Late inflammatory and thrombotic changes in irradiated hearts of C57BL/6 wild-type and atherosclerosis-prone ApoE-deficient mice.

BACKGROUND AND PURPOSE: Radiation-induced heart disease represents a late complication of thoracic radiotherapy. We investigated the inflammatory and thrombotic response after local heart irradiation in wild-type and atherosclerosis-prone mice. MATERIAL AND METHODS: Atherosclerosis-prone ApoE(-/-) and C57BL/6 wild-type mice were sacrificed 20, 40, and 60 weeks after irradiation with 0.2, 2, 8, or 16 Gy. The expression of CD31, vascular cell adhesion molecule-1 (VCAM-1), thrombomodulin (TM), and CD45 were quantified by immunofluorescence staining of heart tissue sections. RESULTS: Microvascular density decreased at 40 weeks after 16 Gy in C57BL/6 but not in ApoE(-/-) mice. CD31 expression declined in C57BL/6 mice at 40 weeks (8 Gy), but increased in ApoE(-/-) mice at 20 (2/8/16 Gy) and 60 weeks (16 Gy). Capillary area decreased in C57BL/6 at 40 weeks (8/16 Gy) but increased in ApoE(-/-) mice at 20 weeks (16 Gy). Endocardial VCAM-1 expression remained unchanged. TM-positive capillaries decreased at 40 weeks (8/16 Gy) in C57BL/6 and at 60 weeks (2/16 Gy) in ApoE(-/-) mice. Leukocyte infiltration transiently rose 40 weeks after 8 Gy (only ApoE(-/-)) and 16 Gy. After receiving a low irradiation dose of 0.2 Gy, no significant changes were observed in any of the mouse models. CONCLUSION: This study demonstrated that local heart irradiation affects microvascular structure and induces inflammatory/thrombotic responses in mice in a dose- and time-dependent manner. Thereby, significant prothrombotic changes were found in both strains, although they were progressive in ApoE(-/-) mice only. Proinflammatory responses, like the increase of adhesion molecules and leukocyte infiltration, were more pronounced and occurred at lower doses in ApoE(-/-) vs. C57BL/6 mice. These findings indicate that metabolic risk factors, such as decreased ApoE lipoproteins, may lead to an enhanced proinflammatory and prothrombotic late response in locally irradiated hearts.

Local heart irradiation of ApoE(-/-) mice induces microvascular and endocardial damage and accelerates coronary atherosclerosis.

BACKGROUND AND PURPOSE: Radiotherapy of thoracic and chest-wall tumors increases the long-term risk of radiation-induced heart disease, like a myocardial infarct. Cancer patients commonly have additional risk factors for cardiovascular disease, such as hypercholesterolemia. The goal of this study is to define the interaction of irradiation with such cardiovascular risk factors in radiation-induced damage to the heart and coronary arteries. MATERIAL AND METHODS: Hypercholesterolemic and atherosclerosis-prone ApoE(-/-) mice received local heart irradiation with a single dose of 0, 2, 8 or 16 Gy. Histopathological changes, microvascular damage and functional alterations were assessed after 20 and 40 weeks. RESULTS: Inflammatory cells were significantly increased in the left ventricular myocardium at 20 and 40 weeks after 8 and 16 Gy. Microvascular density decreased at both follow-up time-points after 8 and 16 Gy. Remaining vessels had decreased alkaline phosphatase activity (2-16 Gy) and increased von Willebrand Factor expression (16 Gy), indicative of endothelial cell damage. The endocardium was extensively damaged after 16 Gy, with foam cell accumulations at 20 weeks, and fibrosis and protein leakage at 40 weeks. Despite an accelerated coronary atherosclerotic lesion development at 20 weeks after 16 Gy, gated SPECT and ultrasound measurements showed only minor changes in functional cardiac parameters at 20 weeks. CONCLUSIONS: The combination of hypercholesterolemia and local cardiac irradiation induced an inflammatory response, microvascular and endocardial damage, and accelerated the development of coronary atherosclerosis. Despite these pronounced effects, cardiac function of ApoE(-/-) mice was maintained.

In vivo measurement of swine endocardial convective heat transfer coefficient.

We measured the endocardial convective heat transfer coefficient h at 22 locations in the cardiac chambers of 15 pigs in vivo. A thin-film Pt catheter tip sensor in a Wheatstone-bridge circuit, similar to a hot wire/film anemometer, measured h. Using fluoroscopy, we could precisely locate the steerable catheter sensor tip and sensor orientation in pigs' cardiac chambers. With flows, h varies from 2500 to 9500 W/m2 x K. With zero flow, h is approximately 2400 W/m2 x K. These values of h can be used for the finite element method modeling of radiofrequency cardiac catheter ablation.

Increased deposition of von Willebrand factor in the rat heart after local ionizing irradiation.

BACKGROUND AND PURPOSE: Von Willebrand factor (vWf), a glycoprotein involved in blood coagulation, is synthesized by endothelial cells. Increased amounts of vWf in blood plasma or tissue samples are indicative of damaged endothelium. In the present study, mRNA expression and localization of vWf were determined in irradiated rat heart tissue. MATERIAL AND METHODS: Sprague-Dawley rats received local heart irradiation with a single dose of 0, 15, or 20 Gy. Hearts were dissected at different time points (up to 16 months) after irradiation. In a second experiment, rats were injected with the radioprotector amifostine (160 mg/kg, i. p.) 15-20 min before irradiation and sacrificed after 6 months. Immunohistochemistry was performed using a polyclonal anti-vWf antibody. Serial sections were subjected to a general rat endothelial cell immunostaining (RECA-1) or a collagen staining (picrosirius red). mRNA expression was determined by using PCR. RESULTS: In control tissue, all endothelial cells lining the lumen of the endocardium and coronary arteries, but not capillary endothelial cells, were stained for vWf. 1 month after irradiation with both 15 and 20 Gy, myocardial capillaries became immunoreactive. From 3 months onward, staining was observed also within the extracellular matrix (ECM) of fibrotic areas. At mRNA level, no changes in vWf could be observed at all time points after irradiation, suggesting that vWf deposition was not due to increased biosynthesis of the protein. In sections of amifostine-treated rat hearts, vWf staining was increased to a lesser extent. CONCLUSION: These dose- and time-dependent increases in deposition of vWf indicate the presence of damaged endothelium in the irradiated rat heart. These increases in vWf accumulation precede development of fibrosis in the subendocardial layer and myocardium of the left ventricles, right ventricles, and atria.

[Radiation-induced cardiac disease]. / Strahlenschaden des Herzens.

Radiation-induced effects may damage various cardiac structures chronically and cause heart valve dysfunction as well as occlusive lesions of coronary and other arteries exposed to radiation. A 72-year-old woman with a history of radiation treatment after breast cancer was admitted 25 years later with symptoms of tachycardia and acute dyspnea. We found valvular thickening, medium to severe valvular dysfunction and high grade occlusive coronary artery disease in proximal portions. The left subclavian artery also was affected. Surgical treatment was required immediately. Long-term follow-up cardiac evaluation even in asymptomatic patients is mandatory to uncover cardiac injuries by radiation. To lower the risk and maximize the benefit, early intervention by valvular replacement and myocardial revascularization is indicated. Restrictive myopathy and chronic pericarditis increase risk and have to be clarified. Diagnosis in these radiation exposed patients can be made by typical findings. Echocardiography is of eminent relevancy.

Myocardial temperatures during in vivo endocardial Nd:YAG laser irradiation.

To determine safety and efficacy of neodymium:YAG laser irradiation of the endocardium, temperatures at both the epicardium and the endocardium were recorded for thermal damage evaluation. A total of 48 coagulation lesions were created at power settings of 20 and 30 W in 20 open chest dogs by transcatheter endocardial laser irradiation. Tissue temperatures were monitored by epicardial thermography (Tepi), and by endocardial thermocouples at the catheter tip (Tprox) and 4 mm below the endocardial surface (Tdist). In group I the optical fiber extended 1 mm from the catheter and irradiation times ranged from 3 to 60 sec. Tepi reached > or = 57 degrees after a weighted average of 5 sec of laser irradiation (n = 44). In group II the fiber was retracted 1 mm from the catheter tip, and irradiation times were 100 to 150 sec. Tepi reached > or = 57 degrees C after a weighted average of 30 sec (n = 4). Blood vessels were recognized as heat sinks until coagulation occurred. Lesion volume showed a proportional increase with total delivered energy. From the observed timeframes in epicardial temperature rise it is suggested that total direct light absorption at the epicardium was the main contribution to Tepi, and the Nd:YAG laser can efficiently create transmural lesions. The epicardial temperatures remained below 80 degrees C in combination with the constant movement of the epicardial wall suggested safety from thermal damage to the ambient organs.

Radiofrequency endocardial catheter ablation of accessory atrioventricular pathway atrial insertion sites.

BACKGROUND: High rates of success using radiofrequency ablation energy have rapidly transformed catheter ablation from an investigational procedure to the nonpharmacological therapy of choice for symptomatic Wolff-Parkinson-White syndrome. Prior studies of radiofrequency accessory pathway ablation were based on a ventricular approach. Risks associated with prolonged arterial catheter manipulation, retrograde left ventricular catheterization, and production of ventricular lesions required for successful ventricular insertion ablation can be avoided using atrial insertion ablation procedures. The purpose of the present study was to define the safety and efficacy of accessory pathway ablation using radiofrequency energy delivered solely to accessory atrioventricular pathway atrial insertion sites. METHODS AND RESULTS: One hundred fourteen patients with accessory pathway-mediated tachycardia underwent attempted radiofrequency current ablation at the accessory pathway atrial insertion site. All catheters were introduced transvenously. Left-sided accessory pathways were approached using transseptal left atrial catheterization techniques. Retrograde localization of the atrial insertion site during reentrant tachycardia was characterized by 40 +/- 15-msec local ventriculoatrial and 79 +/- 17-msec surface QRS to local atrial electrogram intervals. Presumed accessory pathway potentials were present in only 30% of ablation site electrograms. Successful ablation required 6.2 +/- 5.3 radiofrequency energy applications. Cumulative energy dose required for success was 2,341 +/- 2,233 J. There were no complications associated with transseptal catheterization. Energy delivery to accessory pathway atrial insertion sites was associated with non-life-threatening complications in two patients. Recurrent conduction requiring repeat ablation occurred in 10 of 115 (9%) successfully ablated accessory pathways, all within 1 month of the ablation procedure. After 21.2 +/- 4.6 months of follow-up, 108 of 114 (95%) patients are asymptomatic and without evidence of accessory pathway conduction. CONCLUSIONS: The atrial insertion approach to accessory pathway ablation is safe and highly effective. This approach compares favorably with the retrograde ventricular insertion ablation technique. Atrial insertion ablation eliminates the need to produce ventricular lesions and avoids the risks of prolonged arterial catheter manipulation and retrograde left ventricular catheterization.

Effects of multipolar electrode radiofrequency energy delivery on ventricular endocardium.

This study examined the effects of radiofrequency energy applied in a bipolar fashion with single as compared with multiple sequential applications at the canine endocardium. In this closed-chest model, radiofrequency energy (750 kHz) was delivered between two adjacent poles of an electrode catheter. Single applications were performed at distinct sites in the left (n = 30) and right ventricles (n = 29) of 13 normal dogs. A multiple sequential technique, which enlarges the ablated endocardial surface, was applied in the left (n = 13) and right ventricles (n = 4) of seven normal dogs and six dogs with remote myocardial infarction. Single applications (199 +/- 200 joules) resulted in lesions with a volume of 0.12 +/- 0.06 cm3 (range 0.03 to 0.31 cm3) and an endocardial surface area of 0.29 +/- 0.15 cm2 (range 0.06 to 0.63 cm2). Changes at the catheter/tissue interface led to a rise in impedance, restricting further enlargement of the necrosis. Sequential delivery of radiofrequency energy between poles 1 and 2, 2 and 3, and 3 and 4 of a quadripolar electrode catheter repeated 9 to 11 times in slightly different positions allowed a cumulative energy of 6571 +/- 3857 joules to be applied to the endocardium, resulting in a lesion volume of 0.84 +/- 0.38 cm3, with an endocardial lesion surface area of 3.7 +/- 1.2 cm2 (range 2.9 to 5.1 cm2). Histologically, all radiofrequency lesions were restricted to the endocardium/subendocardium with a small border zone of injury. Aggressive stimulation techniques did not induce ventricular tachycardia in any of the dogs before and 19 +/- 11.4 days after multiple sequential ablations.(ABSTRACT TRUNCATED AT 250 WORDS)

Control of radiofrequency lesion size by power regulation.

The influence of power and exposure duration on lesion size in radiofrequency catheter ablation was investigated in 15 closed-chest dogs. Radiofrequency energy was delivered to the right ventricular endocardium between the tip of a standard 6F electrode catheter and a large W and durations of 5, 10, 20, 30, and 60 seconds. At necropsy 1 week later, well-demarcated homogeneous lesions were found when power had exceeded a threshold level that decreased from 1.8 W at 5 seconds to 0.7 W at 60 seconds. Lesion size ranged from 0 to 7.5 mm in depth and 0 to 9 mm in diameter. For the 5, 10, and 20 second ablations, lesion size was determined by exposure duration and power level. However, after a 20 second exposure, lesion size had reached maturity and was related to delivered power only. Therefore, a gradual, controlled growth of the lesion can be obtained by a stepwise increase of the radiofrequency power level with ample exposure duration at each level to allow for stabilization. At levels exceeding 7 W, the formation of a thin insulating layer of blood coagulum on the electrode surface caused an abrupt increase of impedance within approximately 30 seconds. Therefore, lesion size is limited to 8.5 mm in radiofrequency ablation with a standard 6F endocardial electrode catheter.

Effects of pulse excimer laser irradiation on the human left ventricular wall.

This study was to assess the potential application of excimer lasers in the ablation of myocardium in vitro for the treatment of constant ventricular tachycardia or hypertrophic cardiomyopathy. A fresh human heart and EMG model 103 XeCl pulse excimer laser machine were used. The pulse repetition rate varied from 1 to 7 Hz. Irradiation directly on the left endocardial and epicardial walls lasted for 10 seconds and was repeated 3 times, creating 3 craters. The histological changes were examined by light microscope. Results showed very close relations between the depth or volume of vaporized craters and the pulse repetition rate on the endocardial (r = 0.9674, P less than 0.001 and r = 0.8962, P less than 0.01, respectively) and epicardial walls (r = 0.9602, P less than 0.001 and r = 0.9612, P less than 0.001, respectively). A sharp, clear border without debris or coagulating necrosis was seen under the microscope. We concluded that the pulse excimer laser, differing from Ar+ or Nd:YAG lasers, might be a powerful tool for manipulating the human ventricular wall, but more work needs to be done before it can be widely applied in the treatment of cardiovascular disease.