Emilio Antonio Luca Gianicolo

Ionizing radiation and atherosclerosis: Current knowledge and future challenges

The evaluation of the health effects of low-dose ionizing radiation has always been a focus of debate and investigation within the scientific community. During the last decade, epidemiological studies provided evidence that an excess risk of cardiovascular diseases (CVDs) can be associated with moderate and low dose radiation. The precise quantification of CVD risk in the low-dose radiation range (<500 mSv) is not well characterized, and it is unclear whether there is a threshold dose below which there is no risk. A limited number of studies with imaging surrogate endpoints and cardiovascular biomarkers in asymptomatic patients revealed early signs of cardiovascular alterations, even at a low dose. In vitro studies have shown that several mechanisms, including endothelial dysfunction, inflammation, oxidative stress, alterations of coagulation and platelet activity may have a relevant role in radiation-induced cardiovascular effects. Exposure to high-dose data in experimental models accelerates the development of atherosclerosis, predisposing to the formation of an inflammatory, thrombotic plaque phenotype, especially in animals that are genetically predisposed to this disease. On the contrary, low dose exposure produced both protective and detrimental effects, suggesting that multiple mechanisms may influence radiation-induced atherosclerosis. However, only very limited and specific information can be obtained from cell cultures and animal models. Planned studies of radiation-exposed cohorts need to be conducted to explore biological mechanisms of low-dose radiation-associated cardiovascular disease. Further investigations with functional imaging to assess vascular function and cardiovascular biomarkers have great potential for providing new insights into low-dose radiation cardiovascular risk, especially in occupational exposure and modern medicine.

N-TERMINAL PRO-B-TYPE NATRIURETIC PEPTIDE PLASMA LEVELS AS A POTENTIAL BIOMARKER FOR CARDIAC DAMAGE AFTER RADIOTHERAPY IN PATIENTS WITH LEFT-SIDED BREAST CANCER

PURPOSE Adjuvant radiotherapy (RT) after breast-conserving surgery has been associated with increased cardiovascular mortality. Cardiac biomarkers may aid in identifying patients with radiation-mediated cardiac dysfunction. We evaluated the correlation between N-terminal pro-B–type natriuretic peptide (NT-proBNP) and troponin (TnI) and the dose of radiation to the heart in patients with left-sided breast cancer. METHODS AND MATERIALS NT-proBNP and TnI plasma concentrations were measured in 30 left-sided breast cancer patients (median age, 55.0 years) 5 to 22 months after RT (Group I) and in 30 left-sided breast cancer patients (median age, 57.0 years) before RT as control group (Group II). Dosimetric and geometric parameters of heart and left ventricle were determined in all patients of Group I. Seventeen patients underwent complete two-dimensional echocardiography. RESULTS NT-proBNP levels were significantly higher (p = 0.03) in Group I (median, 90.0 pg/ml; range, 16.7–333.1 pg/ml) than in Group II (median, 63.2 pg/ml; range, 11.0–172.5 pg/ml). TnI levels remained below the cutoff threshold of 0.07 ng/ml in both groups. In patients with NT-proBNP values above the upper limit of 125 pg/ml, there were significant correlations between plasma levels and V(3 Gy)(%) (p = 0.001), the ratios (p = 0.01), the ratios D(15 cm)(3)/D(50%) (Gy) (p = 0.008) for the heart and correlations between plasma levels and V(2 Gy) (%) (p = 0.002), the ratios (p = 0.03), and the ratios (p = 0.05) for the ventricle. CONCLUSIONS Patients with left-sided breast cancer show higher values of NT-pro BNP after RT when compared with non–RT-treated matched patients, increasing in correlation with high doses in small volumes of heart and ventricle. The findings of this study show that the most important parameters are not the mean doses but instead the small percentage of organ volumes (heart or ventricle) receiving high dose levels, supporting the notion that the heart behaves as a serial organ.

Maternal and Paternal Environmental Risk Factors, Metabolizing GSTM1 and GSTT1 Polymorphisms, and Congenital Heart Disease

Congenital heart defects (CHDs) are the most prevalent of all birth malformations arising from the complex interplay of environmental exposures and genes. Modifiable environmental risk factors are still largely unknown, especially for paternal exposure. The aim of the present study was to examine the association between the environmental exposures of both parents and CHD risk and to explore the modification effect of metabolizing gene polymorphisms in children who lack the genetic capacity to produce the glutathione S-transferase (GST) GSTM1 and GSTT1 enzymes. A total of 330 parents of a child with CHD and 330 parents of a child without any congenital malformations were compared in terms of lifestyle habits and toxicant exposure. GST gene polymorphisms were investigated in 180 patients with CHD (104 males, age 4.9 ± 5.8 years). Paternal smoking (≥15 cigarettes/day) was significantly associated with CHD risk (odds ratio [OR] 2.1, 95% confidence interval [CI] 1.3 to 3.5, p = 0.002). Both maternal (OR 2.6, 95% CI 1.6 to 4.2, p <0.0001) and paternal (OR 2.5, 95% CI 1.6 to 3.8, p <0.0001) occupational/environmental exposures increased the risk of CHD. Also, a significant additive risk (OR 4.5, 95% CI 2.5 to 8.3, p <0.0001) was found when both parents were exposed to toxicants. Both maternal (OR 3.6, 95% CI 1.1 to 11.2, p = 0.03) and paternal (OR 3.3, 95% CI 1.0 to 10.8, p = 0.03) exposure to toxicants increased the CHD risk in children who carried the combined null GST genotypes. The effect for the combined null GST genotypes was also stronger (OR 6.5, 95% CI 1.5 to 28.0) when both parents were exposed. In conclusion, paternal smoking and exposure to toxicants for both parents affect the risk of children with CHD. Polymorphisms in GST genes can modify a persons risk of toxicant exposure-induced disease.

Effects of external irradiation of the neck region on intima media thickness of the common carotid artery

BackgroundSeveral studies have shown that common carotid intima-media thickness (IMT) is increased after radiotherapy (RT) to the head and neck. However, further studies are needed to define the exact mechanism of radiation-induced injury in large vessels, investigate the relationship between radiation dose and large vessel injury and evaluate the rate of progress of atherosclerosis in irradiated vessels.ObjectivesTo investigate whether external irradiation to the carotid area has any effect on IMT of the common carotid artery in a group of patients who received RT vs control group matched for age, gender and race.MethodsWe studied 19 patients (10 male; 47.8 ± 17.4 years) during a 5-month period (January 2009-July 2009); they had completed RT with a mean of 2.9 years before (range: 1 month-6 years) The mean radiation dose to the neck in the irradiated patients was 41.2 ± 15.6 Gy (range: 25-70 Gy). Common carotid IMT was measured with echo-color Doppler. Nineteen healthy adult patients (10 male; 47.8 ± 17.6) were recruited as a control group.ResultsIMT was not significantly higher in patients when compared to the control group (0.59 ± 0.16 vs 0.56 ± 0.16 mm, p = 0.4). There was no significant difference between the two groups in relation to the absence (p = 0.7) or presence (p = 0.6) of vascular risk factors. Although the difference did not reach statistical significance (p = 0.1), the irradiated young patients (age ≤ 52 years) had IMT measurements higher (0.54 ± 0.08 mm) than the non-irradiated young patients (0.49 ± 0.14 mm). The mean carotid IMT increased with increasing doses of radiation to the neck (p = 0.04).ConclusionThis study shows that increased IMT of the common carotid artery after RT is radiation-dose-related. Therefore it is important to monitor IMT, which can be used as an imaging biomarker for early diagnosis of cerebrovascular disease in patients who have had radiotherapy for treatment of cancer of the head and neck and who are at increased risk for accelerated atherosclerosis in carotid arteries.

Geometric and dosimetric approach to determine probability of late cardiac mortality in left tangential breast irradiation: comparison between wedged beams and field-in-field technique.

PURPOSE To evaluate the probability of late cardiac mortality resulting from left breast irradiation planned with tangential fields and to compare this probability between the wedged beam and field-in-field (FIF) techniques and to investigate whether some geometric/dosimetric indicators can be determined to estimate the cardiac mortality probability before treatment begins. METHODS AND MATERIALS For 30 patients, differential dose-volume histograms were calculated for the wedged beam and FIF plans, and the corresponding cardiac mortality probabilities were determined using the relative seriality model. As a comparative index of the dose distribution uniformity, the planning target volume (PTV) percentages involved in 97-103% of prescribed dose were determined for the two techniques. Three geometric parameters were measured for each patient: the maximal length, indicates how much the heart contours were displaced toward the PTV, the angle subtended at the center of the computed tomography slice by the PTV contour, and the thorax width/thickness ratio. RESULTS Evaluating the differential dose-volume histograms showed that the gain in uniformity between the two techniques was about 1.5. With the FIF technique, the mean dose sparing for the heart, the left anterior descending coronary artery, and the lung was 15% (2.5 Gy vs. 2.2 Gy), 21% (11.3 Gy vs. 9.0 Gy), and 42% (8.0 Gy vs. 4.6 Gy) respectively, compared with the wedged beam technique. Also, the cardiac mortality probability decreased by 40% (from 0.9% to 0.5%). Three geometric parameters, the maximal length, angle subtended at the center of the computed tomography slice by the PTV contour, and thorax width/thickness ratio, were the determining factors (p = .06 for FIF, and p = .10 for wedged beam) for evaluating the cardiac mortality probability. CONCLUSION The FIF technique seemed to yield a lower cardiac mortality probability than the conventional wedged beam technique. However, although our study demonstrated that FIF technique improved the dose coverage of the PTV, the restricted number of patients enrolled and the short follow-up did not allow us to evaluate and compare the breast cancer survival rates of the patients.

Congenital anomalies among live births in a high environmental risk area—A case-control study in Brindisi (southern Italy)

Maternal exposure to ambient pollution has been increasingly linked to the risk of congenital anomalies (CAs) in the fetus and newborns. Recently, a descriptive study in the high environmental risk city of Brindisi (Italy) revealed an increased prevalence of total CAs, especially congenital heart disease (CHD) and ventricular septal defects (VSDs), both at the local level and in comparison with the pool of EUROCAT registries. This paper concerns a population-based case control study to investigate the association between maternal exposure to air pollutants - sulfur dioxide (SO2) and total suspended particulate (TSP) matter - and the risk of CA. Cases were newborns up to 28 days of age, born to mothers resident in Brindisi between 2001 and 2010, and discharged with a diagnosis of CA. Cases and controls were individually matched according to sex, socio-economic status of the census area of residence of the mother, and year of beginning of pregnancy. Up to four controls were extracted for each case. Concentration data from monitoring stations were used to estimate air pollution exposure. Each case and control was assigned pollutant concentration values as mean and 90th percentile of the daily average values during weeks 3-8 of pregnancy. Exposure as both continuous and categorical variables was considered and a conditional logistic regression model was constructed to quantify the odds ratios of exposure to air pollutants and the occurrence of total CAs, CHDs and VSDs. We found exposure to the 90th percentile of SO2 to be associated with CHDs (p for trend =0.01) and VSDs (p for trend <0.05). Findings for TSP were less consistent. In conclusion, in the studied area, maternal exposure to sulfur dioxide increased risk of CHD.

Spatial variability of air pollutants in the city of Taranto, Italy and its potential impact on exposure assessment

Epidemiological studies typically use monitored air pollution data from a single station or as averaged data from several stations to estimate population exposure. In industrialized urban areas, this approach may present critical issues due to the spatial complexities of air pollutants which are emitted by different sources. This study focused on the city of Taranto, which is one of the most highly industrialized cities in southern Italy. Epidemiological studies have revealed several critical situations in this area, in terms of mortality excess and short-term health effects of air pollution. The aims of this paper are to study the variability of air pollutants in the city of Taranto and to interpret the results in relation to the applicability of the data in assessing population exposure. Meteorological and pollution data (SO2, NO2, PM10), measured simultaneously and continuously during the period 2006–2010 in five air quality stations, were analyzed. Relative and absolute spatial concentration variations were investigated by means of statistical indexes. Results show significant differences among stations. The highest correlation between stations was observed for PM10 concentrations, while critical values were found for NO2. The worst values were observed for the SO2 series. The high values of 90th percentile of differences between pairs of monitoring sites for the three pollutants index suggest that mean concentrations differ by large amounts from site to site. The overall analysis supports the hypothesis that various parts of the city are differently affected by the different emission sources, depending on meteorological conditions. In particular, analysis revealed that the influence of the industrial site may be primarily identified with the series of SO2 data which exhibit higher mean concentration values and positive correlations with wind intensity when the monitoring station is downwind from the industrial site. Results suggest evaluating the population exposure to air pollutants in industrialized cities by taking into account the possible zones of influence of different emission sources. More research is needed to identify an indicator, which ought to be a synthesis of several pollutants, and take into account the meteorological variables.

Smoking and congenital heart disease: the epidemiological and biological link.

Cigarette smoking is a powerful human germ cell mutagen and teratogen. Congenital heart defects (CHD) is the most prevalent of all birth defects and leading cause of death in the first year of life. The purpose of this article is to review the epidemiology of the impact of cigarette smoking on CHD risk as well as to discuss the potential biological mechanisms of smoking-mediated abnormal cardiac development. Although epidemiological studies of association between parental smoking and CHD are limited, biological evidence support the concept that cigarette smoking may substantially contribute to the aetiology of CHD through induction of either male and female germ-cell mutation or interference with epigenetic pathways. Further research is needed to better define the relationship between parental smoking and the risk of heart defects as well as to assess parental-fetal gene-smoking interactions.

Congenital anomalies among live births in a polluted area. A ten-year retrospective study

BackgroundCongenital anomalies and their primary prevention are a crucial public health issue. This work aimed to estimate the prevalence of congenital anomalies in Brindisi, a city in southeastern Italy at high risk of environmental crisis.MethodsThis research concerned newborns up to 28 days of age, born between 2001 and 2010 to mothers resident in Brindisi and discharged with a diagnosis of congenital anomaly. We classified cases according to the coding system adopted by the European Network for the Surveillance of Congenital Anomalies (EUROCAT). Prevalence rates of congenital anomalies in Brindisi were compared with those reported by EUROCAT. Logistic regression models were adapted to evaluate the association between congenital anomalies and municipality of residence of the mother during pregnancy.ResultsOut of 8,503 newborns we recorded 194 subjects with congenital anomalies (228.2/10,000 total births), 1.2 times higher than the one reported by the EUROCAT pool of registries. We observed 83 subjects with congenital heart diseases with an excess of 49.1%. Odds Ratios for congenital heart diseases significantly increased for newborns to mothers resident in Brindisi (OR 1.75 CI 95% 1.30-2.35).ConclusionsOur findings indicated an increased prevalence of Congenital Anomalies (especially congenital heart diseases) in the city of Brindisi. More research is needed in order to analyze the role of factors potentially involved in the causation of congenital anomalies.

Sixteen-year air quality data analysis of a high environmental risk area in Southern Italy

The Brindisi area is characterized by the presence of industries with high environmental impact, located along its eastern border. Epidemiological studies have revealed several critical situations: two short-term (2003–2005) epidemiological studies have shown that PM10 and NO2 are adversely associated with daily hospital admissions: one of the two pointed to the associations with wind blowing from the southern, eastern and western sectors. This study aims to expand the time span of available air quality data in order to provide a more complete and extensive epidemiological study. Multi-year series (from 1992 to 2007) of SO2, NO2, and TSP concentration data are presented and analyzed. Data show a significant downward trend of SO2 from 1992 to 2007, while for the TSP series, the downward trend is limited to the period 1992–1994. Marked seasonal trends are evident for all three pollutants, especially for NO2 and TSP. The NO2 series shows higher levels in winter. Inversely, the TSP series shows its maximum values during the summer months, associated with a moderate correlation with temperature and a poor correlation with other pollutants. Analysis of the series for wind sectors revealed the influence of the industrial site and of the harbor. The concentration series exhibit high concentration values and stronger correlations between them and with meteorology for wind blowing from the eastern sectors. Overall analysis supports the hypothesis of a different origin for TSP during the year and for different wind regimes and therefore possible size and chemical differences in TSP, which should be further investigated due to their health implications.