Konstantin Alexiou

Pushing the limits—further evolutions of transcatheter valve procedures in the mitral position, including valve-in-valve, valve-in-ring, and valve-in-native-ring

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.

Transapical transcatheter aortic valve implantation vs conventional aortic valve replacement in high-risk patients with previous cardiac surgery: a propensity-score analysis

OBJECTIVES The present analysis compared clinical and mid-term outcomes of patients with previous cardiac surgery undergoing transapical transcatheter aortic valve implantation (TAVI) with propensity-matched patients undergoing conventional redo aortic valve replacement (cAVR). METHODS Since 2008, 508 patients were treated with TAVI. Fifty-three of these patients presented with a history of cardiac surgery and underwent transapical TAVI using the Edwards SAPIEN bioprosthesis. A propensity-matched control group of 53 patients receiving cAVR was generated out of the hospitals database. The mean age for all the patients was 77.8 ± 4.5 years. The logistic EuroSCORE was 28.4 ± 13.6% in mean, and mean EuroSCORE II was 8.56 ± 3.93%. The mean follow-up time was 245 ± 323 days, which equated to a total of 700 patient-months. RESULTS The observed hospital mortality did not differ significantly between TAVI and cAVR (TAVI: 9.4% and cAVR: 5.7%; P = 0.695). Six-month survival was 83.0% for the TAVI and 86.8% for the cAVR patients (P = 0.768). Postoperative bleedings (TAVI: 725 ± 1770 ml and cAVR: 1884 ± 6387; P = 0.022), the need for transfusion (TAVI: 1.7 ± 5.3 vs cAVR: 6.2 ± 13.7 units packed red blood cells (PRBC); P = 0.030), consecutive rethoracotomy (TAVI: 1.9% vs cAVR: 16.9%; P = 0.002) and postoperative delirium (TAVI: 11.5% vs cAVR: 28.3%; P = 0.046) were more common in the cAVR patients. The TAVI patients suffered more frequently from respiratory failure (TAVI: 11.3% vs cAVR: 0.0%; P = 0.017) and mean grade of paravalvular regurgitation (TAVI: 0.8 ± 0.2 vs cAVR: 0.0; P = 0.047). Although primary ventilation time (P = 0.020) and intensive care unit stay (P = 0.022) were shorter in the TAVI patients, mean hospital stay did not differ significantly (P = 0.108). CONCLUSIONS Transapical TAVI as well as surgical aortic valve replacement provided good clinical results. The pattern of postoperative morbidity and mortality was different for both entities, but the final clinical outcome did not differ significantly. Both techniques can be seen as complementary approaches by means of developing a tailor-made and patient-orientated surgery.

Relaxin improves TNF-α-induced endothelial dysfunction: the role of glucocorticoid receptor and phosphatidylinositol 3-kinase signalling.

AIMS Human relaxin-2 influences renal and cardiovascular functions. We investigated its effects on experimental endothelial dysfunction. METHODS AND RESULTS Acetylcholine-mediated vasodilation of rat aortic rings, impaired by 48 h tumour necrosis factor-α (TNF-α) treatment, was dose-dependently improved by relaxin co-incubation, an effect sensitive to phosphatidylinositol 3-kinase (PI3K) inhibition and the glucocorticoid receptor (GR) antagonist RU-486. TNF increased endothelial nitric oxide synthase (eNOS) phosphorylation at Thr495 and decreased total eNOS expression and both basal and stimulated eNOS activity. Relaxin co-incubation did not affect eNOS expression but improved its activity via PI3K-dependent Thr495 dephosphorylation and Ser1177 phosphorylation, and additional Ser633 phosphorylation. Via GR, relaxin attenuated the TNF-related stimulation of endothelin-1 expression, superoxide and nitrotyrosine formation, and arginase II expression. Relaxin restored, via GR-CCAAT/enhancer-binding protein-β (c/EBP-β)-mediated promoter stimulation, the compromised expression of superoxide dismutase-1 (SOD1). In rat aortic endothelial cells, relaxin activated protein kinase B (Akt) and repressed TNF-induced nuclear factor-κB and activator protein-1. Finally, the relevance of the different findings to the model used was proved by pharmacological interventions. CONCLUSION Relaxin improved endothelial dysfunction by promoting eNOS activity, suppressing endothelin-1 and arginase-II expression, and up-regulating SOD1 via GR, GR-c/EBP-β, and PI3K-Akt pathways. This corroborates the notion that it functions as an endogenous and potentially therapeutic vasoprotector.

Coronary constriction and consequent cardiodepression in pulmonary embolism are mediated by pulmonary big endothelin and enhanced in early endothelial dysfunction.

OBJECTIVES Myocardial ischemia plays a central role in the development of right ventricular failure after acute pulmonary embolism. This study investigates whether pulmonary mediators act specifically on coronary tone and cardiac contractile function in acute pulmonary microembolization and whether such effects are altered in the case of early systemic atherosclerosis. We employ a novel model of serial perfusion in which an isolated rabbit heart is perfused with the effluent of the same animals isolated lung. DESIGN Controlled experiment using isolated organs. SETTING Experimental laboratory. SUBJECTS Male New Zealand White rabbits (controls). Age-matched, male Watanabe rabbits (hypercholesterolemic, development of accelerated atherosclerosis). INTERVENTIONS Seven isolated control and seven isolated Watanabe hearts were perfused with the saline effluent of the same animals isolated lung. After the assessment of the baseline data, the lungs were gradually embolized with glass beads measuring 100 microm in diameter to induce an increase in mean pulmonary arterial pressure from 6 to 8 mm Hg, at baseline, up to 25 mm Hg. MEASUREMENTS AND MAIN RESULTS Pulmonary embolization to 25 mm Hg evoked a coronary constriction, measured as coronary flow decrease to 89 +/- 7% of the baseline value in controls. In the Watanabe group, coronary constriction was significantly enhanced, compared with controls, with coronary flow decreasing to 76 +/- 6% of the baseline value. In both groups, coronary constriction was followed by a deterioration in cardiac contractile performance. This cardiodepression was significantly deeper in Watanabe hearts with respect to both maximum ventricular pressures and maximum rates of pressure development and decline. Coronary constriction and cardiodepression were prevented by coronary infusion of the nonselective endothelin antagonist PD-145065, the endothelinA antagonists A-127722 and BQ-123, and the endothelin-converting enzyme inhibitor phosphoramidon. Concentration of big endothelin in pulmonary effluent increased from 5.6 +/- 0.3 pmol/L in controls and 5.6 +/- 0.2 pmol/L in the Watanabe group, at baseline, to 8.8 +/- 0.4 pmol/L in controls and 8.9 +/- 0.4 pmol/L in the Watanabe group, at 25 mm Hg pulmonary arterial pressure. Endothelin was not detectable at any time during the experiment in pulmonary effluent. The coronary gradient, calculated as a difference in concentration between coronary and pulmonary effluent, was negative for big endothelin and positive for endothelin in both groups. CONCLUSIONS We have demonstrated that an increase in pulmonary release of big endothelin occurs during lung embolism, which, in turn, results in coronary constriction and consequent cardiodepression. This action of big endothelin is based on its local coronary conversion into endothelin. In addition, coronary endothelial dysfunction, attributed to early systemic atherosclerosis, was shown to represent a specific risk factor in these events.

Relaxin protects rat lungs from ischemia-reperfusion injury via inducible NO synthase: role of ERK-1/2, PI3K, and forkhead transcription factor FKHRL1.

Introduction 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. Materials and Methods 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. Results 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. Conclusion 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.

The Positive Inotropic Effect of Relaxin-2 in Human Atrial Myocardium is Preserved in End-Stage Heart Failure: Role of Gi-Phosphoinositide-3 Kinase Signaling

BACKGROUND Relaxin-2, a candidate drug for acute heart failure, has been tested successfully in the first human trials. We investigated relaxins inotropic effects in human myocardium. METHODS AND RESULTS In atrial samples from donor (n = 7) and failing (n = 7) hearts, relaxin-2 evoked remarkable positive inotropic effects: showing a half maximum effective concentration of < 1 nmol/L, the maximum peak developed tension (PDT) rose to approximately 270% of baseline, without differences between failing and nonfailing myocardium. The effects critically depended on protein kinase A activation and inhibition of the transient potassium outward current; phosphoinositide-3 kinase inhibition and pertussis toxin pretreatment moderately blunted the effects in nonfailing but markedly suppressed them in failing myocardium. Action potential recordings revealed identical effects of inhibition of the transient potassium outward current and relaxin. In ventricular myocardium, however, relaxin did not show any inotropic effects. The expression of the RXFP1 receptor was moderately decreased in failing compared with nonfailing atrial myocardium but not detectable in any ventricular samples. CONCLUSIONS Relaxin is a positive inotrope in nonfailing and failing human atria, with critical involvement of protein kinase A and inhibition of the transient potassium outward current and an increasing role for G(i) protein-phosphoinositide-3 kinase signaling in failing myocardium.

Relaxin is a candidate drug for lung preservation: Relaxin-induced protection of rat lungs from ischemia-reperfusion injury

BACKGROUND Pulmonary injury leading to early allograft dysfunction is caused by ischemia-reperfusion injury (IR) and originates from multiple pathogenic events, including endothelial damage, neutrophil extravasation into tissue, and peroxidation of cell membrane lipids, followed by pulmonary cell alterations and edema. The potent vasoconstrictor and proinflammatory mediator endothelin (ET)-1 plays a major role in this cascade. This study was conducted to determine whether treatment with relaxin, an anti-inflammatory and vasoactive hormone, prevents IR. METHODS Isolated male Wistar rat lungs were perfused in a recirculatory model in the presence of 5-nmol/liter relaxin (n = 17) or vehicle alone (n = 14). After IR (60 minutes each) we determined wet-to-dry weight ratio, and levels of ET-1, neutrophil elastase (NE), myeloperoxidase (MPO), and malondialdehyde (MDA). RESULTS IR lungs displayed significantly elevated W/D ratios after IR compared with control lungs (p = 0.001). In the presence of relaxin, the values obtained under IR conditions were significantly reduced compared with those in the vehicle-treated IR group, but not significantly different from those obtained in the control + relaxin group (p = 0.079). The IR-stimulated increase in ET-1, NE, MPO, and MDA (3.6-, 8.4-, 6.0- and 3.0-fold over baseline, p < 0.001) was significantly reduced by relaxin (p < 0.007). CONCLUSION These results show that human relaxin exerts a protective effect in IR-induced lung injury, likely due to ET reduction, endothelial protection, decreased leukocyte recruitment, and hindrance of free radical-mediated tissue injury, which renders relaxin a candidate drug for lung preservation.

The impact of preoperative neurological events in patients suffering from native infective valve endocarditis

OBJECTIVES Infective native valve endocarditis (NVE) complicated by a preoperative neurological event still remains a surgical challenge. Particularly, great uncertainty exists with regard to the optimal timing of surgery. We call for a multidisciplinary team approach for individualized risk estimation and analysed our experience obtained over the past decade. METHODS Between 1997 and 2012, a total of 495 patients underwent valve surgery for the treatment of NVE. Of these, 70 (14.1%) patients suffered from NVE complicated by an acute neurological event and formed the study group. The remaining 425 (85.9%) patients served as the control group. The mean age of the predominantly male (80.0%) study population was 54 ± 14 years. EuroSCORE and EuroSCORE II predicted a high surgical risk (24.9 ± 6.8 and 10.8 ± 8.1%, respectively). The mean follow-up time was 4.0 ± 3.1 years, ranging up to 15.6 years with an interquartile range from 1.7 to 5.4 years. An interdisciplinary team consisting of a cardiac surgeon, a cardiologist and a neurologist made the decision for surgery. RESULTS Observed neurological deficits mainly consisted of ischaemic stroke (75.7%), meningoencephalitis (12.9%) and intracerebral haemorrhage (8.6%). The mean time interval between the neurological event and surgery was 8.7 ± 10.3 days for all patients, 8.0 ± 7.0 days for ischaemic stroke and 17 ± 24 days for intracerebral haemorrhage. Postoperatively, most of the patients experienced no change (22.9%) or even improvement (67.1%) of their neurological symptoms. Only 10.0% showed further deterioration of their neurological status. This was particularly true for patients suffering from intracerebral haemorrhage, with 33.3% experiencing further neurological impairment. The presence of a preoperative neurological event was identified as an independent risk factor for in-hospital mortality (OR 2.66; 95% CI: 1.02-6.78; P = 0.046) but not for mortality during further follow-up (P = 0.257). The hospital mortality rate was 17.2%; and the 1-, 5- and 10-year survival rates were 74.3, 68 ± 5.0 and 67.1 ± 9.0%, respectively. CONCLUSIONS NVE complicated by neurological events remains a challenging disease with high mortality and morbidity. Cardiac surgery seemed to be safe in the observed time interval, particularly for patients suffering from ischaemic stroke. A multidisciplinary approach is advocated for very individualized risk estimation.

Stimulation of pulmonary big endothelin-1 and endothelin-1 by antithrombin III: a rationale for combined application of antithrombin III and endothelin antagonists in sepsis-related acute respiratory distress syndrome?

Objectives Antithrombin (AT) III reduces lung damage in animal models of septic acute respiratory distress syndrome (ARDS), which is generally attributed to stimulation of endothelial prostacyclin synthesis. However, clinical studies have failed so far to demonstrate mortality reduction by application of AT III. We investigated whether AT III stimulates pulmonary prostacyclin release. In addition, we hypothesized that it may promote pulmonary endothelins, thereby mitigating its own protective effect in the course of ARDS. Design Controlled experiment using isolated organs. Setting Experimental laboratory. Subjects Male Wistar rats. Interventions Isolated lungs were perfused over 120 mins in recirculatory mode in the presence of 50 &mgr;g/mL endotoxin (n = 11), 2 U/mL AT III (n = 10), 5 U/mL AT III (n = 13), endotoxin plus 2 U/mL AT III (n = 5), or vehicle alone (controls, n = 13), respectively. Measurements and Main Results We determined the effects of AT III on vascular release of thromboxane B2, 6-keto-prostaglandin-F1&agr;, big endothelin-1, and endothelin-1. Control lungs released 59 ± 23 pg/mL thromboxane B2, 1480 ± 364 pg/mL 6-keto-prostaglandin-F1&agr;, 15.2 ± 4.5 pg/mL big endothelin-1, and 0.46 ± 0.13 pg/mL endothelin-1. Exposure to endotoxin increased thromboxane B2 release 2.9-fold, 6-keto-prostaglandin-F1&agr; release 1.6-fold, and endothelin-1 1.6-fold (p < .05 each); levels of big endothelin-1 were unchanged. AT III at 2 U/mL elevated production of big endothelin-1 (1.7-fold) and endothelin-1 (1.2-fold) (p < .05 for both). AT III at 5 U/mL enhanced levels of big endothelin-1 (1.6-fold) and endothelin-1 (1.3-fold) (p < .05 for both). Neither dose of AT III affected thromboxane B2 or 6-keto-prostaglandin-F1&agr; concentrations. Application of 2 U/mL AT III plus endotoxin stimulated big endothelin-1 production (2.6-fold) compared with endotoxin or AT III alone (p < .05 for both), but did not further elevate endothelin-1 release. Conclusions AT III does not stimulate pulmonary prostacyclin, but promotes pulmonary release of big endothelin-1 and endothelin-1 under basal and, particularly, under septic conditions, which may blunt the AT III-induced lung protection during ARDS. Therefore, we suggest combined application of AT III and endothelin antagonists in animal models of septic ARDS.

Transcatheter aortic valve implantation reduces grade of concomitant mitral and tricuspid valve regurgitation and pulmonary hypertension

OBJECTIVES The presence of concomitant mitral (MR) or tricuspid regurgitation (TR) is a common issue in patients undergoing transcatheter aortic valve implantation (TAVI). The objective was (i) to analyse the outcomes of patients with concomitant moderate or more severe MR, (ii) to compare the outcomes with those of TAVI patients without concomitant MR and (iii) to evaluate the impact of TAVI on grade of concomitant MR. METHODS For creating a homogeneous study group, the study was restricted to transapical (TA)-TAVI patients. Since 2008, 615 patients have undergone TAVI at our institution, 386 of these using the TA approach with the Edwards SAPIEN™ bioprosthesis. Out of these, 116 (30.1%) presented with concomitant moderate or more severe MR. Mean logistic European System for Cardiac Operative Risk (EuroSCORE) was 18.1 ± 11.5%, EuroSCORE II 5.4 ± 0.7%. Intra- and post-hospital course, change in grade of MR, TR, right ventricular systolic pressure (RVSP) and tricuspid annular plane systolic excursion (TAPSE) were particularly analysed. Outcomes were compared with those of the remaining TA-TAVI patients (n = 270). Mean follow-up time was 471 ± 391 days, giving a total of 135 patient-years. RESULTS Three patients (2.6%) died during primary hospital stay. Estimated 1-, 2-, 3- and 4-year survival rates were 76.7, 75.6, 68.3 and 50.6% for study and 78.1, 77.8, 61.1 and 55.0% for control groups, respectively. Postoperative morbidity and mortality did not differ significantly from those of the control group. Postoperatively, a significant reduction in MR (2.1 ± 0.2 to 1.5 ± 0.7; P < 0.01) and TR (1.9 ± 0.5 to 1.5 ± 0.7; P < 0.01) was observed. Likewise, RVSP decreased significantly from 46 ± 16 to 39 ± 15 mmHg (P < 0.01) and TAPSE non-significantly (21.9 ± 7.3 to 19.5 ± 5.5 mm; P = 0.07). After 3-6 months, 68.9% of the patients were at New York Heart Association (NYHA) Class I or II, 25% at Class III and 6.0% downgraded to Class IV. A reason for remaining in NYHA Class III or downgrading to NYHA Class IV could not be detected, and particularly, there was no impact of grade of MR/TR, left ventricular ejection fraction, TAPSE or right ventricular endsystolic pressure (RVESP) on outcomes or NYHA class. CONCLUSION TA-TAVI in patients with concomitant moderate or more severe MR provides results comparable with those of TA-TAVI in general. Concomitant MR had no significant impact on the short- and mid-term outcomes. A significant reduction in MR, TR and pulmonary hypertension was observed after TA-TAVI during short-term follow-up. Nonetheless, a relevant number of patients did not experience an improvement in NYHA class.