Roles of sensory nerves in the regulation of radiation-induced structural and functional changes in the heart.

PURPOSE: Radiation-induced heart disease (RIHD) is a chronic severe side effect of radiation therapy of intrathoracic and chest wall tumors. The heart contains a dense network of sensory neurons that not only are involved in monitoring of cardiac events such as ischemia and reperfusion but also play a role in cardiac tissue homeostasis, preconditioning, and repair. The purpose of this study was to examine the role of sensory nerves in RIHD. METHODS AND MATERIALS: Male Sprague-Dawley rats were administered capsaicin to permanently ablate sensory nerves, 2 weeks before local image-guided heart x-ray irradiation with a single dose of 21 Gy. During the 6 months of follow-up, heart function was assessed with high-resolution echocardiography. At 6 months after irradiation, cardiac structural and molecular changes were examined with histology, immunohistochemistry, and Western blot analysis. RESULTS: Capsaicin pretreatment blunted the effects of radiation on myocardial fibrosis and mast cell infiltration and activity. By contrast, capsaicin pretreatment caused a small but significant reduction in cardiac output 6 months after irradiation. Capsaicin did not alter the effects of radiation on cardiac macrophage number or indicators of autophagy and apoptosis. CONCLUSIONS: These results suggest that sensory nerves, although they play a predominantly protective role in radiation-induced cardiac function changes, may eventually enhance radiation-induced myocardial fibrosis and mast cell activity.

Leg heating using far infra-red radiation in patients with chronic heart failure acutely improves the hemodynamics, vascular endothelial function, and oxidative stress.

BACKGROUND: Systemic thermal therapy (STT) has been associated with beneficial effects in patients with chronic heart failure (CHF). The fact, however, that it requires a dedicated as well as spacious facility and trained personnel makes it difficult to practice in the daily care of patients with CHF. OBJECTIVE: The aim of this study was to determine whether the leg thermal therapy (LTT) has a positive impact similar to that of STT in patients with CHF. Methods and Results Twenty patients with CHF (57 ± 17 years old, left ventricular ejection fraction=30 ± 10%) received LTT (45°C) for 20 minutes. Immediately after the treatment, the core temperature had increased (+0.3 ± 0.3°C) (p<0.01). While the LTT had no significant effects on the heart rate, systolic arterial pressure, and diastolic blood pressure, it increased the cardiac output (mixed venous oxygen saturation; +2 ± 3%) and decrease the pulmonary capillary wedge pressure (-2 ± 2 mmHg). The LTT significantly improved the flow-mediated vasodilatation (FMD) from 4.8 ± 2.6 to 7.1 ± 3.6%, the antioxidative markers, thiol from 4.0 ± 0.7 to 4.5 ± 0.9 µmoL/g, and the marker of oxidative deoxyribonucleic acid (DNA) damage, urine 8-hydroxy-2'deoxyguanosine (8OHdG) from 100 to 82 ± 3%, respectively (p<0.05). No patient had any adverse effects associated with LTT. Conclusion LTT acutely improved FMD, and oxidative stress in patients with CHF. Although the long-term effect of LTT remains to be investigated, its practicality which is comparable to that of STT would make it an attractive therapeutic strategy for patients with CHF.

Effect of deep brain stimulation of the posterior hypothalamic area on the cardiovascular system in chronic cluster headache patients.

The objective of this study was to determine the cardiovascular effects of chronic stimulation of the posterior hypothalamic area (PHA) in cluster headache (CH) patients. Systolic and diastolic blood pressure (SBP, DBP), cardiac output, total peripheral resistance (TPR), heart rate (HR) and breathing were monitored at supine rest and during head-up tilt test (HUTT), Valsalva manoeuvre, deep breathing, cold face test and isometric handgrip in eight drug-resistant chronic CH patients who underwent monolateral electrode implantation in the PHA for therapeutic purposes. Autoregressive power spectral analysis (PSA) of HR variability (HRV) was calculated at rest and during HUTT. Each subject was studied before surgery (condition A) and after chronic deep brain stimulation (DBS) of PHA (condition B). Baseline SBP, DBP, HR and cardiovascular reflexes were normal and similar in both conditions. With respect to condition A, DBP, TPR and the LF/HF obtained from the PSA of HRV were significantly (P < 0.05) increased during HUTT in condition B. In conclusion, chronic DBS of the PHA in chronic CH patients is associated with an enhanced sympathoexcitatory drive on the cardiovascular system during HUTT.

Splanchnic blood flow and oxygen consumption: effects of enteral nutrition and dopexamine in the elderly cardiac surgery patient.

BACKGROUND: After cardiac surgery, patients are at risk of organ dysfunction because of decreased perfusion. Different measures have been used to increase the splanchnic blood flow. We compared the effects of enteral nutrition and dopexamine on the cardiac output, splanchnic blood flow and oxygen consumption. METHODS: Sixteen patients undergoing cardiac surgery were included. Indocyanine green extraction and thermodilution were used for repeated measurements of the splanchnic blood flow and cardiac output. On the first post-operative day, indocyanine green infusion was started. Patients were randomized to start with dopexamine (Dpx group) or enteral nutrition (EN group). After 180 min, both groups received a combination of dopexamine and enteral nutrition. Blood gases from the hepatic vein and pulmonary and radial arteries were analysed repeatedly. RESULTS: In the Dpx group, the cardiac index increased with dopexamine infusion, but not when enteral nutrition was added. In the EN group, enteral nutrition alone did not increase the cardiac index, but dopexamine addition increased the cardiac index in this group. The splanchnic blood flow increased initially in the Dpx group, but then returned to baseline and remained constant on addition of enteral nutrition. In the EN group, the splanchnic blood flow initially remained at baseline, but increased after dopexamine addition. There was no difference between the groups with regard to systemic or splanchnic oxygen consumption or the oxygen extraction ratio. In the Dpx group, lactate increased from baseline with no further increase on addition of enteral nutrition. Lactate was unchanged in the EN group. CONCLUSIONS: Dopexamine and enteral nutrition caused no adverse effects on oxygen consumption or the oxygen extraction ratio. Enteral nutrition did not increase the splanchnic blood flow or cardiac index. Dopexamine increased the systemic blood flow with only a transient effect on the splanchnic blood flow. Dopexamine increased the lactate concentration, possibly indicating a more ischaemic condition.

Sympathoimmune anomalies underlying the response to stressful challenge in human immunodeficiency virus spectrum disease.

OBJECTIVE: This study examined immune, endocrine, and cardiovascular reactivity during stressful behavioral challenge in human immunodeficiency virus (HIV) seropositive (HIV+) and seronegative (HIV-) men and women and assessed whether immunocellular reactivity was differentially associated with concomitant alterations in sympathetic response. METHODS: The 133 HIV+ [84 asymptomatic, 49 symptomatic] and 92 HIV- subjects completed a speech stress reactivity protocol. RESULTS: Immunocellular reactivity to the speech stressor did not differ among asymptomatic and symptomatic HIV+ groups; however, relative to seronegatives, reactivity differences were present. Specifically, HIV+ subjects exhibited greater increases in total number of T cells, as well as in cytotoxic/suppressor T cells, activated T cells, and activated cytotoxic/suppressor T cells, and less increase in natural killer (NK) cell numbers. In addition, less stress-induced increase in NK cell cytotoxicity was observed along with greater suppression of the lymphoproliferative response to mitogen stimulation in the HIV+ group. Although no group differences in catecholamine reactivity were observed, the association of immunoreactivity with catecholamine responsiveness differed between serostatus groups. Specifically, the HIV+ subjects compared with HIV- subjects displayed greater lymphocytosis per unit change in norepinephrine; whereas NK cell reactivity was positively related to epinephrine responsiveness, but only in the HIV- group. These findings were present even after controlling for age and body mass, as well as other potential influences on immunocellular migration, such as cortisol levels and prevailing cardiac output. CONCLUSION: Early in HIV spectrum disease, functional abnormalities in the stress-induced migratory ability of specific immunocellular subsets are present that may reflect an underlying pathophysiological alteration in sympathoimmune communication.

Effects of amifostine on radiation-induced cardiac damage.

The purpose of this study was to investigate whether administration of amifostine prior to irradiation could reduce radiation damage of the rat heart. Female Spraque-Dawley rats were randomized to receive single-dose irradiation (0-22.5 Gy) locally to the heart. Fifteen to twenty minutes before radiation exposure, the animals received either intraperitoneally administered amifostine (160 mg/kg) or buffered saline solution. At 6 months post-irradiation, cardiac function was assessed by the in vitro working rat heart preparation. The severity of interstitial and/or perivascular fibrosis in different anatomical regions of the rat heart was assessed using a semi-quantitative scoring system. Radiation exposure to doses > or = 20 Gy markedly reduced coronary flow, aortic flow and cardiac output. Administration of amifostine prior to radiotherapy afforded protection against these effects and normal cardiac output was maintained, even after 22.5 Gy. A small, non-significant, reduction in histological damage (i.e. perivascular fibrosis and interstitial fibrosis) was also apparent in animals treated with amifostine. There was a clear protective effect of amifostine on the severity and extent of macroscopic damage in lung tissue included in the cardiac irradiation field. The findings of this study suggest that a single dose of amifostine administered prior to irradiation is effective in reducing cardiac damage.

Late response to whole-lung irradiation alone and with whole-body hyperthermia in dogs.

The late effects of whole-lung irradiation with and without whole-body hyperthermia were studied in beagle dogs. The reference doses ranged from 18 to 49.5 Gy given in 1.5-Gy fractions over 6 weeks. Whole-body hyperthermia was given in three 2-h treatments to a deep rectal temperature of 42.0 degrees C. Radiation was given simultaneously with hyperthermia on those days. Physiological and histopathological responses were evaluated. Physiological changes included decreases in cardiac output, systemic blood pressure, dynamic compliance and serotonin uptake. Early changes included an increase in extravascular water and total protein in the lavage. These changes were considered mild, were compensated for and occurred only in dogs receiving doses of 40.5 Gy or greater given in 1.5-Gy fractions over 6 weeks. Histopathological changes were typical of irradiated lung and included pleural fibrosis, interstitial fibrosis, fibrotic foci, and peribronchial and perivascular fibrosis. There was no enhancement of late injury to lung by hyperthermia seen in this study.

Changes in cardiac performance and sympathetic stimulation during and after fractionated radiotherapy in a rat model.

The consequences of fractionated irradiation on the number of cardiac alpha- and beta-adrenergic receptors, myocardial norepinephrine concentration and in vitro assessed heart function were studied in Sprague-Dawley rats. Animals were locally irradiated on the thorax with a total dose of 50 Gy, in 5 weeks, using two different fractionation schemes (5 x 2.0 Gy/week and 3 x 3.3 Gy/week). Functional and biochemical assays were performed during treatment and at 6 months after initiation of treatment. During fractionated irradiation, the numbers of alpha- and beta-adrenergic receptors tended to rise. During this period, myocardial norepinephrine concentration remained fairly constant and no decrease in cardiac output was observed. At 6 months, a significant increase of the numbers of alpha- and beta-adrenergic receptors was observed in the 3.3 Gy/fraction group compared to age-matched controls, p = 0.012 and p = 0.02, respectively. At this time point, the myocardial norepinephrine concentration had decreased below control levels (p = 0.008 for the 3.3. Gy/fraction schedule, and p = 0.03 for the 2.0 Gy/fraction schedule). At 6 months, the cardiac output declined to 61% (p = 0.009) and 69% (p = 0.04) of control values for the 3.3 and 2.0 Gy/fraction schedules, respectively. The present data clearly show development of late cardiac sequelae caused by fractionated thorax irradiation with a total dose of 50 Gy. Moreover, this study lends support to the importance of fraction size with regard to the severity of the radiation-induced cardiac damage.

Unilateral radiation pneumonitis in sheep: physiological changes and bronchoalveolar lavage.

Radiation pneumonitis is a life-threatening result of therapeutic thoracic irradiation, yet its mechanisms are poorly understood. We studied the effects of unilateral lung irradiation (3,000 rad) in sheep from the immediate response to the later development of radiation pneumonitis. We defined radiation pneumonitis by its diagnostic clinical feature, radiographic infiltration of the irradiated zone with a straight margin corresponding to the radiation port. The immediate response in the few hours after irradiation was characterized by cough, labored respiration, hypoxemia (arterial PO2 decreased 19 Torr), mild pulmonary hypertension (pulmonary arterial pressure increased 20%), and lymphopenia. Hemodynamics and gas exchange returned to normal by day 2 but became abnormal again before or during radiation pneumonitis at 32 +/- 2 days. Respiratory distress, hypoxemia, and pulmonary hypertension recurred during radiation pneumonitis. Bronchoalveolar lavage during radiation pneumonitis contained increased neutrophils (19 +/- 4%, control = 7%), increased protein (0.27 +/- 0.1 g/dl, control = 0.12 +/- 0.03), and severely impaired ability to lower surface tension. Alveolar macrophages from both lungs during unilateral radiation pneumonitis exhibited impaired generation of superoxide after phorbol myristate (only a 30% increase). Normal control alveolar macrophages increased superoxide production after stimulation greater than 400%. We conclude that unilateral lung irradiation in sheep causes a mild immediate response followed by radiation pneumonitis at 1 mo. Unilateral radiation pneumonitis in this model is associated with ipsilateral neutrophilic alveolitis, increased bronchoalveolar lavage protein, and impaired surfactant function, as well as bilateral functional abnormalities of alveolar macrophages.

Effects of single doses of radiation on cardiac function in the rat.

The hearts of rats were irradiated locally to single doses of X-ray in the range of 20-50 Gy. The mean latency period between treatment and death ranged from 550 +/- 12 days to 260 +/- 13 days for animals irradiated with doses of 20 and 50 Gy. The growth rate and cardiac output was followed for a period of 10 months after treatment. In irradiated animals, there was a delay in growth and the rate of growth plateaued at approximately 6 months after treatment. Cardiac output was measured by an external counting technique. There was a general decline in cardiac output at time intervals from 4 to 10 months after irradiation. This reduction in cardiac output was dose-dependent. A single dose of 30 Gy reduced the cardiac output to approximately 70% of the control value, 6 months after irradiation.

Measure of blood flow by the multiple radioactive microsphere technique in radiated gastrointestinal tissue.

In this study, two different radioactive microspheres were used to measure blood flow of an irradiated segment of small intestine in four dogs before, and 12 days after, irradiation with 2000 rad. The technique and implications are discussed. Using multiple radioactive microspheres, the study demonstrated an increased blood flow in irradiated tissues twelve days after a single dose of 2000 rad. There was also an increase in blood flow to adjoining nonradiated segments of intestine in the same animal. These observations may be of significance in clinical applications of radiation therapy and surgery. A major surgical concern is the impaired healing of irradiated tissue in the immediate postradiation period. The mechanism of this has generally implicated decreases in the perfusion of irradiated tissue. No decrease in blood flow was shown in this study, suggesting that other mechanisms, e.g., stem cell depletion, should be considered. Further studies of this type are recommended to increase understanding of the blood flow in irradiated tissue.

Effect of therapeutic-dose irradiation on left ventricular function in conscious dogs.

Every week, 8 conscious, chronically instrumented dogs underwent left ventricular (LV) function studies before, during, and after cardiac irradiation with cobalt 60 (myocardial dose of 5,000 rads at 200 rads per day through a 5 X 5 cm port). During the weekly LV function studies, left atrial pressures were raised by rapid infusion of balanced saline solution. Heart rate, aortic pressures, left and right atrial pressures, LV pressure, left ventricular end-diastolic pressure (LVEDP), and maximum rate of rise of LV pressure were recorded. Electrocardiograms were made. Cardiac outputs were obtained by thermodilution. Stroke volume, LV stroke work, and LV minute work were calculated. LV function curves were constructed each week. All dogs lost weight and became irritable after approximately 800 rads. The electrocardiograms showed signs of myocardial injury after 1,200 rads. All variables were slightly depressed during the first 8 weeks following irradiation. At the eleventh week, both left atrial pressure and LVEDP increased significantly and LV function declined. There was also clinical evidence of LV failure at rest and after volume loading. This study documents that external cardiac irradiation, in a therapeutic dose and schedule range, causes depression of LV function. These functional changes were partially reversed when the follow-up study was continued to six months after irradiation.

[Pulmoscintigraphic long-term observations during postoperative irradiation of the mammary region (author's transl)]. / Lungenszintigraphische Langzeitbeobachtungen bei postoperativer Bestrahlung der Mammaregion

The effect of ionizing rays on the pulmonary tissue during postoperative high-voltage therapy of breast cancer was investigated by a long-term study with the help of X-rays and nuclear techniques. The results prove that--in spite of optimal irradiation techniques--a local reduction of the pulmonary perfusion takes place as well as a shift of the cardiac output into other pulmonary areas, which are not exposed to the irradiation. Hereby, the pulmonary global function shows no significant change, as other authors have already pointed out. Likewise, no alteration was seen of the simple X-ray film after the use of this irradiation technique. In the pulmonary scintigram, however, a local reduction of the pulmonary perfusion was already seen after the application of 1500 rd, which increased still more in the posttherapeutic period. There were no signs of relapses within the observation period of more than 17 months.