Prediction of response to cardiac resynchronization therapy using left ventricular pacing lead position and cardiovascular magnetic resonance derived wall motion patterns: a prospective cohort study.

BACKGROUND: Despite marked benefits in many heart failure patients, a considerable proportion of patients treated with cardiac resynchronization therapy (CRT) fail to respond appropriately. Recently, a "U-shaped" (type II) wall motion pattern identified by cardiovascular magnetic resonance (CMR) has been associated with improved CRT response compared to a homogenous (type I) wall motion pattern. There is also evidence that a left ventricular (LV) lead localized to the latest contracting LV site predicts superior response, compared to an LV lead localized remotely from the latest contracting LV site. METHODS: We prospectively evaluated patients undergoing CRT with pre-procedural CMR to determine the presence of type I and type II wall motion patterns and pre-procedural echocardiography to determine end systolic volume (ESV). We assessed the final LV lead position on post-procedural fluoroscopic images to determine whether the lead was positioned concordant to or remote from the latest contracting LV site. CRT response was defined as a ≥ 15% reduction in ESV on a 6 month follow-up echocardiogram. RESULTS: The study included 33 patients meeting conventional indications for CRT with a mean New York Heart Association class of 2.8 ± 0.4 and mean LV ejection fraction of 28 ± 9%. Overall, 55% of patients were echocardiographic responders by ESV criteria. Patients with both a type II pattern and an LV lead concordant to the latest contracting site (T2CL) had a response rate of 92%, compared to a response rate of 33% for those without T2CL (p = 0.003). T2CL was the only independent predictor of response on multivariate analysis (odds ratio 18, 95% confidence interval 1.6-206; p = 0.018). T2CL resulted in significant incremental improvement in prediction of echocardiographic response (increase in the area under the receiver operator curve from 0.69 to 0.84; p = 0.038). CONCLUSIONS: The presence of a type II wall motion pattern on CMR and a concordant LV lead predicts superior CRT response. Improving patient selection by evaluating wall motion pattern and targeting LV lead placement may ultimately improve the response rate to CRT.

Relationship between mechanical dyssynchrony and intra-operative electrical delay times in patients undergoing cardiac resynchronization therapy.

BACKGROUND: It is important to understand the relationship between electrical and mechanical ventricular activation in CRT patients. By measuring local electrical activation at multiple locations within the coronary veins and myocardial contraction at the same locations in the left ventricle, we determined the relationship between electrical and mechanical activation at potential left ventricular pacing locations. METHODS: In this study, mechanical contraction times were computed using high temporal resolution cine cardiovascular magnetic resonance (CMR) data, while electrical activation times were derived from intra-procedural local electrograms. RESULTS: In our cohort, there was a strong correlation between electrical and mechanical delay times within each patient (R2=0.78 ± 0.23). Additionally, the latest electrically activated location corresponded with the latest mechanically contracting location in 91% of patients. CONCLUSIONS: This study provides initial evidence that our method of obtaining non-invasive mechanical activation patterns accurately reflects the underlying electromechanical substrate of intraventricular dyssynchrony.

Breaking the rules: sex roles and genetic mating system of the pheasant coucal.

Generally in birds, the classic sex roles of male competition and female choice result in females providing most offspring care while males face uncertain parentage. In less than 5% of species, however, reversed courtship sex roles lead to predominantly male care and low extra-pair paternity. These role-reversed species usually have reversed sexual size dimorphism and polyandry, confirming that sexual selection acts most strongly on the sex with the smaller parental investment and accordingly higher potential reproductive rate. We used parentage analyses and observations from three field seasons to establish the social and genetic mating system of pheasant coucals, Centropus phasianinus, a tropical nesting cuckoo, where males are much smaller than females and provide most parental care. Pheasant coucals are socially monogamous and in this study males produced about 80% of calls in the dawn chorus, implying greater male sexual competition. Despite the substantial male investments, extra-pair paternity was unusually high for a socially monogamous, duetting species. Using two or more mismatches to determine extra-pair parentage, we found that 11 of 59 young (18.6%) in 10 of 21 broods (47.6%) were not sired by their putative father. Male incubation, starting early in the laying sequence, may give the female opportunity and reason to seek these extra-pair copulations. Monogamy, rather than the polyandry and sex-role reversal typical of its congener, C. grillii, may be the result of the large territory size, which could prevent females from monopolising multiple males. The pheasant coucal's exceptional combination of classic sex-roles and male-biased care for extra-pair young is hard to reconcile with current sexual selection theory, but may represent an intermediate stage in the evolution of polyandry or an evolutionary remnant of polyandry.

Development of isothiocyanate-enriched broccoli, and its enhanced ability to induce phase 2 detoxification enzymes in mammalian cells.

Broccoli florets contain low levels of 3-methylsuphinylpropyl and 4-methylsulphinylbutyl glucosinolates. Following tissue disruption, these glucosinolates are hydrolysed to the corresponding isothiocyanates (ITCs), which have been associated with anticarcinogenic activity through a number of physiological mechanisms including the induction of phase II detoxification enzymes and apoptosis. In this paper, we describe the development of ITC-enriched broccoli through the introgression of three small segments of the genome of Brassica villosa, a wild relative of broccoli, each containing a quantitative trait locus (QTL), into a broccoli genetic background, via marker-assisted selection and analysis of glucosinolates in the florets of backcross populations. Epistatic and heterotic effects of these QTLs are described. The ITC-enriched broccoli had 80-times the ability to induce quinone reductase (a standard assay of phase II induction potential) when compared to standard commercial broccoli, due both to an increase in the precursor glucosinolates and a greater conversion of these into ITCs.

Intermittent antegrade tepid versus cold blood cardioplegia in elective myocardial revascularization.

BACKGROUND: The ideal temperature for blood cardioplegia administration remains controversial. METHODS: Fifty-two patients who required elective myocardial revascularization were prospectively randomized to receive intermittent antegrade tepid (29 degrees C; group T, 25 patients) or cold (4 degrees C; group C, 27 patients) blood cardioplegia. RESULTS: The two cohorts were similar with respect to all preoperative and intraoperative variables. The mean septal temperature was higher in group T (T, 29.6 degrees +/- 1.1 degrees C versus 17.5 degrees +/- 3.0 degrees C; p < 0.0001). After reperfusion, group T exhibited significantly greater lactate and acid release despite similar levels of oxygen extraction (p < 0.05). The creatine kinase-MB isoenzyme release was significantly lower in group T (764 +/- 89 versus 1,120 +/- 141 U x h/L; p < 0.04). Hearts protected with tepid cardioplegia demonstrated significantly increased ejection fraction with volume loading, improvement in left ventricular function at 12 hours, and decreased need for postoperative inotropic support (p < 0.05). The frequency of ventricular defibrillation after cross-clamp removal was lower in this cohort (p < 0.05). There were no hospital deaths, and both groups had similar postoperative courses. CONCLUSIONS: Intermittent antegrade tepid blood cardioplegia is a safe and efficacious method of myocardial protection and demonstrates advantages when compared with cold blood cardioplegia in elective myocardial revascularization.

Control of flower development and phyllotaxy by meristem identity genes in antirrhinum.

The flower meristem identity genes floricaula (flo) and squamosa (squa) promote a change in phyllotaxy from spiral to whorled in Antirrhinum. To determine how this might be achieved, we have performed a combination of morphological, genetic, and expression analyses. Comparison of the phenotypes and RNA expression patterns of single and double mutants with the wild type showed that flo and squa act together to promote flower development but that flo is epistatic to squa with respect to early effects on phyllotaxy. We propose that a common process underlies the phyllotaxy of wildtype, flo, and squa meristem development but that the relative timing of primordium initiation or growth is altered. This process depends on two separable events: setting aside zones for potential primordium initiation and partitioning these zones into discrete primordia. Failure of the second event can lead to the formation of continuous double spirals, which are occasionally seen in flo mutants.

Effects of elevated intracellular magnesium on cytoskeletal integrity.

Increasing the intracellular magnesium concentration of PtK2 cells by 1 mM or more resulted in the disassembly of the interphase microtubule array over a period of 5 min after microinjection. This effect was found to be both transient and fully reversible, with the microtubule arrays reforming after further incubation. These effects were studied using immunofluorescence microscopy of fixed cells, and also in living cells using rhodamine-tubulin or rhodamine-conjugated anti-tubulin antibodies and image intensification and enhancement techniques. Simultaneously and accompanying the disassembly of the microtubule arrays the F-actin stress fibres also disappeared, usually leaving the peripheral and perinuclear F-actin microfilaments intact. In contrast, increasing intracellular magnesium appeared to have no effect on the vimentin-containing intermediate filaments of PtK2 cells. These effects on the cytoskeleton were specific to magnesium and could not be mimicked by either microinjection of injection buffer of equivalent ionic strength or sham injection. Raising the intracellular free calcium to the same extent resulted in the disassembly of the microtubule network, but appeared to have no effect on the F-actin stress fibres.

Distribution of F-actin during cleavage of the Drosophila syncytial blastoderm.

The process of cleavage during the syncytial blastoderm stage of the Drosophila embryo was studied in fixed whole-mounts using a triple-staining technique. Plasmalemma was stained with Concanavalin A conjugated to tetramethylrhodamine isothiocyanate, the underlying cortical F-actin with a fluorescein derivative of phalloidin, and nuclei with 4',-6 diamidine-2-phenylindole dihydrochloride. The surface caps, which overlie the superficial nuclei at this stage, were found to be rich in F-actin as compared with the rest of the cortex. After the caps formed, they extended over the surface and flattened. Whilst this was occurring the F-actin network within the caps became more diffuse. By the end of the expansion process F-actin had become concentrated at both poles of the caps. The caps then split in two. The cleavage was not accompanied by the formation of any apparent contractile ring of microfilaments across the cap, rather the break region was depleted in F-actin. The cortical actin associated with each half of the old cap then became reorganized around a nucleus to form a new daughter cap, and the cycle began again.

F-actin distribution during the cellularization of the Drosophila embryo visualized with FL-phalloidin.

The changing distribution of polymerized actin during the cellularization of the Drosophila blastoderm was investigated in fixed whole embryos using FL-phalloidin as a specific stain. Prior incubation of FL-phalloidin with F-actin from both rabbit and locust muscle blocked the staining action, whereas G-actin at the same concentration had no effect. At the initiation of cellularization bands of F-actin filaments, shaped into rough hexagons, were found around each forming cell close to the surface bulges. These bands interlinked across the whole embryo. Above the level of the hexagons was a fine meshwork of F-actin associated with many folds of the plasmalemma. Below the hexagons was a layer of small irregular actin aggregates. During the process of cellularization the hexagonal actin network was associated with the tips of the extending plasmalemmas until the cells reached their full length. It is suggested that this actin network acts as a contractile ring system which cleaves the embryo into cells. The network was then found to rapidly break down. Microfilament bundles formed rings associated with the bases of the cells. These are presumed to cleave off the fully formed cells from the underlying yolk sac. During the first phase of cell membrane growth the fine F-actin meshwork remained associated with the apical plasmalemmas. However, the mesh rapidly disappeared during the second period of extension. After this, actin aggregates were visible close to the apical surfaces of the cells. F-actin was also observed to be associated with the newly formed plasmalemmas along their length during the whole of the process of cleavage.

Changes in the distribution of cortical myosin during the cellularization of the Drosophila embryo.

Changes in the distribution of myosin during the formation of the cellular blastoderm of Drosophila melanogaster were followed by staining sections of embryos with antibodies to myosin. These were visualized with indirect immunofluorescence. Prior to the start of cell membrane extension myosin is distributed between the nuclear caps as a thin sub-plasmalemma layer. There is also myosin present beneath the surface of the caps. When plasmalemma growth occurs, myosin is associated with the furrow canals, the tips of the advancing membranes. The fluorescence is distributed in an approximately hexagonal pattern around the growth points of each cell. The hexagons are joined up forming a network. It is suggested that this myosin is associated with bundles of microfilaments, orientated parallel to the surface, to form many interlocking contractile rings. The simultaneous contraction of these rings causes the cleavage of the blastoderm. During the first phase of membrane growth, myosin is also associated with the apical surfaces of the forming cells. At this stage these surfaces are rich in microvilli. However, by the time the furrow canals have reached the bases of the cells much of this myosin has disappeared. At about this time the apical surface becomes taut with a loss of the microvilli.

Comparison of bubble and membrane oxygenators in short and long perfusions.

Eighty patients had cardiopulmonary bypass (CPB), half having short (109 +/- 11 minutes) perfusions and half having long (188 +/- 14 min) perfusions. Twenty patients in each group were perfused with bubble oxygenators (Bentley, Harvey, or Galen) and 20 with membrane oxygenators (Modulung or Teflo). Hemodilution to a hematocrit value of 22.5% +/- 1.4% and hypothermia to 28 degrees +/- 2 degrees C were used in all patients. Complete hemograms, sequential multiple analyzer 18 tests, coagulation profiles, blood gases and pH, three immunoglobulins, and two complement fraction proteins were sampled as follows: three times before perfusion, one to ten times during perfusion, 1 hour immediately after perfusion, and 4, 24, and 48 hours postoperatively. Data in concentration terms were compared statistically and reported as mean and standard error for each subset. Additionally, rates of gain or loss were calculated in terms of quantity per liter of blood pumped per minute. During perfusion for both duration sets, use of a membrane oxygenator resulted in greater pump flows (4.55 +/- 0.15 L/min versus 3.75 +/- 0.11 L/min), lower total peripheral resistances (1,125 +/- 63 dynes.sec.cm-5 versus 1,652 +/- 115 dynes.sec.cm-5), and greater urinary outputs (9.4 +/- 1.1 ml/min versus 2.2 +/- 0.6 ml/min) than in the bubble oxygenator subsets. Comparisons of measured and calculated data in the immediate postperfusion interval showed no differences between bubble and membrane oxygenator subsets for short perfusions. In long perfusions, the membrane subset had lower plasma hemoglobin and white cell concentrations and generation rates, smaller (3 to 8 1/2 times) losses of IgG, IgM, C3 and shed blood necessitating less transfusion, and greater C4 losses. The membrane oxygenator systems used were more complex and costly and offered no advantages for short perfusion in adults. In anticipated long perfusions or where bleeding may be a problem, a membrane oxygenator appears more efficacious than bubble systems. For perfusions of less than 2 hours, membrane oxygenators had no biochemical or hematologic advantage over the bubble devices used in this study.