Actual Pacemaker Longevity: The Benefit of Stimulation by Automatic Capture Verification

Background: We evaluated the impact of an algorithm for automatic right ventricular (RV) stimulation compared to fixed‐output pacing (FOP) stimulation on actual pacemaker longevity over a 9‐year follow‐up. Methods: Prospective observation of 300 patients implanted with VDDR/DDDR pacemakers in 1999–2000 up to October 31, 2008. Sixty‐one patients were paced by Autocapture? pacing (ACP), 239 were paced by FOP; they were seen twice yearly at the pacemaker clinic. Factors known to affect pacemaker longevity were collected: median heart rate, %A&V paced activity, pacing output, and impedance. Patients dead before pacemaker replacement, lost to follow‐up, or who developed permanent atrial fibrillation were excluded from analysis. Results: One hundred twenty‐six of three hundred patients completed the study. Adverse clinical events due to an increased RV threshold occurred in two FOP patients compared to none among ACP. Pacemaker replacement occurred in 1/34 ACP patients versus 60/92 FOP patients (P < 0.001). ACP was the single independent predictor of pacemaker longevity at multivariable analysis (hazard ratio = 0.03, P < 0.001) either in the overall population or in the specific patients subgroups (sick sinus syndrome, atrioventricular block, and neurally mediated syncope). Conclusions: Automatic verification of stimulation is reliable at long term, and warrants superior safety in the event of pacing threshold changes. It allows a significant longevity increase compared to FOP stimulation that may heavily impact the patients’ quality of life and the cost of pacing therapy. Moreover, it is a fundamental technology in a strategy of remote patient and device monitoring, and may enable automatic device follow‐up operated by trained, nonmedical personnel. (PACE 2010; 873–881)     

EXPRESSION OF ICAM-1 AND VCAM-1 IN HUMAN MALIGNANT MESOTHELIOMA

Intercellular adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule-1 (VCAM-1) are cytokine-inducible adhesion molecules which recognize ligands that are highly expressed on leukocytes. Expression of ICAM-1 and VCAM-1 was investigated in tissue sections of 16 cases of malignant mesothelioma (seven epithelial, eight biphasic, and one sarcomatoid) using immunohistochemistry. Neoplastic cells were diffusely and intensely stained for ICAM-1 in all cases. VCAM-1 was detected in 14 of 16 cases. The percentage of VCAM-1-positive tumour cells was more than 50 per cent in eight cases and the staining was observed mainly in epithelial-like cells. VCAM-1 was rarely expressed in other malignant tumours of epithelial origin, being present in only 1 of 58 cases of carcinoma originating from different anatomical sites. At the cellular level, ICAM-1 and VCAM-1 appeared co-distributed, the staining for both being cytoplasmic with a membrane reinforcement. The regulation of VCAM-1 expression by neoplastic mesothelial cells was investigated in vitro using 14 mesothelioma cell lines. ICAM-1 was expressed by cultured cells of all mesothelioma cell lines, even in the absence of cytokines. VCAM-1 was detected in 10–50 per cent of the cells in three non-stimulated mesothelioma cell lines (mero-95, mero-96, and mero-134), and was absent or poorly expressed in the remaining 11. Exposure of a negative cell line (mero-48a) to an optimal concentration of tumour necrosis factor alpha (TNFα) or interleukin-13 (IL-13) for 6–18 h resulted in the induction of VCAM-1 mRNA synthesis and in VCAM-1 expression at the membrane level in 60–70 per cent of the cells. These findings are consistent with the possibility that TNFα, IL-13, or other activating signals are released in the tumour micro-environment and regulate the expression of VCAM-1 in malignant mesothelioma cells.     

Elevated Cell Invasion in a Tumor Sphere Culture of RSV-M Mouse Glioma Cells

Cancer stem cells (CSCs) are the sole population possessing high self-renewal activity in tumors, with their existence affecting tumor recurrence. However, the invasive activity of CSCs has yet to be fully understood. In this article, we established a tumor sphere culture of RSV-M mouse glioma cells (RSV-M-TS) and evaluated their migration and invasion activities. Histological analysis of a tumor formed by cranial injection of the RSV-M-TS cells showed highly invasive properties and similarities with human malignant glioma tissues. When the migration activity of both RSV-M and RSV-M-TS cells were compared by intracranial injection, rapid migration of RSV-M-TS cells was observed. To confirm the invasive capabilities of RSV-M-TS cells, a three-dimensional collagen invasion assay was performed in vitro using RSV-M, RSV-M-TS, and RSV-M-TS cells cultured with medium containing serum. RSV-M and RSV-M-TS cultured with medium containing serum for 8 days indicated low migration activity, while moderate invasion activity was observed in RSV-M-TS cells. This activity was further enhanced by incubation with medium containing serum overnight. To identify the genes involved in this invasion activity, we performed quantitative polymerase chain reaction (PCR) array analysis of RSV-M and RSV-M-TS cells. Of 84 cancer metastasis-related genes, up-regulation was observed in 24 genes, while 4 genes appeared to be down-regulated in RSV-M-TS cells. These results suggest that the enhanced invasive activity of glioma sphere cells correlates with a number of tumor metastasis-related genes and plays a role in the dissemination and invasion of glioma cells.     

Effects of Cardiac Resynchronization Therapy on Diastolic Function: Evaluation by Radionuclide Angiography

While the beneficial effects of cardiac resynchronization therapy (CRT) on left ventricular (LV) systolic function have been demonstrated, no information is available regarding its effects on LV diastolic function during exercise. Using radionuclide angiography, we prospectively evaluated the effects of CRT on diastolic function at rest and during exercise in 15 patients consecutively referred for CRT. All patients underwent equilibrium Tc⁹⁹ radionuclide angiography with bicycle exercise performed (1) at baseline; (2) immediately after CRT implantation, in spontaneous rhythm and during CRT; and (3) after 3 months of biventricular stimulation. Diastolic function was assessed by measurements of peak filling rate (PFR). At baseline, activation of biventricular stimulation influenced PFR neither at rest (1.06 ± 0.34 vs 1.07 ± 0.50 mL/s during spontaneous rhythm, P = 0.9) nor during exercise (1.45 ± 0.62 vs 1.33 ± 0.48 mL/s, P = 0.3). At 3 months, improvements were observed in New York Heart Association functional class and systolic function. By contrast, no improvement in diastolic function was observed either at rest (PFR = 1.11 ± 0.45 vs 1.07 ± 0.50 mL/s in spontaneous rhythm at baseline, P = 0.6) or during exercise (1.23 ± 0.50 vs 1.33 ± 0.48 mL/s, P = 0.2). These observations indicate that the intermediate benefits conferred by CRT on LV systolic function at rest and during exercise were not accompanied by similar improvements in diastolic function .     

Relationship Between Global Myocardial Index and Automatic Left Ventricular Border Detection Pattern to Identify Biventricular Pacing Candidates

Objective of the Study: to evaluate the relation between global myocardial index (GMI) and the pattern of left ventricular (LV) volume curves variation, using automatic border detection (ABD), and their role in assessing LV asynchrony.
Methods: We studied 52 patients (mean age = 55 ± 17 years) with dilated cardiomyopathy. QRS duration (QRSd) and GMI were measured. Currently accepted TDI and M-mode parameters were used to indicate LV dyssynchrony. On-line continuous LV volume changes were recorded using ABD. Ejection time (ET ABD) was measured from the ABD wave-forms as time interval between maximal and minimal volume variation during LV electromechanical systole. We derived the ejection time index (ETiABD) as the ratio between ET ABD and RR interval (ETiABD = ET/RR).
Results: 31 patients had a QRSd >120 ms and 21 patients had a QRSd <120 ms. Ventricular dyssynchrony was observed in 39 patients (29 patients had a QRSd > 120 ms). GMI was significantly higher in patients with, than in patients without ventricular dyssynchrony (1.06 ± 0.18 vs 0.73 ± 0.13, P = 0.0001), while ETABD was significantly smaller (233 ± 39 ms vs 321 ± 28 ms, P = 0.0001). The corresponding difference for ETiABD was 26.9 ± 6.8% vs 6.3 ± 4%, P < 0.0001. By simple regression analysis an inverse linear correlation was observed between GMI and ETiABD (r²=–0.51, P < 0.0001). The pattern of ABD waveforms showed increased isovolumic contraction and relaxation times in patients with LV asynchrony, similar to the GMI pattern.
Conclusions: Regional delays in ventricular activation cause uncoordinated and prolonged ventricular contractions, with lengthening of the isovolumic contraction and relaxation times and shortening of the time available for filling and ejection. GMI explores these parameters and together with ABD might be useful to identify patients with ventricular asynchrony.     

Studies on the Mechanism of Hypoproteinemia in Gastric Cancer: 2. Albumin Leakage into Gastric Juice in Rats with N-Methyl- N'-Nitro-N-Nitrosoguanidine Induced Gastric Cancer

In a previous paper, we reported that the leakage of serum albumininto the gastric juice definitely increased in six out of 30patients suffering from gastric cancer and discussed the mechanismsof albumin leakage into the stomach lumen. In this study, we measured the leakage of scrum albumin intothe gastric juice of rats with gastric cancer induced by N-methyl-N'-nitro-N-nitrosoguanidine(MNNG). Nine through 12 months after the beginning of MNNG administration,several rats began to show adenocarcinoma in the glandular stomach.Albumin leakage of these rats increased notably compared tonon-tumor-developing rats. In the 15th month, all the rats wereafflicted with gastric cancer, accompanied by a high leakageof serum albumin. To study the mechanism of albumin leakage, leakage of serumalbumin into the gastric juice was measured in rats which hadundergone various treatments, such as thoracic duct ligation,subcutaneous transplantation of Yoshida sarcoma, administrationof toxohormone and experimental ulccration of the stomach. Therats which were given thoracic duct ligation or those whichwere administered toxohormone all showed mild increase in theleakage of serum albumin, and a significant increase in theleakage was detected in rats bearing subcutaneously transplantedYoshida sarcoma nine or more days after transplantation. Onthe other hand, the leakage scarcely increased in the rats withexperimental gastric ulcer. From these results, we considered that the causes of albuminleakage into the gastric juice in cases with gastric cancercan be attributed not only to the local changes of the gastricwall but also to a systemic phenomenon associated with the tumor-bearinghost. ^*This study was supported by a grant from the Ministry of Healthand Welfare.     

Efficacy and side effects of intermittent recombinant interferon-α2a in chronic aggressive hepatitis C: With or without initial daily administration

To investigate the therapeutic effect and incidence of side effects of recombinant interferon-α2a (IFN-α) in chronic aggressive hepatitis C under stratification by administration mode, a study was conducted by assigning patients to either group A (daily consecutive administration of 9 million units (MU) IFN-α for 2 weeks and, thereafter, 3 MU intermittently 3 times weekly for 22 weeks) or group B (exclusively intermittent administration; 9 MU IFN-α twice weekly or 6 MU IFN-α thrice weekly for 24 weeks). The 28 patients in group A received IFN-α for 24 weeks up to a total dose of 324 MU and the 53 patients in group B received the same for 24 weeks up to a total dose of 432 MU. When recovery was defined as the absence of hepatitis C virus (HCV)-RNA 6 months after the completion of treatment, the rate of recovery for group A was 32.1% and that for group B was 37.7%, the latter being higher but without significance. Side effects in groups A and B consisted of leucopenia occupying 14.3 and 7.5%, respectively, and thrombocytopenia occupying 42.9 and 11.3%, respectively; group B exhibited lower values for both side effects. No difference was detected between these groups in other side effects, including pyrexia, generalized malaise, arthralgia or psilosis. Intermittent administration from the outset permitted shortened duration of hospitalization and earlier rehabilitation. Intermittent administration of INF-α is required when treating patients with chronic hepatitis C showing lower leucocyte or platelet counts.     

Case Report: Agranulocytosis induced by interferon-α therapy for chronic hepatitis C

A 60-year-old woman presented with chronic active hepatitis C whose HCV-RNA genotype was II according to Okamoto's classification and serum HCV-RNA concentration was 10⁴ copies/mL. Agranulocytosis was induced 13 days from the commencement of interferon (IFN)-α 2b (6 MU/day) therapy, so the IFN therapy was immediately discontinued. The agranulocytosis improved rapidly with the administration of a granulocyte colony stimulating factor (G-CSF). The possibility that IFN was associated with maturational arrest of myeloid progenitor cells was considered. During the course of 3 years of follow-up, her liver function has remained normal and serum HCV-RNA remains negative.