New St. Jude Medical Portico™ transcatheter aortic valve: features and early results.

Patients with symptomatic aortic valve disease who are inoperable or have high surgery-related risks may be treated with transcatheter aortic valve implantation devices. With this method increasingly applied, device innovations are aimed at achieving improved procedural results and therapeutic outcome. This paper describes the innovations implemented in the St. Jude Medical Portico™ system for transcatheter aortic valve implantation, the application of this system and initial clinical experience.

Experience using the new GORE Septal Occluder at the margins.

Complex atrial anatomy continues to challenge transcatheter device closure of septal defects. Devices and technology continue to evolve. We report three cases from our institution where the new Gore Septal Occluder was utilized for the closure of a lateral tunnel fenestration, a moderate-sized secundum atrial septal defect and a long tunnel patent foramen ovale. Each case highlights the successful use of this new generation device in challenging circumstances.

Permanent pacemaker insertion after CoreValve transcatheter aortic valve implantation: incidence and contributing factors (the UK CoreValve Collaborative).

BACKGROUND: Permanent pacemaker (PPM) requirement is a recognized complication of transcatheter aortic valve implantation. We assessed the UK incidence of permanent pacing within 30 days of CoreValve implantation and formulated an anatomic and electrophysiological model. METHODS AND RESULTS: Data from 270 patients at 10 centers in the United Kingdom were examined. Twenty-five patients (8%) had preexisting PPMs; 2 patients had incomplete data. The remaining 243 were 81.3±6.7 years of age; 50.6% were male. QRS duration increased from 105±23 to 135±29 milliseconds (P<0.01). Left bundle-branch block incidence was 13% at baseline and 61% after the procedure (P<0.001). Eighty-one patients (33.3%) required a PPM within 30 days. Rates of pacing according to preexisting ECG abnormalities were as follows: right bundle-branch block, 65.2%; left bundle-branch block, 43.75%; normal QRS, 27.6%. Among patients who required PPM implantation, the median time to insertion was 4.0 days (interquartile range, 2.0 to 7.75 days). Multivariable analysis revealed that periprocedural atrioventricular block (odds ratio, 6.29; 95% confidence interval, 3.55 to 11.15), balloon predilatation (odds ratio, 2.68; 95% confidence interval, 2.00 to 3.47), use of the larger (29 mm) CoreValve prosthesis (odds ratio, 2.50; 95% confidence interval, 1.22 to 5.11), interventricular septum diameter (odds ratio, 1.18; 95% confidence interval, 1.10 to 3.06), and prolonged QRS duration (odds ratio, 3.45; 95% confidence interval, 1.61 to 7.40) were independently associated with the need for PPM. CONCLUSION: One third of patients undergoing a CoreValve transcatheter aortic valve implantation procedure require a PPM within 30 days. Periprocedural atrioventricular block, balloon predilatation, use of the larger CoreValve prosthesis, increased interventricular septum diameter and prolonged QRS duration were associated with the need for PPM.

Clopidogrel in non-ST segment elevation acute coronary syndromes: an overview of the submission by the British Cardiac Society and the Royal College of Physicians of London to the National Institute for Clinical Excellence, and beyond.

A comprehensive appraisal was undertaken on behalf of the British Cardiac Society and the Royal College of Physicians of London to assess the use of clopidogrel in acute coronary syndromes. The appraisal was submitted to the National Institute for Clinical Excellence (NICE) in August 2003 and contributed to the development of the recently published guidelines for the use of clopidogrel in acute coronary syndromes. The submission to NICE and more recent publications evaluating the use of clopidogrel are reviewed.

Complications of transcatheter closure of atrial septal defects.

Transcatheter device closure of atrial septal defects has proved to be remarkably successful, and is usually preferred by both patients and parents. But how does it compare with the gold standard of surgical closure?

The intercellular adhesion molecule-1 (ICAM-1) gene K469E polymorphism is not associated with ischaemic heart disease: an investigation using family-based tests of association.

The possible role of the K469E polymorphism in the intercellular adhesion molecule-1 (ICAM-1) gene in the susceptibility to ischaemic heart disease (IHD) was investigated in a well-defined Irish population using two recently described family-based tests of association. One thousand and twelve individuals from 386 families with at least one member prematurely affected with IHD were genotyped for the ICAM-1 K469E polymorphism. Using the combined transmission disequilibrium test (TDT)/sib-TDT and the pedigree disequilibrium test (PDT), no association between the ICAM-1 K469E polymorphism and IHD was found. Our data demonstrate that, in an Irish population, the ICAM-1 K469E polymorphism is not associated with IHD.

Lack of association between the -2518G/A polymorphism of the MCP-1 gene and ischaemic heart disease: a family-based investigation.

Using two recently described family-based tests of association, the possible role of the functional -2518G/A polymorphism in the promoter region of the monocyte chemoattractant protein-1 (MCP-1) gene in the susceptibility to ischaemic heart disease (IHD) was investigated in a well-defined Irish population. One thousand and twelve individuals from 386 families with at least one member prematurely affected with IHD were genotyped for the MCP-1 -2518G/A polymorphism. Using the combined transmission disequilibrium test and the pedigree disequilibrium test, no association between the MCP-1 -2518G/A polymorphism and IHD was found. Our data demonstrate that, in an Irish population, the MCP-1 -2518G/A polymorphism is not strongly associated with IHD.

Investigation of the C242T polymorphism of NAD(P)H oxidase p22 phox gene and ischaemic heart disease using family-based association methods.

Ischaemic heart disease is a complex phenotype arising from the interaction of genetic and environmental factors. Excessive production of reactive oxygen species leading to endothelial dysfunction is believed to be important in the pathogenesis of ischaemic heart disease. The NAD(P)H oxidase system generates superoxide anions in vascular cells; however, the role of the C242T polymorphism of the NAD(P)H oxidase p22 phox gene in ischaemic heart disease is unclear due to contradictory results from case-control studies. Consequently, we applied family-based association tests to investigate the role of this polymorphism in ischaemic heart disease in a well-defined Irish population. A total of 1023 individuals from 388 families (discordant sibships and parent/child trios) were recruited. Linkage disequilibrium between the polymorphism and ischaemic heart disease was tested using the combined transmission disequilibrium test (TDT)/sib-TDT (cTDT) and pedigree disequilibrium test (PDT). Both cTDT and PDT analyses found no statistically significant excess transmission of either allele to affected individuals (P =0.30 and P =0.28, respectively). Using robust family-based association tests specifically designed for the study of complex diseases, we found no evidence that the C242T polymorphism of the p22 phox gene has a significant role in the development of ischaemic heart disease in our population.

Suspected angina pectoris: a rapid-access chest pain clinic.

We prospectively evaluated a rapid-access chest pain clinic in terms of clinical diagnoses, outcomes, morbidity and mortality at 3 months follow-up in patients, and cost-effectiveness. All patients seen at the clinic from February 1999 to December 2000 were assessed. Referring doctors indicated the management they would have provided had the clinic been unavailable, to allow a cost-effectiveness analysis. Overall, 709 patients were referred, 471 (66%) from General Practitioners, 212 (30%) from Accident and Emergency doctors and 26 (4%) from other sources. All had recent onset, or increasing frequency of ischaemic-type chest pain (excluding those with suspected myocardial infarction or rest chest pain angina). Fifty-one (7%) had acute coronary syndromes, 119 (17%) had stable ischaemic heart disease, 144 (20%) had possible ischaemic heart disease, and 395 (56%) were considered to have non-ischaemic symptoms. Some 70% of patients were seen within 24 h. Only 57 patients (8%) were admitted. Had the clinic been unavailable, 160 patients would have been admitted. Out-patient cardiology appointments were arranged for 116 patients (16%), and 429 patients (60%) were discharged directly. Follow-up data at 3 months were obtained from 565/567 eligible patients (99.6%). No major cardiac events (death/myocardial infarction) occurred in those with non-ischaemic chest pain. There were five deaths (including one due to cancer) and three patients had a myocardial infarction (event rate 1%). There were eleven readmissions for angina: six were in patients with acute coronary syndromes, and four of these six were awaiting revascularization. The estimated net saving was pound 58/patient. A rapid-access chest pain clinic offers a prompt, safe and cost-effective service in a challenging group of patients.

The dorsal neural tube organizes the dermamyotome and induces axial myocytes in the avian embryo.

Somites, like all axial structures, display dorsoventral polarity. The dorsal portion of the somite forms the dermamyotome, which gives rise to the dermis and axial musculature, whereas the ventromedial somite disperses to generate the sclerotome, which later comprises the vertebrae and intervertebral discs. Although the neural tube and notochord are known to regulate some aspects of this dorsoventral pattern, the precise tissues that initially specify the dermamyotome, and later the myotome from it, have been controversial. Indeed, dorsal and ventral neural tube, notochord, ectoderm and neural crest cells have all been proposed to influence dermamyotome formation or to regulate myocyte differentiation. In this report we describe a series of experimental manipulations in the chick embryo to show that dermamyotome formation is regulated by interactions with the dorsal neural tube. First, we demonstrate that when a neural tube is rotated 180 degrees around its dorsoventral axis, a secondary dermamyotome is induced from what would normally have developed as sclerotome. Second, if we ablate the dorsal neural tube, dermamyotomes are absent in the majority of embryos. Third, if we graft pieces of dorsal neural tube into a ventral position between the notochord and ventral somite, a dermamyotome develops from the sclerotome that is proximate to the graft, and myocytes differentiate. In addition, we also show that myogenesis can be regulated by the dorsal neural tube because when pieces of dorsal neural tube and unsegmented paraxial mesoderm are combined in tissue culture, myocytes differentiate, whereas mesoderm cultures alone do not produce myocytes autonomously. In all of the experimental perturbations in vivo, the dorsal neural tube induced dorsal structures from the mesoderm in the presence of notochord and floorplate, which have been reported previously to induce sclerotome. Thus, we have demonstrated that in the context of the embryonic environment, a dorsalizing signal from the dorsal neural tube can compete with the diffusible ventralizing signal from the notochord. In contrast to dorsal neural tube, pieces of ventral neural tube, dorsal ectoderm or neural crest cells, all of which have been postulated to control dermamyotome formation or to induce myogenesis, either fail to do so or provoke only minimal inductive responses in any of our assays. However, complicating the issue, we find consistent with previous studies that following ablation of the entire neural tube, dermamyotome formation still proceeds adjacent to the dorsal ectoderm. Together these results suggest that, although dorsal ectoderm may be less potent than the dorsal neural tube in inducing dermamyotome, it does nonetheless possess some dermamyotomal-inducing activity. Based on our data and that of others, we propose a model for somite dorsoventral patterning in which competing diffusible signals from the dorsal neural tube and from the notochord/floorplate specify dermamyotome and sclerotome, respectively. In our model, the positioning of the dermamyotome dorsally is due to the absence or reduced levels of the notochord-derived ventralizing signals, as well as to the presence of dominant dorsalizing signals. These dorsal signals are possibly localized and amplified by binding to the basal lamina of the ectoderm, where they can signal the underlying somite, and may also be produced by the ectoderm as well.

Development of dopaminergic neurons in the human substantia nigra.

A series of 29 human embryonic brains were examined in order to characterize the ontogeny of dopaminergic neurons within the developing substantia nigra. Embryos from Postconception Weeks 4.0 to 11.2 (last menstrual period 6.0-13.2) were studied. Immunohistochemical staining was performed using a polyclonal antibody to tyrosine hydroxylase. Tyrosine hydroxylase-like immunoreactivity was first seen in cells of the ventral mesencephalon at 6.5 weeks adjacent to the ventricular zone. Ventral migration of TH-positive cells began at 6.7 weeks. Neural process extension was first identified in tyrosine hydroxylase-positive neurons at 8.0 weeks. The ascending nigrostriatal bundle was also first demonstrated at 8.0 weeks. Tyrosine hydroxylase containing neurites were seen initially in the developing putamen at 9.0 weeks. Only a few tyrosine hydroxylase-positive cells remained adjacent to the ventricular zone at Week 10.0 and all had disappeared from the ventricular zone by 11.2 weeks. At this latter stage, a large number of dopaminergic cells had elaborated neural processes. The sequence of developmental events of human mesencephalic dopaminergic neurons is similar to the equivalent period of ontogeny in other mammals. The duration of the developmental period is, however, significantly protracted.

Xenografting of fetal pig ventral mesencephalon corrects motor asymmetry in the rat model of Parkinson's disease.

A suspension of cells from embryonic day 21 fetal pig ventral mesencephalon was transplanted into the striatum of 20 immunosuppressed rats with 6-hydroxydopamine-induced lesions of the nigrostriatal dopamine pathway. Of these rats, 15 showed reduction of amphetamine-induced ipsilateral rotation by 9 weeks and complete reversal of rotation by 14-17 weeks. Animals maintained stable reversal of rotations (contralateral direction) until cessation of Cyclosporin A (CyA) treatment at 15-20 weeks. Within 4-9 weeks after CyA removal, these rats showed exclusively ipsilateral rotations during behavioral testing which were comparable to pre-transplant levels, suggesting that the grafts were rejected upon cessation of CyA treatment. Rats were sacrificed and tyrosine hydroxylase (TH) immunohistochemistry was performed at several time points, both on and off CyA, to examine a possible correlation between the degree of rotational behavior and the number of TH-positive surviving grafted cells. Staining showed large numbers (230-12,329) of TH-positive surviving cells in animals displaying a high degree of rotational correction (1.6 to -9.6 net ipsilateral rotations/min) after cessation of CyA treatment. Two control groups, those transplanted with non-neuronal cells from the pig ventral mesencephalon (n = 5) and those receiving only daily CyA injections (n = 4) showed no significant reduction of net ipsilateral rotations throughout the experiment. No TH-positive surviving cells were seen in the one non-neuronal transplant analyzed. This data demonstrates long-term retention of xenografted tissue with immunosuppression and its concomitant restoration of normal motor behavior in the rat model of Parkinson's disease.