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

BACKGROUND: 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.

Transgelin: a new gene involved in LDL endocytosis identified by a genome-wide CRISPR-Cas9 screen.

A significant proportion of patients with elevated LDL and a clinical presentation of familial hypercholesterolemia do not carry known genetic mutations associated with hypercholesterolemia, such as defects in the LDL receptor. To identify new genes involved in the cellular uptake of LDL, we developed a novel whole-genome clustered regularly interspaced short palindromic repeat-Cas9 KO screen in HepG2 cells. We identified transgelin (TAGLN), an actin-binding protein, as a potentially new gene involved in LDL endocytosis. In silico validation demonstrated that genetically predicted differences in expression of TAGLN in human populations were significantly associated with elevated plasma lipids (triglycerides, total cholesterol, and LDL-C) in the Global Lipids Genetics Consortium and lipid-related phenotypes in the UK Biobank. In biochemical studies, TAGLN-KO HepG2 cells showed a reduction in cellular LDL uptake, as measured by flow cytometry. In confocal microscopy imaging, TAGLN-KO cells had disrupted actin filaments as well as an accumulation of LDL receptor on their surface because of decreased receptor internalization. Furthermore, TAGLN-KO cells exhibited a reduction in total and free cholesterol content, activation of SREBP2, and a compensatory increase in cholesterol biosynthesis. TAGLN deficiency also disrupted the uptake of VLDL and transferrin, other known cargoes for receptors that depend upon clathrin-mediated endocytosis. Our data suggest that TAGLN is a novel factor involved in the actin-dependent phase of clathrin-mediated endocytosis of LDL. The identification of novel genes involved in the endocytic uptake of LDL may improve the diagnosis of hypercholesterolemia and provide future therapeutic targets for the prevention of cardiovascular disease.

Bayesian network analysis of panomic biological big data identifies the importance of triglyceride-rich LDL in atherosclerosis development.

Introduction: We sought to explore biomarkers of coronary atherosclerosis in an unbiased fashion. Methods: We analyzed 665 patients (mean ± SD age, 56 ± 11 years; 47% male) from the GLOBAL clinical study (NCT01738828). Cases were defined by the presence of any discernable atherosclerotic plaque based on comprehensive cardiac computed tomography (CT). De novo Bayesian networks built out of 37,000 molecular measurements and 99 conventional biomarkers per patient examined the potential causality of specific biomarkers. Results: Most highly ranked biomarkers by gradient boosting were interleukin-6, symmetric dimethylarginine, LDL-triglycerides [LDL-TG], apolipoprotein B48, palmitoleic acid, small dense LDL, alkaline phosphatase, and asymmetric dimethylarginine. In Bayesian analysis, LDL-TG was directly linked to atherosclerosis in over 95% of the ensembles. Genetic variants in the genomic region encoding hepatic lipase (LIPC) were associated with LIPC gene expression, LDL-TG levels and with atherosclerosis. Discussion: Triglyceride-rich LDL particles, which can now be routinely measured with a direct homogenous assay, may play an important role in atherosclerosis development. Clinical trial registration: GLOBAL clinical study (Genetic Loci and the Burden of Atherosclerotic Lesions); [https://clinicaltrials.gov/ct2/show/NCT01738828?term=NCT01738828&rank=1], identifier [NCT01738828].

Left Ventricular Systolic Function Has Strong Independent Genetic Background from Diastolic Function: A Classical Twin Study.

Background and Objectives: No data are available on whether the heritability of left ventricle (LV) systolic and diastolic parameters are independent of each other. Therefore, our aim was to assess the magnitude of common and independent genetic and environmental factors defining LV systolic and diastolic function. Materials and Methods: We analyzed 184 asymptomatic twins (65% female, mean age: 56 ± 9 years). Transthoracic echocardiography was performed to measure LV systolic (global longitudinal and circumferential strain; basal and apical rotation) and diastolic (early diastolic velocity of mitral inflow and lateral mitral annulus tissue; deceleration time and early diastolic strain rate) parameters using conventional and speckle-tracking echocardiography. Genetic structural equation models were evaluated to quantify the proportion of common and specific genetic (Ac, As) and environmental factors (Ec, Es) contributing to the phenotypes. Results: LV systolic parameters had no common genetic or environmental heritability (Ac range: 0-0%; Ec range: 0-0%; As range: 57-77%; Es range: 24-43%). Diastolic LV parameters were mainly determined by common genetic and environmental effects (Ac range: 9-40%; Ec range: 11-49%; As range: 0-29%; Es range: 0-51%). Systolic parameters had no common genetic or environmental factors (Ac = 0%; Ec = 0%) with diastolic metrics. Conclusions: Systolic LV parameters have a strong genetic predisposition to any impact. They share no common genetic or environmental factors with each other or with diastolic parameters, indicating that they may deteriorate specifically to given effects. However, diastolic functional parameters are mainly affected by common environmental influences, suggesting that pathological conditions may deteriorate them equally. Estimation of the genetic and environmental influence and interdependence on systolic and diastolic LV function may help the understanding of the pathomechanism of different heart failure classification types.

Standardised computed tomographic assessment of left atrial morphology and tissue thickness in humans.

AIMS: Left atrial (LA) remodelling is a common feature of many cardiovascular pathologies and is a sensitive marker of adverse cardiovascular outcomes. The aim of this study was to establish normal ranges for LA parameters derived from coronary computed tomographic angiography (CCTA) imaging using a standardised image processing pipeline to establish normal ranges in a previously described cohort. METHODS: CCTA imaging from 193 subjects recruited to the Budapest GLOBAL twin study was analysed. Indexed LA cavity volume (LACVi), LA surface area (LASAi), wall thickness and LA tissue volume (LATVi) were calculated. Wall thickness maps were combined into an atlas. Indexed LA parameters were compared with clinical variables to identify early markers of pathological remodelling. RESULTS: LACVi is similar between sexes (31 ml/m2 v 30 ml/m2) and increased in hypertension (33 ml/m2 v 29 ml/m2, p = 0.009). LASAi is greater in females than males (47.8 ml/m2 v 45.8 ml/m2 male, p = 0.031). Median LAWT was 1.45 mm. LAWT was lowest at the inferior portion of the posterior LA wall (1.14 mm) and greatest in the septum (median = 2.0 mm) (p < 0.001). Conditions known to predispose to the development of AF were not associated with differences in tissue thickness. CONCLUSIONS: The reported LACVi, LASAi, LATVi and tissue thickness derived from CCTA may serve as reference values for this age group and clinical characteristics for future studies. Increased LASAi in females in the absence of differences in LACVi or LATVi may indicate differential LA shape changes between the sexes. AF predisposing conditions, other than sex, were not associated with detectable changes in LAWT.Clinical trial registration:http://www.ClinicalTrials.gov/NCT01738828.

Environmental Factors Slightly Outweigh Genetic Influences in the Development of Pancreatic Lipid Accumulation: A Classical Twin Study.

Background: Several studies showed that lipid accumulation in the pancreas (NAFPD: nonalcoholic fatty pancreas disease) may lead to different pancreatic disorders, including beta-cell dysfunction. The role of genetic and environmental factors in pancreatic lipid accumulation is unclear. We evaluated the magnitude of genetic and environmental impact on pancreatic lipid content within a cohort of adult twin pairs. Patients and Methods: We investigated 136 twin subjects [monozygotic (MZ, n = 86) and dizygotic (DZ, n = 50) same-gender twins (age 57.7 ± 9.1 years; body mass index [BMI] 28.0 ± 4.4 kg/m2; females 64.7%)] with a 256-slice computed tomography (CT)-scanner. Using nonenhanced CT images, we calculated the average value of pancreatic attenuation expressed in Hounsfield unit (HU) suggesting pancreatic lipid content. Crude data were adjusted to age, sex, BMI, and hemoglobinA1c values. Intrapair correlations were established, and structural equation models were used for quantifying the contribution of additive genetic (A), common environmental (C), and unique environmental (E) components to the investigated phenotype. Results: The study cohort represented a moderately overweight, middle-aged Caucasian population. Average pancreatic attenuation was 48.9 ± 11.9 HU in MZ and 49.0 ± 13.0 HU in DZ twins (P = 0.934). The intrapair correlation between HU values was stronger in MZ compared to DZ twins (rMZ = 0.536, P < 0.001; rDZ = 0.115, P = 0.580). Using the structural equation model, a greater unique environmental influence [E: 54%, 95% confidence interval (CI) 19%-66%] and a moderate additive genetic dependence (A: 46%, 95% CI 34%-81%) were found. Conclusions: The results of our classical twin study indicate that environmental (lifestyle) influences slightly outweigh genetic effects on the phenotypic appearance of pancreatic lipid accumulation known as NAFPD.

Comprehensive coronary plaque assessment in patients with obstructive sleep apnea.

Obstructive sleep apnea (OSA) is associated with an increased risk of cardiovascular disease. Previous studies have assessed the relationship between OSA and coronary artery disease (CAD) using coronary artery calcium score (CAC) measurements. However, limited data are available regarding the association of OSA with non-calcified plaque burden. We therefore aimed to assess the relationship between CAD severity as assessed by coronary computed tomography angiography (CTA) and OSA. Forty-one adult subjects (59 ± 9 years, 15 men) underwent a 256-slice coronary CTA, which was followed by a diagnostic attended cardiorespiratory polygraphy (n = 13) or polysomnography (n = 28). Segment involvement score (SIS), segment stenosis score (SSS) and CAC were used to quantify total CAD burden. Correlation analysis was used to assess potential associations between CAD and OSA. Twenty-two patients were diagnosed with OSA. SIS and SSS were elevated in OSA (2.90 ± 2.78 versus 1.79 ± 2.39 and 4.91 ± 5.94 versus 1.79 ± 4.54, OSA versus controls, SIS and SSS respectively, both p < 0.01) and correlated with OSA severity as measured by the apnea-hypopnea index (AHI, r = 0.41 and 0.43, p < 0.01) and oxygen desaturation index (ODI, r = 0.45 and 0.46, p < 0.01). However, no significant correlation was observed between CAC and OSA. Compared to CAC, SIS and SSS provide additional information on coronary plaque burden in OSA, which shows a significant association with OSA.

Genetically determined pattern of left ventricular function in normal and hypertensive hearts.

We sought to assess the inheritance of left ventricular (LV) function using speckle-tracking echocardiography and the impact of hypertension on modifying the genetically determined pattern of contraction in a population of twins. We recruited 92 Caucasian twin pairs, including 74 hypertensive (HTN) siblings. Beyond standard echocardiographic protocol, a speckle-tracking analysis was performed, including global longitudinal strain (GLS). Systolic function, as assessed by ejection fraction, showed moderate heritability (61%); however, GLS showed higher and dominant heritability (75%). Heterogeneity models revealed that there were no differences between the HTN and non-HTN subjects regarding the heritability of GLS. However, the heritability estimates of diastolic function parameters, including early diastolic strain rate, were low. LV systolic biomechanics is highly heritable. GLS shows dominant heritability, despite the presence of early-stage hypertensive heart disease. Early diastolic parameters are rather determined by environmental factors. These findings suggest the presence of a genetic framework that conserves systolic function despite the expression of diastolic dysfunction and may underlie the phenotypic progression towards heart failure with preserved ejection fraction.

Proposed Standardized Neurological Endpoints for Cardiovascular Clinical Trials: An Academic Research Consortium Initiative.

Surgical and catheter-based cardiovascular procedures and adjunctive pharmacology have an inherent risk of neurological complications. The current diversity of neurological endpoint definitions and ascertainment methods in clinical trials has led to uncertainties in the neurological risk attributable to cardiovascular procedures and inconsistent evaluation of therapies intended to prevent or mitigate neurological injury. Benefit-risk assessment of such procedures should be on the basis of an evaluation of well-defined neurological outcomes that are ascertained with consistent methods and capture the full spectrum of neurovascular injury and its clinical effect. The Neurologic Academic Research Consortium is an international collaboration intended to establish consensus on the definition, classification, and assessment of neurological endpoints applicable to clinical trials of a broad range of cardiovascular interventions. Systematic application of the proposed definitions and assessments will improve our ability to evaluate the risks of cardiovascular procedures and the safety and effectiveness of preventive therapies.

Discordant response of low-density lipoprotein cholesterol and lipoprotein(a) levels to monoclonal antibodies targeting proprotein convertase subtilisin/kexin type 9.

BACKGROUND: Clinical trials testing proprotein convertase subtilisin/kexin type 9 inhibitors (PCSK9i) have demonstrated an unanticipated but significant lipoprotein (a) (Lp(a))-lowering effect, on the order of 25% to 30%. Although the 50% to 60% reduction in low-density lipoprotein (LDL)-cholesterol (LDL-C) achieved by PCSK9i is mediated through its effect on LDL receptor (LDLR) preservation, the mechanism for Lp(a) lowering is unknown. OBJECTIVE: We sought to characterize the degree of concordance between LDL-C and Lp(a) lowering because of PCSK9i in a standard of care patient cohort. METHODS: Participants were selected from our Center for Preventive Cardiology, an outpatient referral center in a tertiary academic medical center. Subjects were included in this study if they had (1) at least 1 measurement of LDL-C and Lp(a) before and after initiation of the PCSK9i; (2) baseline Lp(a) > 10 mg/dL; and (3) continued adherence to PCSK9i therapy. They were excluded if (1) they were undergoing LDL apheresis; (2) pre- or post-PCSK9i LDL-C or Lp(a) laboratory values were censored; or (3) subjects discontinued other lipid-modifying therapies. In total, 103 subjects were identified as taking a PCSK9i and 26 met all inclusion and exclusion criteria. Concordant response to therapy was defined as an LDL-C reduction >35% and an Lp(a) reduction >10%. RESULTS: The cohort consisted of 26 subjects (15 females, 11 males, mean age 63 ± 12 years). Baseline mean LDL-C and median Lp(a) levels were 167.4 ± 72 mg/dL and 81 mg/dL (interquartile range 38-136 mg/dL), respectively. The average percent reductions in LDL-C and Lp(a) were 52.8% (47.0-58.6) and 20.2% (12.2-28.1). The correlation between %LDL and %Lp(a) reduction was moderate, with a Spearman's correlation of 0.56 (P < .01). All subjects except for 1 had a protocol-appropriate LDL-C response to therapy. However, only 16 of the 26 (62%; 95% confidence interval 41%-82%) subjects had a protocol-concordant Lp(a) response. Although some subjects demonstrated negligible Lp(a) reduction associated with PCSK9i, there were some whose Lp(a) decreased as much as 60%. CONCLUSIONS: In this standard-of-care setting, we demonstrate moderate correlation but large discordance (∼40%) in these 2 lipid fractions in response to PCSK9i. The results suggest that pathways beyond the LDLR are responsible for Lp(a) lowering and indicate that PCSK9i have the potential to significantly lower Lp(a) in select patients, although confirmation in larger multicenter studies is required.

Proposed Standardized Neurological Endpoints for Cardiovascular Clinical Trials: An Academic Research Consortium Initiative.

Surgical and catheter-based cardiovascular procedures and adjunctive pharmacology have an inherent risk of neurological complications. The current diversity of neurological endpoint definitions and ascertainment methods in clinical trials has led to uncertainties in the neurological risk attributable to cardiovascular procedures and inconsistent evaluation of therapies intended to prevent or mitigate neurological injury. Benefit-risk assessment of such procedures should be on the basis of an evaluation of well-defined neurological outcomes that are ascertained with consistent methods and capture the full spectrum of neurovascular injury and its clinical effect. The Neurologic Academic Research Consortium is an international collaboration intended to establish consensus on the definition, classification, and assessment of neurological endpoints applicable to clinical trials of a broad range of cardiovascular interventions. Systematic application of the proposed definitions and assessments will improve our ability to evaluate the risks of cardiovascular procedures and the safety and effectiveness of preventive therapies.

Aortic root dimensions are predominantly determined by genetic factors: a classical twin study.

OBJECTIVES: Previous studies using transthoracic echocardiography (TTE) observed moderate heritability of aortic root dimensions. Computed tomography angiography (CTA) might provide more accurate heritability estimates. Our primary aim was to assess the heritability of the aortic root with CTA. Our secondary aim was to derive TTE-based heritability and compare this with the CTA-based results. METHODS: In the BUDAPEST-GLOBAL study 198 twin subjects (118 monozygotic, 80 dizygotic; age 56.1 ± 9.4 years; 126 female) underwent CTA and TTE. We assessed the diameter of the left ventricular outflow tract (LVOT), annulus, sinus of Valsalva, sinotubular junction and ascending aorta. Heritability was assessed using ACDE model (A additive genetic, C common environmental, D dominant genetic, E unique environmental factors). RESULTS: Based on CTA, additive genetic effects were dominant (LVOT: A = 0.67, E = 0.33; annulus: A = 0.76, E = 0.24; sinus of Valsalva: A = 0.83, E = 0.17; sinotubular junction: A = 0.82, E = 0.18; ascending aorta: A = 0.75, E = 0.25). TTE-derived measurements showed moderate to no genetic influence (LVOT: A = 0.38, E = 0.62; annulus: C = 0.47, E = 0.53; sinus of Valsalva: C = 0.63, E = 0.37; sinotubular junction: C = 0.45, E = 0.55; ascending aorta: A = 0.67, E = 0.33). CONCLUSION: CTA-based assessment suggests that aortic root dimensions are predominantly determined by genetic factors. TTE-based measurements showed moderate to no genetic influence. The choice of measurement method has substantial impact on heritability estimates. KEY POINTS: • Aortic root dimensions are determined by genetic and environmental effects. • Transthoracic echocardiography (TTE) demonstrated moderate to no genetic effects on aortic root dimensions. • Computed tomography angiography might provide more accurate heritability estimates compared to TTE. • Three-dimensional imaging techniques are needed to reliably quantify aortic root dimensions.

Variation in PCSK9 and HMGCR and Risk of Cardiovascular Disease and Diabetes.

BACKGROUND: Pharmacologic inhibitors of proprotein convertase subtilisin-kexin type 9 (PCSK9) are being evaluated in clinical trials for the treatment of cardiovascular disease. The effect of lowering low-density lipoprotein (LDL) cholesterol levels by inhibiting PCSK9 on the risk of cardiovascular events or diabetes is unknown. METHODS: We used genetic scores consisting of independently inherited variants in the genes encoding PCSK9 and 3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMGCR; the target of statins) as instruments to randomly assign 112,772 participants from 14 studies, with 14,120 cardiovascular events and 10,635 cases of diabetes, to groups according to the number of LDL cholesterol-lowering alleles that they had inherited. We compared the effects of lower LDL cholesterol levels that were mediated by variants in PCSK9, HMGCR, or both on the risk of cardiovascular events and the risk of diabetes. RESULTS: Variants in PCSK9 and HMGCR were associated with nearly identical protective effects on the risk of cardiovascular events per decrease of 10 mg per deciliter (0.26 mmol per liter) in the LDL cholesterol level: odds ratio for cardiovascular events, 0.81 (95% confidence interval [CI], 0.74 to 0.89) for PCSK9 and 0.81 (95% CI, 0.72 to 0.90) for HMGCR. Variants in these two genes were also associated with very similar effects on the risk of diabetes: odds ratio for each 10 mg per deciliter decrease in LDL cholesterol, 1.11 (95% CI, 1.04 to 1.19) for PCSK9 and 1.13 (95% CI, 1.06 to 1.20) for HMGCR. The increased risk of diabetes was limited to persons with impaired fasting glucose levels for both scores and was lower in magnitude than the protective effect against cardiovascular events. When present together, PCSK9 and HMGCR variants had additive effects on the risk of both cardiovascular events and diabetes. CONCLUSIONS: In this study, variants in PCSK9 had approximately the same effect as variants in HMGCR on the risk of cardiovascular events and diabetes per unit decrease in the LDL cholesterol level. The effects of these variants were independent and additive. (Funded by the Medical Research Council and the National Heart, Lung, and Blood Institute.).

Neurologic Complications of Unprotected Transcatheter Aortic Valve Implantation (from the Neuro-TAVI Trial).

Cerebral embolization during transcatheter aortic valve implantation (TAVI) can lead to a spectrum of clinically relevant manifestations, ranging from overt stroke to mild neurologic or cognitive deficits and subclinical cerebral infarcts. This study sought to determine the frequency of neurologic injury, cerebral ischemic lesions, and cognitive dysfunction in subjects undergoing contemporary commercial TAVI in the United States. Neuro-TAVR is the first prospective, multicenter study to use serial systematic neurologic and cognitive assessments and diffusion-weighted magnetic resonance imaging (at 4 ± 2 days after procedure) to investigate the incidence and severity of neurologic injury after contemporary unprotected TAVI in the United States. A total of 44 consecutive patients underwent TAVI at 5 US sites. Diffusion-weighted magnetic resonance imaging lesions were detected in 94%, with a mean of 10.4 ± 15.3 lesions per subject and a median total lesion volume of 295 mm3 (interquartile range 71.6 to 799.6 mm3). New neurologic impairment (worsening in National Institutes of Health Stroke Scale score from baseline with new cerebral lesions) occurred in 22.6% (7 of 31) of subjects at discharge and 14.8% (4 of 27) at 30 days. In addition, cognitive decrements from baseline were identified by the Montreal Cognitive Assessment in 33% (12 of 36) of subjects at discharge and 41% (13 of 32) at 30 days. In conclusion, this contemporary cohort of US patients confirms that TAVI results in cerebral infarction in most patients and that 1 in 5 patients have measurable neurologic impairment and 1 in 3 patients have decrease in cognitive measures by Montreal Cognitive Assessment score after TAVI, reinforcing the need for methods to mitigate the risk of brain injury during TAVI.

Comparison of Quantity of Coronary Atherosclerotic Plaques Detected by Computed Tomography Versus Angiography.

Numerous clinical studies using coronary computed tomography angiography (CTA) and conventional invasive coronary angiography (ICA) confirmed the strong relation between atherosclerotic disease burden and risk of adverse events. Few studies have compared coronary CTA and ICA regarding semiquantitative plaque burden measurements, reproducibility, and cardiovascular risk assessment. We enrolled 71 consecutive patients (mean age 62 ± 9 years, 37% women) from the Genetic Loci and the Burden of Atherosclerotic Lesions study (NCT01738828), who underwent 256-slice multidetector row coronary CTA and ICA at a single site. On average, 42 ± 32 days passed between the 2 examinations. A total of 1,016 coronary segments were imaged by both CTA and ICA according the 18-segment Society of Cardiovascular Computed Tomography classification. We excluded 16 segments treated with coronary stents. Overall, 1,000 segments were evaluated for the presence of stenosis severity (<25%: minimal, 25% to 49%: mild, 50% to 70%: moderate, 70% to 99%: severe, 100%: occlusion). We calculated the segment involvement score (SIS) and segment stenosis score. Patients were classified into 4 groups: extensive obstructive (SIS >4 and ≥50% stenosis), extensive nonobstructive (SIS >4 and <50% stenosis), nonextensive obstructive (SIS ≤4 and ≥50% stenosis), or nonextensive nonobstructive (SIS ≤4 and <50% stenosis). CTA detected coronary artery plaques in 49%, whereas ICA showed coronary plaques in 24% of the analyzed 1,000 segments (p <0.001). CTA detected atherosclerotic plaque in 35% of coronary segments where ICA was negative, whereas ICA detected plaque only in 3% of segments where CTA was negative. CTA-based segment scores were significantly greater, SIS: 6.9 ± 3.0 versus 3.3 ± 2.0, segment stenosis score: 16.4 ± 8.8 versus 9.4 ± 6.8 (p <0.001 for both). In conclusion, coronary CTA detected approximately twice as many coronary segments with plaque compared to ICA, which resulted in 52% of the patients being assigned to a greater risk category.

Rationale, Design, and Methodological Aspects of the BUDAPEST-GLOBAL Study (Burden of Atherosclerotic Plaques Study in Twins-Genetic Loci and the Burden of Atherosclerotic Lesions).

The heritability of coronary atherosclerotic plaque burden, coronary geometry, and phenotypes associated with increased cardiometabolic risk are largely unknown. The primary aim of the Burden of Atherosclerotic Plaques Study in Twins-Genetic Loci and the Burden of Atherosclerotic Lesions (BUDAPEST-GLOBAL) study is to evaluate the influence of genetic and environmental factors on the burden of coronary artery disease. By design this is a prospective, single-center, classical twin study. In total, 202 twins (61 monozygotic pairs, 40 dizygotic same-sex pairs) were enrolled from the Hungarian Twin Registry database. All twins underwent non-contrast-enhanced computed tomography (CT) for the detection and quantification of coronary artery calcium and for the measurement of epicardial fat volumes. In addition, a single non-contrast-enhanced image slice was acquired at the level of L3-L4 to assess abdominal fat distribution. Coronary CT angiography was used for the detection and quantification of plaque, stenosis, and overall coronary artery disease burden. For the primary analysis, we will assess the presence and volume of atherosclerotic plaques. Furthermore, the 3-dimensional coronary geometry will be assessed based on the coronary CT angiography datasets. Additional phenotypic analyses will include per-patient epicardial and abdominal fat quantity measurements. Measurements obtained from monozygotic and dizygotic twin pairs will be compared to evaluate the genetic or environmental effects of the given phenotype. The BUDAPEST-GLOBAL study provides a unique framework to shed some light on the genetic and environmental influences of cardiometabolic disorders.

Coronary artery calcium: 0.5 mm slice-thickness reconstruction with adjusted attenuation threshold outperforms 3.0 mm by validating against spatially registered intravascular ultrasound with radiofrequency backscatter.

RATIONALE AND OBJECTIVES: Coronary artery calcium (CAC) images can be reconstructed with thinner slice thickness on some modern multidetector-row computed tomography scanners without additional radiation. We hypothesized that the isotropic 0.5-mm CAC reconstruction outperforms the conventional 3.0-mm reconstruction in detecting and quantifying coronary calcium, and we proposed to compare them by validating against spatially registered intravascular ultrasound with radiofrequency backscatter-virtual histology (IVUS-VH). MATERIALS AND METHODS: Twenty-seven patients were enrolled, and 5976 mm of coronary arteries were analyzed. A semiautomatic software was developed to coregister CAC and IVUS-VH on a detailed slice-by-slice basis. Calcium detection and calcium volume quantification were evaluated and compared using varying calcium attenuation thresholds. Algorithms for deriving individualized optimal threshold and comparable Agatston score on the 0.5-mm reconstruction were developed. RESULTS: The isotropic 0.5-mm reconstruction achieved significantly higher area under receiver-operating curve than the conventional 3.0-mm reconstruction (0.9 vs. 0.74, P < .001). Using the optimal threshold, the 0.5-mm reconstruction had higher sensitivity (0.79 vs. 0.65), specificity (0.85 vs. 0.77), positive predictive value (0.42 vs. 0.29), and negative predictive value (0.97 vs. 0.94) than the 3.0 mm. Individualized optimal threshold was significantly correlated with the image noise (r = 0.66, P < .001) in the 0.5-mm reconstruction. CONCLUSIONS: By optimizing the calcium threshold, the 0.5-mm reconstruction is superior to the conventional 3.0-mm in detecting and quantifying calcium, which may improve the clinical value of CAC without additional radiation.

Accuracy of intravascular ultrasound and optical coherence tomography in identifying functionally significant coronary stenosis according to vessel diameter: A meta-analysis of 2,581 patients and 2,807 lesions.

INTRODUCTION: Accuracy of intracoronary imaging to discriminate functionally significant coronary stenosis according to vessel diameter remains to be defined. METHODS: PubMed, Scopus, and Google Scholar were systematically searched for studies assessing diagnostic accuracy (area under the receiver operating characteristic curve [AUC], the primary end point) and sensitivity and specificity (the secondary end points) of minimal luminal area (MLA) or of minimal luminal diameter (MLD) derived from intravascular ultrasound (IVUS) or optical coherence tomography (OCT) to detect functionally significant stenosis as determined with fractional flow reserve (FFR). RESULTS: Fifteen studies were included, 2 with 110 patients analyzing only left main (LM), 5 with 224 patients and 306 lesions using OCT, and 9 with 1532 patients and 1681 lesions with IVUS. Median MLA for the OCT studies was 1.96 mm(2) (1.85-1.98 mm(2)), 2.9 mm(2) (2.7-3.1 mm(2)) for MLA of all lesions assessed with IVUS, 2.8 mm(2) (2.7-2.9 mm(2)) for lesions with an angiographic diameter >3 mm, 2.4 mm(2) (2.4-2.5 mm(2)) for lesions <3 mm, and 5.4 mm(2) (5.1-5.6 mm(2)) for LM lesions. For OCT-MLA, AUC was 0.80 (0.74-0.86), with a sensitivity of 0.81 (0.74-0.87) and specificity of 0.77 (0.71-0.83), whereas OCT-MLD had an AUC of 0.85 (0.79-0.91), sensitivity of 0.74 (0.69-0.78), and specificity of 0.70 (0.68-0.73). For IVUS-MLA, AUC was 0.78 (0.75-0.81) for all lesions, 0.78 (0.73-0.84) for vessels with a diameter >3 mm, and 0.79 (0.70-0.89) for those with a diameter <3 mm. Left main AUC was 0.97 (0.93-1). CONCLUSION: Intravascular ultrasound and OCT had modest diagnostic accuracy for identification hemodynamically significant lesions, also with specific cutoff for different diameters. Invasive imaging for assessment of LM severity demonstrated excellent correlation with FFR. What is already known about this subject? Fractional flow reserve represents the criterion standard to evaluate the prognostic value of coronary stenosis, whereas its relationship with IVUS and OCT remains to be assessed. What does this study add? Despite improvement, IVUS and OCT do not predict functional stenosis, even with dedicated cutoff, apart from LM disease. How might this impact on clinical practice? The recent guidelines of myocardial revascularization have stressed the crucial role of FFR before performing percutaneous coronary intervention on LM, whereas intravascular imaging is often exploited to drive revascularization. The present analysis stresses the point that LM percutaneous coronary intervention may be driven only by intravascular imaging, given the high accuracy for significant ischemic lesions, whereas for other vessels, these 2 techniques mirror 2 different aspects.