Effect of genetic and environmental influences on cardiometabolic risk factors: a twin study

<p>Abstract</p> <p>Background</p> <p>Both genetic and environmental factors play a role in the pathogenesis of type 2 diabetes and cardiovascular diseases. The magnitude of genetic and environmental influences may vary in different populations and can be investigated by twin studies.</p> <p>Methods</p> <p>In this cross-sectional study, 101 (63 monozygotic and 38 dizygotic) adult twin pairs (n = 202; mean age: 44.3 ± 15.8 years) were investigated. Past medical history was recorded and physical examination was performed. Fasting venous blood samples were taken for measuring laboratory parameters. For assessing heritability of 14 cardiovascular risk factors, the structural equation (A-C-E) model was used.</p> <p>Results</p> <p>The following risk factors were highly (> 70.0%) or moderately (50.0 - 69.0%) heritable: weight (88.1%), waist circumference (71.0%), systolic blood pressure (57.1%), diastolic blood pressure (57.7%), serum creatinine (64.1%), fibrinogen (59.9%), and serum C-reactive protein (51.9%). On the other hand, shared and unique environmental influences had the highest proportion of total phenotypic variance in serum total cholesterol (46.8% and 53.2%), serum HDL-cholesterol (58.1% and 14.9%), triglycerides (0.0% and 55.9%), fasting blood glucose (57.1% and 42.9%), fasting insulin (45.4% and 54.5%), serum uric acid (46.0% and 31.3%), and serum homocysteine (71.8% and 28.2%, respectively).</p> <p>Conclusion</p> <p>Some cardiometabolic risk factors have strong heritability while others are substantially influenced by environmental factors. Understanding the special heritability characteristics of a particular risk factor can substantiate further investigations, especially in molecular genetics. Moreover, identifying genetic and environmental contribution to certain cardiometabolic risk factors can help in designing prevention and treatment strategies in the population investigated.</p

Neutrophil-to-Lymphocyte Ratio Is an Independent Risk Factor for Coronary Artery Disease in Central Obesity

Several inflammatory biomarkers were found to be associated with an increased risk of cardiovascular disease. Neutrophil-to-lymphocyte ratio (NLR) is a marker of subclinical inflammation that increases with the stress response. Visceral adiposity index (VAI) calculated as a combination of anthropometric and metabolic parameters reflects both the extent and function of visceral adipose tissue. Given the association of subclinical inflammation with both obesity and cardiovascular diseases, it is plausible that the inflammation-CVD association is modulated by the amount and function of adipose tissue. Thus, our aim was to examine the association between NLR and coronary artery calcium score (CACS), an intermediate marker of coronary artery disease in asymptomatic patients across VAI tertiles. Methods: Data from 280 asymptomatic participants of a cardiovascular screening program were analysed. In addition to the collection of lifestyle and medical history, a non-contrast cardiac CT scan and laboratory tests were performed on all participants. Multivariate logistic regression was conducted with CACS > 100 as the outcome and with conventional cardiovascular risk factors and NLR, VAI, and NLR by VAI tertile as predictors. Results: We found an interaction between VAI tertiles and NLR; NLR values were similar in the lower VAI tertiles, while they were higher in the CACS > 100 in the 3rd VAI tertile (CACS ≤ 100: 1.94 ± 0.58 vs. CACS > 100: 2.48 ± 1.1, p = 0.008). According to multivariable logistic regression, the interaction between NLR and VAI tertiles remained: NLR was associated with CACS > 100 in the 3rd VAI tertile (OR = 1.67, 95% CI 1.06-2.62, p = 0.03) but not in the lower tertiles even after adjustment for age, sex, smoking, history of hypertension, hyperlipidaemia, and diabetes mellitus, as well as high-sensitivity C-reactive protein. Our findings draw attention to the independent association between subclinical, chronic, systemic inflammation and subclinical coronary disease in obesity

Heritability of Coronary Artery Disease: Insights From a Classical Twin Study

Genetics have a strong influence on calcified atherosclerotic plaques; however, data regarding the heritability of noncalcified plaque volume are scarce. We aimed to evaluate genetic versus environmental influences on calcium (coronary artery calcification) score, noncalcified and calcified plaque volumes by coronary computed tomography angiography in adult twin pairs without known coronary artery disease. METHODS: In the prospective BUDAPEST-GLOBAL (Burden of Atherosclerotic Plaques Study in Twins—Genetic Loci and the Burden of Atherosclerotic Lesions) classical twin study, we analyzed twin pairs without known coronary artery disease. All twins underwent coronary computed tomography angiography to assess coronary atherosclerotic plaque volumes. Structural equation models were used to quantify the contribution of additive genetic, common environmental, and unique environmental components to plaque volumes adjusted for age, gender, or atherosclerotic cardiovascular disease risk estimate and statin use. RESULTS: We included 196 twins (mean age±SD, 56±9 years, 63.3% females), 120 monozygotic and 76 same-gender dizygotic pairs. Using structural equation models, noncalcified plaque volume was predominantly determined by environmental factors (common environment, 63% [95% CI, 56%–67%], unique environment, 37% [95% CI, 33%–44%]), while coronary artery calcification score and calcified plaque volumes had a relatively strong genetic heritability (additive genetic, 58% [95% CI, 50%–66%]; unique environmental, 42% [95% CI, 34%–50%] and additive genetic, 78% [95% CI, 73%–80%]; unique environmental, 22% [95% CI, 20%–27%]), respectively. CONCLUSIONS: Noncalcified plaque volume is mainly influenced by shared environmental factors, whereas coronary artery calcification score and calcified plaque volume are more determined by genetics. These findings emphasize the importance of early lifestyle interventions in preventing coronary plaque formation. REGISTRATION: URL: https://www.clinicaltrials.gov; Unique identifier: NCT01738828

Esmolol is noninferior to metoprolol in achieving a target heart rate of 65 beats/min in patients referred to coronary CT angiography: A randomized controlled clinical trial.

BACKGROUND: Coronary CT angiography (CTA) is an established tool to rule out coronary artery disease. Performance of coronary CTA is highly dependent on patients' heart rates (HRs). Despite widespread use of beta-blockers for coronary CTA, few studies have compared various agents used to achieve adequate HR control. OBJECTIVE: We sought to assess if the ultrashort-acting beta-blocker intravenous esmolol is at least as efficacious as the standard of care intravenous metoprolol for HR control during coronary CTA. METHODS: Patients referred to coronary CTA with a HR >65 beats/min despite oral metoprolol premedication were enrolled in the study. We studied 412 patients (211 male; mean age, 57 +/- 12 years). Two hundred four patients received intravenous esmolol, and 208 received intravenous metoprolol with a stepwise bolus administration protocol. HR and blood pressure were recorded at arrival, before, during, immediately after, and 30 minutes after the coronary CTA scan. RESULTS: Mean HRs of the esmolol and metoprolol groups were similar at arrival (78 +/- 13 beats/min vs 77 +/- 12 beats/min; P = .65) and before scan (68 +/- 7 beats/min vs 69 +/- 7 beats/min; P = .60). However, HR during scan was lower in the esmolol group vs the metoprolol group (58 +/- 6 beats/min vs 61 +/- 7 beats/min; P < .0001), whereas HRs immediately and 30 minutes after the scan were higher in the esmolol group vs the metoprolol group (68 +/- 7 beats/min vs 66 +/- 7 beats/min; P = .01 and 65 +/- 8 beats/min vs 63 +/- 8 beats/min; P < .0001; respectively). HR </=65 beats/min was reached in 182 of 204 patients (89%) who received intravenous esmolol vs 162 of 208 of the patients (78%) who received intravenous metoprolol (P < .05). Of note, hypotension (systolic BP <100 mm Hg) was observed right after the scan in 19 patients (9.3%) in the esmolol group and in 8 patients (3.8%) in the metoprolol group (P < .05), whereas only 5 patients (2.5%) had hypotension 30 minutes after the scan in the esmolol group compared to 8 patients (3.8%) in the metoprolol group (P = .418). CONCLUSION: Intravenous esmolol with a stepwise bolus administration protocol is at least as efficacious as the standard of care intravenous metoprolol for HR control in patients who undergo coronary CTA

The effect of four-phasic versus three-phasic contrast media injection protocols on extravasation rate in coronary CT angiography: a randomized controlled trial.

OBJECTIVES: Contrast media (CM) extravasation is a well-known complication of CT angiography (CTA). Our prospective randomized control study aimed to assess whether a four-phasic CM administration protocol reduces the risk of extravasation compared to the routinely used three-phasic protocol in coronary CTA. METHODS: Patients referred to coronary CTA due to suspected coronary artery disease were included in the study. All patients received 400 mg/ml iomeprol CM injected with dual-syringe automated injector. Patients were randomized into a three-phasic injection-protocol group, with a CM bolus of 85 ml followed by 40 ml of 75%:25% saline/CM mixture and 30 ml saline chaser bolus; and a four-phasic injection-protocol group, with a saline pacer bolus of 10 ml injected at a lower flow rate before the three-phasic protocol. RESULTS: 2,445 consecutive patients were enrolled (mean age 60.6 +/- 12.1 years; females 43.6%). Overall rate of extravasation was 0.9% (23/2,445): 1.4% (17/1,229) in the three-phasic group and 0.5% (6/1,216) in the four-phasic group (p = 0.034). CONCLUSIONS: Four-phasic CM administration protocol is easy to implement in the clinical routine at no extra cost. The extravasation rate is reduced by 65% with the application of the four-phasic protocol compared to the three-phasic protocol in coronary CTA. KEY POINTS: * Four-phasic CM injection-protocol reduces extravasation rate by 65% compared to three-phasic. * The saline pacer bolus substantially reduces the risk of CM extravasation. * The implementation of four-phasic injection-protocol is at no cost

A metabolikus szindróma összetevőinek genetikai meghatározottsága: ikervizsgálatok eredményei [Heritability of the risk factors characteristic for the metabolic syndrome: a twin study]

A metabolikus szindrómára jellemző cardiovascularis kockázati tényezők alakulásában örökletes és környezeti tényezők is szerepet kapnak. A genetikai és környezeti tényezők jellegzetességei populációkként változhatnak. Célkitűzés: Az ikervizsgálat célja a metabolikus szindrómában szereplő cardiovascularis kockázati tényezők genetikai, illetve környezeti meghatározottságának megállapítása volt. Módszer: A tanulmányban 101 egészséges felnőtt ikerpár (63 pár monozigóta, 38 pár azonos nemű dizigóta; n = 202, életkor: 43,3±15,8 év) szerepelt. Fizikális vizsgálat után a betegek kérdőívet töltöttek ki, majd éhomi vérvételre került sor. A statisztikai értékelés során a genetikai, a közös és egyéni környezeti determináltság százalékos arányát jelző öröklődési indexek meghatározása történt az A-C-E strukturált egyenletmodell illeszkedése alapján. Az adatok életkorra, nemre (Modell-1), illetve életkorra, nemre, BMI- és haskörfogatértékre korrigáltak (Modell-2). Eredmények: A haskörfogat (illetve a többi antropometriai paraméter [testmagasság, testsúly]) alakulása terén egyértelműen dominált a genetikai meghatározottság (Modell-1-érték: 71,0–88,1%). Kevésbé markánsan voltak az örökletes tényezők a meghatározók a szisztolés és a diasztolés vérnyomásérték alakulására (Modell-2-érték: 57,1% és 57,7%). A Modell-2-érték alapján az egyéni környezeti tényezők játszottak jelentősebb szerepet a szérumtriglicerid értékének (55,9%) alakulásában, míg a közös környezeti determináltság volt a meghatározó a szérum-HDL-koleszterin (58,1%) és az éhomi vércukor (57,1%) értékének alakulásában. A Modell-1- és Modell-2-értékek összehasonlítása arra utalt, hogy az antropometriai paraméterek (BMI, haskörfogat) csak kis hányadban (0,0–17,1%) kaptak szerepet a metabolikus szindróma genetikai és környezeti összetevőinek determináltságában. Következtetések: Felnőtt, magukat egészségesnek tartó egyének körében a metabolikus szindróma komponensei között a genetikai tényezőknek meghatározó szerepe van a haskörfogat és a vérnyomás alakulása terén, míg a szérumtriglicerid-, a HDL-koleszterin- és az éhomi vércukorérték alakulására környezeti tényezők vannak elsősorban befolyással. Az egyes kockázati tényezők eltérő öröklődése kétségessé teszi a metabolikus szindróma eredeti, egységes kóroktanon alapuló koncepciójának helyességét. A vizsgálat eredményei egyéni és társadalmi szinten egyaránt segíthetik a primer cardiovascularis prevenció megtervezését és kivitelezését. Orv. Hetil., 2011, 152, 1265–1271. | Both genetic and environmental factors play role in the pathogenesis of the metabolic syndrome. The magnitude of genetic and environmental influences on the components of metabolic syndrome may vary in different populations. Aims: The present study was aimed to determine the effects of genetic and environmental factors on risk factors characteristic for the metabolic syndrome. Methods: A total of 101 (63 monozygotic and 38 dizygotic) adult twin pairs (n = 202; mean age: 43.3±15.8 years) were investigated. Medical history was recorded and physical examination was carried out for each subject. Fasting venous blood samples were used for measuring laboratory parameters. The presented estimates include the heritability structural equation (A-C-E) model results. In Model-1, all presented parameters are age- and gender- corrected. In Model-2, parameters were corrected for age, gender, body mass index and waist circumference. Results: Heritability in waist circumference (as well as in other anthropometric parameters such as weight and height) was high (Model-1: 71.0–88.1%). Similarly, genetic factors had the highest proportion of total phenotypic variance in systolic and diastolic blood pressure (Model-2: 57.1% and 57.7%, respectively). Based on the results of Model-2, unique environmental factors dominate alterations in serum triglycerides values (55.9%) while shared environmental factors proved to be substantial in alterations of HDL-cholesterol and fasting blood glucose values (58.1% and 57.1%, respectively). Comparing the results of Model-1 and Model-2, the difference in A-C-E model varied from 0.0% to 17.1%, indicating that only a minor proportion of genetic and environmental influences can be explained by the effects of anthropometric parameters. Conclusions: Among adult Hungarian healthy people, genetic factors have substantial influence on waist circumference and blood pressure values while environmental factors dominate alterations in serum triglycerides, HDL-cholesterol and fasting blood glucose values. The different heritability of individual risk factors challenges the original unifying concept of the metabolic syndrome. The results may be useful for establishing and implementing primary cardiovascular prevention both at individual and population levels. Orv. Hetil., 2011, 152, 1265–1271

Neutrophil-to-Lymphocyte Ratio Is an Independent Risk Factor for Coronary Artery Disease in Central Obesity

Several inflammatory biomarkers were found to be associated with an increased risk of cardiovascular disease. Neutrophil-to-lymphocyte ratio (NLR) is a marker of subclinical inflammation that increases with the stress response. Visceral adiposity index (VAI) calculated as a combination of anthropometric and metabolic parameters reflects both the extent and function of visceral adipose tissue. Given the association of subclinical inflammation with both obesity and cardiovascular diseases, it is plausible that the inflammation–CVD association is modulated by the amount and function of adipose tissue. Thus, our aim was to examine the association between NLR and coronary artery calcium score (CACS), an intermediate marker of coronary artery disease in asymptomatic patients across VAI tertiles. Methods: Data from 280 asymptomatic participants of a cardiovascular screening program were analysed. In addition to the collection of lifestyle and medical history, a non-contrast cardiac CT scan and laboratory tests were performed on all participants. Multivariate logistic regression was conducted with CACS > 100 as the outcome and with conventional cardiovascular risk factors and NLR, VAI, and NLR by VAI tertile as predictors. Results: We found an interaction between VAI tertiles and NLR; NLR values were similar in the lower VAI tertiles, while they were higher in the CACS > 100 in the 3rd VAI tertile (CACS ≤ 100: 1.94 ± 0.58 vs. CACS > 100: 2.48 ± 1.1, p = 0.008). According to multivariable logistic regression, the interaction between NLR and VAI tertiles remained: NLR was associated with CACS > 100 in the 3rd VAI tertile (OR = 1.67, 95% CI 1.06–2.62, p = 0.03) but not in the lower tertiles even after adjustment for age, sex, smoking, history of hypertension, hyperlipidaemia, and diabetes mellitus, as well as high-sensitivity C-reactive protein. Our findings draw attention to the independent association between subclinical, chronic, systemic inflammation and subclinical coronary disease in obesity

Genetic impact dominates over environmental effects in development of carotid artery stiffness

Arterial stiffness is an independent predictor of cardiovascular, cerebrovascular and all-cause mortality. Quantifying the genetic influence on the stiff arterial phenotype allows us to better predict the development of arterial stiffness. In this study, we aimed to determine the heritability of carotid artery stiffness in healthy twins. We studied 98 twin pairs of both sexes. We determined carotid artery stiffness locally using echo tracking and applanation tonometry. We estimated the heritability of stiffness parameters using structural equation modeling. The carotid distensibility coefficient showed the highest heritability (64%, 95% confidence interval 45-77%). The incremental elastic modulus, compliance and stiffness index beta also showed substantial heritability (62%, 61% and 58%, respectively). The remaining 36-42% phenotypic variance was attributed to unshared environmental effects. Genetic influence appears to dominate over environmental factors in the development of carotid artery stiffness. Environmental factors may have an important role in favorably influencing the genetic predisposition for accelerated arterial stiffening.Hypertension Research advance online publication, 3 October 2013; doi:10.1038/hr.2013.133