highly responsive to ACM-characteristic excess TGF-ß1.

CPAP Effects on Oxygen Delivery in One-Lung Ventilation During Minimally Invasive Surgical Ablation for Atrial Fibrillation in The Supine Position.

OBJECTIVE: In minimally invasive surgical ablation for atrial fibrillation during video-assisted thoracoscopy surgery, one-lung ventilation (OLV) with a double- lumen tube is commonly employed. In contrast with the majority of thoracic procedures, the patient lies supine; thus, the protective effect of gravity is lost and intrapulmonary shunt remains high. To decrease intrapulmonary shunt and to increase oxygenation, many strategies are utilized: high inspiratory fraction of oxygen (FIO2), positive end-expiratory pressure on the ventilated lung, and continuous positive airway pressure (CPAP) on the deflated lung. DESIGN: The authors performed a prospective, single- center, randomized study to evaluate the effect of additional CPAP in the nonventilated lung on oxygen delivery during surgical ablation for atrial fibrillation via video-assisted thoracoscopy in the supine position. SETTING: University hospital Centro Cardiologico Monzino IRCCS, Milano, Italy. PARTICIPANTS: Twenty-two patients scheduled for minimally invasive surgical ablation for atrial fibrillation. INTERVENTIONS: The patients underwent pressure-controlled ventilation, adjusting inspiratory pressure to obtain a tidal volume of 7 mL/kg while keeping FIO2 constantly 1.0, a respiratory rate to maintain arterial partial pressure of carbon dioxide (PaCO2) between 35 and 40 mmHg, and positive end-expiratory pressure of 5 cmH2O. During OLV, inspiratory pressure was reduced to obtain a tidal volume of 5 mL/kg, maintaining FIO2 of 1.0, a respiratory rate to maintain PaCO2 between 35 and 40 mmHg with capnothorax of 10 cmH2O. The patients were then randomized into the CPAP group (CPAP 10 cmH20 on deflated lung) and NO CPAP group. Inotropic agents (dopamine or dobutamine) were used if cardiac index fell below 1.5 L/min/m2. MEASUREMENTS AND MAIN RESULTS: Twenty-two patients were enrolled, randomized, and completed the study. Median age was 62 years. The difference in arterial partial pressure of oxygen between the 2 groups was shy of significance, p = 0.16. Cardiac index progressively increased during OLV until the end of the procedure in both groups (p < 0.01) and was maintained above 1.5 mL/min/m2 during the whole study time. Arterial oxygen content remained stable during the entire procedure in both groups (p = 0.27). Oxygen delivery index (DO2I) increased significantly during the procedure (p < 0.01); nevertheless, the difference in DO2I between the CPAP and NO CPAP group was nonsignificant (p = 0.61). Intrapulmonary shunt (Qs/Qt) increased during OLV (p < 0.01 for the time effect) and remained high until total lung ventilation was reintroduced. No difference in Qs/Qt was observed between the CPAP and NO CPAP groups (p = 0.98). Similarly, mean pulmonary artery pressure increased significantly during OLV and remained high at the end of the procedure in both groups (time effect p < 0.01). CONCLUSIONS: During OLV for atrial fibrillation surgical ablation in the supine position, CPAP on the deflated lung seemed to be ineffective to reduce Qs/Qt or to increase arterial partial pressure of oxygen and DO2I, provided cardiac output was maintained above 1.5 L/min/m2.

Mitro-aortic valve-in-valve procedures: Many challenges in little space.

Multiple valve replacements are known to carry additional risk of morbidity and mortality in redo context. Currently, a transcatheter-based valve-in-valve approach could be useful in reducing potential serious consequences. On the other hand, this approach poses several technical challenges regarding the device and the procedural aspects. We present the case of a 78-year-old man who presented with symptoms of heart failure due to mitral and aortic bioprosthesis degenerations who was deemed to be at extremely high risk for a conventional redo surgery. A two-step transcatheter-based approach was planned and a transfemoral aortic valve-in-valve procedure was followed by a transapical mitral valve-in-valve implantation with a favorable early and long-term outcome.

In vivo comparison of the optiflow and EZ glide aortic dispersion cannulas.

OBJECTIVES: Morbidity associated with coronary artery bypass grafts and embolization during aortic cannulation is strongly related to patient characteristics/comorbidities, arterial cannulation site used and the shape of arterial cannulae tips. The desired features of an arterial cannula should be to mitigate the morbid effects of these cannulas and to focus on achieving higher blood flows with lower cannula pressures (CPs). MATERIALS AND METHODS: To evaluate the in vivo performance of two aortic dispersion flow cannulas: the Optiflow (Sorin Group, Italy) and EZ Glide (Edwards Lifesciences). They were evaluated for CPs, pump-flow rates (FRs), and plasma-free hemoglobin (Hb) over a 12-month period. Data were collected in a prospective, randomized (1:1), nonblinded, monocentric study with a cohort of 30 patients (optiflow group N = 15; EZ Glide group N = 15). RESULTS: The optiflow cannula was found to have decreasing CPs as the pump FRs were increased (112.3 ± 10.9 vs 131.1 ± 11.4 mm Hg; P < .001). Results indicated no significant differences between groups for increases in plasma free Hb (P = .41) and total microembolic signals counts during the period of cardiac surgery (P = .63). CONCLUSIONS: Both optiflow and EZ Glide dispersion flow arterial cannulas performed well, but the optiflow cannula demonstrated an ability to increase pump FRs with lower arterial line and CPs than the EZ Glide cannula. This implies an ability to improve peripheral perfusion while reducing cannula shear stress and the risk of endothelial damage, thereby having the potential to reduce the risk of atherosclerotic plaque dislodgement.

Composite graft using an Edwards Intuity Elite rapid deployment bioprosthesis for aortic root replacement.

We describe a technique using an Edwards Intuity Elite rapid deployment bioprosthesis to construct a composite graft for an aortic root replacement.

Normal human mitral valve proteome: A preliminary investigation by gel-based and gel-free proteomic approaches.

The mitral valve is a highly complex structure which regulates blood flow from the left atrium to the left ventricle (LV) avoiding a significant forward gradient during diastole or regurgitation during systole. The integrity of the mitral valve is also essential for the maintenance of normal LV size, geometry, and function. Significant advances in the comprehension of the biological, functional, and mechanical behavior of the mitral valve have recently been made. However, current knowledge of protein components in the normal human mitral valve is still limited and complicated by the low cellularity of this tissue and the presence of high abundant proteins from the extracellular matrix. We employed here an integrated proteomic approach to analyse the protein composition of the normal human mitral valve and reported confident identification of 422 proteins, some of which have not been previously described in this tissue. In particular, we described the ability of pre-MS separation technique based on liquid-phase IEF and SDS-PAGE to identify the largest number of proteins. We also demonstrated that some of these proteins, e.g. αB-Crystallin, septin-11, four-and-a-half LIM domains protein 1, and dermatopontin, are synthesised by interstitial cells isolated from human mitral valves. These initial results provide a valuable basis for future studies aimed at analysing in depth the mitral valve protein composition and at investigating potential pathogenetic molecular mechanisms. Data are available via ProteomeXchange with identifier PXD004397.

Postdilatation ballooning of an Edwards ELITE rapid deployment bioprosthesis for a severe paravalvular leak.

Severe paravalvular leak may be observed following rapid deployment aortic valve implantation. We report an open off-label use of postdilatation ballooning of an Edwards Intuity ELITE aortic prosthesis to manage an intraoperative paravalvular leak.

Acute aortic insufficiency due to rupture of an aortic valve commissure.

Myxomatous degeneration generally involves the atrioventricular valves (mitral and tricuspid). Rarely, it may affect the aortic or pulmonary valve. We report a case of an acute severe aortic insufficiency due to a rupture of a commissure of the aortic valve in a patient who had previously undergone mitral valve surgery for myxomatous mitral valve prolapse.

Aortic valve neocuspidization and bioprosthetic valves: Evaluating turbulence haemodynamics.

Aortic valve disease is often treated with bioprosthetic valves. An alternative treatment is aortic valve neocuspidization which is a relatively new reparative procedure whereby the three aortic cusps are replaced with patient pericardium or bovine tissues. Recent research indicates that aortic blood flow is disturbed, and turbulence effects have yet to be evaluated in either bioprosthetic or aortic valve neocuspidization valve types in patient-specific settings. The aim of this study is to better understand turbulence production in the aorta and evaluate its effects on laminar and turbulent wall shear stress. Four patients with aortic valve disease were treated with either bioprosthetic valves (n=2) or aortic valve neocuspidization valvular repair (n=2). Aortic geometries were segmented from magnetic resonance images (MRI), and 4D flow MRI was used to derive physiological inlet and outlet boundary conditions. Pulsatile large-eddy simulations were performed to capture the full range of laminar, transitional and turbulence characteristics in the aorta. Turbulence was produced in all aortas with highest levels occurring during systolic deceleration. In the ascending aorta, turbulence production is attributed to a combination of valvular skew, valvular eccentricity, and ascending aortic dilation. In the proximal descending thoracic aorta, turbulence production is dependent on the type of arch-descending aorta connection (e.g., a narrowing or sharp bend) which induces flow separation. Laminar and turbulent wall shear stresses are of similar magnitude throughout late systolic deceleration and diastole, although turbulent wall shear stress magnitudes exceed laminar wall shear stresses between 27.3% and 61.1% of the cardiac cycle. This emphasises the significance of including turbulent wall shear stress to improve our comprehension of progressive arterial wall diseases. The findings of this study recommend that aortic valve treatments should prioritise minimising valvular eccentricity and skew in order to mitigate turbulence generation.

See It Best: A Propensity-Matched Analysis of Ultrasound-Guided versus Blind Femoral Artery Puncture in Balloon-Expandable TAVI.

Background: Currently, transcatheter aortic valve implantation (TAVI) is the standard procedure recommended for patients over 75 years of age with symptomatic aortic valve stenosis. Percutaneous transfemoral (TF) access is the main route used to perform the procedure. Among periprocedural complications, access-related ones are the most frequent, potentially leading to prolonged in-hospital stays and transfusions. Methods: We performed a retrospective analysis of prospectively collected data on consecutive patients undergoing TF-TAVI with the latest generation balloon-expandable transcatheter valve between 2013 and 2022. Results: A total of 600 patients were analyzed, differentiating the population between ultrasound-guided and blind common femoral artery puncture. Valve Academic Research Consortium 3 (VARC-3)criteria were used to report at 30 days and follow-up. In our propensity-matched comparison of the two groups, we found a strong reduction in access-related complications in the echo-guided group, particularly in terms of reduction of major and minor bleedings. We also found a significant trend in reduction of local complications, such as pseudoaneurysms, hematomas, arterio-venous fistulas, dissection of the femoral or iliac arteries, and stenosis. Conclusions: Although there is a lack of consensus on the role of ultrasound-guided puncture, we found better outcomes for patients having an echo-guided puncture of the main access, particularly with regard to access-related complications, early mobilization, and early discharge home.

Aortic valve leaflet glycosaminoglycans composition and modification in severe chronic valve regurgitation.

BACKGROUND AND AIM OF THE STUDY: The surgical segments of aortic valve leaflets from patients with severe chronic aortic regurgitation were analyzed (by percentage and structure) for their content of complex polysaccharides and glycosaminoglycans (GAGs), and compared with control segments. METHODS: The GAG, hyaluronic acid (HA), chondroitin sulfate (CS) and dermatan sulfate (DS) and disaccharide contents were determined in segments (leaflet, root attachment region and belly) of aortic valve leaflets (non-coronary, left coronary and right coronary) using a multi-analytical approach. RESULTS: The aortic valve leaflets showed the presence of HA and CS/DS, with an overall charge density of -0.51-0.55. The CS/DS polymers showed a 4-sulfated/6-sulfated ratio of -0.70-0.77 in the belly, and -1.60-1.72 in commissure parts (-/+124%). The total amount of GAGs was -1.60-2.40 microg/mg of tissue. A significant increase in sulfated GAGs was observed in all valve parts in patients suffering from severe aortic insufficiency, as well as an increase in the 4-sulfated/6-sulfated ratio in the leaflet belly (-/+102%). CONCLUSION: It is speculated that differences in 4-sulfated/6-sulfated ratio determined in the belly and leaflet attachment region-commissure parts of the leaflets may correlate with the tensile or compressive loading of normal aortic valve regions. At the same time, it may be assumed that the increase in sulfated GAGs and 4-sulfated/6-sulfated ratio in the leaflet belly of valves taken from patients suffering severe aortic insufficiency was consistent with an altered matrix microstructure capable of influencing the hydration of these pathological tissues, and of conditioning their mechanical weakness.