Andrea Molnár

Heritability of central blood pressure and arterial stiffness: a twin study.

Objective: Central blood pressure and aortic stiffness have been consistently reported as strong cardiovascular risk factors. Twin studies by comparing identical with nonidentical twins produce information on the relative contribution of genes and environment. Methods: One hundred and fifty-four monozygotic (MZ) and 42 dizygotic (DZ) twin pairs (age 43 ± 17 years) from Hungary and the United States underwent brachial and central augmentation index (AIx), brachial and central pressure, and aortic pulse wave velocity (PWV) measurements with the invasively validated Arteriograph device. Bivariate Cholesky decomposition models were applied. Results: Age-adjusted, sex-adjusted and country-adjusted heritability was 60.0% for central SBP [95% confidence interval (CI), 44.8–69.6%], 50.1% for aortic PWV (95%CI, 26.0–66.8%), 48.7% for aortic AIx (95%CI, 1.7–74.0%), 46.8% for brachial AIx (95%CI, 1.1–73.8%), 46.7% for central pulse pressure (PP) (95%CI, 12.4–61.4%), and 30.0% for brachial PP (95%CI, 0.0–53.4%). Central SBP and PP had strong bivariate correlations with brachial (r = 0.461 and 0.425) and central AIx (r = 0.457 and 0.419), as well as with aortic PWV (r = 0.341 and 0.292, all P < 0.001). Brachial PP had a weak correlation with brachial AIx (r = −0.118, P < 0.05), central AIx (r = −0.122, P < 0.05), and none with aortic PWV (r = 0.08, P = n.s.). Genetic factors explained a moderate phenotypic correlation between central PP, SBP, brachial SBP and aortic PWV. Conclusions: Central systolic and PPs, brachial PP, AIx, aortic PWV are moderately heritable. A moderate genetic covariance among aortic PWV and central PP, central SBP and brachial SBP was found.

Heritability of non-alcoholic fatty liver disease and association with abnormal vascular parameters: A twin study

Non‐alcoholic fatty liver disease (NAFLD) has been linked to increased cardiovascular morbidity. However, genetic factors have an unclear role in this condition.

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.

Evidence for a Strong Genetic Influence on Carotid Plaque Characteristics An International Twin Study

Background and Purpose— Few family studies reported moderate genetic impact on the presence and scores of carotid plaques. However, the heritability of carotid plaque characteristics remains still unclear. Twin studies more reliably estimate the relative contribution of genes to these traits in contrast to family study design. Methods— One hundred ninety-two monozygotic and 83 dizygotic adult twin pairs (age 49±15 years) from Italy, Hungary, and the United States underwent B-mode and color Doppler ultrasound of bilateral common, internal, and external carotid arteries. Results— Age-, sex-, and country-adjusted heritability was 78% for the presence of carotid plaque (95% CI, 55%–90%), 74% for plaque echogenicity (hypoechoic, hyperechoic, or mixed; 95% CI, 38%–87%), 69% for plaque size (area in mm2 in longitudinal plane; < or >50 percentile; 95% CI, 16%–86%), 74% for plaque sidedness (unilateral or bilateral; 95% CI, 25%–90%), 74% for plaque numerosity (95% CI, 26%–86%), 68% (95% CI, 40%–84%), and 66% (95% CI, 32%–90%) for the presence of plaque in carotid bulbs and proximal internal carotid arteries. No role of shared environmental factors was found. Unique environmental factors were responsible for the remaining variance (22%–34%). Controlling for relevant covariates did not change the results significantly. Conclusions— The heritability of ultrasound characteristics of carotid plaque is high. Unshared environmental effects account for a modest portion of the variance. Our findings should stimulate the search for genes responsible for these traits.

Transfemoral endovascular treatment of proximal common carotid artery lesions: A single-center experience on 153 lesions

PURPOSE To assess primary success and safety of percutaneous transluminal angioplasty (PTA) and/or stenting of ostial/proximal common carotid artery lesions (pCCA) and to compare its 30-day stroke/mortality level with the literature data for surgical options. METHODS A total of 147 patients (153 stenoses, 6 recurrent) (71 female; 121 left) with significant diameter stenosis (>70% in symptomatic, n = 46; >85% in asymptomatic, n = 101 patients) of pCCA treated between 1994 and 2006 were retrospectively reviewed. With the exception of one, all procedures were performed using a transfemoral approach. A stent was implanted in 108 (70.5%) of cases. Stents were not available in the early years of our experience, but gradually became a routine practice. Embolic protection devices were used in 16 cases. Follow-up included neurological examination, carotid duplex scan, and office/telephone interview. RESULTS Primary technical success was 98.7% (151/153 stenoses). There were no deaths. Periprocedural (<48 hours) neurological complications included 3/153 (2.0%) ipsilateral major strokes and 4/153 (2.6%) TIAs (including one contralateral TIA). There were 8/153 (5.2%) access site hematomas, 1/153 (0.7%) bradycardia, and 1/153 (0.7%) acute left ventricular failure with respiratory distress. Follow-up was achieved in 115/147 patients (78.2%) undergoing 120 procedures for a mean of 24.7 months and revealed one additional contralateral TIA and one additional minor stroke in an asymptomatic patient. In patients with follow-up, the 30-day procedural death/all-stroke rate was 3/120 (2.5%) The cumulative primary patency rate in the 115 patients with follow-up was 97.9% +/- 2.1% at 1 year, 82.0% +/- 7.1% at 4-years, and 73.5% +/- 12.7% at 7 years. The cumulative secondary patency rate was 100% at 1 year, 88.0% +/- 7.0% at 4 years, and 88.0% +/- 11% at 7 years. Log-rank test showed no statistical difference (P = .82) in primary cumulative patency between PTA alone (n = 34) or PTA/stent (n = 86). CONCLUSION Transfemoral PTA/stenting appears to be appropriate treatment option for ostial/proximal common carotid artery significant stenoses. This study should also draw attention to the lack of data on natural history or effect of best medical treatment alone for these lesions, making evidence-based decision currently impossible for treatment of symptomatic or asymptomatic ostial and proximal common carotid artery significant stenoses.

Identification of differentially expressed genes in the developing antler of red deer Cervus elaphus

Understanding the molecular mechanisms underlying bone development is a fundamental and fascinating problem in developmental biology, with significant medical implications. Here, we have identified the expression patterns for 36 genes that were characteristic or dominant in the consecutive cell differentiation zones (mesenchyme, precartilage, cartilage) of the tip section of the developing velvet antler of red deer Cervus elaphus. Two major functional groups of these genes clearly outlined: six genes linked to high metabolic demand and other five to tumor biology. Our study demonstrates the advantages of the antler as a source of mesenchymal markers, for distinguishing precartilage and cartilage by different gene expression patterns and for identifying genes involved in the robust bone development, a striking feature of the growing antler. Putative roles for “antler” genes that encode α-tropomyosine (tpm1), transgelin (tagln), annexin 2 (anxa2), phosphatidylethanolamine-binding protein (pebp) and apolipoprotein D (apoD) in intense but still controlled tissue proliferation are discussed.

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.

Protein kinase C contributes to the maintenance of contractile force in human ventricular cardiomyocytes

Prolonged Ca2+ stimulations often result in a decrease in contractile force of isolated, demembranated human ventricular cardiomyocytes, whereas intact cells are likely to be protected from this deterioration. We hypothesized that cytosolic protein kinase C (PKC) contributes to this protection. Prolonged contracture (10 min) of demembranated human cardiomyocytes at half-maximal Ca2+ resulted in a 37 ± 5% reduction of active force (p < 0.01), whereas no decrease (2 ± 3% increase) was observed in the presence of the cytosol (reconstituted myocytes). The PKC inhibitors GF 109203X and Gö 6976 (10μmol/liter) partially antagonized the cytosol-mediated protection (15 ± 5 and 9 ± 2% decrease in active force, p < 0.05). Quantitation of PKC isoform expression revealed the dominance of the Ca2+-dependent PKCα over PKCδ and PKCϵ (189 ± 31, 7 ± 3, and 7 ± 2 ng/mg protein, respectively). Ca2+ stimulations of reconstituted human cardiomyocytes resulted in the translocation of endogenous PKCα, but not PKCβ1, δ, and ϵ from the cytosol to the contractile system (PKCα association: control, 5 ± 3 arbitrary units; +Ca2+, 39 ± 8 arbitrary units; p < 0.01, EC50,Ca = 645 nmol/liter). One of the PKCα-binding proteins were identified as the thin filament regulatory protein cardiac troponin I (TnI). Finally, the Ca2+-dependent interaction between PKCα and TnI was confirmed using purified recombinant proteins (binding without Ca2+ was only 28 ± 18% of that with Ca2+). Our data suggest that PKCα translocates to the contractile system and anchors to TnI in a Ca2+-dependent manner in the human heart, contributing to the maintenance of contractile force.

Twins lead to the prevention of atherosclerosis: Preliminary findings of international twin study 2009

Introduction Atherosclerosis is an inflammatory process in which the artery wall thickens as a result of plaque deposition, but this process may be preceded by increased arterial stiffness. We sought to evaluate the influence of genetics and shared and unshared environmental components on the onset of atherosclerosis. Methods A total of 135 monozygotic (MZ) and 70 dizygotic (DZ) twin pairs (mean age 49 ± 16 years) underwent carotid intima media thickness (IMT; carotid analyzer) and arterial stiffness (augmentation index on brachial artery [Aixbra], pulse wave velocity on aorta [PWVao]; TensioMed Arteriograph) measurements. Results Age-adjusted intraclass correlations were greater in MZ than in DZ pairs for proximal right common carotid artery (CCA; MZ = 0.19, DZ = 0.06), proximal and distal left CCA (MZ = 0.27, DZ = 0.06; MZ = 0.27, DZ = 0.13, respectively), and proximal left internal carotid artery (ICA; MZ = 0.39, DZ = −0.54), suggesting a moderate genetic effect. Heritability was estimated to be 18% (95% confidence interval [CI] = 3–33) for proximal right CCA, 26% and 27% for proximal and distal left CCA, respectively, and 38% (95% CI = 26–49) for proximal left ICA. Regarding distal right CCA and proximal right ICA, no genetic effects were detected. Age-adjusted intraclass correlation of Aixbra and PWVao were 0.65 (95% CI = 0.55–0.72) and 0.46 (95% CI = 0.33–0.57) in MZ, 0.42 (95% CI = 0.24–0.57) and 0.28 (95% CI = 0.08–0.47) in DZ pairs; heritability 45% (95% CI = 12–71%) and 42% (95% CI = 2–57%) adjusted by age, respectively. Conclusions The investigated parameters appeared to be only moderately influenced by genetic factors. Environmental factors of relevance for these measures appeared not to be shared within family but related to individual experience (e.g., smoking habits, diet, and physical activity). Atherosclerosis detection at an early stage is necessary for treatment to prevent serious complications such as stroke and heart attack.

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.