Performance and clinical comparison between left ventricular quadripolar and bipolar leads in cardiac resynchronization therapy: Observational research.

AIM: To evaluate Attain Performa (Medtronic, Dublin, Ireland) quadripolar lead performance in clinical practice and, secondarily, to compare its long term clinical outcomes vs bipolar leads for left ventricular (LV) pacing. METHODS AND RESULTS: We retrospectively analyzed clinical, procedural and follow-up data of 215 patients implanted with a quadripolar lead. One hundred and twenty one patients implanted with bipolar lead were selected to compare long-term clinical outcomes. The quadripolar lead was implanted in the target vein in 196 patients (91%) without acute dislodgements. In 50% of patients the chosen final pacing configuration at implant would not have been available with bipolar leads. A dedicated quadripolar pacing vector was chosen more frequently when the LV tip location was apical than otherwise (65.6% vs 42.7%, p=0.003). After a median follow-up of 14 months, the LV pacing threshold was less than 2.5V at 0.4ms in 98 patients (90%) with a safety margin between phrenic nerve and LV pacing threshold >3V in 97 patients (89%). We observed a slight trend toward a lower risk of heart failure worsening and a lower incidence of ventricular arrhythmias and pulmonary congestion in patients implanted with quadripolar leads compared with the control group. CONCLUSION: Quadripolar leads improve the management of phrenic nerve stimulation at no trade-off with pacing threshold and lead stability. Quadripolar leads seems to be associated with a lower incidence of VT/VF and pulmonary congestion, when compared with bipolar leads, but further investigations are necessary to confirm that this positive effect is associated with better LV reverse remodeling.

Study of a low-dose capsule filling process by dynamic and static tests for advanced process understanding.

Precise filling of capsules with doses in the mg-range requires a good understanding of the filling process. Therefore, we investigated the various process steps of the filling process by dynamic and static mode tests. Dynamic tests refer to filling of capsules in a regular laboratory dosator filling machine. Static tests were conducted using a novel filling system developed by us. Three grades of lactose excipients were filled into size 3 capsules with different dosing chamber lengths, nozzle diameters and powder bed heights, and, in the dynamic mode, with two filling speeds (500, 3000 caps/h). The influence of the gap at the bottom of the powder container on the fill weight and variability was assessed. Different gaps resulted in a change in fill weight in all materials, although in different ways. In all cases, the fill weight of highly cohesive Lactohale 220 increased when decreasing the gap. Furthermore, experiments with the stand-alone static test tool indicated that this very challenging powder could successfully be filled without any pre-compression in the range of 5 mg-20 mg with acceptable RSDs. This finding is of great importance since for very fine lactose powders high compression ratios (dosing-chamber-length-to-powder-bed height compression ratios) may result in jamming of the piston. Moreover, it shows that the static mode setup is suitable for studying fill weight and variability. Since cohesive powders, such as Lactohale 220, are hard to fill, we investigated the impact of vibration on the process. Interestingly, we found no correlation between the reported fill weight changes in dynamic mode at 3000 cph and static mode using similar vibration. However, we could show that vibrations during sampling in the static mode dramatically reduced fill weight variability. Overall, our results indicate that by fine-tuning instrumental settings even very challenging powders can be filled with a low-dose dosator capsule filling machine. This study is a further step towards a scientific qualification of dosator nozzles for low-fill weight (1-45 mg) capsule filling.

The effect of material attributes and process parameters on the powder bed uniformity during a low-dose dosator capsule filling process.

The objective of this work was to assess the effect of process parameters of a dosator nozzle machine on the powder bed uniformity of inhalation powders with various characteristics during a low-dose dosator capsule filling process. Three grades of lactose excipients were extensively characterized and filled into size 3 capsules using different dosing chamber lengths (2.5, 5mm), nozzle diameters (1.9, 3.4mm), powder bed heights (5, 10mm) and filling speeds (500, 3000capsules/h). The fill weight and the weight variability of Lactohale 100 (large particles, good flowability, low cohesion) remained almost the same, regardless of the process parameters throughout the capsule filling run time. Moreover, for this powder an increase in the fill weight at a higher filling speed was observed in all cases. Fill weight variability was significantly higher for lower dosing chamber volumes at a filling speed of 3000 capsules per hour. Lactohale 220 (small particles, poor flowability, high cohesion) delivered entirely different results. After a certain run time, depending on instrumental settings, a 'steady-state' with constant fill weights and low weight variability was achieved. For this highly cohesive powder, a high dosing chamber volume requires a low filling speed in order for the powder to completely fill the dosator nozzle. Moreover, it was established that a dosing chamber length of 2.5mm and a powder bed height of 10mm were required due to the powder's high fill weight variability over time, while the dosator size had no effect on it. In summary, the layer uniformity, the fill weight and the weight variability strongly depend on the powder characteristics and the instrumental settings. The results indicate that Lactohale 220 requires special attention during low-dose capsule filling. The study presents excellent insights into the effect of material attributes and process parameters on the layer uniformity and the quality of end product.

Development of a design space and predictive statistical model for capsule filling of low-fill-weight inhalation products.

The objectives of this study were to develop a predictive statistical model for low-fill-weight capsule filling of inhalation products with dosator nozzles via the quality by design (QbD) approach and based on that to create refined models that include quadratic terms for significant parameters. Various controllable process parameters and uncontrolled material attributes of 12 powders were initially screened using a linear model with partial least square (PLS) regression to determine their effect on the critical quality attributes (CQA; fill weight and weight variability). After identifying critical material attributes (CMAs) and critical process parameters (CPPs) that influenced the CQA, model refinement was performed to study if interactions or quadratic terms influence the model. Based on the assessment of the effects of the CPPs and CMAs on fill weight and weight variability for low-fill-weight inhalation products, we developed an excellent linear predictive model for fill weight (R(2 )= 0.96, Q(2 )= 0.96 for powders with good flow properties and R(2 )= 0.94, Q(2 )= 0.93 for cohesive powders) and a model that provides a good approximation of the fill weight variability for each powder group. We validated the model, established a design space for the performance of different types of inhalation grade lactose on low-fill weight capsule filling and successfully used the CMAs and CPPs to predict fill weight of powders that were not included in the development set.

Accuracy of micro powder dosing via a vibratory sieve-chute system.

This paper describes a powder dosing system with a vibratory sieve mounted on a chute that doses particles into a capsule. Vertical vibration occurred with a broad range of frequencies and amplitudes. During dosing events, the fill weight was accurately recorded via a capacitance sensor, covering the capsules and making it possible to analyze filling characteristics, that is, the fill rates and their robustness. The range of frequencies and amplitudes was screened for settings that facilitated reasonable (no blocking, no spilling) fill rates for three lactose powders. The filling characteristics were studied within this operating space. The results reveal similar operating spaces for all investigated powders. The fill rate robustness varied distinctly in the operating space, which is of prime importance for selecting the settings for continuous feeding applications. In addition, we present accurate dosing studies utilizing the knowledge about the filling characteristics of each powder.

Supraventricular arrhythmia before and after surgical closure of atrial septal defects: spectrum, prognosis and management.

UNLABELLED: Supraventricular arrhythmias are often observed in patients before and after atrial septal defect repair. Although several papers report different incidences of sustained supraventricular arrhythmias, postoperative 'incisional' macroreentrant tachycardias have not been systematically investigated. METHODS: We reviewed 136 consecutive patients (79 female, 57 male, mean age 36.8+/-17.8 years) who underwent atrial septal defect repair at our institutions between January 1990 and January 1999. Coexisting valve disease requiring surgical intervention was noted in 13 patients (9.5%). The mean follow-up period was 78.8+/-30.1 months. RESULTS: Sustained supraventricular arrhythmias occurred in 12 patients (8.8%) before surgery (atrial fibrillation in 11 patients). Using multivariate analysis the occurrence of arrhythmia significantly correlated with the presence of coexisting heart disease (P< 0.001) and age at surgery (P=0.011) After surgery sustained supraventricular arrhythmias were recorded in 16 patients (11.7%). Eleven of them had atrial fibrillation, permanent in 8 cases, 4 'incisional' macroreentrant atrial tachycardia and 1 atrioventricular re-entry tachycardia. There was a significant correlation between pre and postoperative arrhythmia (P< 0.001). Two of the 4 patients with macroreentrant atrial tachycardia underwent successful radiofrequency catheter ablation, whereas the arrhythmia was controlled medically in the remaining 2 patients. CONCLUSIONS: Atrial fibrillation remains the most frequent form of arrhythmia before and after surgical closure of atrial septal defects in adulthood, and relates to age at the time of repair and coexisting heart disease. Incisional macroreentrant atrial tachycardia is an identifiable, albeit less common, form of tachycardia, which can be treated by transcatheter ablation.

Active versus borderline myocarditis: clinicopathological correlates and prognostic implications.

OBJECTIVE: To compare active (AM) with borderline (BM) myocarditis to verify whether the pathological distinction between the two forms may help to identify patients with different clinical and haemodynamic characteristics and to aid prognosis. MATERIALS: Myocarditis was diagnosed in 56 patients on endomyocardial biopsy (EMB) within one year from clinical onset of the disease between 1991 and 1998. Fourteen patients were excluded because of a lack of adequate and complete information. EMBs and clinical records of the 42 remaining patients were reviewed. Immunohistochemistry on bioptic samples was regularly performed. Polymerase chain reaction (PCR) for a panel of viruses was performed in 23 patients (55%). Clinicopathological correlations were calculated. RESULTS: The histological diagnosis was AM in 26 patients (62%) and BM in 16 (38%). Significant differences were found in the following parameters: presence of left bundle branch block on ECG (AM 2 (8%) v BM 5 (31%), p = 0.05); left ventricular volume on echocardiogram (mean (SD) AM 90 (42) ml/m(2) v BM 128 (50) ml/m(2), p = 0.002); mass to volume ratio (AM 1.0 (0) v BM 0.8 (0.1), p = 0.03); time interval between clinical onset of the disease and EMB (AM 40 (55) v BM 90 (93) days, p = 0.04); and degree of inflammatory infiltrates, scored on a scale of 0 to 3 (AM 1.65 (0.8) v BM 0.85 (0.3), p = 0.004). In 6 of 15 patients (40%) with AM and in 2 of 8 (25%) with BM, a viral genome was detected by PCR (NS). At follow up, no differences in death or heart transplantation were detected between the two forms (AM 4 patients (15%) v BM 2 patients (12.5%)). Three of eight PCR positive patients (37.5%) and 1 of 15 virus negative patients (7%) died or underwent heart transplantation. CONCLUSIONS: BM seems to encompass inflammatory forms with a less aggressive inflammatory infiltrate evolving towards left ventricular dilatation. The term "chronic myocarditis" seems to be more appropriate. The absence of myocyte necrosis does not predict a more favourable prognosis, whereas the absence of a viral genome seems to predict it.

Myocarditis mimicking acute myocardial infarction: role of endomyocardial biopsy in the differential diagnosis.

OBJECTIVE: To test the hypothesis, using endomyocardial biopsies, that unexplained cases of apparent acute myocardial infarction were caused by myocarditis. MATERIAL: Between 1992 and 1998, 12 patients were admitted to the coronary care unit with severe chest pain, ST segment elevation, increased serum creatine kinase and MB isoenzyme, and with wall motion abnormalities on echocardiogram highly suggestive of acute myocardial infarction. These patients were further investigated by endomyocardial biopsy, as their coronary angiograms were normal. A diagnosis of myocarditis was made according to the Dallas criteria. A panel of antibodies was used for immunohistochemical characterisation of inflammatory cell infiltrate. Polymerase chain reaction (PCR) was used to detect viral genomes in seven cases. RESULTS: Haematoxylin and eosin staining of the endomyocardial biopsy showed active myocarditis in six patients and borderline myocarditis in one. Immunohistochemistry was positive for inflammatory cell infiltrates in 11 patients, including all the seven who were positive on haematoxylin and eosin staining according to the Dallas criteria. Only one patient had no evidence of inflammation. PCR was positive in two patients, both for Epstein-Barr virus. Follow up showed complete resolution of echocardiographic abnormalities in all patients except one. CONCLUSIONS: Myocarditis can mimic acute myocardial infarction in patients with angiographically normal coronary arteries, leading to errors of treatment. In patients with apparent myocardial infarction and a normal coronary angiogram, endomyocardial biopsy may help in the diagnosis of myocarditis. The sensitivity of endomyocardial biopsy was enhanced by using immunohistochemical and molecular biological techniques.

Histologic findings in the conduction system after cardiac transplantation and correlation with electrocardiographic findings.

The study of the sinus node and the specialized atrioventricular junction by serial sections in cardiac transplantation revealed that acute rejection involving the conduction system was equally severe as the working myocardium, with the exception of the His bundle. During acute rejection, the sudden appearance of a first-degree atrioventricular block may suggest severe involvement of the conduction system with impending cardiac arrest.

Morphologic spectrum of primary restrictive cardiomyopathy.

A restrictive hemodynamic profile with left ventricular (LV) end-diastolic volume < 100 ml/m2 and LV end-diastolic pressure > 18 mm Hg, in the absence of endomyocardial, pericardial, and specific cardiomyopathy, is a peculiar feature of primary restrictive cardiomyopathy. From 1985 to 1994, 7 hearts of patients who met the above hemodynamic criteria and underwent endomyocardial biopsy because of heart failure, were studied through gross (5 cardiectomies and 2 autopsies), histologic, and electron microscopic investigations. Ages ranged from 9 to 48 years (mean age 29 +/- 13). Four patients (57%) had a positive family history: 2 for hypertrophic and 2 for restrictive cardiomyopathy. Three patterns were identified in the 7 hearts: (1) pure restrictive form in 4 cases with mass/volume ratio 1.2 +/- 0.5 g/ml, ejection fraction 58 +/- 5%, LV end-diastolic volume 67.5 +/- 12.6 ml/m2, LV end-diastolic pressure 26.7 +/- 3.5 mm Hg; (2) hypertrophic-restrictive form in 2 cases with mass/volume ratio 1.5 +/- 0.07 g/ml, ejection fraction 62 +/- 1%, LV end-diastolic volume 69 +/- 10 ml/m2, LV end-diastolic pressure 30 +/- 7 mm Hg; and (3) mildly dilated restrictive form in 1 case with mass/volume ratio 0.9 g/ml, ejection fraction 25%, LV end-diastolic volume 98 ml/m2, LV end-diastolic pressure 40 mm Hg. Histology and electron microscopy disclosed myocardial and myofibrillar disarray and endoperimysial interstitial fibrosis in each pattern. The familial forms suggest the presence of a genetic abnormality. Primary restrictive cardiomyopathy may present with or without hypertrophy and shares similar microscopic pictures with hypertrophic cardiomyopathy. The 2 entities may represent a different phenotypic expression of the same genetic disease.