Laura Sabatino

Subclinical Carotid Atherosclerosis and Early Vascular Aging From Long-Term Low-Dose Ionizing Radiation Exposure: A Genetic, Telomere, and Vascular Ultrasound Study in Cardiac Catheterization Laboratory Staff

OBJECTIVES This study sought to assess the association between long-term radiation exposure in the catheterization laboratory (cath lab) and early signs of subclinical atherosclerosis. BACKGROUND There is growing evidence of an excess risk of cardiovascular disease at low-dose levels of ionizing radiation exposure. METHODS Left and right carotid intima-media thickness (CIMT) was measured in 223 cath lab personnel (141 male; age, 45 ± 8 years) and 222 unexposed subjects (113 male; age, 44±10 years). Leukocyte telomere length (LTL) was evaluated by quantitative reverse transcriptase polymerase chain reaction. The DNA repair gene XRCC3 Thr241Met polymorphism was also analyzed to explore the possible interaction with radiation exposure. The occupational radiological risk score (ORRS) was computed for each subject on the basis of the length of employment, individual caseload, and proximity to the radiation source. A complete lifetime effective dose (mSv) was recorded for 57 workers. RESULTS Left, right, and averaged CIMTs were significantly increased in high-exposure workers compared with both control subjects and low-exposure workers (all p values<0.04). On the left side, but not on the right, there was a significant correlation between CIMT and ORRS (p=0.001) as well as lifetime dose (p=0.006). LTL was significantly reduced in exposed workers compared with control subjects (p=0.008). There was a significant correlation between LTL and both ORRS (p=0.002) and lifetime dose (p=0.03). The XRCC3 Met241 allele presented a significant interaction with high exposure for right side (pinteraction=0.002), left side (pinteraction<0.0001), and averaged (pinteraction<0.0001) CIMTs. CONCLUSIONS Long-term radiation exposure in a cath lab may be associated with increased subclinical CIMT and telomere length shortening, suggesting evidence of accelerated vascular aging and early atherosclerosis.

The Mediterranean Lifestyle as a Non-Pharmacological and Natural Antioxidant for Healthy Aging

Oxidative stress has been suggested to affect age-associated physiological dysfunction. Therefore, it is speculated that antioxidant supplements could have a potential role in preventing age-related diseases and death. Among different dietary habits, the highly antioxidant Mediterranean dietary pattern, which includes high vegetable and fruit intake, consumption of legumes, cereals, and fish, low intake of meat and dairy derivatives, moderate red wine consumption, and use of extra-virgin olive oil, is characterized by other aspects than food, such as conviviality, sensory stimulation, socialization, biodiversity, and seasonality that can reinforce the Mediterranean diet’s (MeD) beneficial effects on wellbeing, quality of life, and healthy aging. The present review aims to discuss available data on the relationship between oxidative stress and aging, biomarkers of oxidative stress status, protective effects of the MeD, and the adoption of the Mediterranean lifestyle as a non-pharmacological and natural tool to cope with oxidative stress damage for a longer life span, and—even more important—healthy aging beyond the biological, psychological, and social challenges that old age entails.

Nonthyroidal illness syndrome in off-pump coronary artery bypass grafting

BACKGROUND Cardiopulmonary bypass (CPB) is an established cause of nonthyroidal illness syndrome (NTIS). Off-pump coronary artery bypass (OPCAB) has been reported to be less invasive than coronary artery bypass grafting (CABG) with CPB. We prospectively evaluated thyroid metabolism in OPCAB patients. METHODS We analyzed free thyroid hormones (FT3 and FT4), thyroid-stimulating hormone (TSH), and reverse T3 (rT3) in 20 consecutive patients undergoing CABG surgery. Nine patients underwent CABG with CPB, and 11 underwent OPCAB. Blood samples were taken on admission, on the day of surgery (7:30 AM), after sternotomy, at the end of the operation, and at 2, 6, 12, 24, 36, 48, 72, 96, 120, and 144 hours postoperatively. The concentrations of FT3, FT4, and TSH were determined on each sample. Reverse T3 concentration was measured in 10 patients up to 48 hours and at 144 hours postoperatively. RESULTS Baseline, operative, and postoperative variables were similar in the two groups. FT3 concentration dropped significantly (p < 0.0001), reaching its lowest value 12 hours postoperatively. There were no significant differences between CPB and OPCAB patients. FT4 varied significantly in both groups (p < 0.0001), but remained in the normal range. TSH variation was not significant. rT3 concentration rose significantly (p = 0.0002) in both groups, peaking 24 hours after surgery. CONCLUSIONS. OPCAB induces a NTIS similar to that observed after CPB, probably due to the inhibition of T4 conversion to T3. This finding suggests that NTIS is a nonspecific response to stress. CPB should not be considered as the sole trigger of NTIS in cardiac surgical patients.

Telomere shortening and ionizing radiation: A possible role in vascular dysfunction?

Abstract Purpose: In recent years, growing epidemiological evidence has linked ionizing radiation exposure to cardiovascular atherosclerotic disease. However, there are still major gaps in the knowledge of the molecular mechanisms of radiation-induced vascular disease, especially for low-dose levels. Telomeres, repetitive DNA sequences of (TTAGGG)n located at the ends of eukaryotic chromosomes, play a role in regulating vascular aging, and shorter leukocyte telomere length has been demonstrated to predict cardiovascular disease and mortality. There is also evidence supporting the crucial role of telomeres in the formation of chromosome and chromatid aberrations induced by ionizing radiation. Conclusions: The purpose of the present paper is to review the recent advances in the biological mechanisms determining telomere length erosion after ionizing radiation exposure as well as to examine the hypothesis that telomere shortening may be the crucial mediator leading to detrimental vascular effects after ionizing radiation exposure.

Development of a new multiplex quantitative real‐time PCR assay for the detection of the mtDNA4977 deletion in coronary artery disease patients: A link with telomere shortening

Mitochondrial DNA (mtDNA) and telomere shortening have been proposed as important contributors to vascular disease and atherogenesis. The role of mitochondrial and telomere alterations has been examined frequently, but usually separately. Recently, an integrated model in which DNA damage and metabolic pathways intersect in age‐associated cardiovascular disease has been proposed. In this study we developed a fast and reliable real‐time PCR‐based procedure to investigate relative quantification of the 4,977 bp mitochondrial DNA deletion (also indicated as “mtDNA4977 deletion”), employing TaqMan probes with a multiplex approach. As a validation of the assay, a nested PCR coamplification was performed. Telomere shortening was evaluated by a real‐time monochrome multiplex PCR technique employing a SybrGreen‐based analysis. The study of mtDNA4977 deletion and telomere shortening was carried out in atrial biopsies from 11 patients undergoing coronary artery (n = 5) and valve surgery (n = 6). The relative quantifications showed that the amount of mtDNA4977 deletion was greater in tissue of patients with coronary artery disease (CAD) (P = 0.01) and that telomere length (expressed as telomere length relative to a single copy reference gene) was significantly shorter in tissue of CAD patients, compared to patients without CAD (P = 0.03). Moreover, most conventional risk factors were significantly more frequent in CAD patients, smoking and dyslipidemia having the strongest association with the degree of mtDNA4977deletion and a significant correlation with telomere attrition (P = 0.02 and P = 0.006, respectively). In conclusion, the present study suggests that mtDNA4977 deletion and telomere shortening may represent additional and synergic major risk factors for the pathogenesis of CAD and its complications. Environ. Mol. Mutagen. 54:299–307, 2013.

Is the Vascular System a Main Target for Thyroid Hormones? From Molecular and Biochemical Findings to Clinical Perspectives

The cardiovascular system is an important target for thyroid hormones (THs). Until recently, our understanding of the biological role of THs has been largely based on a catalog of effects observed in excess or deficiency of THs. In the last decades, however, some important progress has been done in defining the molecular and biochemical basis of thyroid hormone action at the cellular and nuclear level. Most of the molecular and cellular mechanisms responsible for the effects of THs on the heart have been clarified, whereas few data are available about the mechanisms of action of THs on the vasculature. Data reported so far describe the thyroid hormone effects on the vascular system as indirect consequences of thermogenic or hemodynamic derangements. The aim of this review is to focus on the direct role of THs in the vascular system, to analyze the main factors involved in this regulatory process, to evaluate the causes of imbalance, their relationships to some pathophysiological conditions, and, finally, to hypothesize effective therapeutic approaches. Our review considers data on the molecular and biochemical properties of iodothyronine deiodinases, with particular attention to D2, the enzyme for the local conversion of the precursor thyroxine (T4) into the biologically active triiodothyronine (T3). We summarize data on the deiodinase tissue distribution, subcellular localization, topology and structure-activity relationships. We also discuss the physiological role of deiodinases and their involvement in the TH-mediated regulation of vascular function.

The Stimulative Effect of T3 and T4 on Human Myocardial Endothelial Cell Proliferation, Migration and Angiogenesis

Angiogenesis, the process involving the growth of new blood vessels from pre-existing vessels, may be a target for combating diseases characterized by either poor vascularisation or abnormal vasculature as in cardiovascular diseases. Thyroid hormones (THs) are strong proangiogenic factors whose action starts at the plasma membrane integrin αvβ3 protein transducing rapid nongenomic signals on tumor thyroid cells. The tetraiodothyroacetic acid (Tetrac) inhibits the binding of TH to integrin receptor αVs3 blocking angiogenesis. Growing evidences suggest that, also in heart, Triiodothyronine (T3) and Thyroxine (T4) triggered nongenomic pathways through their binding to integrin receptor αVβ3 inducing capillary proliferation. The angiogenic activity of T3 and T4 has been studied by the chick choriallontoic endothelial cell microtubule assay and the human dermal microvascular endothelial cells microtubule assay. The aim of this work was to evaluate the direct stimulative activity of T3 and T4 on human cardiac microvascular endothelial cell (HMVEC-C) proliferation, migration and tube formation, employing Tetrac as inhibitor. Our in vitro study indicates that T3 and T4 directly stimulate angiogenesis in HMVEC-C observed as capillary density, cell proliferation and cell migration. In all models, Tetrac (5 μM) inhibited the proangiogenic effect of T3 and T4 suggesting its integrin-mediated action. Sq RT-PCR assay revealed that T3, and in less extent T4, increased the expression of angiogenic genes such as angiopoietin-1 (Angpt-1), angio-associated migratory cell protein (AAMP) and vascular endothelial growth factor (VEGF), whereas when the cells were pre-incubated with Tetrac this effect was abolished. In conclusion, our results show that THs stimulate angiogenesis, suggesting a potential therapeutic role aimed at increasing capillary density in cardiac diseases.

A023 The circolatory model in metabolic studies of rapidly renewed hormones: Application to ANP kinetics

Pilo, A., G. Iervasi, A. Clerico, F. Vitek, S. Berti, C. Palmieri, A. Biagini, and L. Donato. Circulatory model in metabolic studies of rapidly renewed hormones: application to ANP kinetics. Am. J. Physiol. 274 (Endocrinol. Metab. 37): E560–E572, 1998.—In an attempt to identify and quantify the sites of atrial natriuretic peptide (ANP) degradation, a new tracer experiment has been developed. 125I-ANP was injected as a bolus just upstream from the right atrium, and blood was sampled from two different sites (pulmonary artery and aorta) in eight cardiac patients. Data were analyzed using a physiologically based circulatory model consisting of three blocks in series (right heart, lungs and left heart, and periphery) supplied by the same flow (cardiac output, measured by thermodilution); the extraction coefficients of the three blocks and of the whole body could be determined from the areas under tracer concentration curves in plasma (AUCs). The values for AUCs (means 6 SD) were 64.8 6 9.4 and 65.5 6 10.7% dose·l21 ·min21 for pulmonary artery and aorta curves, respectively; the area under the pulmonary artery curve could be subdivided into the area under the first-pass curve (30.6 6 4.7% dose· l21 ·min21) and the area under the recirculating curve (34.0 6 7.7% dose· l21 ·min21). The metabolic clearance rate of 125IANP, computed as dose divided by the area under the recirculating curve, was 3.1 6 0.7 l/min, and the whole body extraction was 47.6 6 6.6%. In our patients with myocardial dysfunction, neither right heart block nor lungs and left heart block significantly extracted ANP, and periphery block accounted for almost all removal of the hormone from the blood.

Uric Acid for Cardiovascular Risk: Dr. Jekyll or Mr. Hide?

Uric acid (UA) is a potent endogenous antioxidant. However, high concentrations of this molecule have been associated with cardiovascular disease (CVD) and renal dysfunction, involving mechanisms that include oxidative stress, inflammatory processes, and endothelial injury. Experimental and in vitro results suggest that this biomarker behaves like other antioxidants, which can shift from the physiological antioxidant action to a pro-oxidizing effect according to their level and to microenvironment conditions. However, data on patients (general population or CAD cohorts) are controversial, so the debate on the role of hyperuricemia as a causative factor for CVD is still ongoing. Increasing evidence indicates UA as more meaningful to assess CVD in women, even though this aspect needs deeper investigation. It will be important to identify thresholds responsible for UA “biological shift” from protective to harmful effects in different pathological conditions, and according to possible gender-related differences. In any case, UA is a low-tech and inexpensive biomarker, generally performed at patient’s hospitalization and, therefore, easily accessible information for clinicians. For these reasons, UA might represent a useful additive tool as much as a CV risk marker. Thus, in view of available evidence, progressive UA elevation with levels higher than 6 mg/dL could be considered an “alarm” for increased CV risk.

Thyroid hormone and heart failure: from myocardial protection to systemic regulation

Heart failure (HF) is an intriguing model of chronic disease. It starts as an organ disorder developing, in its progression, into a systemic disease in which the dysfunction of other organs plays a relevant clinical and prognostic impact. Furthermore, continuous activation of systemic pathways plays a role in disease progression, switching their effect from protective to harmful. In this combination of organ dysfunction and systemic derangement, thyroid hormone (TH) have an important regulative impact from cardiovascular to systemic level and from molecular/cellular processes to clinical setting. Whether it is accepted to include TH and thyroid stimulating hormone assessment in the clinical HF course, the next challenge will be to ascertain the benefit of TH replacement therapy in HF patients, taking into consideration the type of hormone to administer, dosage and treatment schedule.