Genetic and environmental factors on heart rate, mean arterial pressure and carotid intima-media thickness: A longitudinal twin study.

BACKGROUND: Heart rate (HR), mean arterial pressure (MAP) and carotid intima-media thickness (cIMT) are moderately heritable cardiovascular traits, but the environmental effects on the longitudinal change of their heritability have never been investigated. METHODS: 368 Italian and Hungarian twins (107 monozygotic, 77 dizygotic) underwent oscillometric measurement and B-mode sonography of bilateral carotid arteries in 2009/2010 and 2014. Within- -individual/cross-study wave, cross-twin/within-study wave and cross-twin/cross-study wave correlations were estimated, and bivariate Cholesky models were fitted to decompose the total variance at each wave and covariance between study waves into additive genetic, shared and unique environmental components. RESULTS: For each trait, a moderate longitudinal stability was observed, with within-individual/crosswave correlations of 0.42 (95% CI: 0.33-0.51) for HR, 0.34 (95% CI: 0.24-0.43) for MAP, and 0.23 (95% CI: 0.12-0.33) for cIMT. Cross-twin/cross-wave correlations in monozygotic pairs were all significant and substantially higher than the corresponding dizygotic correlations. Genetic continuity was the main source of longitudinal stability, with across-time genetic correlations of 0.52 (95% CI: 0.29-0.71) for HR, 0.56 (95% CI: 0.31-0.81) for MAP, and 0.36 (95% CI: 0.07-0.64) for cIMT. Overlapping genetic factors explained respectively 57%, 77%, and 68% of the longitudinal covariance of the HR, MAP and cIMT traits. CONCLUSIONS: Genetic factors have a substantial role in the longitudinal change of HR, MAP and cIMT; however, the influence of unique environmental factors remains relevant. Further studies should better elucidate whether epigenetic mechanisms have a role in influencing the stability of the investigated traits over time.

Genetic and environmental determinants of longitudinal stability of arterial stiffness and wave reflection: a twin study.

BACKGROUND: We aimed at evaluating the impact of genetic and environmental factors on longitudinal changes in aortic pulse wave velocity (aPWV) and aortic augmentation index (aAIx). METHOD: Three hundred and sixty-eight Italian and Hungarian adult twins (214 monozygotic, 154 dizygotic) underwent repeated evaluations of aPWV and aAIx (TensioMed Arteriograph). Within-individual/cross-wave, cross-twin/within-wave and cross-twin/cross-wave correlations were calculated; bivariate Cholesky models were fitted to calculate additive genetic (A), shared environmental (C) and unique environmental (E) components. RESULTS: For both aPWV and aAIx, cross-twin correlations in monozygotic pairs (r between 0.35 and 0.56) were all significant and always higher than in dizygotic pairs, both at wave 1 and at wave 2. Heritability and unshared environmental proportion of variance at each wave were substantially time-invariant for aPWV (heritability 0.51, 95% CI 0.36-0.63 at wave 1; 0.49, 95% CI 0.34-0.62 at wave 2), whereas for aAIx, we observed a diminished genetic effect (heritability 0.57, 95% CI 0.45-0.67 at wave 1; 0.37, 95% CI 0.21-0.51 at wave 2). Overlapping genetic factors explained a high proportion (0.88, 95% CI 0.61-1.00) of longitudinal covariance for aPWV, and had a relatively lower impact on aAIx (0.55, 95% CI 0.35-0.70). Genetic correlations of aPWV (r = 0.64, 95% CI 0.42-0.85) and aAIx (r = 0.70, 95% CI 0.52-0.87) between waves were lower than 1, suggesting a potential contribution of novel genetic variance on arterial stiffening. CONCLUSION: Changes in aPWV and aAIx over time are largely genetically determined. Our results might stimulate further studies on genetic and epigenetic factors influencing the process of vascular ageing.

MicroV Technology to Improve Transcranial Color Coded Doppler Examinations.

The purpose of this review is to provide an update on technology related to Transcranial Color Coded Doppler Examinations. Microvascularization (MicroV) is an emerging Power Doppler technology which can allow visualization of low and weak blood flows even at high depths, thus providing a suitable technique for transcranial ultrasound analysis. With MicroV, reconstruction of the vessel shape can be improved, without any overestimation. Furthermore, by analyzing the Doppler signal, MicroV allows a global image of the Circle of Willis. Transcranial Doppler was originally developed for the velocimetric analysis of intracranial vessels, in particular to detect stenoses and the assessment of collateral circulation. Doppler velocimetric analysis was then compared to other neuroimaging techniques, thus providing a cut-off threshold. Transcranial Color Coded Doppler sonography allowed the characterization of vessel morphology. In both Color Doppler and Power Doppler, the signal overestimated the shape of the intracranial vessels, mostly in the presence of thin vessels and high depths of study. In further neurosonology technology development efforts, attempts have been made to address morphology issues and overcome technical limitations. The use of contrast agents has helped in this regard by introducing harmonics and subtraction software, which allowed better morphological studies of vessels, due to their increased signal-to-noise ratio. Having no limitations in the learning curve, in time and contrast agent techniques, and due to its high signal-to-noise ratio, MicroV has shown great potential to obtain the best morphological definition.

Correction: Heritability of the dimensions, compliance and distensibility of the human internal jugular vein wall.

[This corrects the article DOI: 10.1371/journal.pone.0192948.].

Investigation of circle of Willis variants and hemodynamic parameters in twins using transcranial color-coded Doppler sonography.

Morphological and hemodynamic variations of the circle of Willis (CW) may have an important impact on cerebrovascular events. However, the environmental and genetic influence remains unclear. For this reason we studied the variations and hemodynamic parameters of the CW in twins using transcranial color-coded sonography (TCCS). Sixty-four twins, 19 monozygotic (MZ) and 13 dizygotic (DZ) pairs from the Italian Twin Registry (average age 45.0 ± 13.7 years) underwent TCCS and risk factor assessment. We examined CW morphology and recorded peak systolic velocity (PSV), end-diastolic velocity (EDV) and pulsatility index (PI). Raw heritability was determined for hemodynamic parameters, whereas concordance and discordance rates were calculated for CW morphological variants. A normal CW anatomy was observed in the majority of MZ and DZ twins (76.5% and 92.3%, respectively). The most frequent variant was a missing anterior cerebral artery (ACA). There was no significant difference in the prevalence of most CW variants depending on the zigosity. Concordance rates were low regarding the presence of variant CW anatomy both in MZ and DZ groups (0.14 and 0.00, respectively). Women had a significantly higher PI in vertebral arteries (VA) and in the right ACA (p = 0.01, p = 0.02 and p < 0.01, respectively). An inverse correlation was observed between hemodynamic parameters and age. Morphological variants of the CW do not seem to be heritable; they are most likely determined by environmental factors. In contrast, hemodynamic parameters of the CW are moderately heritable and this might have implications in the management and prevention of cerebrovascular diseases.

Heritability of the dimensions, compliance and distensibility of the human internal jugular vein wall.

AIMS: The elasticity of the internal jugular vein (IJV) is a major determinant of cerebral venous drainage and right atrium venous return. However, the level of genetic determination of IJV dimensions, compliance and distensibility has not been studied yet. METHODS: 170 adult Caucasian twins (43 monozygotic [MZ] and 42 dizygotic [DZ] pairs) were involved from the Italian twin registry. Anteroposterior and mediolateral diameters of the IJV were measured bilaterally by ultrasonography. Measurements were made both in the sitting and supine positions, with or without Valsalva maneuver. Univariate quantitative genetic modeling was performed. RESULTS: Genetic factors are responsible for 30-70% of the measured properties of IJV at higher venous pressure even after adjustment for age and gender. The highest level of inheritance was found in the supine position regarding compliance (62%) and venous diameter during Valsalva (69%). Environmental and measurement-related factors instead are more important in the sitting position, when the venous pressure is low and the venous lumen is almost collapsed. The range of capacity changes between the lowest and highest intraluminal venous pressure (full distension range) are mainly determined by genetic factors (58%). CONCLUSIONS: Our study has shown substantial heritability of IJV biomechanics at higher venous pressures even after adjustment for age and gender. These findings yield an important insight to what degree the geometric and elastic properties of the vascular wall are formed by genetic and by environmental factors in humans.

Genetic influence on femoral plaque and its relationship with carotid plaque: an international twin study.

To disentangle genetic and environmental influences on the development of femoral plaques using a population of adult twins. To evaluate the potential role of shared genetic and environmental factors in the co-occurrence of femoral and carotid plaques. The sample included 566 twins belonging to 164 monozygotic (MZ) and 119 dizygotic (DZ) twin pairs, who underwent peripheral arterial assessment by B-mode ultrasound in different centers. The variance in femoral plaques onset was due to genetic factors and the remaining 50% was explained by common (15%) and unique (35%) environmental factors. Findings on sidedness and number of femoral plaques indicated that also these traits were mainly under genetic control. No effect of common environment was found on plaques composition, and variability of this trait was explained by genetics (64%) and unique environment (36%). Covariation between the liabilities to carotid and femoral plaques was mainly attributed to shared genes (77%), with the remaining 23% explained by individual-specific environmental factors shared by the two districts. Inter-individual differences in plaque onset as well as in their number, sidedness and composition are mainly genetic in origin. The results on the cooccurrence of carotid and femoral plaque underline the genetic role in atherogenesis.

Vertebral Artery Diameter and Flow: Nature or Nurture.

BACKGROUND AND PURPOSE: In contrast with the carotid arteries, the vertebral arteries (VAs) show considerable variation in length, caliber, and vessel course. This study investigated whether the variation in diameter and flow characteristics of the VAs might be inherited. METHODS: A total of 172 Italian twins from Padua, Perugia, and Terni (54 monozygotic, 32 dizygotic) recruited from the Italian Twin Registry underwent B-mode and pulsed-wave Doppler ultrasound assessment of their VAs. VA diameters, peak systolic velocity (PSV) and end diastolic velocity (EDV) were assessed at the level of a horizontal V2 segment. Univariate quantitative genetic modeling was performed. RESULTS: Fourteen percent of the sample had VA hypoplasia. Within pair correlation in monozygotic twins was higher than in dizygotics (.552 vs. .229) for VA diameter. Age- and sex-adjusted genetic effect, under the most parsimonious model, accounted for 54.7% (95% CI: 42.2-69.1%) of the variance of VA diameter, and unshared environmental effect for 45.3% (95% CI: 30.9-57.8%). No heritability was found for the PSV of VA, but shared (34.1%; 95% CI: 16.7-53.7%) and unshared (65.9%; 95% CI: 45.9-83.1%) environmental factors determined the variance. EDV of VA is moderately genetically influenced (42.4%; 95% CI: 16.1-64.9%) and also determined by the unshared environment (57.6%; 95% CI: 34.7-83.7%). CONCLUSIONS: The diameter of the VAs is moderately genetically determined. Different factors influence the PSV and EDV of VAs, which may highlight the complex hemodynamic background of VA flow and help to understand the vertebral flow anomalies found by ultrasound.

Heritability of the femoral intima media thickness.

BACKGROUND: The measurement of femoral intima-media thickness (IMT) is underutilized in the clinical practice, although it is a surrogate marker of cardiovascular disease. MATERIALS AND METHODS: 388 Hungarian and Italian twins (121 monozygotic, 73 dizygotic pairs) underwent bilateral B-mode sonography of femoral arteries. IMT was measured by semiautomated software, where available, or by calipers. RESULTS: Within-pair correlation in monozygotic twins was higher than in dizygotics for each parameter. Age-, sex- and country-adjusted genetic effect accounted for 43.9% (95% confidence interval, CI 21.3%-65.2%) and 47.2% (95% CI, 31.4%-62.6%) of the variance of common and superficial femoral artery IMT, respectively, and unshared environmental effect for 56.1% (95% CI 34.6%-78.5%) and 52.8% (95% CI, 37.2%-68.5%). These results did not change significantly after correcting for body mass index or central systolic blood pressure. CONCLUSIONS: Genetic factors have a moderate role in the determination of common and superficial femoral IMT; however, the influence of environmental (lifestyle) factors remains still relevant. Environmental factors may have a role in influencing the genetic predisposition for femoral vascular hypertrophy.

Italian symptomatic intracranial atherosclerosis study (ISIDE) : A multicenter transcranial ultrasound evaluation.

There are currently no data available on the prevalence of symptomatic intracranial atherosclerosis (ICAS) in Italy. The aim of this prospective, multicenter, hospital-based, transcranial ultrasound study was to establish the prevalence of ICAS among patients hospitalized with acute ischemic stroke. At 11 stroke centers across Italy, patients consecutively admitted for their first ever acute ischemic stroke were assessed prospectively over a 24-month period either with transcranial color-coded Doppler sonography (TCCS) or transcranial Doppler (TCD) according to validated criteria. ICAS was diagnosed when there was an evidence of a cerebral infarction in the territory of a ≥50 % stenosis detected by TCCS/TCD and confirmed by magnetic resonance angiography or computed tomography angiography. A total of 1134 patients were enrolled, 665 of them (58.6 %) men, with a mean age of 71.2 ± 13.3 years. ICAS was recorded in 99 patients (8.7 % of the whole sample, 8.9 % among Caucasians), most commonly located in the anterior circulation (63 of 99, 5.5 %). After adjusting for potential confounders, multivariate analysis identified carotid/vertebral ≥50 % stenosis [odds ratio (OR) 2.59, 95 % (confidence interval) CI 1.77-6.33; P = 0.02] and hypercholesterolemia (OR 1.38, 95 % CI 1.02-1.89; P = 0.02) as being independently associated with ICAS. ICAS is a surprisingly relevant cause of ischemic stroke in Italy, identified in almost 9 % of first-ever stroke patients. It is more prevalent in the anterior circulation and independently associated with hemodynamically significant cervical vessel atherosclerosis and hypercholesterolemia. These findings support the systematic use of transcranial ultrasound to identify ICAS in patients presenting with acute ischemic stroke and in cases with ≥50 % cervical vessel stenoses.

No signs of intracranial arterial vasoconstriction in transient global amnesia.

BACKGROUND AND PURPOSE: The current theories to explain the pathophysiology of transient global amnesia (TGA) involve epilepsy, migraine, and hippocampal ischemia which might be determined by venous congestion or arterial vasoconstriction triggered by Valsalva-associated maneuvers in susceptible individuals. METHODS: Seventy-five TGA patients [mean age 60.3 ± 8.0 years, 44 (59%) females] and 75 age- and gender-matched controls were enrolled into a case-control study and underwent extracranial and transcranial arterial echo-color Doppler sonography. RESULTS: Intracranial arterial obstructions of the posterior circulation were neither observed in TGA patients nor in controls. There was no significant difference between the two groups with regard to intima-media thickness of the common carotids (.73 ± .07 vs. .72 ± .06), cervical vessel atherosclerosis (13% vs. 15%), >50% intracranial stenosis of the anterior circulation arteries (3% vs. 3%), resistance index values of the vertebral arteries at rest and during Valsalva maneuver (.69 ± .08 vs. .67 ± .09) and pulsatility index values of the major intracranial arteries at rest and during Valsalva maneuver. No difference in all study items was found between patients assessed during or soon after the TGA episode. CONCLUSIONS: Extra-intracranial atherosclerosis does not play a pathogenic role in TGA and no supporting evidence for the arterial vasoconstriction hypothesis of TGA emerged from this study.

Connective tissue anomalies in patients with spontaneous cervical artery dissection.

OBJECTIVE: To investigate the prevalence of connective tissue abnormalities in patients with spontaneous cervical artery dissections (sCeAD). METHODS: We systematically assessed clinically detectable signs of connective tissue aberration in a series of consecutive patients with sCeAD and of age- and sex-matched patients with ischemic stroke unrelated to CeAD (non-CeAD IS) by a standard examination protocol including 68 items, and performed extensive molecular investigation for hereditary connective tissue disorders in all patients with sCeAD. RESULTS: The study group included 84 patients with sCeAD (mean age, 44.5 ± 7.8 years; 66.7% men) and 84 patients with non-CeAD IS. None of the patients with sCeAD met clinical or molecular diagnostic criteria for established hereditary connective tissue disorder. Connective tissue abnormalities were detected more frequently in the group of patients with sCeAD than in the group of those with non-CeAD IS (mean number of pathologic findings, 4.5 ± 3.5 vs 1.9 ± 2.3; p < 0.001). Eighty-one patients (96.4%) in the sCeAD group had at least one detectable sign compared with 55 patients (66.7%) in the group with non-CeAD IS (p < 0.001). Skeletal, ocular, and skin abnormalities, as well as craniofacial dysmorphisms, were the clinical signs more strongly associated with sCeAD. Signs suggesting connective tissue abnormality were also more frequently represented in patients with sCeAD than in patients with traumatic CeAD (28.6%, p < 0.001; mean number of pathologic findings, 1.7 ± 3.7, p = 0.045). CONCLUSIONS: Connective tissue abnormalities are frequent in patients with sCeAD. This reinforces the hypothesis that systemic aberrations of the connective tissue might be implicated in the pathogenesis of the disease.

Bioimpedance analysis of body composition in an international twin cohort.

OBJECTIVE: Multiple twin studies have demonstrated the heritability of anthropometric and metabolic traits. However, assessment of body composition parameters by bioimpedance analysis (BIA) has not been routinely performed in this setting. DESIGN: A cross-sectional study. SETTING: Study subjects were recruited and assessed at twin festivals or at major university hospitals in Italy, Hungary, and the United States to estimate the influence of genetic and environmental components on body composition parameters in a large, wide age range, international twin cohort by using bioelectrical impedance analysis. SUBJECTS: 380 adult twin pairs (230 monozygotic and 150 dizygotic pairs; male:female ratio, 68:32; age years 49.1 ± 15.4; mean ± standard deviation; age range 18-82) were included in the analysis. RESULTS: Heritability was calculated for weight (82%; 95% confidence interval [CI]: 78-85), waist and hip circumferences (74%; 95%CI: 68-79), body fat percentage (74%; 95%CI: 69-79), fat-free mass (74%; 95%CI: 69-79) and body mass index (79%; 95%CI: 74-83). The completely environmental model showed no impact of shared environmental effects on the variance, while unshared environmental effects were estimated as between 18% and 26%. CONCLUSIONS: BIA findings provide additional evidence to the heritability of anthropometric attributes related to obesity and indicate the practical value of this simple method in supporting efforts to prevent obesity-related adverse health events.

Coagulation activation in children with sickle cell disease is associated with cerebral small vessel vasculopathy.

BACKGROUND: Thrombotic complications in Sickle Cell Disease (SCD) arise since infancy, but the role of the coagulation system in children has been poorly explored. To determine its role in the development of clinical complications in childhood we measured coagulation and endothelial parameters in children with SCD at steady state. METHODS: Markers of thrombin generation, fibrin dissolution and endothelial activation were evaluated in 38 children with SS-Sß°, 6 with SC disease and 50 age and blood group matched controls. Coagulation variables were correlated with markers of hemolysis and inflammation, with the presence of cerebral and lung vasculopathy and with the frequency of clinical complications. RESULTS: SS-Sß° patients presented higher levels of factor VIII, von Willebrand factor antigen (VWF:Ag) and collagen binding activity, tissue plasminogen activator antigen (t-PA:Ag), D-dimer, p-selectin, prothrombin fragment1+2 (F1+2) and lower ADAMTS-13:activity/VWF:Ag (p<0.05) compared to controls and SC patients. In SS-Sß° patients coagulation variables correlated positively with markers of inflammation, hemolysis, and negatively with HbF (p<0.05). Patients with cerebral silent infarcts showed significant decrease in t-PA:Ag and ADAMTS-13 Antigen and a tendency toward higher D-dimer, F1+2, TAT compared to patients without them. D-dimer was associated with a six fold increased risk of cerebral silent infarcts. No correlation was found between coagulation activation and large vessel vasculopathy or other clinical events except for decreased t-PA:Ag in patients with tricuspid Rigurgitant Velocity >2.5m/sec. CONCLUSIONS: SS-Sß° disease is associated with extensive activation of the coagulation system at steady state since young age. ADAMTS-13 and t-PA:Ag are involved in the development of cerebral silent infarcts.

Genetic and environmental effects on carotid flow velocities: an international twin study.

INTRODUCTION: Altered carotid blood flow velocities (CFV) have a complex background but the underlying genetic contribution is still unclear. We sought to evaluate the influence of genetics, shared and unshared environmental components on individual differences of CFV. METHODS: 193 healthy twin pairs, 126 monozygotic (MZ) and 67 dizygotic (DZ) (mean age 53 ± 14 years) recruited in Italy, in the United States and in Hungary underwent bilateral color-coded Doppler flow assessment of the common carotid artery (CCA) and of the internal carotid artery (ICA) in order to assess the peak systolic (PSV) and end diastolic (EDV) velocities. Means of bilateral CFV values were used in the analysis. RESULTS: Age- and country-adjusted intra-class correlations were higher in monozygotic than in dizygotic pairs for mean PSV of the ICA indicating a heritability of 63%. Unique environmental factors contributed to 37% of ICA PSV. With regards to the mean PSV and EDV of the CCA, and EDV of the ICA, heritability analysis indicated no discernible role for genetic components, while the contributions of shared and unshared environmental factors ranged between 56% and 63%, and between 37% and 44% adjusted for age and country, respectively. Mean ICA/CCA ratio was driven by unique environmental factors (82%) with modest heritability (18%). CONCLUSIONS: Our study showed that the heritability of ICA PSV and ICA/CCA ratio is moderate, while the findings do not support heritability of other investigated CFV values. Environmental effects account for a moderate to major portion of the variance. These findings support the value of early ultrasound screening as well as the prevention of modifiable environmental factors in case of altered carotid flow velocities.

Association of body mass index with arterial stiffness and blood pressure components: a twin study.

RATIONALE: Obesity, blood pressure and arterial stiffness are heritable traits interconnected to each other but their possible common genetic and environmental etiologies are unknown. METHODS: We studied 228 monozygotic and 150 dizygotic twin pairs aged 18-82 years from Italy, Hungary and the United States, of which 45 monozygotic and 38 dizygotic pairs were discordant for body mass index (BMI; intrapair difference (Δ) in BMI ≥ 3 kg/m(2)). Blood pressure components and arterial stiffness were measured by TensioMed Arteriograph. RESULTS: Hypertension was more prevalent among obese than non-obese individuals (55% vs. 29%, p < 0.001). Age-, sex- and country-adjusted heritability estimates were high for hemodynamic measures (45%-58%) and BMI (78%). According to bivariate Cholesky decomposition, phenotypic correlations between BMI and blood pressure components (r = -0.15 to 0.24, p < 0.05) were largely explained by additive genetic factors (65%-77%) with the remaining explained by the unique environment. When controlling for genetic factors within all monozygotic pairs, ΔBMI was significantly correlated with Δbrachial systolic blood pressure (SBP) and diastolic blood pressure (DBP), Δmean arterial pressure, and Δaortic SBP (r = 0.15-0.17, p < 0.05). For the same measures, heavier co-twins of BMI-discordant monozygotic pairs had significantly higher values than their leaner counterparts (p < 0.05). CONCLUSION: Blood pressure components are moderately correlated with BMI, largely because of shared genetic factors. However, for the association of BMI with brachial SBP and DBP, aortic SBP and mean arterial pressure, acquired, modifiable factors were also found to be important.

Intellectual function evaluation of first generation immigrant children with sickle cell disease: the role of language and sociodemographic factors.

BACKGROUND: Sickle Cell Disease (SCD) is the most common genetic disease worldwide. Neurological events are among the most worrisome clinical complications of SCD and are frequently accompanied by cognitive impairment. Intellectual function in SCD may vary according to genetic and environmental factors. Immigrant children with SCD are increasing at a global level and display specific health care needs. The aim of our multicenter study was to describe the intellectual function of first generation African immigrants with SCD and the influence of sociodemographic factors on its characteristics. METHODS: The Wechsler Intelligence Scales were administered to evaluate broad intellectual functions in children with SCD and in age-matched healthy siblings. Patients' clinical, socio-demographic, Magnetic Resonance Imaging (MRI) and Angiography (MRA) data were correlated to intellectual function scores. RESULTS: 68 children, mean age 8.95 years were evaluated. 72% spoke three languages, 21% two. FSIQ was <75 in 25% of the children. Mean VIQ was lower than PIQ in 75%. Mean verbal subtest scores were lower than performance scores. Female gender, number of languages spoken at home and mother's employment were associated with single subtest performances (p < 0.05). MRA was abnormal in 73.4% and MRI in 35.9%. No significant correlation was established between silent lesions and intellectual function, even if patients with lesions performed worse. Fifteen siblings performed better than patients on cognitive domains, including language (p < 0.05). CONCLUSIONS: Immigrant bilingual children with SCD seem to display a rate of cognitive impairment similar to their monolingual counterparts but a more pronounced and precocious onset of language difficulties. Adjunctive tests need to be considered in this group of patients to better define their specific deficits.

Genetic influence on the relation between exhaled nitric oxide and pulse wave reflection.

Nitric oxide has an important role in the development of the structure and function of the airways and vessel walls. Fractional exhaled nitric oxide (FE(NO)) is inversely related to the markers and risk factors of atherosclerosis. We aimed to estimate the relative contribution of genes and shared and non-shared environmental influences to variations and covariation of FE(NO) levels and the marker of elasticity function of arteries. Adult Caucasian twin pairs (n = 117) were recruited in Hungary, Italy and in the United States (83 monozygotic and 34 dizygotic pairs; age: 48 ± 16 SD years). FE(NO) was measured by an electrochemical sensor-based device. Pulse wave reflection (aortic augmentation index, Aix(ao)) was determined by an oscillometric method (Arteriograph). A bivariate Cholesky decomposition model was applied to investigate whether the heritabilities of FE(NO) and Aix(ao) were linked. Genetic effects accounted for 58% (95% confidence interval (CI): 42%, 71%) of the variation in FE(NO) with the remaining 42% (95%CI: 29%, 58%) due to non-shared environmental influences. A modest negative correlation was observed between FE(NO) and Aix(ao) (r = -0.17; 95%CI:-0.32,-0.02). FE(NO) showed a significant negative genetic correlation with Aix(ao) (r(g) = -0.25; 95%CI:-0.46,-0.02). Thus in humans, variations in FE(NO) are explained both by genetic and non-shared environmental effects. Covariance between FE(NO) and Aix(ao) is explained entirely by shared genetic factors. This is consistent with an overlap among the sets of genes involved in the expression of these phenotypes and provides a basis for further genetic studies on cardiovascular and respiratory diseases.

Genetic and environmental factors on the relation of lung function and arterial stiffness.

BACKGROUND: An association between reduced lung function and increased cardiovascular risk has been reported, but the underlying mechanisms are unknown. The aim of this study was to assess the heritability of lung function and to estimate its genetic association with arterial stiffness. METHODS: 150 monozygotic and 42 dizygotic healthy Hungarian and American Caucasian twin pairs (age 43 ± 17 years) underwent spirometry (forced vital capacity/FVC/, forced expiratory volume in 1 s/FEV1/; MIR Minispir, USA); and their brachial and central augmentation indices (AIx), and aortic pulse wave velocity (PWV) were measured by oscillometric Arteriograph (TensioMed Ltd, Budapest, Hungary). Phenotypic correlations and bivariate Cholesky decomposition models were applied. RESULTS: Age-, sex-, country- and smoking-adjusted heritability of FEV1, percent predicted FEV1, FVC and percent predicted FVC were 73% (95% confidence interval /CI/: 45-85%), 28% (95% CI: 0-67%), 68% (95% CI: 20-81%) and 45% (95% CI: 0-66%), respectively. Measured and percent predicted FVC and FEV1 values showed no significant phenotypic correlations with AIx or aortic PWV, except for phenotypic twin correlations between measured FEV1, FVC with brachial or aortic augmentation indices which ranged between -0.12 and -0.17. No genetic covariance between lung function and arterial stiffness was found. CONCLUSIONS: Lung function is heritable and the measured FVC and FEV are phenotypically, but not genetically, associated with augmentation index, a measure of wave reflection. This relationship may in turn reveal further associations leading to a better mechanistic understanding of vascular changes in various airway diseases.