Valve-in-Valve TAVR: State-of-the-Art Review.

An increasing number of surgically implanted bioprostheses will require re-intervention for structural valve deterioration. Valve-in-valve transcatheter aortic valve replacement (ViV TAVR) has become an alternative to reoperative surgery, currently approved for high-risk and inoperable patients. Challenges to the technique include higher rates of prosthesis-patient mismatch and coronary obstruction, compared to native valve TAVR. Herein, we review results of ViV TAVR and novel techniques to overcome the aforementioned challenges.

Evolution of percutaneous balloon aortic valvuloplasty in the treatment of patients with aortic stenosis.

Symptomatic, severe aortic stenosis (AS) is associated with a dismal prognosis with conservative management only; the mortality rate is >50% at two years with medical treatment alone. In 1986, Cribier first introduced the percutaneous balloon aortic valvuloplasty (BAV) concept in patients with acquired severe AS. The initial enthusiasm surrounding this technique, touted as an alternative to surgical aortic valve replacement (SAVR) in older patients with AS, waned with subsequent large registries, which showed failure of the procedure to alter the natural history of calcific AS and its associated procedural morbidity. For many years BAV has been used as palliative treatment for short-term symptom relief in elderly, non-surgical patients. The timely surge in transcatheter aortic valve replacement (TAVR) rejuvenated and resurrected the dormant field of BAV. By its use to predilate the stenosed valve for easier delivery of the prosthesis, valvuloplasty now plays an integral role in the majority of TAVR procedures. BAV is successfully used as a bridge to SAVR and TAVR with better outcomes and is used as a standalone treatment for symptom relief in high-risk patients and for temporary stabilization of hemodynamically unstable patients. BAV can be used as a selection tool to determine if the patient will benefit from valve replacement if they have other comorbidities, such as severe pulmonary hypertension, severe lung disease, very poor ejection fraction, or frailty.

Clinical results of drug eluting stents compared to bare metal stents for patients with ST elevation acute myocardial infarction.

OBJECTIVE: To investigate the clinical outcomes in patients with ST segment elevation acute myocardial infarction (STEMI) treated with drug eluting stents (DES) versus a matched control group of patients with STEMI treated with bare metal stents (BMS). METHODS: This registry included 122 patients with STEMI undergoing primary coronary angioplasty with DES implantation at our institution. The control group consisted of 506 patients implanted with BMS, who were matched for age, infarct location, and diabetic status. The incidences of major adverse cardiac events (MACE) including target vessel/lesion revascularization (TVR/TLR) and stent thrombosis were assessed up to 12 months. RESULTS: Twelve months follow up showed a non-significant trend towards reduced deaths (3.3% versus 7.1%, P=0.1), significantly reduced recurrent MI (0.0% versus 6.1%, P=0.02), TVR (5.7% versus 15.2%, P=0.006) and TLR (2.5% versus 14.0%, P=0.004) events in the DES group as compared to BMS group. The composite incidences of MACE at 12 months follow-up was lower in the DES group (11.5%) as compared to the BMS group (21.3%, P=0.01). CONCLUSION: According to our experiences, the use of DES in STEMI is safe and effective as compared to BMS. DES was effective in reducing the incidence of restenosis outcomes and overall adverse cardiac events up to 12 months.

Initial clinical experience with a hand-held device (Thrombocheck) for the detection of bileaflet prosthetic valve malfunction.

BACKGROUND AND AIM OF THE STUDY: Early recognition of subclinical prosthetic valve malfunction may promote early treatment and avoidance of serious complications. Echocardiography cannot be applied on a daily basis; thus, a hand-held device (Thrombocheck) which is capable of detecting subtle changes in the acoustic sounds of prosthetic valve has been developed for the routine home monitoring of heart valve function. Herein is reported the authors' initial clinical experience with this device. METHODS: Seventy-one consecutive patients with one or more bileaflet prosthetic mechanical valves at any position were assessed both by transthoracic echocardiography (TTE) and by Thrombocheck. These patients attended the authors' clinic for either routine echocardiography (n = 62) or for the detection of prosthetic valve malfunction (n = 9). Cinefluoroscopy and transesophageal echocardiography were used selectively to confirm prosthetic valve malfunction. The Thrombocheck was held for 1 min in the subxiphoid position perpendicular to the patient, and indicated either normal function (OK), abnormal function (Warning) or 'no signal'. RESULTS: The study patients had in total 82 bileaflet valves (47 mitral, 31 aortic, four tricuspid). Eight patients (11.3%) had a 'no signal' indication. Of the remaining 63 patients, 10 (15.9%) had a 'warning' alarm (eight patients had current abnormal leaflet motion, one patient had a recent history of abnormal leaflet motion, and one had no evidence of prosthetic valve malfunction). The sensitivity and specificity for detecting abnormal prosthetic valve malfunction were 90% and 98%, respectively. CONCLUSION: The Thrombocheck had an excellent sensitivity and specificity for the detection of prosthetic valve malfunction in a cohort of patients with bileaflet mechanical prosthetic heart valves.

Oral versus intravenous antibiotic treatment for febrile neutropenia in cancer patients.

BACKGROUND: Fever occurring in a neutropenic patient remains a common life-threatening complication of cancer chemotherapy. The common practice is to admit the patient to hospital and treat empirically with intravenous broad-spectrum antibiotics. Oral therapy could be an alternative approach for selected patients. OBJECTIVES: To compare the efficacy of oral antibiotics versus intravenous (IV) antibiotic therapy in febrile neutropenic cancer patients. SEARCH STRATEGY: We searched the Cochrane Cancer Network Register of trials (November 2002), the Cochrane Library (issue 2, 2002), MEDLINE (1966 to 2002), EMBASE (January 1980 to 2002) and LILACS (1982 to 2002). We searched several databases for ongoing trials. We checked the conference proceedings of the Interscience Conference of Antimicrobial Agents and Chemotherapy (ICAAC) 1995 to 2002 and all references of included studies and major reviews were scanned. SELECTION CRITERIA: Randomised controlled trials comparing oral antibiotic/s to intravenous antibiotic/s for the treatment of neutropenic cancer patients with fever. The comparison between the two could be started initially (initial oral), or following an initial course of intravenous antibiotic treatment (sequential). DATA COLLECTION AND ANALYSIS: Two reviewers independently assessed trial eligibility, methodological quality and extracted data. Data concerning mortality, treatment failures and adverse events were extracted from included studies assuming an "intention-to-treat" basis for the outcome measures whenever possible. Relative risks (RR) with 95% confidence intervals (CI) for dichotomous data were estimated. MAIN RESULTS: Fifteen trials (median mortality 0, range 0 to 8.8%) were included in the analyses. The mortality rate was similar comparing oral to intravenous antibiotic treatment (RR 0.91, 95% CI 0.51 to 1.62, 7 trials, 1223 patients). Treatment failure rates were also similar (RR 0.94, 95% CI 0.84 to 1.05, all trials). No significant heterogeneity was shown for all comparisons but adverse events. This effect was stable in a wide range of patients. Quinolones alone or combined with another antibiotics were used with comparable results. Adverse reactions, mostly gastrointestinal were more common with oral antibiotics. REVIEWERS' CONCLUSIONS: Based on the present data, oral treatment is an acceptable alternative to intravenous antibiotic treatment in febrile neutropenic cancer patients (excluding patients with acute leukaemia) who are haemodynamically stable, without organ failure, not having pneumonia, infection of a central line or a severe soft-tissue infection. The wide confidence interval for mortality allows the present use of oral treatment in groups of patients with an expected low risk for mortality, and further research should be aimed at clarifying the definition of low risk patients.

N-terminal sequences direct the autophosphorylation states of the FER tyrosine kinases in vivo.

p94(fer) and p51(ferT) are two tyrosine kinases which share identical SH2 and kinase domains but differ in their N-terminal regions. While p94(fer) is expressed in most mammalian cells, the accumulation of p51(ferT) is restricted to meiotic spermatocytes. Here we show that the different N-terminal tails of p94(fer) and p51(ferT) direct different autophosphorylation states of these two kinases in vivo. N-terminal coiled-coil domains cooperated to drive the oligomerization and autophosphorylation in trans of p94(fer). Moreover, the ectopically expressed N-terminal tail of p94(fer) could act as a dominant negative mutant and associated with the endogenous p94(fer) protein in CHO cells. This increased significantly the percentage of cells residing in the G0/G1 phase, thus suggesting a role for p94(fer) in the regulation of G1 progression. Unlike p94(fer), overexpressed p51(ferT) was not autophosphorylated in COS1 cells. However, removal of the unique N-terminal 43 aa of p51(ferT) or the replacement of this region by a parallel segment from p94(fer) endowed the modified p51(ferT) with the ability to autophosphorylate. The unique N-terminal sequences of p51(ferT) thus interfere with its ability to autophosphorylate in vivo. These experiments indicate that the N-terminal sequences of the FER tyrosine kinases direct their different cellular autophosphorylation states, thereby dictating their different cellular functions.

FER kinase activation of Stat3 is determined by the N-terminal sequence.

p94(fer) and p51(ferT) are two tyrosine kinases that share identical SH2 and kinase domains but differ in their N-terminal regions. To further explore the cellular functions of these two highly related tyrosine kinases, their subcellular distribution profiles and in vivo phosphorylation activity were followed using double immunofluorescence assay. When combined with immunoprecipitation analysis, this assay showed that p94(fer) can lead to the tyrosine phosphorylation and activation of Stat3 but not of Stat1 or Stat2. Native p94(fer) exerted this activity when residing in the cytoplasm. However, modified forms of p94(fer), which are constitutively nuclear, could also lead to the phosphorylation of Stat3. Endogenous Stat3 and p94(fer) co-immunoprecipitated with each other, thus proving the interaction of these two proteins in vivo. Unlike p94(fer), p51(ferT) did not induce the phosphorylation of Stat3 but led to the phosphorylation of other nuclear proteins. Replacing the unique 43-amino acid-long N-terminal tail of p51(ferT) with a parallel segment from the N-terminal tail of p94(fer) did not change the subcellular localization of p51(ferT) but enabled it to activate Stat3. Thus the different N-terminal sequences of p94(fer) and p51(ferT) can affect their ability to induce phosphorylation of Stat3 and most probably direct their different cellular functions.

Cell cycle-dependent nuclear accumulation of the p94fer tyrosine kinase is regulated by its NH2 terminus and is affected by kinase domain integrity and ATP binding.

p94fer and p51ferT are two tyrosine kinases that are encoded by differentially spliced transcripts of the FER locus in the mouse. The two tyrosine kinases share identical SH2 and kinase domains but differ in their NH2-terminal amino acid sequence. Unlike p94fer, the presence of which has been demonstrated in most mammalian cell lines analyzed, the expression of p51ferT is restricted to meiotic cells. Here, we show that the two related tyrosine kinases also differ in their subcellular localization profiles. Although p51ferT accumulates constitutively in the cell nucleus, p94fer is cytoplasmic in quiescent cells and enters the nucleus concomitantly with the onset of S phase. The nuclear translocation of the FER proteins is driven by a nuclear localization signal (NLS), which is located within the kinase domain of these enzymes. The functioning of that NLS depends on the integrity of the kinase domain but was not affected by inactivation of the kinase activity. The NH2 terminus of p94fer dictated the cell cycle-dependent functioning of the NLS of FER kinase. This process was governed by coiled-coil forming sequences that are present in the NH2 terminus of the kinase. The regulatory effect of the p94fer NH2-terminal sequences was not affected by kinase activity but was perturbed by mutations in the kinase domain ATP binding site. Ectopic expression of the constitutively nuclear p51ferT in CHO cells interfered with S-phase progression in these cells. This was not seen in p94fer-overexpressing cells. The FER tyrosine kinases seem, thus, to be regulated by novel mechanisms that direct their different subcellular distribution profiles and may, consequently, control their cellular functioning.

Tyrosine phosphorylation of the TATA element modulatory factor by the FER nuclear tyrosine kinases.

The FER locus in the mouse encodes two tyrosine kinases, p94fer and p51ferT. While p94fer accumulates in the cytoplasm and nucleus of most mammalian cells the expression of p51ferT is restricted to the nucleus of meiotic primary spermatocytes. The cellular function of the FER kinases is not understood, nor has a substrate for these enzymes been characterized. To identify putative substrates of p94fer and p51ferT, the two enzymes were used as 'baits' in the yeast two-hybrid screening system. cDNAs encoding the mouse TATA element modulatory factor (TMF) were repeatedly isolated in this assay. TMF was previously shown to bind the TATA element in RNA polymerase II promoters and impaired their functioning in a cell free transcription system. Both p94fer and p51ferT phosphorylated the TMF protein in in vitro and in vivo kinase assays. Sequential deletions showed that the carboxy-terminal region of TMF was essential for phosphorylation. In situ hybridization analysis revealed the preferential accumulation of TMF transcripts in meiotic spermatogenic and oogenic cells. p94fer and p51ferT may thus modulate the suppressive activity of TMF during cellular growth and in defined differentiation processes.