[Freiburg index of patient satisfaction: interdisciplinary validation of a new psychometric questionnaire to describe treatment-related patient satisfaction]. / Freiburger Index für Patientenzufriedenheit: Interdisziplinäre Validierung eines psychometrischen Instrumentes zur Erfassung behandlungsbezogener Patientenzufriedenheit.

BACKGROUND: The recently introduced Freiburg index of patient satisfaction (FIPS) is a new questionnaire to assess treatment-related patient satisfaction after surgery and interventional procedures. The questionnaire had first been tested psychometrically in a mixed population of urology patients. The current study describes the results of an interdisciplinary validation. In addition, an English version is presented. METHODS: The questionnaire was used in two cohorts of cardiology (n = 120) and surgical (n = 127) patients. The evaluation included a comprehensive methodological and statistical evaluation including validation in comparison to the ZUF-8 questionnaire. RESULTS: The psychometric evaluation showed good results. The analyzed samples showed no missing values or ceiling effects. Furthermore, a high reliability (Cronbach's alpha 0.82), unidimensionality, sufficient distribution of values and validity (high correlation to the ZUF-8, r = 0.65, p < 0.001) of the questionnaire could be confirmed. CONCLUSIONS: The FIPS constitutes an interdisciplinary validated questionnaire to evaluate treatment-related patient satisfaction which can be used to objectify and compare results from clinical studies and quality in patient care. Colleagues of English-speaking countries are invited to participate in the validation of the hereby presented English version.

Effects of 32P radioactive stents on in-stent restenosis in a double stent injury model of the porcine coronary arteries.

BACKGROUND: The major limitation of coronary stenting remains in-stent restenosis, due to the development of neointimal proliferation. Radioactive stents have demonstrated the ability to reduce this proliferation in the healthy nonatherosclerotic porcine animal model. However, inhibition of tissue proliferation in the in-stent restenotic lesion in a porcine model is not well characterized. The objective of this study was to examine the efficacy and safety of the 32P radioactive stent for the treatment of in-stent restenosis in a double stent injury model of the porcine coronaries. METHODS AND MATERIALS: Eighteen coronary arteries in 9 pigs underwent nonradioactive stent (8 mm in length) implantation. Thirty days after the initial stent implantation, a 32P radioactive stent (18 mm in length) with an activity of 0 and 18 microCi was implanted to cover the initial stent. The swine were killed 30 days after the second stent implantation. Histomorphometric analysis was performed for vessel area (VA), stent strut area (SSA), intimal area (IA), and lumen area (LA). RESULTS: Injury scores, VA, SSA, and LA were similar among the control and radiated groups. Neointimal formation was significantly reduced after placement of radioactive stents as compared to control in both the overlapped (0.93 +/- 0.12 vs. 1.31 +/- 0.51 mm(2), p < 0.05) and nonoverlapped segments (1.14 +/- 0.21 vs. 1.91 +/- 1.04 mm(2), p < 0.05). The smooth muscle cell index in the neointima was reduced. Intimal fibrin was increased in the radiated group as compared to the control (p < 0.01 respectively). CONCLUSIONS: 32P radioactive stents may be safe and effective in reducing neointimal formation leading to in-stent restenosis. Longer follow-up will be required to examine whether these positive findings can be maintained.

Decreased adventitial neovascularization after intracoronary irradiation in swine: a time course study.

BACKGROUND: Intracoronary radiation (IR) suppresses the formation of neointima after arterial injury in swine, through mechanisms incompletely understood. Neointimal development appears related to expansion of adventitial microvessels; we therefore examined the hypothesis that IR inhibits neointima formation through an anti-angiogenic effect. METHODS AND RESULTS: Juvenile swine were treated with either 0 or 15 Gy (192)Ir (gamma-source) and euthanized 3, 7, or 14 days later or treated with 18 Gy (90)Y (beta-source) and euthanized after 14 days. Adventitial area (AA), intimal area (IA), IA corrected for medial fracture length, and adventitial vessel area were assessed in both injured and uninjured segments by computer-aided histomorphometry on Verhoeff-Von Giesson stained sections. Adventitial vessel count (AVC) was enumerated visually on hematoxylin and eosin stained sections and confirmed by anti-factor VIII-associated antigen immunostaining for endothelial cells. AA and IA were reduced in injured arteries subjected to IR as compared to controls. The AVC was significantly lower in injured irradiated arterial segments as well as all uninjured segments as compared with injured control segments. In the injured and irradiated arteries, the AVC remained unchanged at 3, 7, and 14 days. The injured segments of arteries treated with IR demonstrated a significantly lower adventitial microvessel density (AVC/AA) as compared to the injured control segments. Comparison of gamma- and beta-irradiation at 14 days did not show any differences for vessel parameters and measurements of adventitial microvessels. IA and AVC were correlated positively (R(2) = 0.63, alpha = 0.79, p < 0.01). CONCLUSION: IR induced an early and sustained anti-angiogenic effect between 3 and 14 days. The relation between IA and AVC may indicate an antiproliferative effect associated with an anti-angiogenic effect independent of the type of radiation. CONDENSED ABSTRACT: Intracoronary radiation suppresses neointima formation after arterial injury in swine, through mechanisms and with consequences that are not fully known. Reduction of angiogenesis may inhibit restenosis. In the present study, intimal area and adventitial area were reduced in the intracoronary radiation groups 3-14 days after arterial injury as compared to their respective controls, with a parallel reduction in the adventitial vessel count and adventitial vessel density. Intimal area and adventitial vessel count were correlated positively. Neointima reduction after intracoronary radiation may depend not only on an antiproliferative effect but also on an anti-angiogenic effect.

A novel 32P deployable balloon system inhibits formation of neointima in porcine coronary arteries after balloon-overstretching injury.

BACKGROUND: Intracoronary radiation has shown the potential to reduce formation of neointima in porcine models of restenosis. OBJECTIVE: To investigate the feasibility, safety, and efficacy of a new 'deployable-balloon' device with radioisotope 32P integrated into the balloon material. METHODS: Ten swine were subjected to balloon-overstretching injury in 20 coronary arteries and were randomly allocated to receive a radiation dose of 0, 15, or 20Gy prescribed to 1 mm from the surface of the radioactive balloon material. The animals were killed 4 weeks after the procedure. Their coronaries were perfusion fixed and stained. Vessel parameters (area of intima and length of fracture) and area of thrombus area were analyzed by computer-aided histomorphometry. RESULTS: Radiation treatment with the new 32P balloon device was performed without complications. The lengts of fracture for the three groups were similar (NS). Formation of neointima after balloon injury was less in members of the radiated groups than it was in controls (area of intima/length of fracture was 0.70 +/-0.12 mm for controls, 0.08+/-0.13mm with 15 Gy, and 0.07+/-0.17 mm with 20 Gy; P < 0.001). Vessels treated with 20 Gy had a greater total area of thrombus (0.00+/-0.00 versus 0.51+/-0.98 mm2, P< 0.01). CONCLUSIONS: Intracoronary radiation therapy using a new 32P deployable-balloon system is feasible and safe. A radiation dose of 15 Gy was sufficient to inhibit neointimal response in the porcine coronary-balloon-injury model.

Differential remodeling after balloon overstretch injury and either beta- or gamma-intracoronary radiation of porcine coronary arteries.

BACKGROUND: Restenosis is a consequence of both neointimal hyperplasia and vessel remodeling. Prior studies have shown that intracoronary radiation (IR) prevents neointima accumulation, but its contribution to vessel remodeling is unknown. The purpose of this study was to evaluate the effect of IR on differential vascular remodeling after balloon angioplasty in porcine coronary arteries. METHODS: A total of 20 juvenile swine (30 coronary arteries) were subjected to overstretch balloon injury (BI) followed by IR with either beta- or gamma-radiation ((90)Y or (192)Ir). After 2 weeks following treatment, serial tissue sections were perfusion fixed and stained by hematoxylin and eosin (H&E), Verhoeff von Giesson (VVG), or Masson Trichrome. Adventitial area (AA), lumen area (LA), vessel area (VA), intimal area (IA), and IA corrected for medial fracture length (IA/FL) were quantified by digital image analysis. The vessel circumference was divided into two regions containing (1) the undisrupted region (UReg) with the undisrupted arc of media and internal elastic lamina (IEL) and (2) the disrupted region (DReg) with the disrupted arc between the medial tears. Quantitative regional analysis was performed by (1) measuring the IEL to define the UReg, (2) calculating the area of the UReg with the perimeter value derived from measurement of the IEL, and (3) calculating the DReg as follows: LA+IA-UReg. Immunohistochemical smooth muscle cell alpha-actin and Masson Trichrome were quantified by digital image analysis. RESULTS: The IA/FL was significantly smaller following treatment with (90)Y or (192)Ir vs. control (P<.01). A smaller AA was obtained following IR with both beta- and gamma-sources vs. control (P<.01). The UReg calculation was smaller in the irradiated arteries as compared to control (beta: 2.3+/-0.4 mm(2), gamma: 2.1+/-0.5 mm(2), P<.01 vs. control; control: 3.6+/-0.7 mm(2)). In contrast, the DReg was increased following IR, as demonstrated by the FL and the calculated area of the injured segment (control: 2.7+/-0.5 mm(2); beta: 5.5+/-1.1 mm(2), gamma: 5.5+/-1.1 mm(2), P<.01 vs. control). Adventitial alpha-actin positive cell density (CD) was decreased after IR; however, the collagen density was similar. In contrast, the neointimal collagen density in the injured segment was significantly decreased following IR. CONCLUSION: We consider that the global arterial remodeling after IR is a heterogeneous process that includes the absence of retraction in an UReg and a positive remodeling in the DReg as shown in the porcine coronary model. These changes in adventitia and neointima appear to contribute to differential vascular remodeling caused by IR in injured vessels.

Delayed re-endothelialization and T-cell infiltration following intracoronary radiation therapy in the porcine model.

PURPOSE: To evaluate the late induction of apoptosis following intracoronary radiation (IR) and the effects of IR on inflammatory cells. METHODS AND MATERIALS: Porcine coronaries were injured by balloon overstretch followed by either 0 or 15 Gy of 192Ir prescribed to 2 mm from the center of the source. Swine were euthanized at 3, 7, and 14 days posttreatment, and arteries were stained for markers of smooth muscle cells (SMCs alpha-actin), T cells (CD3), macrophages, endothelial cells, and apoptotic nuclei (terminal uridine nick end labeling, TUNEL). Intimal area (IA) and IA corrected for medial fracture length (IA/FL) were quantified by digital image analysis, which was also used to quantify the distribution of immunostain-positive cells in the adventitia, media, and neointima, respectively. RESULTS: IA/FL was significantly reduced following treatment with 15 Gy, in association with decreased SMC density. Following injury and IR, TUNEL- and CD3-positive cell density increased significantly, and density of macrophages was increased in the adventitia and neointima. Staining for endothelial cells revealed a delay of re-endothelialization after radiation treatment. CONCLUSION: Increased T-cell infiltration at the medial tear following IR, perhaps due to incomplete re-endothelialization, may indicate incomplete healing. The elevated apoptosis of these infiltrating T cells may indicate a mechanism for the resolution of inflammation.

Edge stenosis and geographical miss following intracoronary gamma radiation therapy for in-stent restenosis.

OBJECTIVES: We sought to determine the relationship between geographical miss (GM) and edge restenosis (ERS) following intracoronary radiation therapy. BACKGROUND: Edge restenosis may be a limitation of intracoronary irradiation to prevent in-stent restenosis (ISR). Inadequate radiation source coverage of the injured segment (GM) has been proposed as a cause of ERS. We studied the relationship between GM and ERS following 192Ir treatment of ISR. METHODS: There were 100 patients with native vessel ISR in WRIST (Washington Radiation for In-Stent Restenosis Trial), in which patients with ISR were first treated with conventional techniques and then randomized to gamma irradiation (192Ir) or placebo. Geographical miss was defined as segments proximal or distal to the treated lesion that were subjected to injury during primary intervention but were not covered by the radiation source. RESULTS: Geographical miss was documented in 56 of 164 edges (34%). Edge restenosis was noted at eight of 80 radiated edges and in four of 84 placebo edges. In the irradiated group, ERS was observed in 21% of edges with GM and in 40% of edges without GM (p = 0.035). In contrast, in the placebo group, ERS was observed in only 7% of edges with GM and in 4% of edges without GM (p = NS). The late edge lumen loss was higher in the irradiated group with GM as compared to placebo with GM (0.74 +/- 0.57 vs. 0.41 +/- 0.50 mm, p = 0.016). CONCLUSIONS: Edge restenosis following gamma irradiation treatment of ISR is related to GM: a mismatch between the segment of artery injured during the primary catheter-based intervention and the length of the radiation source.

Intravascular radiation accelerates atherosclerotic lesion formation of hypercholesteremic rabbits.

OBJECTIVES: The purpose of the present study is to evaluate the effect of intravascular radiation (IR) on the arterial wall of uninjured vessels in the hypercholesteremic rabbit model. METHODS: Aortas of 24 New Zealand white rabbits were treated with either intravascular 192-Ir gamma-radiation (15 Gy at 2 mm from the center of the source) or were exposed to the source catheter without radiation (sham controls). Following the radiation treatment, the animals were fed a 2% cholesterol diet until euthanasia at 2 (n=8) or 6 (n=16) weeks. Arteries were analyzed using light and scanning electron microscopy (SEM); transforming growth factor beta (TGF-beta) 1, a promoter of connective tissue deposition, was also monitored. RESULTS: At 2 weeks, SEM analysis showed well-aligned endothelial cells in nonradiated segments, whereas irradiated arteries consistently contained adherent and subendothelial macrophages with focal areas of endothelial disruption. Further radiated segments at 2 weeks showed a 7-fold increase in active TGF beta-1 over nonradiated segments. At 6 weeks, there was a significant increase in plaque and vessel wall area relative to control arteries, however, no differences were noted in the density of actin-positive smooth muscle cells (SMCs) or macrophages. Similarly, no differences were noted in cell proliferation between groups as evidenced by the marker bromodeoxyuridine (BrdU). In contrast, nonirradiated segments frequently contained cellular areas with extracellular lipid. CONCLUSION: Exposure of previously uninjured vessels to IR and hypercholesterolemia is associated with increased plaque burden and leads to more advanced plaque types. Special care should be taken to minimize radiation exposure in normal vascular segments in hypercholesterolemic patients undergoing radiation therapy.

Intracoronary brachytherapy not associated with changes in major side branches.

Intravascular radiation (IR) is emerging as a potential solution for the prevention and treatment of restenosis. Subacute thrombosis late coronary occlusion of the target lesion after intracoronary brachytherapy has been described in two studies. None of these studies assessed in detail the evolution of side branches following IR. The purpose of this study was to determine the frequency of side-branch occlusion in patients undergoing IR. We evaluated the procedural and 6-month follow-up angiograms of 170 consecutive patients enrolled in the GAMMA-I and WRIST studies who presented a major side branch (diameter > 1.5 mm) at the treated lesion. Major side branches treated during the procedure and/or total occlusion of the main branch were excluded for analysis. Sixty-three patients (control = 30, irradiated = 33) were identified and side branches were classified in one of three categories: no significant stenosis, > 50% stenosis, and occluded. The baseline patient and lesion characteristics were similar among the classified groups. No difference was observed between the control and irradiated arteries after the procedure for side-branch occlusion (14% and 9%, P = NS). A significant decrease of restenosis was observed after IR compared to control (20% vs. 70%: P < 0.001). The patency rates and rates of side-branch occlusion were similar between the two groups. However, in the control group, 50% of the side-branch occlusions that occurred after the procedure were patent at 6-month follow-up. In contrast, in the irradiated group, the incidence of side-branch occlusion increased from 9% to 15% at 6-month follow-up in the irradiated group. Low doses of radiation applied to noninjured side branches are not associated with adverse effects. The absence of restoration patency followed by IR is most likely a consequence of a delayed healing process.

Vascular repair after balloon overstretch injury in porcine model effects of intracoronary radiation.

OBJECTIVES: The purpose of this study was to evaluate the effect of IR on thrombus formation and dissection repair following overstretch balloon injury in porcine coronary arteries. BACKGROUND: Exposure of blood to the injured arterial wall after percutaneous transluminal coronary angioplasty (PTCA) induces thrombus formation and inflammation in the dissection plane. Neointima formation is related to smooth muscle cell (SMC) proliferation and migration into the preformed thrombus. Intracoronary radiation (IR) with doses of 10 to 25 Gy using either beta or gamma emitters can prevent neointima accumulation by reducing SMC proliferation. However, there are some indications that IR may delay the process of dissection repair after PTCA. The purpose of this study was to evaluate the effect of IR on thrombus formation and dissection repair after overstretch balloon injury in porcine coronary arteries. METHODS: Forty porcine coronaries were injured by balloon overstretch followed by either 0 or 18 Gy of 90Y prescribed to 1.2 mm from the balloon center. The animals were euthanized 14 days after treatment, and intimal area (IA) and IA corrected for medial fracture length (IA/FL) were quantified by digital image analysis. Dissections were quantified by tracing the length, thickness and area behind the dissection flap. The rate of dissections was calculated for each group. Thrombi were identified and designated as intraluminal thrombus or thrombus within dissection planes (mural thrombus), and area measurements were obtained. RESULTS: The irradiated group showed a significant reduction of IA/FL (0.55 +/- 0.29 vs. 0.05 +/- 0.09; p < 0.001). No difference was observed in the rate of dissection between control and irradiated arteries (77% vs. 88%, respectively). The control group showed a smaller dissection area (0.19 +/- 0.28 mm2 vs. 0.32 +/- 0.29 mm2; p < 0.05) with smaller mural thrombi (0.03 +/-0.01 mm2 vs. 0.29 +/- 0.30 mm2; p < 0.001). A strong correlation between dissection area and neointima area was observed only in the control group (R2 = 0.474; p < 0.003; alpha0.05 = 0.862). A positive correlation between mural thrombus and dissection area was observed only in the irradiated group (R2 = 0.889; p < 0.001; alpha0.05 = 1.00). CONCLUSIONS: These results suggest that the dissection area may be a useful parameter by which to quantify the extent of injury and repair after IR and may indicate an incomplete healing process after IR at this time point.

Anti-restenotic effect of copper-62 liquid-filled balloon in porcine coronary arteries: novel use of a short half-life positron emitter.

PURPOSE: To determine the efficacy of the use of copper-62, a positron emitter with a half-life of 9.7 minutes, as an intracoronary brachytherapy (IRBT) source in the prevention of neointima formation (NF) following overstretch balloon injury (BI) in the porcine model. METHODS AND MATERIALS: Sixteen swine were treated after BI to their left anterior descending (LAD), left circumflex (LCX), and/or right coronary artery (RCA). Twelve of the injured arteries received placebo and 10 received 25 Gy, delivered to 0.5 mm from the surface of the treatment balloon filled with liquid (62)Cu. Dosimetry was based on Monte Carlo calculations. Two weeks after treatment, the animals were sacrificed, and the treated coronaries were perfusion-fixed and stained. Intimal area (IA) and medial fracture length (FL) were analyzed by computer-aided histomorphometry. RESULTS: The ((62)Zn/(62)Cu) generator, together with a rapid concentration process, was successful in delivering the short-lived (62)Cu at the high concentration required for intravascular brachytherapy (IVBT). The fracture length in the two groups was similar (2.10 +/- 0.57; 2.02 +/- 0.77; p = NS). Arteries studied showed significant reduction in NF (IA: 0.23 +/- 0.47 mm(2) vs. 1.08 +/- 0.57 mm(2); p < 0.01. IA/FL = 0.09 +/- 0.17 mm vs. 0.51 +/- 0.21 mm; p < 0.01). CONCLUSIONS: This study demonstrated that use of liquid (62)Cu as an IVBT source is safe and feasible. All 16 swine tolerated the treatment well with no radiation-induced side effects or symptoms throughout the 2-week period. The isotope delivered the dose necessary to inhibit NF in the porcine coronary BI model.

Modulation of protein expression and activity by radiation: relevance to intracoronary radiation for the prevention of restenosis.

Restenosis is a common complication of percutaneous transluminal coronary angioplasty. Recent studies have demonstrated a striking reduction in the neointimal hyperplasia characteristic of restenosis following intracoronary radiation (IR), but the mechanisms by which radiation reduces neointima formation following balloon overstretch injury are not elucidated fully. In addition to direct antimitotic effects mediated via oxygen free radicals, ionizing radiation can induce the expression of numerous genes and thereby mediate indirect effects. Additionally, IR prevents restenosis at the cost of decreased healing and increased thrombosis, and we suggest that these adverse reactions can be modulated by adjunct pharmacology or gene-based strategies. This review discusses several genes and proteins modulated by radiation in the context of arterial injury, and their possible therapeutic relevance.

Apoptosis after stent implantation compared with balloon angioplasty in rabbits. Role of macrophages.

Both cell proliferation and apoptosis (programmed cell death) are supposed to play a role in restenosis after angioplasty. We studied these processes in smooth muscle cells (SMCs) and macrophages 1, 4, and 12 weeks after balloon angioplasty or Palmaz-Schatz stent implantation in rabbit iliac arteries. Proliferating cells were visualized by immunostaining with antibodies directed against proliferating cell nuclear antigen. Apoptotic cells were detected using the TUNEL (terminal deoxynucleotidyl transferase-mediated dUTP nick and labeling) technique, propidium iodide staining, and transmission electron microscopy. At all time points, the neointimal cross-sectional area of the arteries was twofold to fourfold greater after stent implantation than after balloon angioplasty. The total number of neointimal cells was similar 1 and 12 weeks after both interventions. The neointimal cell density, however, decreased by 58% between the 1st and the 12th week after stent implantation compared with a 20% decrease after balloon angioplasty (P < .01). Stent implantation induced more cell proliferation but also more apoptosis in the media than balloon angioplasty after 1 and 4 weeks. In addition, stent implantation caused more macrophage accumulation and apoptosis in the neointima, but cell proliferation rates did not differ significantly in comparison with balloon angioplasty. The higher rate of apoptosis in the neointima 1 week after stent implantation compared with balloon angioplasty is due to an increased rate of SMC and macrophage death. Macrophage accumulation and apoptosis in the early phase after stent implantation appear to play a role in extracellular matrix secretion, which increases neointima formation after 4 and 12 weeks compared with balloon angioplasty in this model.