Active mitral ring for post-surgical remote correction of residual mitral regurgitation on the beating heart†

OBJECTIVES Residual mitral regurgitation after valve repair worsens patients' clinical outcome. Postimplant adjustable mitral rings potentially address this issue, allowing the reshaping of the annulus on the beating heart under echocardiography control. We developed an original mitral ring allowing valve geometry remodelling after the implantation and designed an animal study to assess device effectiveness in correcting residual mitral regurgitation. METHODS The device consists of two concentric rings: one internal and flexible, sutured to the mitral annulus and a second external and rigid. A third conic element slides between the two rings, modifying the shape of the flexible ring. This sliding element is remotely activated with a rotating tool. Animal model: in adult swine, under cardio pulmonary bypass and cardiac arrest, we shortened the primary chordae of P2 segment to reproduce Type III regurgitation and implanted the active ring. We used intracardiac ultrasound to assess mitral regurgitation and the efficacy of the active ring to correct it. RESULTS Severe mitral regurgitation (3+ and 4+) was induced in eight animals, 54 ± 6 kg in weight. Vena contracta width decreased from 0.8 ± 0.2 to 0.1 cm; proximal isovelocity surface area radius decreased from 0.8 ± 0.2 to 0.1 cm and effective regurgitant orifice area decreased from 0.50 ± 0.1 to 0.1 ± 0.1 cm2. Six animals had a reversal of systolic pulmonary flow that normalized following the activation of the device. All corrections were reversible. CONCLUSIONS Postimplant adjustable mitral ring corrects severe mitral regurgitation through the reversible modification of the annulus geometry on the beating heart. It addresses the frequent and morbid issue of recurrent mitral valve regurgitatio

Transapical aortic valve replacement in extreme-risk patients: outcome, risk factors and mid-term results

OBJECTIVES Transcatheter aortic valve replacement (TAVR) provides good results in selected high-risk patients. However, it is unclear whether this procedure carries advantages in extreme-risk profile patients with logistic EuroSCORE above 35%. METHODS From January 2009 to July 2011, of a total number of 92 transcatheter aortic valve procedures performed, 40 ‘extreme-risk' patients underwent transapical TAVR (TA-TAVR) (EuroSCORE above 35%). Variables were analysed as risk factors for hospital and mid-term mortality, and a 2-year follow-up (FU) was obtained. RESULTS The mean age was: 81 ± 10 years. Twelve patients (30%) had chronic pulmonary disease, 32 (80%) severe peripheral vascular disease, 14 (35%) previous cardiac surgery, 19 (48%) chronic renal failure (2 in dialysis), 7 (17%) previous stroke (1 with disabilities), 3 (7%) a porcelain aorta and 12 (30%) were urgent cases. Mean left ventricle ejection fraction (LVEF) was 49 ± 13%, and mean logistic EuroSCORE was 48 ± 11%. Forty stent-valves were successfully implanted with six Grade-1 and one Grade-2 paravalvular leakages (success rate: 100%). Hospital mortality was 20% (8 patients). Causes of death following the valve academic research consortium (VARC) definitions were: life-threatening haemorrhage (1), myocardial infarction (1), sudden death (1), multiorgan failure (2), stroke (1) and severe respiratory dysfunction (2). Major complications (VARC definitions) were: myocardial infarction for left coronary ostium occlusion (1), life-threatening bleeding (2), stroke (2) and acute kidney injury with dialysis (2). Predictors for hospital mortality were: conversion to sternotomy, life-threatening haemorrhage, postoperative dialysis and long intensive care unit (ICU) stay. Variables associated with hospital mortality were: conversion to sternotomy (P = 0.03), life-threatening bleeding (P = 0.02), acute kidney injury with dialysis (P = 0.03) and prolonged ICU stay (P = 0.02). Mean FU time was 24 months: actuarial survival estimates for all-cause mortality at 6 months, 1 year, 18 months and 2 years were 68, 57, 54 and 54%, respectively. Patients still alive at FU were in good clinical condition, New York Heart Association (NYHA) class 1-2 and were never rehospitalized for cardiac decompensation. CONCLUSIONS TA-TAVR in extreme-risk patients carries a moderate risk of hospital mortality. Severe comorbidities and presence of residual paravalvular leakages affect the mid-term survival, whereas surviving patients have an acceptable quality of life without rehospitalizations for cardiac decompensatio

Pyrrolidine dithiocarbamate administered during ex-vivo lung perfusion promotes rehabilitation of injured donor rat lungs obtained after prolonged warm ischemia.

Damaged lung grafts obtained after circulatory death (DCD lungs) and warm ischemia may be at high risk of reperfusion injury after transplantation. Such lungs could be pharmacologically reconditioned using ex-vivo lung perfusion (EVLP). Since acute inflammation related to the activation of nuclear factor kappaB (NF-κB) is instrumental in lung reperfusion injury, we hypothesized that DCD lungs might be treated during EVLP by pyrrolidine dithiocarbamate (PDTC), an inhibitor of NF-κB. Rat lungs exposed to 1h warm ischemia and 2 h cold ischemia were subjected to EVLP during 4h, in absence (CTRL group, N = 6) or in presence of PDTC (2.5g/L, PDTC group, N = 6). Static pulmonary compliance (SPC), peak airway pressure (PAWP), pulmonary vascular resistance (PVR), and oxygenation capacity were determined during EVLP. After EVLP, we measured the weight gain of the heart-lung block (edema), and the concentration of LDH (cell damage), proteins (permeability edema) and of the cytokines IL-6, TNF-α and CINC-1 in bronchoalveolar lavage (BAL), and we evaluated NF-κB activation by the degree of phosphorylation and degradation of its inhibitor IκBα in lung tissue. In CTRL, we found significant NF-κB activation, lung edema, and a massive release of LDH, proteins and cytokines. SPC significantly decreased, PAWP and PVR increased, while oxygenation tended to decrease. Treatment with PDTC during EVLP inhibited NF-κB activation, did not influence LDH release, but markedly reduced lung edema and protein concentration in BAL, suppressed TNFα and IL-6 release, and abrogated the changes in SPC, PAWP and PVR, with unchanged oxygenation. In conclusion, suppression of innate immune activation during EVLP using the NF-κB inhibitor PDTC promotes significant improvement of damaged rat DCD lungs. Future studies will determine if such rehabilitated lungs are suitable for in vivo transplantation

Treatment of pleural malignancies by photo-induction combined to systemic chemotherapy: Proof of concept on rodent lung tumors and feasibility study on porcine chest cavities

Background: Low-dose, Visudyne (R)-mediated photodynamic therapy (photo-induction) was shown to selectively enhance tumor vessel transport causing increased uptake of systemically administered chemotherapy in various tumor types grown on rodent lungs. The present experiments explore the efficacy of photo-induced vessel modulation combined to intravenous (IV) liposomal cisplatin (Lipoplatin (R)) on rodent lung tumors and the feasibility/toxicity of this approach in porcine chest cavities. Material and Methods: Three groups of Fischer rats underwent orthotopic sarcoma (n = 14), mesothelioma (n = 14), or adenocarcinoma (n = 12) implantation on the left lung. Half of the animals of each group had photoinduction (0.0625 mg/kg Visudyne (R), 10 J/cm(2)) followed by IV administration of Lipoplatin (R) w (5 mg/kg) and the other half received Lipoplatin (R) without photo-induction. Then, two groups of minipigs underwent intrapleural thoracoscopic (VATS) photo-induction (0.0625 mg/kg Visudyne (R); 30 J/cm(2) hilum; 10 J/cm(2) apex/diaphragm) with in situ light dosimetry in combination with IV Lipoplatin (R) administration (5 mg/kg). Protocol I (n = 6) received Lipoplatin (R) immediately after light delivery and Protocol II (n = 9) 90 minutes before light delivery. Three additional animals received Lipoplatin (R) and VATS pleural biopsies but no photo-induction (controls). Lipoplatin (R) concentrations were analyzed in blood and tissues before and at regular intervals after photo-induction using inductively coupled plasma mass spectrometry. Results: Photo-induction selectively increased Lipoplatin (R) uptake in all orthotopic tumors. It significantly increased the ratio of tumor to lung Lipoplatin (R) concentration in sarcoma (P = 0.0008) and adenocarcinoma (P = 0.01) but not in mesothelioma, compared to IV drug application alone. In minipigs, intrapleural photo-induction combined to systemic Lipoplatin (R) was well tolerated with no toxicity at 7 days for both treatment protocols. The pleural Lipoplatin (R) concentrations were not significantly different at 10 and 30 J/cm(2) locations but they were significantly higher in protocol I compared to II (2.37 +/- 0.7 vs. 1.37 +/- 0.7 ng/mg, P < 0.001). Conclusion: Visudyne (R)-mediated photo-induction selectively enhances the uptake of IV administered Lipoplatin (R) in rodent lung tumors. Intrapleural VATS photo-induction with identical treatment conditions combined to IV Lipoplatin chemotherapy is feasible and well tolerated in a porcine model. Lasers Surg. Med. 47:807-816, 2015. (C) 2015 Wiley Periodicals, Inc

Experimental ex vivo lung perfusion with sevoflurane: effects on damaged donor lung grafts

Abstract OBJECTIVES Volatile anaesthetics can provide significant protection against reperfusion injury in various experimental settings. The aim of this study was to assess the potential of sevoflurane treatment, the most commonly used volatile anaesthetic in modern anaesthesia, in rat lungs donated after circulatory death and reconditioned in an ex vivo lung perfusion (EVLP) system. METHODS Fifteen rats were sacrificed and divided into 3 groups. In the control and sevoflurane groups, the heart-lung blocks were exposed to 1 h of warm ischaemia and 2 h of cold ischaemia and were mounted on an EVLP circuit for 3 h, in the absence or in the presence of 2% sevoflurane. In the baseline group, heart-lung blocks were harvested immediately after euthanasia. Physiological data, lung nitro-oxidative stress, lactate dehydrogenase (LDH), expression of cytokines, oedema and histopathological findings were assessed during or post-EVLP. RESULTS The sevoflurane group showed significantly reduced LDH (8.82 ± 3.58 arbitrary unit vs 3.80 ± 3.02 arbitrary unit, P = 0.03), protein carbonyl (1.17 ± 0.44 nmol⋅mg−1 vs 0.55 ± 0.11 nmol⋅mg−1, P = 0.006), 3-nitrotyrosine (197.44 ± 18.47 pg⋅mg−1 vs 151.05 ± 23.54 pg⋅mg−1, P = 0.004), cytokine-induced neutrophil chemoattractant factor 1 (1.17 ± 0.32 ng⋅mg−1 vs 0.66 ± 0.28 ng⋅mg−1, P = 0.03) and tumour necrosis factor alpha (1.50 ± 0.59 vs 0.59 ± 0.38 ng⋅mg−1, P = 0.02) when compared with the control group. In addition, sevoflurane lungs gained significantly less weight (0.72 ± 0.09 g vs 0.72 ± 0.09 g, P = 0.044), had less perivascular oedema (0.58 ± 0.09 vs 0.47 ± 0.07, P = 0.036), and improved static pulmonary compliance (+0.215 ml⋅cmH2O−1, P = 0.003) and peak airways pressure (-1.33 cmH2O, P = 0.04) but similar oxygenation capacity (+1.61 mmHg, P = 0.77) and pulmonary vascular resistances (+0.078 mmHg⋅min⋅ml−1, P = 0.15) when compared with the control group. CONCLUSIONS These findings suggest that the potential of sevoflurane in protecting the lungs donated after cardiac death and reconditioned using EVLP could improve the outcome of these lungs following subsequent transplantation

Pulmonary vascular resistance and oxygenation index during EVLP.

<p>Pulmonary vascular resistance (A) was calculated as (mean pulmonary artery pressure - left atrial pressure)/perfusion flow). The oxygenation capacity (B) was calculated as the difference in the partial pressure of O₂ between the effluent and the affluent arms of the EVLP circuits. The vascular resistance and oxygenation capacity were computed after 60 minutes of EVLP (baseline values), and every 30 minutes thereafter. Means ± s.e.m. † p < 0.05 vs baseline value; * p<0.05 PDTC vs CTRL (two way ANOVA with Bonferroni’s adjustments for multiples comparisons).</p

Indices of lung edema.

<p>A. Weight gain of the heart-lung blocks expressed in grams, represents the difference between weight of the heart-lung blocks measured before and at the end of EVLP. B. The concentration of proteins in the BAL fluid (in mg^.ml^-1 BAL fluid) was measured as an index of high permeability edema. BASE: BAL fluid and was obtained from normal rats sacrificed without any intervention (Normal, baseline values, N = 3); CTRL: Ischemia followed by EVLP with Steen® solution alone (N = 6); PDTC: Ischemia followed by EVLP with PDTC treatment (N = 6). Means ± s.e.m.* p<0.05 (Heart-lung block weight gain: unpaired <i>t</i> test; Proteins in BAL fluid: ANOVA followed by Tukey’s test).</p