Feasibility and efficacy of the 2.5 L and 3.8 L impella percutaneous left ventricular support device during high-risk, percutaneous coronary intervention in patients with severe aortic stenosis.

OBJECTIVE: Assessment of the feasibility and outcomes of the 2.5 L and 3.8 L Impella cardiac pump in patients with severe aortic stenosis (AS) and left ventricular impairment undergoing percutaneous revascularization (PCI) with or without balloon aortic valvuloplasty (BAV). METHODS: We reviewed the clinical and procedural findings from a consecutive series of unselected patients with severe AS who underwent PCI during Impella support. In addition, we describe novel "balloon-assist" techniques that allowed implantation of Impella into the left ventricle (LV) when initial unassisted attempts failed. RESULTS: Five patients with severe AS were identified (four males, age 78.2 years, aortic valve area (AVA) 0.6 cm(2) , left ventricular ejection fraction (LVEF) 24 ± 5%, mean Society of Thoracic Surgeons (STS) mortality 11% (range 3-17%)). The Impella catheter traversed the aortic valve (AV) unassisted in only one patient, with four cases requiring balloon-assist techniques. All patients underwent planned revascularisation; mean procedure time 177 min (range 135-252 min), mean number of stents 3.4 (range 1-8), with three patients requiring rotational atherectomy. All procedures were well tolerated, with absence of arrhythmia, hypotension, pulmonary edema, stroke, or myocardial infarction. One patient died 48 hr post-PCI of multi-organ failure. The four remaining patients were well at 30 days. CONCLUSION: Implantation of the 2.5 and 3.8 L Impella appears feasible in patients with severe AS and left ventricle (LV) impairment. A balloon-assist technique may be used to facilitate device implantation when initial unassisted attempts fail. Improved hemodynamic stability may enhance the tolerability of lengthy and complex procedures.

The Use and Efficacy of FFR-CT: Real-World Multicenter Audit of Clinical Data With Cost Analysis.

BACKGROUND: Fractional flow reserve-computed tomography (FFR-CT) is endorsed by UK and U.S. chest pain guidelines, but its clinical effectiveness and cost benefit in real-world practice are unknown. OBJECTIVES: The purpose of this study was to audit the use of FFR-CT in clinical practice against England's National Institute for Health and Care Excellence guidance and assess its diagnostic accuracy and cost. METHODS: A multicenter audit was undertaken covering the 3 years when FFR-CT was centrally funded in England. For coronary computed tomographic angiograms (CCTAs) submitted for FFR-CT analysis, centers provided data on symptoms, CCTA and FFR-CT findings, and subsequent management. Audit standards included using FFR-CT only in patients with stable chest pain and equivocal stenosis (50%-69%). Diagnostic accuracy was evaluated against invasive FFR, when performed. Follow-up for nonfatal myocardial infarction and all-cause mortality was undertaken. The cost of an FFR-CT strategy was compared to alternative stress imaging pathways using cost analysis modeling. RESULTS: A total of 2,298 CCTAs from 12 centers underwent FFR-CT analysis. Stable chest pain was the main symptom in 77%, and 40% had equivocal stenosis. Positive and negative predictive values of FFR-CT were 49% and 76%, respectively. A total of 46 events (2%) occurred over a mean follow-up period of 17 months; FFR-CT (cutoff: 0.80) was not predictive. The FFR-CT strategy costs £2,102 per patient compared with an average of £1,411 for stress imaging. CONCLUSIONS: In clinical practice, the National Institute for Health and Care Excellence criteria for using FFR-CT were met in three-fourths of patients for symptoms and 40% for stenosis. FFR-CT had a low positive predictive value, making its use potentially more expensive than conventional stress imaging strategies.

Failure to recapture cardioprotection with high-dose atorvastatin in coronary artery bypass surgery: a randomised controlled trial.

The acute administration of atorvastatin has been reported to reduce myocardial infarct size in animal studies. However, this cardioprotective effect is lost with the chronic administration of atorvastatin, although it can be recaptured by administering an acute high-dose of atorvastatin. We hypothesised that pre-treatment with high-dose atorvastatin, on a background of chronic standard 'statin' therapy, would reduce myocardial injury in patients undergoing elective coronary artery bypass graft (CABG) surgery. One hundred and one consenting patients undergoing elective CABG surgery at a single tertiary cardiac centre were recruited into two randomised controlled, single-blinded clinical studies. Study 1: 45 patients were randomised to receive either 160 mg of atorvastatin 2 h preoperatively and 24 h following surgery or their standard statin therapy. Study 2: 56 patients were randomised to receive either 160 mg of atorvastatin 12 h preoperatively and 24 h following surgery or their standard statin therapy. Blood samples for troponin T and creatine kinase were taken prior to surgery and then at 6, 12, 24, 48 and 72 h post-surgery. Cardiac enzyme levels at each time point and the total area-under curve (AUC) were calculated. The group characteristics and surgical methods were well matched. High-dose atorvastatin was not associated with any significant side effects. There was no significant difference in serum troponin T or creatine kinase in either study at each time point or over 72 h. Study 1: AUC, troponin T: atorvastatin 29.6 ± 34.8 µg/L versus control 25.0 ± 22.0 µg/L:P > 0.05. Creatine kinase: atorvastatin 33,544 ± 20,063 IU/L versus control 30,620 ± 10,776 IU/L:P > 0.05. Study 2: AUC, troponin T: atorvastatin 21.8 ± 14.3 µg/L versus control 20.9 ± 8.7 µg/L:P > 0.05. Creatine kinase: atorvastatin 36,262 ± 28,821 IU/L versus control 33,448 ± 14,984:P > 0.05. There were no differences in postoperative outcomes. We report that the administration of high-dose atorvastatin to low risk patients undergoing elective CABG surgery, who are already on standard dose 'statin' therapy is safe, but does not further reduce perioperative myocardial injury.

Effect of remote ischemic preconditioning on acute kidney injury in nondiabetic patients undergoing coronary artery bypass graft surgery: a secondary analysis of 2 small randomized trials.

BACKGROUND: Novel treatment strategies are required to reduce the development of acute kidney injury (AKI) in patients undergoing cardiac surgery. In this respect, remote ischemic preconditioning (RIPC), a phenomenon in which transient nonlethal ischemia applied to an organ or tissue protects another organ or tissue from subsequent lethal ischemic injury, is a potential renoprotective strategy. STUDY DESIGN: Secondary analysis of 2 randomized trials. SETTING & PARTICIPANTS: 78 consenting selected nondiabetic patients in a university teaching hospital undergoing elective coronary artery bypass graft (CABG) surgery recruited to 2 previously reported randomized studies. INTERVENTION: RIPC consisted of three 5-minute cycles of right forearm ischemia, induced by inflating a blood pressure cuff on the upper arm to 200 mm Hg, with an intervening 5 minutes of reperfusion, during which time the cuff was deflated. The control consisted of placing an uninflated cuff on the arm for 30 minutes. OUTCOMES: AKI measured using Acute Kidney Injury Network (AKIN) criteria, duration of hospital stay, in-hospital and 30-day mortality. RESULTS: Numbers of participants with AKI stages 1, 2, and 3 were 1 (3%), 3 (8%), and 0 in the intervention group compared with 10 (25%), 0, and 0 in the control group, respectively (P = 0.005). The decrease in AKI was independent of the effect of concomitant aortic valve replacement and cross-clamp times, which were distributed unevenly between the 2 groups. LIMITATIONS: Retrospective analysis of data. More patients in the RIPC group underwent concomitant aortic valve replacement with CABG; although we have corrected statistically for this imbalance, it remains an important confounding variable. CONCLUSIONS: RIPC induced using transient forearm ischemia decreased the incidence of AKI in nondiabetic patients undergoing elective CABG surgery in this retrospective analysis. A large prospective clinical trial is required to study this effect and clinical outcomes in patients undergoing cardiac surgery.

Effect of remote ischaemic preconditioning on myocardial injury in patients undergoing coronary artery bypass graft surgery: a randomised controlled trial.

BACKGROUND: Whether remote ischaemic preconditioning, an intervention in which brief ischaemia of one tissue or organ protects remote organs from a sustained episode of ischaemia, is beneficial for patients undergoing coronary artery bypass graft surgery is unknown. We did a single-blinded randomised controlled study to establish whether remote ischaemic preconditioning reduces myocardial injury in these patients. METHODS: 57 adult patients undergoing elective coronary artery bypass graft surgery were randomly assigned to either a remote ischaemic preconditioning group (n=27) or to a control group (n=30) after induction of anaesthesia. Remote ischaemic preconditioning consisted of three 5-min cycles of right upper limb ischaemia, induced by an automated cuff-inflator placed on the upper arm and inflated to 200 mm Hg, with an intervening 5 min of reperfusion during which the cuff was deflated. Serum troponin-T concentration was measured before surgery and at 6, 12, 24, 48, and 72 h after surgery. Analysis was by intention to treat. This trial is registered with ClinicalTrials.gov, number NCT00397163. FINDINGS: Remote ischaemic preconditioning significantly reduced overall serum troponin-T release at 6, 12, 24, and 48 h after surgery. The total area under the curve was reduced by 43%, from 36.12 microg/L (SD 26.08) in the control group to 20.58 microg/L (9.58) in the remote ischaemic preconditioning group (mean difference 15.55 [SD 5.32]; 95% CI 4.88-26.21; p=0.005). INTERPRETATION: We have shown that adult patients undergoing elective coronary artery bypass graft surgery at a single tertiary centre could benefit from remote ischaemic preconditioning, using transient upper limb ischaemia.

Regulating RNA Binding Motif 5 Gene Expression- A Novel Therapeutic Target for Lung Cancer.

RNA-binding motif protein 5 (RBM5), also known as LUCA-15/H37, is a gene that maps to human chromosome 3p21.3, a critical region that is deleted in a large number of human cancers, of which the majority are lung cancers, and that is predicted to contain one or more tumor suppressor genes (TSGs). RBM5 is a tumor suppressor gene and is most frequently deleted at the earliest stage of lung cancer development. It represents a significant area of recent progress in cancer genomic, cytogenetic, and molecular biological research because of its role in the induction of cell cycle arrest and apoptosis and the regulation of inhibition of in lung cancer metastasis. RBM5 is involved in the suppression of epidermal growth factor receptor (EGFR) expression, thus preventing proliferation, angiogenesis, invasion, and metastasis of lung cancer. In this way it exhibits its tumor suppressive capacity during lung cancer progression. Exploration of RBM5's potential importance in inhibiting tumor metastasis includes downstream players in the RBM5-mediated metastasis suppressor pathway(s). This review highlights the differential expression of the RBM5 tumor suppressor gene which impacts cell proliferation and apoptosis control during lung cancer progression. Regulating RBM5 expression may be a novel therapeutic target for lung cancer.

Copine 3 as a Novel Potential Drug Target for Non-Small-Cell Lung Carcinoma.

Cancer originates from uncontrolled cell division in any part of the body. The universal burden of cancer continues to increase, and its treatment remains ever more challenging. Among several cancers, lung cancer is the second most common, causing 1.6 million deaths worldwide per year. Approximately 85% of lung cancers are non-small-cell lung carcinomas (NSCLCs), which are considerably more difficult to treat than other cancers. Although various imaging, biopsy, and histopathological analyses are widely used, there are no effective or reliable biomarkers for detecting early lung carcinoma, particularly NSCLC. For this reason, the identification of novel biomarkers to serve as therapeutic targets is essential to NSCLC treatment. Copines are a family of membrane-binding proteins that are highly conserved, soluble, ubiquitously expressed, calcium dependent, and found in variety of eukaryotic organisms. Recent research suggests that they may mediate various signaling pathways involved in both tumor progression and metastasis. In the copine gene family, copine 3 is a novel player in regulating NSCLC metastasis. This review highlights copine 3 as a prognostic marker as well as a potential therapeutic target for effective treatment of patients with NSCLC.

Epidermal Growth Factor Receptor Tyrosine Kinase: A Potential Target in Treatment of Non-Small-Cell Lung Carcinoma.

Lung cancer is responsible for 1.6 million deaths. Approximately 80%-85% of lung cancers are of the non-small-cell variety, which includes squamous cell carcinoma, adenocarcinoma, and large-cell carcinoma. Knowing the stage of cancer progression is a requisite for determining which management approach-surgery, chemotherapy, radiotherapy, and/or immunotherapy-is optimal. Targeted therapeutic approaches with antiangiogenic monoclonal antibodies or tyrosine kinase inhibitors are one option if tumors harbor oncogene mutations. Another, newer approach is directed against cancer-specific molecules and signaling pathways and thus has more limited nonspecific toxicities. This approach targets the epidermal growth factor receptor (EGFR, HER-1/ErbB1), a receptor tyrosine kinase of the ErbB family, which consists of four closely related receptors: HER-1/ErbB1, HER-2/neu/ErbB2, HER-3/ErbB3, and HER-4/ErbB4. Because EGFR is expressed at high levels on the surface of some cancer cells, it has been recognized as an effective anticancer target. EGFR-targeted therapies include monoclonal antibodies (mAbs) and small-molecule tyrosine kinase inhibitors. Tyrosine kinases are an especially important target because they play an important role in the modulation of growth factor signaling. This review highlights various classes of synthetically derived molecules that have been reported in the last few years as potential EGFR-TK inhibitors (TKIs) and their targeted therapies in NSCLC, along with effective strategies for overcoming EGFR-TKI resistance and efforts to develop a novel potent EGFR-TKI as an efficient target of NSCLC treatment in the foreseeable future.

KAI1/CD82, Metastasis Suppressor Gene as a Therapeutic Target for Non-Small-Cell Lung Carcinoma.

Lung cancer is the most frequent malignancy and the leading cause of cancer-related death worldwide; it is the second most common cancer, comprising 1.69 million deaths worldwide per year. Among these, 85% of lung cancers are non-small-cell lung carcinoma (NSCLC). Metastasis is common in NSCLC patients and are responsible for most deaths. Kang-Ai 1 (KAI1), a tumor metastasis suppressor gene also known as Cluster of Differentiation 82 (CD82), is a member of the membrane tetraspanin protein family, which are capable of inhibiting the metastatic process in NSCLC. KAI1/CD82 suppresses metastasis via multiple mechanisms regulating inhibition of cell motility, adhesion, fusion, and proliferation. KAI1 may attenuate signaling to shut down metastatic colonization through attenuation of epidermal growth factor receptor (EGFR) signaling and inhibition of the Wnt signaling pathways. In this review, we focus on the differential expression of KAI1/CD82, a tumor metastasis suppressor gene that can inhibit cancer invasion and cell metastasis during NSCLC. The differential expression of KAI1/CD82 could prove to be of novel therapeutic significance in treating malignant tumors and in reducing their metastatic potential.

Percutaneous Mechanical Ventricular Support in Acute Cardiac Care: A UK Quaternary Centre Experience Using 2.5L, 3.8L and 5.0L Impella Catheters.

AIMS: The Impella is a percutaneous ventricular assist device. The majority of published data describes the 2.5L and 5.0L devices, and little data is available for the newer 3.8L device. We examined the indications and outcomes from our single-centre "real-world" registry at The Queen Elizabeth Hospital, Birmingham, UK, using all three pump sizes. METHODS AND RESULTS: Records from all patients who underwent attempted Impella-assisted procedures at our centre were examined retrospectively. Impella implantation was attempted in 49 patients (mean age 72 ± 13 years; 80% male) and was successful in 48 (98%). 45 patients underwent high-risk percutaneous coronary intervention (PCI), one patient underwent balloon aortic valvuloplasty and 3 patients had Impella as a bridge to cardiac transplantation. The 2.5L and 3.8L devices were used in 36 (75%) and 11 (23%) patients, respectively, while one patient (2%) had the 5L device. Vascular complications occurred in only one patient (2%) and stroke and peri-procedural myocardial infarction occurred in one patient (2%), while in-hospital mortality was 20% (10/49). CONCLUSIONS: In this large real-world registry, we have demonstrated the safety and feasibility of the Impella device for a wide range of indications. This includes the first series of the 3.8L device which provides superior support with no increase in vascular complications.

1,2-Diazole prevents cisplatin-induced nephrotoxicity in experimental rats.

BACKGROUND: Cisplatin (a platinum-compound) is a anti-neoplastic drug used in the treatment of various cancers but eventually results in severe adverse effects namely nephrotoxicity or renal disorder through generation of reactive oxygen species (ROS). This biochemical measurements and histopathology analysis investigated a possible protective effect of 1,2-diazole with regards to cisplatin-induced nephrotoxicity in experimental animals. METHODS: Animals were divided into four groups of six mice each. Group A: normal control, vehicle (1% (w/v) gum acacia in phosphate buffer saline (PBS)). Group B: cisplatin group, vehicle + cisplatin (7.5 mg/kg). Group C: 1,2-diazole (10 mg/kg) + cisplatin and Group D: silymarin (50 mg/kg) + cisplatin. Each vehicle/drug treatment was given daily via intraperitoneal (ip) injection for 10 consecutive days starting from day 1. On group B, C and D cisplatin was given in single dose only on day 5 one hour post drug administration. Animals were allowed till 10th day and on day 11 all four groups animals were anesthetized. Blood samples were collected and serum was isolated for biochemical measurements. The rats were then euthanized by cervical dislocation and their kidney was recovered and then prepared for biochemical measurements and histopathology analyses. RESULTS: Pretreatment with 1,2-diazole prevented nephrotoxicity induced by cisplatin through a protective mechanism that involved reduction of increased oxidative stress by significantly increasing the enzymatic and non enzymatic antioxidant enzymes such as glutathione peroxidase (GPx), glutathione (GSH) and diminishing the lipid peroxidation (LPO). The pretreatment with 1,2-diazole does not affect superoxide dismutase (SOD), catalase (CAT), serum urea and creatinine level during nephrotoxicity when compared to cisplatin-induced group. Moreover, the 1,2-diazole animals shown significant decrease in urine volume and kidney weight when compared with cisplatin-induced group. Histopathological findings reveals the protective efficacy of 1,2-diazole that restores histopathological changes against nephrotoxicity. CONCLUSION: These analysis will provide a critical evidence that 1,2-diazole could provide a new protective strategy against cisplatin-induced nephrotoxicity.

Kisspeptins (KiSS-1): essential players in suppressing tumor metastasis.

Kisspeptins (KPs) encoded by the KiSS-1 gene are C-terminally amidated peptide products, including KP- 10, KP-13, KP-14 and KP-54, which are endogenous agonists for the G-protein coupled receptor-54 (GPR54). Functional analyses have demonstrated fundamental roles of KiSS-1 in whole body homeostasis including sexual differentiation of brain, action on sex steroids and metabolic regulation of fertility essential for human puberty and maintenance of adult reproduction. In addition, intensive recent investigations have provided substantial evidence suggesting roles of Kisspeptin signalling via its receptor GPR54 in the suppression of metastasis with a variety of cancers. The present review highlights the latest studies regarding the role of Kisspeptins and the KiSS-1 gene in tumor progression and also suggests targeting the KiSS-1/GPR54 system may represent a novel therapeutic approach for cancers. Further investigations are essential to elucidate the complex pathways regulated by the Kisspeptins and how these pathways might be involved in the suppression of metastasis across a range of cancers.

Effect of erythropoietin as an adjunct to primary percutaneous coronary intervention: a randomised controlled clinical trial.

OBJECTIVE: The acute administration of high-dose erythropoietin (EPO) on reperfusing ischaemic myocardium has been reported to halve myocardial infarct (MI) size in preclinical studies, but its effect in ST elevation myocardial infarction patients undergoing primary percutaneous coronary intervention (PPCI) remains unknown. We investigated whether high-dose EPO administered as an adjunct to PPCI reduces MI size. DESIGN: Double-blinded, randomised, placebo-controlled. SETTING: Single tertiary cardiac centre. PATIENTS: Fifty-one ST elevation myocardial infarction patients undergoing PPCI. INTERVENTIONS: Patients were randomly assigned to receive either a single intravenous bolus of EPO (50,000 IU) prior to PPCI with a further bolus given 24 h later (n=26) or placebo (n=25). MAIN OUTCOME MEASURES: MI size measured by 24 h area under the curve troponin T and cardiac magnetic resonance imaging performed on day 2 and at 4 months. RESULTS: EPO treatment failed to reduce MI size (troponin T area under the curve: 114.6±78 µg/ml EPO vs 100.8±68 µg/ml placebo; infarct mass by cardiac magnetic resonance: 33±16 g EPO vs 25±16 g placebo; both p>0.05). Unexpectedly, EPO treatment doubled the incidence of microvascular obstruction (82% EPO vs 47% placebo; p=0.02) and significantly increased indexed left ventricular (LV) end-diastolic volumes (84±10 ml/m(2) EPO vs 73±13 ml/m(2) placebo; p=0.003), indexed LV end-systolic volumes (41±9 ml/m(2) EPO vs 35±11 ml/m(2) placebo; p=0.035) and indexed myocardial mass (89±16 g/m(2) EPO vs 79±11 g/m(2) placebo; p=0.03). At 4 months, there were no significant differences between groups. CONCLUSIONS: High-dose EPO administered as an adjunct to PPCI failed to reduce MI size. In fact, EPO treatment was associated with an increased incidence of microvascular obstruction, LV dilatation and increased LV mass. Clinical Trial Registration Information http://public.ukcrn.org.uk/search/StudyDetail.aspx?StudyID=4058 Unique Identifier=Study ID 4058.

Statins and cardioprotection--more than just lipid lowering?

Lipid-lowering using HMG-CoA reductase inhibitors or statin therapy forms the cornerstone of medical therapy in the primary and secondary prevention of cardiovascular disease. In addition, to the improvements in lipid profile, the beneficial effects elicited by this class of drugs may be attributed to their diverse variety of non-lipid lowering pleiotropic effects, including improved endothelial function, reduced oxidative stress, less platelet adhesion, and increased atherosclerotic plaque stability. A less appreciated effect of statin therapy that has been reported in experimental studies is its cardioprotective effect with respect to its ability to directly protect the myocardium from the detrimental effects of acute ischaemia-reperfusion injury. In the current article we review the cardioprotective effects of statin therapy beyond serum lipid lowering, the underlying mechanisms involved and the potential implications for patients with coronary heart disease.

'Conditioning' the heart during surgery.

Coronary heart disease (CHD) is the leading cause of death worldwide. Coronary artery bypass graft (CABG) surgery remains the procedure of choice for coronary artery revascularisation in a large number of patients with severe CHD. However, the profile of patients undergoing CABG surgery is changing with increasingly higher-risk patients being operated upon, resulting in significant morbidity and mortality in this patient group. Myocardial injury sustained during cardiac surgery, most of which can be attributed to acute myocardial ischaemia-reperfusion injury, is associated with worse short-term and long-term clinical outcomes. Clearly, new treatment strategies are required to protect the heart during cardiac surgery in terms of reducing myocardial injury and preserving left ventricular systolic function, such that clinical outcomes can be improved. 'Conditioning' the heart to harness its endogenous cardioprotective capabilities using either brief ischaemia or pharmacological agents, provides a potentially novel approach to myocardial protection during cardiac surgery, and is the subject of this review article.