Liposomal 1,25 (OH)2 vitamin D3 compounds block proliferation and induce differentiation in myelomonocytic leukaemia cells

The vitamin D₃ derived hormone 1,25 (OH)₂ vitamin D₃ (1,25 D₃) is able to induce growth arrest and differentiation in myelomonocytic leukaemia cells. In order to allow for specific delivery to leukaemic cells the lipophilic compound was incorporated into the lipid membranes of liposomes. Liposomal 1,25 D₃ reduced proliferation as measured by ³H-thymidine incorporation in HL60 leukaemia cells by up to 60%. When liposomes were prepared at different concentrations of 1,25 D₃ 65% inhibition was achieved at 48 n M . The MC 1288 stereoisomer of 1,25 D₃ was more potent and had the same activity at 48 n M .
The effect of the liposomal compounds was specific to myeloid cells as they reduced proliferation in myelomonocytic HL60, monoblastic U937 and monocytic Mono Mac 6 cells but not in the T-cell lines Jurkat and Molt 4.
The antiproliferative effect of liposomal 1,25 D₃ was associated with an induction of differentiation since treated HL60 cells showed a monocytic morphology, increased expression of CD14 and decreased expression of CD33.
When peripheral blood leukaemic cells from M4 and M5 acute myeloid leukaemia (AML) patients were admixed with liposomal compounds an antiproliferative effect was seen in all five cases, including the two cases where free compounds led to enhanced growth. Liposomal delivery of 1,25 (OH)₂ vitamin D₃ may offer a novel approach to treatment of myelomonocytic leukaemia.     

Correlation of Impedance Minute Ventilation with Measured Minute Ventilation in a Rate Responsive Pacemaker

Although rate responsive pacing based on impedance minute ventilation (IMV) is now standard, there is almost no data confirming the relationship between IMV from an implanted pacemaker and measured minute ventilation (VE) during exercise. Nineteen completely paced adults implanted with Medtronic Kappa 400 pacemakers underwent symptom-limited maximal metabolic treadmill testing using a modified Minnesota Pacemaker Response Protocol. Minute ventilation (VE, L/min) was simultaneously measured using the flowmeter of a respiratory metabolic gas analysis system and the transthoracic impedance minute ventilation circuitry of the pacemaker. Correlation coefficients (r) were used to find the best fit line to describe the relationship between the two measurements. Mean (+/- SD) r values for the first, second, and third order polynomial equations and for log and exponential equations were: 0.92 +/- 0.08, 0.94 +/- 0.04, 0.95 +/- 0.04, 0.91 +/- 0.06, and 0.91 +/- 0.07, respectively. None of the r values were statistically different from the first order equation. Transthoracic IMV as measured by the Medtronic Kappa 400 is closely correlated to measured minute ventilation and is represented well by a first order (linear) equation.     

Vibration, Acceleration, Gravitation, and Movement: Activity Controlled Rate Adaptive Pacing During Treadmill Exercise Testing and Daily Life Activities

Activity-based sensors for rate adaptive pacing have been available for several years and now include several different types: vibration; acceleration; gravitation; and movement. However, a systematic comparison evaluating the relative advantages and disadvantages of these various sensors has received little study. The purpose of the present study was to compare these sensor subtypes using treadmill testing and an outdoor test circuit, which simulated daily life activities and included both uphill and downhill walking. Pacemakers were strapped on the chest of healthy volunteers and connected to one channel of an ambulatory recording device, which also recorded the subject's intrinsic heart rate. The pacemakers were programmed using an initial treadmill test to standardize the rate responsive parameters for each device. Nine different pacemaker models were studied including 3 vibration-based (Elite. Synchrony, Metros). 4 acceleration-based (Relay, Excel, Ergos, Trilogy), 1 gravitational-based (Swing), and 1 movement-based (Sensorithm) device. All devices demonstrated a prompt rate response with casual walking on flat ground. The vibration-, gravitational-, and movement-based pacemakers showed a pronounced rate decline during more strenuous work, e.g., walking uphill. This phenomenon was absent in the accelerometer-based units. In particular, the vibration- and movement-based units showed a higher rate with walking downhill compared to uphill. An optimally tuned rote behavior on the treadmill usually did not provide an optimal rate behavior during daily activities and there was a tendency to overstimulation during low workload. The development of the two newest sensors (gravitational and movement) did not result in an improved performance of rate response behavior. Overall, the accelerometer-based pacemakers simulated or paralleled sinus rate behavior the most closely.     

Activity-Controlled Circadian Base Rate

The current pacing rates are clustered around a fixed base rate since pacemaker patients are usually sedentary, resting, or sleeping most of the time. This fixed base rate is either too low for daytime hemodynamic support or too high for nighttime rest and recovery. Multiple Holter studies involving normal individuals have suggested that the resting base rate fluctuates during the course of the day. The circadian base rate (CBR) algorithm was designed to provide patients with a circadian change in paced resting rate and a normal rate distribution. The CBR algorithm, using a sophisticated accelerometer sensor, was developed and tested using the downloaded activity data from patients implanted with Trilogy DR+ pacemakers. Twenty-five patients (19 men, 6 women, age 72 ± 9 years) were studied. Trilogy DR+ is able to record the detailed sensor and system behavior data for a week. During outpatient visits, the pacemaker was interrogated and the data accumulated in the pacemaker memory were downloaded. The CBR algorithm was applied to the activity variance histogram to calculate the base rate and to construct its histogram. The base rates in the CBR histogram are generally below 100 ppm with a distribution that mimics the natural sinus rate distribution of normal subjects. The CBR algorithm provides the highest daytime rates for hemodynamic support and the lowest nighttime rates for cardiac recovery, with a smoothly changing base rate modeling the normal circadian variation in heart rate.     

Influence of Exercise Induced Myocardial Ischemia on Right Ventricular dP/dt: Potential Implications for Rate Responsive Pacing

Background : Right ventricular (RV) dP/dt_max has been used as a simple parameter for rate responsive pacing to simulate the normal sinus node function. However, the effect of acute myocardial ischemia on RV dP/dt_max has not yet been evaluated. Methods : RV high fidelity pressure was measured in 21 patients at rest and during supine bicycle exercise. Nine patients (Group 1 = controls) had no or only minimal alterations of the coronary arteries and 12 (Group 2 =CAD) had significant coronary artery disease with exercise induced left ventricular (LV) wall-motion abnormalities (n = 10) and/or angina pectoris (n = 6). RV pressure and its first derivative (RV dP/dtj were determined by an 8 French micromanometer catheter. The time constant of RV pressure decay (Tau) was calculated from the negative reciprocal of RV pressure versus negative dP/dt during isovolumic relaxation. RV volumes and ejection fraction were calculated from RV biplane angiograms (multiple slice method) at rest and during exercise. Results : Heart rate (HR), RV dP/dt_max and dP/dt_min increased significantly during exercise, whereas Tau decreased. There were no significant differences between the two groups, although RV ejection fraction increased from 67% to 72% in the control group but decreased from 63% to 51% in the CAD group (P < 0.05). An exponential relationship was found between HR and dP/dt_max with a correlation coefficient of 0.82 (P < 0.01; SEE = 7% of the mean value). Conclusions : Acute exercise induced myocardial ischemia does not significantly influence RV dP/dt_max during sinus rhythm. Consequently, this index of RV contractility may be used in patients with coronary artery disease as a simple parameter for rate responsive pacing.     

Autonomic Nervous System-Controlled Cardiac Pacing: A Comparison Between Intracardiac Impedance Signal and Muscle Sympathetic Nerve Activity

BINGGELI, C., et al. : Autonomic Nervous System‐Controlled Cardiac Pacing: A Comparison Between Intracardiac Impedance Signal and and Muscle Sympathetic Nerve Activity. A recently introduced rate responsive cardiac pacing system is based on information derived from the intracardiac impedance signal containing information on the inotropic state of the ventricle. This study compared the inotropic state index (ISI) with muscle sympathetic activity (MSA), both being modulated by the autonomic nervous system. Nine patients (66 ± 3 years, mean ± SEM ) with Inos2DR pacemakers were included. Each patient was studied at rest and during cold pressor test (CPT). Microneurography of the peroneal nerve was performed to measure MSA continuously, which was digitally stored along with continuous surface ECG and blood pressure. The intracardiac impedance signal was transmitted by the pacemaker and stored simultaneously. Linear correlation between ISI and MSA was calculated for the period of the CPT. During CPT, mean systolic blood pressure increased from 122 ± 4 to 149 ± 6 mmHg (P < 0.0001), diastolic blood pressure increased from 74 ± 8 to 86 ± 4 mmHg (P = 0.02 ), and intrinsic heart rate increased from 69 ± 7 to 75 ± 7 beats/mill (P = 0.019 ). ISI increased by 21 ± 7% (P = 0.018 ), MSA by 26 ± 6% (P = 0.004 ). ISI and MSA were positively correlated during the CPT in eight of nine patients (R2 = 0.86–0.99, P < 0.0001 ). Negative correlation was found in one patient (R2 = 0.94 ). This study demonstrates parallel increases of the ISI and MSA during CPT. ISI and MSA showed a close linear relationship during provoked changes of sympathetic activity. These results provide further evidence that the sympathetic nervous system is responsible for the observed ISI changes.     

Acute Hemodynamic Effects of Alternate and Combined Site Pacing in Patients after Cardiac Surgery

We hypothesized that pacing at sites other them the right ventricular (RV) apex or at two or more ventricular sites would activate the myocardium more rapidly and improve cardiac function in patients undergoing coronary revascularization or aortic valve replacement. Epicardial electrodes were placed on the right atrium (A), RV paraseptal area close to the RV apex (B), RV outflow tract (C), LV apex (D), in patients undergoing bypass surgery. At constant rate and AV delay, we measured CO during A pacing, DV1 pacing at B, C, D, and various combinations of sites in random order in ten patients with EF > 50% and 27patients with EF ≤ 50%. When pacing at two sites, we made one electrode a cathode and one an anode and noted two distinct thresholds by careful observation of the 12-lead ECG. There were no significant differences in CO, systemic vascular resistance, systolic, or mean arterial pressure. Significant differences were noted in QRS duration, which increased progressively going from AAI to 3-site, 2-site, and single site pacing (P < 0.05 each comparison). Thus: (1) QRS duration correlated inversely with the number of ventricular sites paced; (2) despite this, CO did not improve irrespective of baseline EF; (3) multisite pacing produced multiple distinct thresholds which appeared to be related to the number of sites paced, and (4) unique ECG patterns confirmed multisite pacing.     

Activity-Sensing Rate Responsive Versus Conventional Fixed-Rate Pacing: A Comparision of Rate Behavior and Patient Well-Being During Routine Daily Exercise

Rate responsive single chamber pacing (WIR) may be the pacemaker of choice in pafients who are not suitable candidates for a dual chamber system. Several studies, most of them performed in an exercise laboratory, have shown a significantly higher exercise capacity demonstrating an improvement in cardiac output and anaerobic threshold compared to conventional fixed rate pacing (VVT). Expressing our idea that stress testing in an “artificial environment” on a bicycle or motor driven treadmill has its limitations and may be difficult to extend into patient's daily life, we designed an outdoor study imitating patient's daily activity. Twenty-one patients with an activity-sensing rate responsive pacemaker performed in a double blind fashion in VVI and VVIR mode the following test circuit: walking 170 meters on flat ground, 210 meters incline, climbing a flight of stairs, and the same circuit in reverse order, and therefore “downhill”. Heart rate behavior was recorded by Holter monitoring and patients subjective feelings of well-being, i.e. fatigue and dyspnea were also evaluated, VVIR pacing responded promptly to exercise, i.e., walking on a flat ground, but no further significant increase in pacing rate was observed in relationship to the strength of physical activity while walking inclined or climbing stairs. While patients became exhausted, a nonphysiological decrease in heart rate sometimes occurred. Despite these limitations 6 of 12 patients who had a paced-only rhythm while exercising in both VVI and VVIR mode reported feeling significantly belter in the VVIR mode, expressing less dyspnea and fatigue. In contrast, two of nine patients having only intermittently paced rhythm preferred the VVIR mode. Patients with lower ejection fraction (EF) were more likely to show subjectively a benefit while exercising in VVIR mode, compared to those with less reduced or normal EF. Despite the technical limitations of using a piezo crystal for rate adaptation, WIR pacing is an important option in paced-only patients, but it seems less beneficial in patients with only intermittent paced rhythm.     

Age and Sex Related Changes in Heart Rate to Ventilation Coupling: Implications for Rate Adaptive Pacemaker Algorithms

Minute ventilation (VE) controlled rate adaptive pacemakers determine the paced rate increase during exercise by measuring changes in transthoracic impedance that have been shown to correlate well with VE. To determine the normal coupling of heart rate (HR) to VE, this relationship was evaluated in 30 younger and 25 older, healthy subjects using peak cardiopulmonary exercise testing. After determining the anaerobic threshold (AT), the linear HR to VE slope was determined both below and above the AT. In addition, the entire curve of the HR to VE relationship was assessed by a "best fit" regression analysis method. The relationship of HR to VE was more often logarithmic in younger as compared to older subjects. The HR to VE slope below the AT was always steeper than above the AT in younger subjects. Females of both age subgroups demonstrated a significantly greater slope below and above the AT. For the appropriate programming of VE controlled, rate responsive pacemakers, one should take into consideration age- and sex-specific differences in the HR to VE relationship throughout exercise. Therefore, age- and sex-specific programmable features for rate responsive parameters should be incorporated into pacemakers using VE controlled rate adaptive algorithms.     

Acute Hemodynamic Effects of Atrioventricular Pacing at Differing Sites in the Right Ventricle Individually and Simultaneously

We hypothesized that pacing, which provided a rapid uniform contraction of the ventricles with a narrower QRS, would produce a better stroke volume and cardiac output (CO). We sought to study whether pacing simultaneously at two sites in the right ventricle (right ventricular apex and outflow tract) would provide a narrower QRS and improved CO in 11 patients undergoing elective electrophysiology studies. Patients were studied by transthoracic echocardiography measurement of CO using the Doppler flow velocity method in normal sinus rhythm, AOO pacing (rate 80), DOO pacing in the right ventricular apex (AV delay 100 ms). DOO pacing in the right ventricular outflow tract, and DOO pacing at both right ventricular sites simultaneously in random order. The COs were 5.42 ± 1.83, 5.61 ± 1.97. 5.67 ± 1.6. 5.84 ± 1.68. and 5.86 ± 1.52 L/min, respectively (no significant difference by repeated measures analysis of variance [ANOVA]). The QRS durations were 0.09 ± 0.02, 0.09 ± 0.02. 0.13 ± 0.027, 0.13 ± 0.03, and 0.11 ± 0.03 sees respectively. Repeated measures ANOVA showed that the QRS duration significantly increased with right ventricular apex or right ventricluar outflow tract pacing compared to sinus rhythm and AOO pacing (P < 0.001) but then diminished with pacing at both sites (P < 0.01). QRS duration was not correlated with CO, however the change in QRS duration correlated significantly with the change in CO when pacing was performed at the two right ventricular sites simultaneoasly. In conclusion, during DOO pacing, there was a trend for pacing in the right ventricular outflow tract or both sites to improve the CO compared to the right ventricular apex. With simultaneous pacing at both ventricular sites, the QRS narrowed. Further studies will be required to see if this approach has value in patients with poor left ventricular function or congestive heart failure.