Impact of mitral geometry and global afterload on improvement of mitral regurgitation after trans-catheter aortic valve implantation.

OBJECTIVE: To assess the impact of mitral geometry, left ventricular (LV) remodelling and global LV afterload on mitral regurgitation (MR) after trans-catheter aortic valve implantation (TAVI). METHODS: In this study, 60 patients who underwent TAVI were evaluated by 3D echocardiography at baseline, 1 month and 6 months after procedure. The proportional change in MR following TAVI was determined by examining the percentage change in vena contracta (VC) at 6 months. Patients having a significant reduction of at least 30% in VC were defined as good responders (GR) and the remaining patients were defined as poor responders (PR). RESULTS: After 6 months of TAVI, 27 (45%) patients were GR and 33 (55%) were PR. There was a significant decrease in 3DE-derived mitral annular diameter and area (P = 0.001), mitral valve tenting area (TA) (P = 0.05), and mitral papillary muscle dyssynchrony index (DSI) (P = 0.05) in the GR group. 3DE-derived LVESV (P = 0.016), LV mass (P = 0.001) and LV DSI, (P = 0.001) were also improved 6 months after TAVI. In addition, valvulo-arterial impedance (ZVA) was significantly higher at baseline in patients with PR (P = 0.028). 3DE-derived mitral annular area (ß: 0.47, P = 0.04), mitral papillary DSI (ß: -0.65, P = 0.012) and ZVA (ß: 0.45, P = 0.028) were the strongest independent parameters that could predict the reduction of functional MR after TAVI. CONCLUSION: GR patients demonstrate more regression in mitral annulus area and diameter after significant decrease in high LVEDP and trans-aortic gradients with TAVI. PR patients appear to have increased baseline ZVA, mitral valve tenting and restriction in mitral valve coaptation. These factors are important for predicting the impact of TAVI on pre-existing MR.

2012 update on the Edwards SAPIENTM transcatheter heart valve.

Last year was the 10th anniversary of the first transcatheter aortic valve implantation (TAVI) performed by Alain Cribier using the Cribier-Edwards transcatheter heart valve (THV). The Edwards SAPIENTM THV (Edwards Lifesciences, Irvine, CA, USA) was the first commercially available balloon-expandable THV to receive CE-Mark certification in Europe for transfemoral and transapical aortic valve implantation in 2007/2008. Outcome of the prospective randomized PARTNER-US trial resulted in FDA approval for TAVI using the Edwards SAPIENTM THV in patients unsuitable for surgery in 2011 and high-risk patients in 2012. This experience, together with results from the SOURCE Registry and National Registries, has resulted in further modifications of valve design and delivery systems, but also improvement in patient selection and procedural techniques. In this manuscript we review the changes made to the newest model of the Edwards SAPIENTM and its delivery systems over time with an emphasis on the SAPIEN XTTM. We also summarize the recent experience presented on the Edwards SAPIENTM and SAPIEN XTTM, new access routes and lessons learned for patient assessment, as well as opportunities for future development of the device.

My rules of a perfect SAPIEN™ transcatheter aortic valve implantation.

Transcatheter aortic valve implantation has been established as an alternative treatment option for those patients with aortic stenosis (AO), who are high risk or unsuitable for surgical aortic valve replacement. Since its introduction, transcatheter aortic valve implantation has been mainly performed either by a percutaneous approach through the femoral arteries or by using a transapical approach via a left-sided mini-thoracotomy. More recently, experience on alternative access routes such as the subclavian artery and the ascending aorta has been reported in a small number of patients. The Edwards SAPIENTM transcatheter heart valve (Edwards Lifesciences, Irvine, CA, USA) was the first balloon-expandable transcatheter heart valve to receive CE-Mark certification in Europe for transfemoral and transapical aortic valve implantation in 2007/2008. However, it also has been used for transcatheter procedures using access through ascending aorta and subclavian artery. Appropriate patient selection is key for a successful transcatheter aortic valve program and should be in the responsibility of the heart team of interventional cardiologists, cardiac surgeons, cardiac imaging specialists, anesthetists and geriatrists. Their mixture of skills will enable the team to build patient care pathways in which patients are assessed regarding cardiac and non-cardiac comorbidities, the most appropriate type of treatment is jointly agreed, and finally various treatment options are delivered. In this review we highlight the cornerstones of a successful transcatheter aortic valve program using the Edwards SAPIENTM valve. We focus in particular on preoperative diagnostics, patient selection and potential strengths and weaknesses of the various access routes to offer a guideline for future experience.

The combined treatment of aortic stenosis and abdominal aortic aneurysm using transcatheter techniques: a case report.

We describe the case of an 85 year old lady with symptomatic aortic stenosis (AS) with a history of previous coronary artery bypass grafting (CABG), who was referred for consideration of aortic valve replacement (AVR). Echocardiography revealed severe AS with peak gradient of 92 mmHg, orifice area of 0.6 cm2 and preserved left ventricular function. Computed tomography (CT) aortogram revealed a diffusely calcified aorta and an infrarenal abdominal aortic aneurysm (AAA) measuring 6.5 cm. For symptomatic and prognostic reasons she needed treatment of both the AAA and AS. Her calculated logistic EuroSCORE for AVR was 39%. Following discussion at a multidisciplinary forum, it was agreed that the best way to offer her treatment with the lowest risk was by using transcatheter techniques for both pathologies. She subsequently underwent transcatheter aortic valve implantation (TAVI) via the transapical approach to treat her AS, and 3 months later, endovascular stenting of her infrarenal AAA. She recovered well from both procedures. At 6 week follow up, her cardiac symptoms had improved considerably, and echocardiography revealed a mean AV gradient of 7 mmHg with good left ventricular function. Ultrasound of her abdomen revealed exclusion of the aneurysm sac with no endoleak. This is the first described case of TAVI and endovascular treatment of an AAA as a staged procedure.

Redox signalling involving NADPH oxidase-derived reactive oxygen species.

Increased oxidative stress plays an important role in the pathophysiology of many diseases such as atherosclerosis, diabetes mellitus, myocardial infarction and heart failure. In addition to the well-known damaging effects of oxygen-free radicals, ROS (reactive oxygen species) also have signalling roles, acting as second messengers that modulate the activity of diverse intracellular signalling pathways and transcription factors, thereby inducing changes in cell phenotype. NADPH oxidases appear to be especially important sources of ROS involved in redox signalling. Seven NADPH oxidase isoforms, known as Noxs (NAPDH oxidases), are expressed in a cell- and tissue-specific fashion. These oxidases are thought to subserve distinct functions as a result of their tightly regulated activation (e.g. by neurohormonal and growth factors and mechanical stimuli) and their specific coupling with distinct downstream signalling pathways. In the present paper, we review the structure and mechanisms of activation of NADPH oxidases and consider their involvement in redox signalling, focusing mainly on the cardiovascular system.

Clinical significance of apoptotic index in non-small cell lung cancer: correlation with p53, mdm2, pRb and p21WAF1/CIP1 protein expression.

PURPOSE: The aim of this study was to assess the prognostic relevance of apoptotic index (AI), considered alone or together with expression of several proteins controlling G1 check point (p53, mdm2, pRb and p21WAF1/CIP1) in non-small cell lung cancer (NSCLC) patients. METHODS: Study group included 50 NSCLC patients who underwent curative pulmonary resection. Apoptosis was detected with the use of TUNEL technique and AI was defined as the number of apoptotic cells per 1,000 tumor cells. The expression of p53, mdm2, pRb and p21WAF1/CIP1 was assessed immunohistochemically. RESULTS: The mean and median AI calculated for all 50 patients was 14 and 9, respectively. Patients with lower (<14) and higher (> or =14) AI constituted 35 (70%) and 15 (30%) of cases, respectively. AI was not correlated with patient clinical characteristics, and expression of p53, pRb and p21WAF1/CIP1 . However, lower AI was correlated with over-expression of mdm2 protein (P=0.04). Median survival for patients with lower and higher AI was 43 months and 22 months, respectively, and 5-year survival probability-60 and 25%, respectively (P=0.03). In multivariate analysis, the only variable associated with shortened survival was AI (P=0.03, HR=2.9, 95% CI 1.95-3.86). CONCLUSIONS: These results suggest that AI correlates with mdm2 protein expression and influences survival in NSCLC.

CGP 41251, a new potential anticancer drug, improves contractility of rat isolated cardiac muscle subjected to hypoxia.

The aim of the present work was to examine the effects of 4'-N-benzoyl staurosporine (CGP 41251), a protein kinase C inhibitor with broad antiproliferative activity in many cell lines, on the rat isolated heart contractility under normoxic and hypoxic conditions. Additionally, we examined the effects of CGP 41251, WB-4101 (alpha1a -adrenoceptor antagonist), chloroethylclonidine (CEC) (alpha1b-adrenoceptor antagonist) and selective damage of endocardial endothelium by Triton X-100 on the protection against hypoxia induced by preconditioning of rat heart tissue. Experiments were performed on rat isolated left ventricular papillary muscle. The following parameters were measured: force of contraction (Fc), velocity of contraction (+dF/dt) and velocity of relaxation (-dF/dt). The temperature of the bath solution was 37 degrees C +/- 0.5 degrees C, and rate of electrical stimulation was 0.5 Hz. At concentrations less than 1 microM CGP 41251 did not cause any changes in contractility of rat heart. At 1 and 3 microM, significant positive inotropic action was observed. Treatment of rat papillary muscle by CGP 41251 at 3 microM reduced decreasing of contractility by simulated hypoxia and reperfusion. Moreover, protective effects of preconditioning was not affected by addition of CGP 41251 neither at 1 nor at 3 microM. Pretreatment with CEC at 3 microM, and selective damage of endocardial endothelium induced by fast (1-s) immersion of papillary muscle in 0.5% Triton X-100, but not pretreatment with WB-4101, abolished the protective effects of preconditioning. The results imply that CGP 41251 improves contractility of heart muscle under normoxic and hypoxic conditions, and does not alter hypoxic preconditioning in rat isolated cardiac tissue. Moreover, it was shown that alpha1b-adrenoceptors and endocardial endothelium are involved in triggering of preconditioning in rat isolated heart muscle.

4-Aminopyridine induces positive lusitropic effects and prevents the negative inotropic action of phenylephrine in the rat cardiac tissue subjected to ischaemia.

The effects of 4-aminopyridine (4-AP) at concentration of 1 mM on the contractility of rat isolated papillary muscle subjected to simulated ischaemia has been evaluated. Additionally, the effects of 4-AP on the phenylephrine inotropic action (a selective agonist of alpha1-adrenergic receptor) on rat isolated cardiac tissue underwent simulated ischaemia and reperfusion was studied. Experiments were performed on rat isolated papillary muscles obtained from left ventricle. The following parameters have been measured: force of contraction (Fc), velocity of contraction (+dF/dt), velocity of relaxation (-dF/dt) and the ratio between time to peak contraction (ttp) and relaxation time at the level of 10% of total contraction amplitude (tt10) as an index of lusitropic effects. Simulated ischaemia lasting 45 min was induced by replacement of standard normoxic solution by no-substrat one gassing with 95% N2/5%CO2. Although 4-AP exerted a slight, but significant positive inotropic action itself, pretreatment with 1 mM of this compound significantly depressed a recovery of Fc and +dF/dt, but improves recovery of -dF/dt in the rat papillary muscle during reperfusion as compared with control group of preparations. Moreover, the paradoxical negative inotropic action of phenylephrine observed in rat stunned papillary muscle was prevented in preparations previously treated by 4-AP. These findings suggest that an inhibition of outward K+ current (probably transient outward and rapid component of delayed rectifying currents at 1 mM of 4-AP) aggravates ischaemia-induced failure in contractility but prevents changes in alpha1-adrenergic receptor signaling pathway occuring during ischaemia.

Experimental hyperlipidemia prevents the protective effect of ischemic preconditioning on the contractility and responsiveness to phenylephrine of rat-isolated stunned papillary muscle.

This study was designed to establish a hyperlipidemic diet (significant increase in the cholesterol and triglycerides blood levels, but without atherogenic changes in heart muscle and coronary vessels) and to investigate the influence of experimental hyperlipidemia on the effects of ischemic preconditioning (PC) of rat-isolated papillary muscle on the time course of contractility during simulated ischemia and reperfusion and responsiveness to phenylephrine under such a condition. The animals were divided in four experimental groups: standard diet-fed control group (SD), SD underwent ischemic preconditioning (SD-PC), hyperlipidemic diet-fed group (HLD) and HLD underOFFt PC (HLD-PC). Force of contraction (Fc), velocity of contraction (+dF/dt), and velocity of relaxation (-dF/dt) were measured. HLD preparations were more sensitive to ischemia then SD ones. PC, performed by 5-min perfusion with no-substrate solution gassing with 95% N2/5% CO2 in the presence of fast electrical stimulation, and 10 min of reperfusion with normal solution and rate of stimulation, significantly increased the resistance of isolated cardiac tissues to simulated ischemia in SD-PC group, but not in HLD-PC group. Negative inotropic action of phenylephrine occured in SD group of preparations after simulated-ischemia/reperfusion period was also prevented by PC. Therefore, we conclude that experimental hyperlipidemia significantly influenced the function of rat heart muscle including the higher sensitivity to ischemia and different reaction to the same PC procedure.

The influence of experimental hyperlipidemia on the time course of contractility during simulated ischaemia and reperfusion and responsiveness to phenylephrine of rat heart papillary muscle.

The aim of this study was to examine the influence of simulated ischaemia on the contractility and responsiveness to phenylephrine of rat isolated papillary muscle in standard diet fed (SD) and hyperlipidemic diet fed (HLD) rats. The following parameters were measured: force of contraction (Fc), rate of rise (+dF/dt) and rate of fall (-dF/dt) of force of contraction, time to peak contraction (ttp) and relaxation time at 10% of total amplitude of contraction (tt10). The baseline values of Fc and +dF/dt, but, not -dF/dt, were significantly lower in HLD group than in SD group. Tissues from HLD rats were more sensitive to ischaemia regarding Fc, +dF/dt and -dF/dt. Moreover, reprefusion completely reversed the effects of ischaemia only in SD rats, but not in HLD rats, regarding Fc and +dF/dt. In contrast, a recovery of -dF/dt during reperfusion occurred only in the HLD group. In SD rats, phenylephrine (10 and 30 microM) had no effect on the contractility or induced megative inotropic effects (100 and 300 microM). Propranolol (1 microM), a non-selective blocker of beta-adrenoceptors, had no effects on this action. Chloroethylclonidine (CEC) (1 microM), a selectivw blocker of alpha 1b-adrenoceptor subtype, but not WB-4101(2-((2,6-dimethoxyphenoxyethyl)amino-methyl-1,4-benzodioxane), a selective blocker of alpha 1a adrenoceptor subtype, abolishes the negative inotropic action of phenylephrine. In HLD rats, phenylephrine had positive inotropic action (10 and 30 microM). The results indicate that hyperlipidemic diet in rats leads to the suppression of force of contraction and velocity of contraction, but not velocity of relaxation of isolated heart muscle. Under such a condition, heart muscle is more sensitive to ischaemia, but has better responsiveness to phenylephrine after ischeamia-reperfusion period.

Different aspects of the effects of thapsigargin on automatism, contractility and responsiveness to phenylephrine in cardiac preparations from rats and guinea pigs.

Sarcoplasmic reticulum (SR) Ca(2+)-ATPase play a very important role in excitation-contraction coupling in the heart. The effects of thapsigargin (TG), a selective inhibitor of SR Ca(2+)-ATPase in the heart muscle, on automatism and contractility of the rat and guinea pig heart were examined. Experiments were performed on isolated right auricula and right ventricle papillary muscle. The following parameters were registered: force of contraction (Fc); rate of rise of force (+dF/dt); rate of fall of force (-dF/dt); time to peak contraction (ttp); duration of relaxation phase of contraction at the level of 10% of total amplitude (tt10); and automatism (b.p.m.). Additionally, the influence of thapsigargin on the effects of phenylephrine on the above mentioned parameters were studied. It was found that TG (1 microM) decreased only the automatism in rat heart, but increased automatism and ttp duration and decreased Fc in guinea pig heart. The positive force-frequency relation in the guinea pig heart was attenuated. The effects of phenylephrine in the rat heart were not significantly different before and after pretreatment with TG. Alternatively, pretreatment with TG exerted a profound influence on the effects of phenylephrine in the guinea pig heart. The results indicate that TG has different effects on the guinea pig and rat hearts. The reason for this could be due to species differences, i.e. the weaker crossing of TG through the membrane of rat myocytes or a different mechanism of Ca2+ homeostasis in rat and guinea pig hearts.