Endovascular treatment of peripheral artery disease with expanded PTFE-covered nitinol stents: interim analysis from a prospective controlled study.

PURPOSE: Current covered peripheral stent designs have significant drawbacks in terms of stent delivery characteristics and flexibility. The aim of this study was to analyze the technical performance, safety and initial clinical efficacy of expanded polytetrafluoroethylene (PTFE)-covered nitinol stents for arteriosclerotic peripheral artery disease. METHODS: Eighty-two patients underwent implantation of PTFE-covered nitinol stents for iliac and/or femoral obstructions. The study was conducted prospectively in seven European centers and one Canadian center. Patients were controlled clinically and by duplex ultrasound follow-up. Data up to discharge were collected in 79 patients. Seventy-four patients have thus far received 1 month follow-up and 32 patients, 6 month follow-up examinations. RESULTS: The average lesion length measured 47 mm for the common and external iliac arteries and 50 mm for the femoral arteries. The mean severity of the stenoses was reduced from 94% to 4% in the iliac arteries and from 98% to 7% in the femoral arteries after stent placement and dilatation. One device deviation (inadvertent stent misplacement) and one puncture-related severe adverse event with formation of a pseudoaneurysm occurred. There were occlusions of the stent in five patients. No infections were noticed. CONCLUSION: The interim analysis of this trial using PTFE-covered nitinol stents indicates that a strategy using primary implantation of this stent type is technically feasible, has an acceptable safety profile and is effective from a short-term perspective.

Local delivery of nadroparin for the prevention of neointimal hyperplasia following stent implantation: results of the IMPRESS trial. A multicentre, randomized, clinical, angiographic and intravascular ultrasound study.

BACKGROUND: We hypothesized that intramural delivery of nadroparin, a low molecular weight heparin, would prevent in-stent restenosis by inhibiting neointimal hyperplasia in an angioplasty model free of arterial remodelling. METHODS AND RESULTS: In a prospective randomized multicentre trial, 250 patients submitted to balloon angioplasty followed by stent implantation were randomized into control group (no local drug delivery) or intramural delivery of nadroparin (2 ml of 2500 anti-Xa-units/ml with a microporous catheter). An ancillary intravascular ultrasound substudy was performed to supplement angiographic data with specific measurements of in-stent neointimal hyperplasia. The primary end-point was the late loss in minimal luminal diameter on the 6 month follow-up angiogram. Secondary end-points included feasibility and safety of local nadroparin delivery, and major adverse cardiac events at 8 weeks and 6 months follow-up. Local delivery of nadroparin was successful in 124 patients (99.2% success rate) and was not associated with an increase in stent thrombosis, coronary artery dissection, side branch occlusion, distal embolization or abrupt arterial closure. At angiographic follow-up, the late loss in lumen diameter was 0.84 +/- 0.62 mm in the control group compared to 0.88 +/- 0.63 mm in the nadroparin group (P=0.56). Angiographic restenosis rate (defined as a >50% diameter stenosis) did not differ in the control group (20%) compared to the nadroparin group (24%). The average area of neointimal tissue within the stent was 2.86 +/- 0.64 mm(2) vs 2.90 +/- 0.53 mm(2) (P=0.57), control vs nadroparin groups. There was no difference in major adverse cardiac events at any time (88.8% vs 89.6% event free survival at 6 months, control vs nadroparin). CONCLUSION: Intramural delivery of nadroparin with a microporous catheter after stent deployment was feasible and safe but had no effect in reducing restenosis or the occurrence of major adverse clinical events over 6 months.

Dynamic adaptation of cardiac oxidative phosphorylation is not mediated by simple feedback control.

The classic idea about regulation of cardiac oxidative phosphorylation (OxPhos) was that breakdown products of ATP (ADP and P(i)) diffuse freely to the mitochondria to stimulate OxPhos. On the basis of this metabolic feedback control system, the response time of OxPhos (t(mito)) is predicted to be inversely proportional to the mitochondrial aerobic capacity (MAC). We determined t(mito) during steps in heart rate in isolated perfused rabbit hearts (n = 16) before and after reducing MAC with nonsaturating doses of oligomycin. The reduction of MAC was quantified in mitochondria isolated from each perfused heart, dividing oligomycin-sensitive, ADP-stimulated state 3 respiration by oligomycin-insensitive uncoupled respiration. The t(mito) to heart rate steps from 60 to 70 and 80 beats/min was 5. 6 +/- 0.6 and 7.2 +/- 0.8 s (means +/- SE) and increased an estimated 34 and 40% for a 50% decrease in MAC (P < 0.05), respectively, which is much less than the 100% predicted by the feedback hypothesis. For steps to 100 or 120 beats/min, t(mito) was 8.3 +/- 0.5 and 11.2 +/- 0.6 s and was not reduced with decreases in MAC (P > 0.05). We conclude that immediate feedback control by quickly diffusing ADP and P(i) cannot explain the dynamic regulation of cardiac OxPhos. Because calcium entry into the mitochondria also cannot explain the first fast phase of OxPhos activation, we propose that delay of the energy-related signal in the cytoplasm dominates the response time of OxPhos.

The dynamic regulation of myocardial oxidative phosphorylation: analysis of the response time of oxygen consumption.

Although usually steady-state fluxes and metabolite levels are assessed for the study of metabolic regulation, much can be learned from studying the transient response during quick changes of an input to the system. To this end we study the transient response of O2 consumption in the heart during steps in heart rate. The time course is characterized by the mean response time of O2 consumption which is the first statistical moment of the impulse response function of the system (for mono-exponential responses equal to the time constant). The time course of O2 uptake during quick changes is measured with O2 electrodes in the arterial perfusate and venous effluent of the heart, but the venous signal is delayed with respect to O2 consumption in the mitochondria due to O2 diffusion and vascular transport. We correct for this transport delay by using the mass balance of O2, with all terms (e.g. O2 consumption and vascular O2 transport) taken as function of time. Integration of this mass balance over the duration of the response yields a relation between the mean transit time for O2 and changes in cardiac O2 content. Experimental data on the response times of venous [O2] during step changes in arterial [O2] or in perfusion flow are used to calculate the transport time between mitochondria and the venous O2 electrode. By subtracting the transport time from the response time measured in the venous outflow the mean response time of mitochondrial O2 consumption (tmito) to the step in heart rate is obtained. In isolated rabbit heart we found that tmito to heart rate steps is 4-12 s at 37 degrees C. This means that oxidative phosphorylation responds to changing ATP hydrolysis with some delay, so that the phosphocreatine levels in the heart must be decreased, at least in the early stages after an increase in cardiac ATP hydrolysis. Changes in ADP and inorganic phosphate (Pi) thus play a role in regulating the dynamic adaptation of oxidative phosphorylation, although most steady state NMR measurements in the heart had suggested that ADP and Pi do not change. Indeed, we found with 31P-NMR spectroscopy that phosphocreatine (PCr) and Pi change in the first seconds after a quick change in ATP hydrolysis, but remarkably they do this significantly faster (time constant approximately 2.5 s) than mitochondrial O2 consumption (time constant 12 s). Although it is quite likely that other factors besides ADP and Pi regulate cardiac oxidative phosphorylation, a fascinating alternative explanation is that the first changes in PCr measured with NMR spectroscopy took exclusively place in or near the myofibrils, and that a metabolic wave must then travel with some delay to the mitochondria to stimulate oxidative phosphorylation. The tmito slows with falling temperature, intracellular acidosis, and sometimes also during reperfusion following ischemia and with decreased mitochondrial aerobic capacity. In conclusion, the study of the dynamic adaptation of cardiac oxidative phosphorylation to demand using the mean response time of cardiac mitochondrial O2 consumption is a very valuable tool to investigate the regulation of cardiac mitochondrial energy metabolism in health and disease.

Function of isolated rabbit hearts perfused with erythrocyte suspension is not stable but improvement may be feasible with hemoglobin solution.

In the present study isolated rabbit hearts were perfused with erythrocyte suspensions (hematocrit 21.5 +/- 0.5%) or hemoglobin solutions according to Langendorff with a constant flow at 37 degrees C. In preliminary experiments three types of stroma-free hemoglobin were used: unmodified, but carefully purified, stroma-free hemoglobin (SFHb), HbNFPLP which is a chemically modified Hb molecule and polyHbNFPLP which is a polymer of HbNFPLP. In hearts perfused with erythrocyte suspensions left ventricular developed pressure and oxygen consumption decreased and perfusion pressure increased steadily from the beginning of the perfusion. Dark spots appeared on the surfaces of these hearts, which were the result of extravasation of erythrocytes. As a consequence capillaries probably became obstructed, leading to reduced cardiac function. Hearts perfused with stroma-free hemoglobin solutions showed an initial increase in left ventricular developed pressure after switching from Tyrode perfusion to perfusion with hemoglobin solutions. Left ventricular developed pressure and perfusion pressure were stable for about 2 hours in hearts perfused with SFHb and were reasonable for 2 hours when the heart was perfused with HbNFPLP or more than 4 hours with polyHbNFPLP. More extensive experiments with stroma-free hemoglobin solutions when these become available in sufficient quantities have, according to the results from preliminary experiments, the potential of showing good oxygen supply resulting in reasonable cardiac function.

Adaptation speed of cardiac mitochondrial oxygen consumption decreases with higher heart rate.

The purpose of the present study was to determine whether the mean response time of cardiac mitochondrial oxygen consumption after a step in metabolic demand is constant in heart muscle, as has already been found for skeletal muscle. The mean response time reflects the average delay between the change in ATP hydrolysis due to a heart rate step and mitochondrial ATP production. Isolated rabbit hearts with a water-filled balloon in the left ventricle were perfused according to Langendorff with a constant flow of Tyrode solution at 28 degrees C. The mean response time increased significantly from 7.6 s for a step in heart rate from 60 to 70 min-1 to 12.1 s for a step from 60 to 120 min-1. The mean response times for heart rate steps downward from 120 min-1 were all approximately 12 s, but for the step from 120 to 140 min-1 the response time was 16.8 s. These results demonstrate that the mean response time of cardiac mitochondrial oxygen consumption in most cases increases with heart rate. These findings are in contrast to those obtained in skeletal muscle, where the response time at which ATP synthesis adapts to a change in work load is constant.

Dynamics of myocardial lactate efflux after a step in heart rate in isolated rabbit hearts.

We investigated whether a glycolytic burst contributes to the initial adaptation of ATP synthesis to increased cardiac metabolic demand. Six isolated rabbit hearts were perfused with glucose-containing Tyrode solution at 28 degrees C. In venous and arterial samples the lactate concentration was determined with a sensitive enzymatic cycling method. After the heart rate was doubled from 60 to 120 beats/min, lactate efflux increased from 0.23 +/- 0.10 (SE) to 0.45 +/- 0.12 mumol.min-1.g-1 dry weight with a mean response time of 21.3 s but without an overshoot. The transport time for lactate is longer than 15.7 s, suggesting that lactate production adapts with a mean response time of less than 6 s. Because no overshoot in lactate efflux was found, it is unlikely that a glycolytic burst after a step in heart rate contributes to the fast adaptation of ATP synthesis to demand in the isolated rabbit heart, although it might be possible that a change in cytosolic lactate production is not reflected in an increase in lactate efflux. Extrapolation of the results of this study to the in vivo situation should be done with caution.

Acidosis slows the response of oxidative phosphorylation to metabolic demand in isolated rabbit heart.

The purpose of this study was to investigate the effect of acidosis on the mean response time of mitochondrial oxygen consumption to steps in heart rate and in left ventricular balloon volume. The mean response time may be viewed as the average delay between a change in adenosine triphosphate (ATP) hydrolysis and oxygen consumption. The mean response time is calculated by subtracting the transport time, required for diffusion of oxygen and for convective transport through the coronary vessels, from the response time measured in the coronary venous effluent. Eight isolated rabbit hearts were perfused according to Langendorff using Tyrode solution at 28 degrees C. Arterial perfusate pH was lowered from 7.30 +/- 0.03 (mean +/- SD) to 6.59 +/- 0.02 by increasing the CO2 tension. At pH 7.3 the mean response time was 12.6 +/- 1.6 s, independent of the time after isolation of the heart. During acidosis, applied 40-75 min after isolation of the heart, the mean response time was 21.4 +/- 0.7 s and increased to 32.6 +/- 4.3 s during acidosis, 85-120 min after isolation. Thus the retardation of the metabolic response by acidosis might depend on the condition of the heart. A decrease of mitochondrial ATP synthetic capacity during acidosis may contribute to the retardation of the metabolic response. Since determination of the mean response time at 37 degrees C is not yet feasible, the experiments were done at 28 degrees C. Extrapolation of our findings to 37 degrees C appears premature.

Mitochondrial dehydrogenase activity affects adaptation of cardiac oxygen consumption to demand.

The effect of regulation of mitochondrial dehydrogenase activities on the mean response time of mitochondrial oxygen consumption, which characterizes the delay between changes in ATP hydrolysis and changes in oxygen consumption, was investigated in isolated rabbit hearts and perfused with Tyrode solution at 28 degrees C. Perfusion with ruthenium red (RR) blocks mitochondrial calcium uptake and thus decreases mitochondrial dehydrogenase activities. Perfusion with pyruvate increases pyruvate dehydrogenase activity. The mean response time was 11.8 +/- 0.7 s (means +/- SE) during control, 12.2 +/- 1.2 s during perfusion with 0.9 microgram/ml RR, and 20.7 +/- 3.4 s during perfusion with 2.1 micrograms/ml RR. Blockade with 0.9 microgram/ml RR, which is presumably partial, did not slow the response, suggesting that mitochondrial calcium uptake may not be rate limiting. Strong blockade of mitochondrial calcium uptake increases the mean response time, presumably due to decreased calcium activation of the mitochondrial dehydrogenases. Perfusion with pyruvate significantly decreased the mean response time to 10.0 +/- 1.4 s compared with 11.9 +/- 0.7 s during perfusion with glucose. This decrease with pyruvate is not compatible with a shift to regulation by high-energy phosphates but may reflect increased mitochondrial oxidative capacity caused by increased NADH levels.

Influence of temperature on the response time of mitochondrial oxygen consumption in isolated rabbit heart.

1. In this study we determined the temperature dependence of the mean response time of cardiac mitochondrial oxygen consumption following steps in metabolic demand. Metabolic demand was altered by stepwise changes in heart rate or in left ventricular volume at 20 and 28 degrees C. 2. Ten isolated rabbit hearts were perfused with Tyrode solution at constant oxygen tension and constant arterial flow. A balloon was inserted in the left ventricle and developed pressure was measured. Coronary venous oxygen tension was measured continuously with a Clark-type oxygen electrode. 3. The mean response time of mitochondrial oxygen consumption is defined as the first statistical moment of the impulse response function. This mean response time of mitochondrial oxygen consumption, following the change in metabolic demand, is calculated from the measured mean response time for the change in coronary venous oxygen tension by subtracting the transport time resulting from diffusion and convective transport in the blood vessels. The transport time is obtained from a model for oxygen transport developed previously. Experimental data, necessary for the model calculation, were obtained from measurement of the coronary venous oxygen tension transients following stepwise changes either in arterial oxygen tension or perfusion flow. 4. The calculated mean response times of mitochondrial oxygen consumption were 26.9 +/- 3.0 s (mean +/- S.E.M.) at 20 degrees C and 14.9 +/- 1.0 s at 28 degrees C. The mean response times of mitochondrial oxygen consumption did not differ significantly for steps in heart rate and in left ventricular volume and between upward and downward steps. 5. We suggest that intracellular calcium concentration is not the sole regulator of mitochondrial oxygen consumption in the isolated rabbit heart, since steps in heart rate and in left ventricular volume showed the same time course of oxygen uptake. 6. The mean response time of mitochondrial oxygen consumption obtained in the isolated rabbit heart at 20 degrees C did not differ significantly from the mean response time of mitochondrial oxygen consumption of isolated rabbit papillary muscle. After combining our data with previously published data on empty beating hearts at 37 degrees C, a Q10, which is the factor by which the mean response time of mitochondrial oxygen consumption increases per 10 degrees C decrease in temperature, of 2.1 was calculated.

Effects of modified hemoglobin solutions on the isolated rabbit heart.

The effects of modified hemoglobin (Hb) solutions on the coronary vasculature were studied. Hearts were perfused according to Langendorff with constant flow of Tyrode solution. The solutions studied were stroma- free Hb, prepared by lysis of red blood cells in water (SFHb-lys), or prepared by swelling of red blood cells in hypotonic phosphate buffer (SFHb). The increase in coronary vascular resistance at a dose of 200 mg Hb/dl was 68% for SFHb-lys and 13% for SFHb, respectively. Addition of the modified Hb solutions HbNFPLP and polyHbNFPLP produced an increase in coronary resistance of 11% and 8%, respectively. The left ventricular developed pressure (LVDP) (control value 72 +/- 12 mm Hg) increased by 18 and 12 mm Hg, respectively, for a dose of 250 mg Hb/dl. When HbNFPLP was converted to its met-Hb form the increase in LVDP was reduced to 3 mmHg and the increase in perfusion pressure to 6 mm Hg. We conclude that elimination of stromal contamination from Hb solutions can diminish vasoconstrictor effects. The increase in cardiac pressure development and in coronary vascular resistance found for dilute modified Hb solutions is partly due to an improved oxygen transport to the heart.

Effect of timing of transient diastolic changes in ventricular filling on LV performance in dogs.

The influence of acute volume changes during diastole on the contractile state of the left ventricle has been studied in the closed-chest dog. Volume changes were introduced by means of a servo-controlled pump system connected to the left ventricular cavity by an apical cannula. Pressure measurements were made in the left ventricle and aorta. Flow sensors in the mitral valve and around the ascending aorta monitored ventricular inflow and outflow patterns. The ventricular performance was evaluated in terms of the ratio between end-systolic pressure and end-systolic volume (P/Ves). By changing the time of occurrence of the volume interventions from the rapid filling phase of diastole to the atrial contraction phase, the relative contributions of rapid filling and atrial contraction to the mitral flow were changed. When the rapid filling was changed by the volume intervention, the effect on the contractile status of the heart, expressed as the P/Ves value, was small. In contrast, when the volume intervention took place during the atrial contraction phase, the effect on the P/Ves value was much larger. Comparison with muscle fiber experiments suggests that length-dependent calcium sensitivity of troponin and length-dependent conductivity of the sarcolemma are the underlying fundamental mechanisms. Therefore, we conclude that the influence of an intervention in ventricular filling on the inotropic state of the left ventricle is dependent on the timing of the intervention.