Objective Transcatheter heart valve (THV) procedures are constantly evolving. We report our experience with valve-in-valve, valve-in-ring, and direct-view valve-in-native-ring implantation in the ...mitral position. Methods Fourteen patients undergoing THV implantation in the mitral position were included. Clinical and postoperative data, including echocardiography and further follow-up, were analyzed. Results Ten valve-in-valve and 2 valve-in-ring procedures were successfully performed using the transapical access route. For the third valve-in-ring procedure we used an antegrade left-atrial access via right anterolateral minithoracotomy. In 1 patient surgical mitral valve replacement was planned. Intraoperatively, the annulus appeared severely calcified and regular implantation of a bioprosthesis was not possible. As a last resort, a 29-mm Sapien XT valve (Edwards Lifesciences Inc, Irvine, Calif) was implanted under direct view. The initial result was satisfactory, but on the first postoperative day relevant paravalvular regurgitation occurred. Subsequently, the valve was fixed to an atrial cuff by 1 running suture. In this series 27-, 29-, and 31-mm bioprostheses and 28- and 30-mm annuloplasty rings were treated with 26- or 29-mm Sapien XT valves. Postoperative echocardiography on day 10 and after 6 weeks revealed good prosthesis function in all cases. In 2 valve-in-valve patients who solely received anticoagulation therapy with acetylsalicylic acid, signs of beginning valve thrombosis occurred after 8 weeks and 3 months, respectively. During further course, valve function was normalized using warfarin therapy. Conclusions Our results demonstrate feasibility of valve-in-valve and valve-in-ring THV procedures in the mitral position. Permanent anticoagulation therapy with warfarin seems to be necessary to prevent valve dysfunction. THV implantation in a calcified native mitral ring for bailout seems not to be reproducible and thus cannot be recommended.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Small-conductance calcium-activated potassium (SK) channels are expressed in the heart of various species, including humans. The aim of the present study was to address whether SK channels play a ...functional role in human atria.
Quantitative real-time PCR analyses showed higher transcript levels of SK2 and SK3 than that of the SK1 subtype in human atrial tissue. SK2 and SK3 were reduced in chronic atrial fibrillation (AF) compared with sinus rhythm (SR) patients. Immunohistochemistry using confocal microscopy revealed widespread expression of SK2 in atrial myocytes. Two SK channel inhibitors (NS8593 and ICAGEN) were tested in heterologous expression systems revealing ICAGEN as being highly selective for SK channels, while NS8593 showed less selectivity for these channels. In isolated atrial myocytes from SR patients, both inhibitors decreased inwardly rectifying K(+) currents by ∼15% and prolonged action potential duration (APD), but no effect was observed in myocytes from AF patients. In trabeculae muscle strips from right atrial appendages of SR patients, both compounds increased APD and effective refractory period, and depolarized the resting membrane potential, while only NS8593 induced these effects in tissue from AF patients. SK channel inhibition did not alter any electrophysiological parameter in human interventricular septum tissue.
SK channels are present in human atria where they participate in repolarization. SK2 and SK3 were down-regulated and had reduced functional importance in chronic AF. As SK current was not found to contribute substantially to the ventricular AP, pharmacological inhibition of SK channels may be a putative atrial-selective target for future antiarrhythmic drug therapy.
Early allograft dysfunction following lung transplantation is mainly an ischemia/reperfusion (IR) injury. We showed that relaxin-2 (relaxin) exerts a protective effect in lung IR, attributable to ...decreases in endothelin-1 (ET-1) production, leukocyte recruitment, and free radical generation. Here, we summarize our investigations into relaxin's signalling.
Isolated rat lungs were perfused with vehicle or 5 nM relaxin (n = 6-10 each). Thereafter, experiments were conducted in the presence of relaxin plus vehicle, the protein kinase A inhibitors H-89 and KT-5720, the NO synthase (NOS) inhibitor L-NAME, the iNOS inhibitor 1400W, the nNOS inhibitor SMTC, the extracellular signal-regulated kinase-1/2 (ERK-1/2) inhibitor PD-98059, the phosphatidylinositol-3 kinase (PI3K) inhibitor wortmannin, the endothelin type-B (ETB) antagonist A-192621, or the glucocorticoid receptor (GR) antagonist RU-486. After 90 min ischemia and 90 min reperfusion we determined wet-to-dry (W/D) weight ratio, mean pulmonary arterial pressure (MPAP), vascular release of ET-1, neutrophil elastase (NE), myeloperoxidase (MPO), and malondialdehyde (MDA). Primary rat pulmonary vascular cells were similarly treated.
IR lungs displayed significantly elevated W/D ratios, MPAP, as well as ET-1, NE, MDA, and MPO. In the presence of relaxin, all of these parameters were markedly improved. This protective effect was completely abolished by L-NAME, 1400W, PD-98059, and wortmannin whereas neither PKA and nNOS inhibition nor ETB and GR antagonism were effective. Analysis of NOS gene expression and activity revealed that the relaxin-induced early and moderate iNOS stimulation is ERK-1/2-dependent and counter-balanced by PI3K. Relaxin-PI3K-related phosphorylation of a forkhead transcription factor, FKHRL1, paralleled this regulation. In pulmonary endothelial and smooth muscle cells, FKHRL1 was essential to relaxin-PI3K signalling towards iNOS.
In this short-time experimental setting, relaxin protects against IR-induced lung injury via early and moderate iNOS induction, dependent on balanced ERK-1/2 and PI3K-FKHRL1 stimulation. These findings render relaxin a candidate drug for lung preservation.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Objective: Aortic valve neocuspidization (AVNeo) using autologous pericardium is a promising technique. Expected advantages are reduced immune response, appropriate biomechanics and lower treatment ...expenses. Nevertheless, autologous pericardium can be affected by patient’s age and comorbidities. Usually, glutaraldehyde (GA) - fixed bovine pericardium is the basic material for aortic valve prostheses, easy available and carefully pre-examined in a standardized fabrication process. Aim of the study is the verification of autologous pericardial tissue homogeneity by analysing tissue thickness, biomechanics and extracellular matrix (ECM) composition. Methods: Segments of human GA-fixed pericardium selected by the surgeon based on visual criteria for cusp pre-cut and remaining after surgical AV replacement were investigated in comparison to bovine standard tissue treated equivalently. Pericardium sampling was performed at up to three positions of each sutured cusp for histological or biomechanical analysis, according to tissue availability. Results and Conclusions: Human pericardia exhibited a higher heterogeneity in collagen content, density of vessel structures and elastic moduli. Thickness, vessel density and collagen and elastin content differed significantly between the species. In contrast, significant interindividual differences were detected in most properties investigated for human pericardial samples but only for tissue thickness in bovine tissues. Higher heterogeneity of human pericardium, differing vessel and collagen content compared to bovine state-of-the-art material might be detrimental for long term AV functionality or deterioration and have to be intensely investigated in patients follow up after autologous cusp replacement.
Graphical Abstract
Background The transcatheter valve-in-valve concept has been described for patients requiring redo valve surgery. We report our experience with transapical mitral valve-in-valve implantation. Methods ...Since 2008, 301 patients were treated with transapical transcatheter valve implantation. Seven of these patients presented with a deteriorated mitral valve bioprosthesis and underwent transapical mitral valve-in-valve implantation. Median age was 79 years. Preoperatively, all patients presented in New York Heart Association functional class III. For risk estimation, The Society of Thoracic Surgeons and European System for Cardiac Operative Risk scores were used and predicted high mortality (mean ± standard error of mean: Society of Thoracic Surgeons mortality, 12.3% ± 2.1%; European System for Cardiac Operative Risk mortality, 58.0% ± 7.0%). Mean follow-up time was 93 ± 29 days, with a total of 21.6 patient-months. Results Preoperatively, all patients who had deteriorated bioprostheses presented with severe regurgitation and increased transvalvular pressure gradients (maximal pressure gradient, 23.9 ± 0.9 mm Hg; mean pressure gradient, 11.3 ± 1.0 mm Hg). One patient was identified with mitral valve stenosis (effective orifice area, 0.25 cm2 ). All patients underwent successful transapical mitral valve-in-valve implantation. Sizes of previously implanted bioprostheses were 27, 29, and 31 mm; Edwards SAPIEN valves at sizes 26 and 29 mm were implanted. Postoperatively, echocardiography revealed excellent hemodynamics with no remaining mitral regurgitation in 5 patients and minimal regurgitation in 2 patients. Transvalvular pressure gradients decreased significantly (maximal pressure gradient, 13.8 ± 2.1 mm Hg; mean pressure gradient 5.7 ± 0.8 mm Hg, p < 0.05). One patient had fatal pneumonia on postoperative day 34. No patient died during further follow-up, and all patients remained in New York Heart Association class I or II. Conclusions Our results demonstrate the feasibility of transapical mitral valve-in-valve implantation for treatment of a degenerated bioprosthesis (size range, 27 to 31 mm) using the Edwards SAPIEN valve in sizes 26 and 29 mm.
Slowly inactivating Na+ channels conducting "late" Na+ current (INa,late) contribute to ventricular arrhythmogenesis under pathological conditions. INa,late was also reported to play a role in ...chronic atrial fibrillation (AF). The objective of this study was to investigate INa,late in human right atrial cardiomyocytes as a putative drug target for treatment of AF. To activate Na+ channels, cardiomyocytes from transgenic mice which exhibit INa,late (ΔKPQ), and right atrial cardiomyocytes from patients in sinus rhythm (SR) and AF were voltage clamped at room temperature by 250-ms long test pulses to -30 mV from a holding potential of -80 mV with a 100-ms pre-pulse to -110 mV (protocol I). INa,late at -30 mV was not discernible as deviation from the extrapolated straight line IV-curve between -110 mV and -80 mV in human atrial cells. Therefore, tetrodotoxin (TTX, 10 μM) was used to define persistent inward current after 250 ms at -30 mV as INa,late. TTX-sensitive current was 0.27±0.06 pA/pF in ventricular cardiomyocytes from ΔKPQ mice, and amounted to 0.04±0.01 pA/pF and 0.09±0.02 pA/pF in SR and AF human atrial cardiomyocytes, respectively. With protocol II (holding potential -120 mV, pre-pulse to -80 mV) TTX-sensitive INa,late was always larger than with protocol I. Ranolazine (30 μM) reduced INa,late by 0.02±0.02 pA/pF in SR and 0.09±0.02 pA/pF in AF cells. At physiological temperature (37°C), however, INa,late became insignificant. Plateau phase and upstroke velocity of action potentials (APs) recorded with sharp microelectrodes in intact human trabeculae were more sensitive to ranolazine in AF than in SR preparations. Sodium channel subunits expression measured with qPCR was high for SCN5A with no difference between SR and AF. Expression of SCN8A and SCN10A was low in general, and lower in AF than in SR. In conclusion, We confirm for the first time a TTX-sensitive current (INa,late) in right atrial cardiomyocytes from SR and AF patients at room temperature, but not at physiological temperature. While our study provides evidence for the presence of INa,late in human atria, the potential of such current as a target for the treatment of AF remains to be demonstrated.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
The causative role of inflammation in hypertension-related cardiovascular diseases is evident and calls for development of specific immunomodulatory therapies. We tested the therapeutic efficacy and ...mechanisms of action of developmental endothelial locus-1 (DEL-1), an endogenous antiinflammatory factor, in angiotensin II- (ANGII-) and deoxycorticosterone acetate-salt-induced (DOCA-salt-induced) cardiovascular organ damage and hypertension. By using mice with endothelial overexpression of DEL-1 (EC-Del1 mice) and performing preventive and interventional studies by injecting recombinant DEL-1 in mice, we showed that DEL-1 improved endothelial function and abrogated aortic adventitial fibrosis, medial thickening, and loss of elastin. DEL-1 also protected the mice from cardiac concentric hypertrophy and interstitial and perivascular coronary fibrosis and improved left ventricular function and myocardial coronary perfusion. DEL-1 prevented aortic stiffness and abolished the progression of hypertension. Mechanistically, DEL-1 acted by inhibiting αvβ3 integrin-dependent activation of pro-MMP2 in mice and in human isolated aorta. Moreover, DEL-1 stabilized αvβ3 integrin-dependent CD25+FoxP3+ Treg numbers and IL-10 levels, which were associated with decreased recruitment of inflammatory cells and reduced production of proinflammatory cytokines in cardiovascular organs. The demonstrated effects and immune-modulating mechanisms of DEL-1 in abrogation of cardiovascular remodeling and progression of hypertension identify DEL-1 as a potential therapeutic factor.
Deep sternal wound infection is a rare but feared complication of median thoracotomies and is usually caused by microorganisms from the patient's skin or mucous membranes, the external environment, ...or iatrogenic procedures. The most common involved pathogens are Staphylococcus aureus, Staphylococcus epidermidis and gram-negative bacteria. We aimed to evaluate the microbiological spectrum of deep sternal wound infections in our institution and to establish diagnostic and treatment algorithms.
We retrospectively evaluated the patients with deep sternal wound infections at our institution between March 2018 and December 2021. The inclusion criteria were the presence of deep sternal wound infection and complete sternal osteomyelitis. Eighty-seven patients could be included in the study. All patients received a radical sternectomy, with complete microbiological and histopathological analysis.
In 20 patients (23%) the infection was caused by S. epidermidis, in 17 patients (19.54%) by S. aureus, in 3 patients (3.45%) by Enterococcus spp., in 14 patients (16.09%) by gram-negative bacteria, while in 14 patients (16.09%) no pathogen could be identified. In 19 patients (21,84%) the infection was polymicrobial. Two patients had a superimposed Candida spp.
Methicillin-resistant S. epidermidis was found in 25 cases (28,74%), while methicillin-resistant S. aureus was isolated in only three cases (3,45%). The average hospital stay for monomicrobial infections was 29.93 ± 13.69 days and for polymicrobial infections was 37.47 ± 19.18 (p = 0.03). Wound swabs and tissue biopsies were routinely harvested for microbiological examination. The increasing number of biopsies was associated with the isolation of a pathogen (4.24 ± 2.22 vs. 2.18 ± 1.6, p < 0,001). Likewise, the increasing number of wound swabs was also associated with the isolation of a pathogen (4.22 ± 3.34 vs. 2.40 ± 1.45, p = 0.011). The median duration of antibiotic treatment was 24.62 (4-90) days intravenous and 23.54 (4-70) days orally. The length of antibiotic treatment for monomicrobial infections was 22.68 ± 14.27 days intravenous and 44.75 ± 25.87 days in total and for polymicrobial infections was 31.65 ± 22.29 days intravenous (p = 0.05) and 61.29 ± 41.45 in total (p = 0.07). The antibiotic treatment duration in patients with methicillin-resistant Staphylococci as well as in patients who developed an infection relapse was not significantly longer.
S. epidermidis and S. aureus remain the main pathogen in deep sternal wound infections. The number of wound swabs and tissue biopsies correlates with accurate pathogen isolation. With radical surgical treatment, the role of prolonged antibiotic treatment remains unclear and should be evaluated in future prospective randomized studies.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Vernakalant is a newly developed antiarrhythmic drug against atrial fibrillation (AF). However, its electrophysiological actions on human myocardium are unknown.
Action potentials (APs) and ion ...currents were recorded in right atrial trabeculae and cardiomyocytes from patients in sinus rhythm (SR) and chronic AF. Vernakalant prolonged early repolarization in SR and AF, but late only in AF. AP amplitude (APA) and dV/dtmax were reduced in a concentration- and frequency-dependent manner with IC50 < 10 µM at >3 Hz. Effective refractory period was increased more than action potential duration (APD) in SR and AF. INa was blocked with IC50s of 95 and 84 µM for SR and AF, respectively (0.5 Hz). Vernakalant did not reduce outward potassium currents compared with time-matched controls. However, area under the current-time curve was reduced due to acceleration of current decline with IC50s of 19 and 12 µM for SR and AF, respectively. Vernakalant had less effect on APD than the IKr blocker E-4031, blocked IK,ACh, and had a small inhibitory effect on IK1 at 30 µM. L-Type Ca(2+) currents (SR) were reduced with IC50 of 84 µM.
Rate-dependent block of Na(+) channels represents the main antiarrhythmic mechanism of vernakalant in the fibrillating atrium. Open channel block of early transient outward currents and IK,ACh could also contribute.
An open operation on the aortic arch is a complex procedure that requires not only surgical expertise but also meticulous management to ensure excellent outcomes. In recent years, the procedure has ...often been performed with the patient under circulatory arrest, with antegrade cerebral perfusion. With such a strategy, efficient monitoring to ensure adequate cerebral perfusion is essential. Here we describe a case of Stanford type A aortic dissection repair in which transcranial Doppler sonography was used as an excellent monitoring tool to allow visualization of cerebral flow and the online status of perfusion, providing instant feedback to allow changes in strategy to optimize inadequate cerebral perfusion.
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