Constraining the Nuclear Symmetry Energy with Multimessenger Resonant Shattering Flares.

Much effort is devoted to measuring the nuclear symmetry energy through neutron star (NS) and nuclear observables. Since matter in the NS core may be nonhadronic, observables like radii and tidal deformability may not provide reliable constraints on properties of nucleonic matter. By performing the first consistent inference using ensembles of core and crust equations of state from astrophysical and nuclear data, we demonstrate that coincident timing of a resonant shattering flare (RSF) and gravitational wave signal during binary NS inspiral probes the crust-core transition region and provides constraints on the symmetry energy comparable to terrestrial nuclear experiments. We show that nuclear masses, RSFs, and measurements of NS radii and tidal deformabilities constrain different density ranges of the equation of state, providing complementary probes.

Basement membrane defects in CD151-associated glomerular disease.

BACKGROUND: CD151 is a cell-surface molecule of the tetraspanin family. Its lateral interaction with laminin-binding integrin ɑ3ß1 is important for podocyte adhesion to the glomerular basement membrane (GBM). Deletion of Cd151 in mice induces glomerular dysfunction, with proteinuria and associated focal glomerulosclerosis, disorganisation of GBM and tubular cystic dilation. Despite this, CD151 is not routinely screened for in patients with nephrotic-range proteinuria. We aimed to better understand the relevance of CD151 in human kidney disease. METHODS: Next-generation sequencing (NGS) was used to detect the variant in CD151. Electron and light microscopy were used to visualise the filtration barrier in the patient kidney biopsy, and immunoreactivity of patient red blood cells to anti-CD151/MER2 antibodies was performed. Further validation of the CD151 variant as disease-causing was performed in zebrafish using CRISPR-Cas9. RESULTS: We report a young child with nail dystrophy and persistent urinary tract infections who was incidentally found to have nephrotic-range proteinuria. Through targeted NGS, a novel, homozygous truncating variant was identified in CD151, a gene rarely reported in patients with nephrotic syndrome. Electron microscopy imaging of patient kidney tissue showed thickening of GBM and podocyte effacement. Immunofluorescence of patient kidney tissue demonstrated that CD151 was significantly reduced, and we did not detect immunoreactivity to CD151/MER2 on patient red blood cells. CRISPR-Cas9 depletion of cd151 in zebrafish caused proteinuria, which was rescued by injection of wild-type CD151 mRNA, but not CD151 mRNA containing the variant sequence. CONCLUSIONS: Our results indicate that a novel variant in CD151 is associated with nephrotic-range proteinuria and microscopic haematuria and provides further evidence for a role of CD151 in glomerular disease. Our work highlights a functional testing pipeline for future analysis of patient genetic variants. A higher resolution version of the Graphical abstract is available as Supplementary information.

Clinical comparison of sub-mm high-resolution non-contrast coronary CMR angiography against coronary CT angiography in patients with low-intermediate risk of coronary artery disease: a single center trial.

BACKGROUND: The widespread clinical application of coronary cardiovascular magnetic resonance (CMR) angiography (CMRA) for the assessment of coronary artery disease (CAD) remains limited due to low scan efficiency leading to prolonged and unpredictable acquisition times; low spatial-resolution; and residual respiratory motion artefacts resulting in limited image quality. To overcome these limitations, we have integrated highly undersampled acquisitions with image-based navigators and non-rigid motion correction to enable high resolution (sub-1 mm3) free-breathing, contrast-free 3D whole-heart coronary CMRA with 100% respiratory scan efficiency in a clinically feasible and predictable acquisition time. OBJECTIVES: To evaluate the diagnostic performance of this coronary CMRA framework against coronary computed tomography angiography (CTA) in patients with suspected CAD. METHODS: Consecutive patients (n = 50) with suspected CAD were examined on a 1.5T CMR scanner. We compared the diagnostic accuracy of coronary CMRA against coronary CTA for detecting a ≥ 50% reduction in luminal diameter. RESULTS: The 50 recruited patients (55 ± 9 years, 33 male) completed coronary CMRA in 10.7 ± 1.4 min. Twelve (24%) had significant CAD on coronary CTA. Coronary CMRA obtained diagnostic image quality in 95% of all, 97% of proximal, 97% of middle and 90% of distal coronary segments. The sensitivity, specificity, positive predictive value, negative predictive value and diagnostic accuracy were: per patient (100%, 74%, 55%, 100% and 80%), per vessel (81%, 88%, 46%, 97% and 88%) and per segment (76%, 95%, 44%, 99% and 94%) respectively. CONCLUSIONS: The high diagnostic image quality and diagnostic performance of coronary CMRA compared against coronary CTA demonstrates the potential of coronary CMRA as a robust and safe non-invasive alternative for excluding significant disease in patients at low-intermediate risk of CAD.

A role for OCRL in glomerular function and disease.

BACKGROUND: Lowe syndrome and Dent-2 disease are caused by mutations in the OCRL gene, which encodes for an inositol 5-phosphatase. The renal phenotype associated with OCRL mutations typically comprises a selective proximal tubulopathy, which can manifest as Fanconi syndrome in the most extreme cases. METHODS: Here, we report a 12-year-old male with nephrotic-range proteinuria and focal segmental glomerulosclerosis on renal biopsy. As a glomerular pathology was suspected, extensive investigation of tubular function was not performed. RESULTS: Surprisingly, whole exome sequencing identified a genetic variant in OCRL (c1467-2A>G) that introduced a novel splice mutation leading to skipping of exon 15. In situ hybridisation of adult human kidney tissue and zebrafish larvae showed OCRL expression in the glomerulus, supporting a role for OCRL in glomerular function. In cultured podocytes, we found that OCRL associated with the linker protein IPIP27A and CD2AP, a protein that is important for maintenance of the podocyte slit diaphragm. CONCLUSION: Taken together, this work suggests a previously under-appreciated role for OCRL in glomerular function and highlights the importance of investigating tubular function in patients with persistent proteinuria.

Genetic testing in steroid-resistant nephrotic syndrome: why, who, when and how?

Steroid-resistant nephrotic syndrome (SRNS) is a common cause of chronic kidney disease in childhood and has a significant risk of rapid progression to end-stage renal disease. The identification of over 50 monogenic causes of SRNS has revealed dysfunction in podocyte-associated proteins in the pathogenesis of proteinuria, highlighting their essential role in glomerular function. Recent technological advances in high-throughput sequencing have enabled indication-driven genetic panel testing for patients with SRNS. The availability of genetic testing, combined with the significant phenotypic variability of monogenic SRNS, poses unique challenges for clinicians when directing genetic testing. This highlights the need for clear clinical guidelines that provide a systematic approach for mutational screening in SRNS. The likelihood of identifying a causative mutation is inversely related to age at disease onset and is increased with a positive family history or the presence of extra-renal manifestations. An unequivocal molecular diagnosis could allow for a personalised treatment approach with weaning of immunosuppressive therapy, avoidance of renal biopsy and provision of accurate, well-informed genetic counselling. Identification of novel causative mutations will continue to unravel the pathogenic mechanisms of glomerular disease and provide new insights into podocyte biology and glomerular function.

Diagnosis and management of iatrogenic cardiac perforation caused by pacemaker and defibrillator leads.

AIMS: Cardiac perforations caused by pacemaker or implantable cardioverter-defibrillator (ICD) leads are uncommon but potentially fatal events. The optimal approach to such cases is unclear. The aim of this study was to identify the optimal imaging modality and management strategy for cardiac perforation. METHODS AND RESULTS: All patients presenting to a single institution with cardiac perforation >24 h since implant between 2011 and 2015 were identified retrospectively. Assessment of the diagnostic performance of pre-extraction chest radiography, transthoracic echocardiography (TTE), and computed tomography (CT) was carried out by blinded review. The method of lead extraction and any associated complications were examined. Eighteen cases of cardiac perforation were identified from 426 lead extraction procedures. Sixteen patients had abnormal electrical parameters at device interrogation. In all cases, the perforating lead was an active fixation model, and in four cases, this was an ICD coil. The accuracy of CT imaging for the diagnosis of cardiac perforation was 92.9%, with sensitivity and specificity of 100 and 85.7%, respectively. This was superior to both TTE (accuracy 62.7%, sensitivity and specificity 41.2 and 84.2%, respectively) and chest radiography (accuracy 61.1%, sensitivity and specificity 27.7 and 94.4%, respectively). Transvenous lead extraction (TLE) was performed in 17 patients, and a hybrid surgical approach in 1 patient. Of those who underwent TLE, there was 100% complete procedural success as per Heart Rhythm Society definitions. CONCLUSION: In the setting of cardiac perforation, CT is the imaging modality of choice. Transvenous lead extraction can be recommended as a safe, efficacious, and versatile intervention.

An insight into transcatheter aortic valve implantation-a perspective from multidetector-computed tomography.

Transcatheter aortic valve implantation (TAVI) has now become an acceptable alternative to surgical aortic valve replacement for patients with severe aortic stenosis at high risk. The early enthusiasm for this technology has not diminished but rather has developed at an unprecedented rate over the last decade. Alongside the developments in implantation technique, transcatheter design, and postprocedural care, cardiac imaging modalities have also had to concurrently evolve to meet the perpetual demand for lower peri- and postprocedural complication rates. Although transthoracic and transesophageal echocardiography remain vital in patient's selection and periprocedural guidance, there is now emerging evidence that indicates that multidetector-computed tomography (MDCT) may also have an equally important role to play. The aim of the current review is to examine the modern role of MDCT in assessing patients with aortic stenosis being considered for TAVI.

The dynamic kidney matrisome - is the circadian clock in control?

The circadian clock network in mammals is responsible for the temporal coordination of numerous physiological processes that are necessary for homeostasis. Peripheral tissues demonstrate circadian rhythmicity and dysfunction of core clock components has been implicated in the pathogenesis of diseases that are characterized by abnormal extracellular matrix, such as fibrosis (too much disorganized matrix) and tissue breakdown (too little matrix). Kidney disease is characterized by proteinuria, which along with the rate of filtration, displays robust circadian oscillation. Clinical observation and mouse studies suggest the presence of 24 h kidney clocks responsible for circadian oscillation in kidney function. Recent experimental evidence has also revealed that cell-matrix interactions and the biomechanical properties of extracellular matrix have key roles in regulating peripheral circadian clocks and this mechanism appears to be cell- and tissue-type specific. Thus, establishing a temporally resolved kidney matrisome may provide a useful tool for studying the two-way interactions between the extracellular matrix and the intracellular time-keeping mechanisms in this critical niche tissue. This review summarizes the latest genetic and biochemical evidence linking kidney physiology and disease to the circadian system with a particular focus on the extracellular matrix. We also review the experimental approaches and methodologies required to dissect the roles of circadian pathways in specific tissues and outline the translational aspects of circadian biology, including how circadian medicine could be used for the treatment of kidney disease.

Multimodality Imaging in Valvular Structural Interventions.

Structural valvular interventions have skyrocketed in the past decade with new devices becoming available and indications for patients who would previously have been deemed inoperable. Furthermore, while echocardiography is the main imaging tool and the first line for patient screening, cardiac magnetic resonance and CT are now essential tools in pre-planning and post-procedural follow-up. This review aims to address imaging modalities and their scope in aortic, mitral and tricuspid structural valvular interventions, including multimodality imaging. Pulmonary valve procedures, which are mostly carried out in patients with congenital problems, are discussed. This article presents a guide on individualised imaging approcahes on each of the available interventional procedures.

Prospective RandOmised Trial of Emergency Cardiac Computerised Tomography (PROTECCT).

OBJECTIVE: Many patients presenting with suspected acute coronary syndrome (ACS) have high-sensitivity cardiac troponin (hs-cTn) concentrations between rule-in and rule-out thresholds and hence need serial testing, which is time consuming. The Prospective RandOmised Trial of Emergency Cardiac Computerised Tomography (PROTECCT) assessed the utility of coronary CT angiography (CCTA) in patients with suspected ACS, non-ischaemic ECG and intermediate initial hs-cTn concentration. METHODS: Patients were randomised to CCTA-guided management versus standard of care (SOC). The primary outcome was hospital length of stay (LOS). Secondary outcomes included cost of in-hospital stay and major adverse cardiac events (MACE) at 12 months of follow-up. Data are mean (SD); for LOS harmonic means, IQRs are shown. RESULTS: 250 (aged 55 (14) years, 25% women) patients were randomised. Harmonic mean (IQR) LOS was 7.53 (6.0-9.6) hours in the CCTA arm and 8.14 (6.3-9.8) hours in the SOC arm (p=0.13). Inpatient cost was £1285 (£2216) and £1108 (£3573), respectively, p=0.68. LOS was shorter in the CCTA group in patients with <25% stenosis, compared with SOC; 6.6 (5.6-7.8) hours vs 7.5 (6.1-9.4) hours, respectively; p=0.021. More referrals for cardiology outpatient clinic review and cardiac CT-related outpatient referrals occurred in the SOC arm (p=0.01). 12-month MACE rates were similar between the two arms (7 (5.6%) in the CCTA arm and 8 (6.5%) in the SOC arm-log-rank p=0.78). CONCLUSIONS: CCTA did not lead to reduced hospital LOS or cost, largely because these outcomes were influenced by the detection of ≥25% grade stenosis in a proportion of patients. TRIAL REGISTRATION NUMBER: NCT03583320.

Multimodal Imaging for Diagnosis of Anomalous Coronary Artery With Subsequent Myocardial Infarction.

Chest pain in young adults is not always benign, and clinical suspicion should prompt further investigations. Multimodal imaging with computed tomography coronary angiography and cardiovascular magnetic resonance can be used to identify anomalous coronary arteries, determine adverse imaging features, and guide subsequent clinical decision making. (Level of Difficulty: Beginner.).

Persistent Post-COVID-19 Interstitial Lung Disease. An Observational Study of Corticosteroid Treatment.

Rationale: The natural history of recovery from severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) remains unknown. Because fibrosis with persistent physiological deficit is a previously described feature of patients recovering from similar coronaviruses, treatment represents an early opportunity to modify the disease course, potentially preventing irreversible impairment.Objectives: Determine the incidence of and describe the progression of persistent inflammatory interstitial lung disease (ILD) following SARS-CoV-2 when treated with prednisolone.Methods: A structured assessment protocol screened for sequelae of SARS-CoV-2 pneumonitis. Eight hundred thirty-seven patients were assessed by telephone 4 weeks after discharge. Those with ongoing symptoms had outpatient assessment at 6 weeks. Thirty patients diagnosed with persistent interstitial lung changes at a multidisciplinary team meeting were reviewed in the interstitial lung disease service and offered treatment. These patients had persistent, nonimproving symptoms.Results: At 4 weeks after discharge, 39% of patients reported ongoing symptoms (325/837) and were assessed. Interstitial lung disease, predominantly organizing pneumonia, with significant functional deficit was observed in 35/837 survivors (4.8%). Thirty of these patients received steroid treatment, resulting in a mean relative increase in transfer factor following treatment of 31.6% (standard deviation [SD] ± 27.6, P < 0.001), and forced vital capacity of 9.6% (SD ± 13.0, P = 0.014), with significant symptomatic and radiological improvement.Conclusions: Following SARS-CoV-2 pneumonitis, a cohort of patients are left with both radiological inflammatory lung disease and persistent physiological and functional deficit. Early treatment with corticosteroids was well tolerated and associated with rapid and significant improvement. These preliminary data should inform further study into the natural history and potential treatment for patients with persistent inflammatory ILD following SARS-CoV-2 infection.

Coagulation derangement and risk factors for valve thrombosis following transcatheter aortic valve implantation.

AIMS: Durability of transcatheter aortic valve implantation (TAVI) is key to its expansion. We sought to identify incidence of valve thrombosis and predictors of valve thrombosis in our single centre with associated coagulation testing pre-TAVI and post-TAVI. METHODS AND RESULTS: This single-centre observational study comprised patients undergoing transfemoral TAVI discussed in the Heart Team meeting . Patients were followed up with echocardiography at 120 days to identify incidence of elevated transvalvular gradient and multivariable analysis was performed to identify factors associated with an increased odds of developing valve thrombosis. In addition, 11 patients underwent baseline, day 1 and day 120 post-TAVI coagulation testing. Between August 2017 and August 2019, 437 consecutive patients underwent transfemoral TAVI. Of these patients, 207/437 (47.4%) had 3-month follow-up echo data available and were analysed. Of these patients, 26/207 (12.6%) had elevated transvalvular gradients. These patients tended to be younger (80±14 vs 83±6 years; p=0.047) with a lower ejection fraction (49±13 vs 54%±11%; p=0.021), with a greater proportion of the population experiencing atrial fibrillation (14/21, 54% vs 68/181, 38%; p=0.067). Following multivariable analysis, there remained a trend towards higher eccentricity index associated with elevated gradients. Baseline (pre-TAVI) elevation of thrombin antithrombin levels (56±63; reference range 1.0-4.1 ng/L) and PF 1+2 (791±632; reference range 69-229 ng/mL) normalised at 120 days post-TAVI CONCLUSION: This study demonstrated that in the cohort of patients undergoing transfemoral TAVI in our centre: younger age, poor ejection fraction, atrial fibrillation and increased baseline eccentricity of the aortic valve annulus were present to a greater extent in patients exhibiting elevated transvalvular gradients at 3-month follow-up. Further work is required to delineate the extent of coagulation derangement and confirm predictors of thrombosis.

Emerging role of cardiac computed tomography in heart failure.

Despite medical advancements, the prognosis of patients with heart failure remains poor. While echocardiography and cardiac magnetic resonance imaging remain at the forefront of diagnosing and monitoring patients with heart failure, cardiac computed tomography (CT) has largely been considered to have a limited role. With the advancements in scanner design, technology, and computer processing power, cardiac CT is now emerging as a valuable adjunct to clinicians managing patients with heart failure. In the current manuscript, we review the current applications of cardiac CT to patients with heart failure and also the emerging areas of research where its clinical utility is likely to extend into the realm of treatment, procedural planning, and advanced heart failure therapy implementation.

Automated quantification of mitral valve geometry on multi-slice computed tomography in patients with dilated cardiomyopathy - Implications for transcatheter mitral valve replacement.

OBJECTIVES: The primary aim of this study was to quantify the dimensions and geometry of the mitral valve complex in patients with dilated cardiomyopathy and significant mitral regurgitation. The secondary aim was to evaluate the validity of an automated segmentation algorithm for assessment of the mitral valve compared to manual assessment on computed tomography. BACKGROUND: Transcatheter mitral valve replacement (TMVR) is an evolving technique which relies heavily on the lengthy evaluation of cardiac computed tomography (CT) datasets. Limited data is available on the dimensions and geometry of the mitral valve in pathological states throughout the cardiac cycle, which may have implications for TMVR device design, screening of suitable candidates and annular sizing prior to TMVR. METHODS: A retrospective study of 15 of patients with dilated cardiomyopathy who had undergone full multiphase ECG gated cardiac CT. A comprehensive evaluation of mitral valve geometry was performed at 10 phases of the cardiac cycle using the recommended D-shaped mitral valve annulus (MA) segmentation model using manual and automated CT interpretation platforms. Mitral annular dimensions and geometries were compared between manual and automated methods. RESULTS: Mitral valve dimensions in patients with dilated cardiomyopathy were similar to previously reported values (MAarea Diastole: 12.22 ±â€¯1.90 cm2), with dynamic changes in size and geometry between systole and diastole of up to 5%. The distance from the centre of the MA to the left ventricular apex demonstrated moderate agreement between automated and manual methods (ρc = 0.90) with other measurements demonstrating poor agreement between the two methods (ρc = 0.75-0.86). CONCLUSIONS: Variability of mitral valve annulus measurements are small during the cardiac cycle. Novel automated algorithms to determine cardiac cycle variations in mitral valve geometry may offer improved segmentation accuracy as well as improved CT interpretation times.

Comprehensive use of cardiac computed tomography to guide left ventricular lead placement in cardiac resynchronization therapy.

BACKGROUND: Optimal lead positioning is an important determinant of cardiac resynchronization therapy (CRT) response. OBJECTIVE: The purpose of this study was to evaluate cardiac computed tomography (CT) selection of the optimal epicardial vein for left ventricular (LV) lead placement by targeting regions of late mechanical activation and avoiding myocardial scar. METHODS: Eighteen patients undergoing CRT upgrade with existing pacing systems underwent preimplant electrocardiogram-gated cardiac CT to assess wall thickness, hypoperfusion, late mechanical activation, and regions of myocardial scar by the derivation of the stretch quantifier for endocardial engraved zones (SQUEEZ) algorithm. Cardiac venous anatomy was mapped to individualized American Heart Association (AHA) bull's-eye plots to identify the optimal venous target and compared with acute hemodynamic response (AHR) in each coronary venous target using an LV pressure wire. RESULTS: Fifteen data sets were evaluable. CT-SQUEEZ-derived targets produced a similar mean AHR compared with the best achievable AHR (20.4% ± 13.7% vs 24.9% ± 11.1%; P = .36). SQUEEZ-derived guidance produced a positive AHR in 92% of target segments, and pacing in a CT-SQUEEZ target vein produced a greater clinical response rate vs nontarget segments (90% vs 60%). CONCLUSION: Preprocedural CT-SQUEEZ-derived target selection may be a valuable tool to predict the optimal venous site for LV lead placement in patients undergoing CRT upgrade.

Comparative efficacy testing - fractional flow reserve by coronary computed tomography for the evaluation of patients with stable chest pain.

BACKGROUND: To evaluate diagnostic strategies in a rapid access chest pain clinic (RACPC) in the United Kingdom and to predict the economical and clinical impacts of incorporating fractional flow reserve by coronary computed tomographic angiography (FFRCT) into future pathways. METHODS: A retrospective analysis of consecutive patients referred to a RACPC in the United Kingdom. All patients had an evaluation of cardiovascular risk factors and symptoms from which the pre-test likelihood (PTL) of coronary artery disease (CAD) was evaluated using the Diamond Forrester (DF) criteria. All investigative strategies and their results were recorded. For the FFRCT economic evaluation of 1000 patients, standard National Health Service Tariffs were then applied and compared with a strategy that utilised FFRCT for varying PTL categories. RESULTS: There were 410 patients with a median age of 57 (31-85) years. The DF criteria classified 39 (9.5%) patients as having a PTL of <10%, 76 (18.5%) 10-29% PTL, 117 (28.5%) 30-60% PTL, 114 (27.8%) 60-90% PTL and 64 (15.6%) >90% PTL. The concordance with the NICE recommended guidelines was <50% with the prevalence of obstructive CAD being <5% in patients with a PTL <90%. A model utilising FFRCT for patients with a PTL 10-90% predicted a 48% and 49% reduction in invasive angiography and percutaneous coronary intervention, a saving of £200 per patient and a reduction in relative adverse event rates of 4%. CONCLUSIONS: The DF algorithm overestimates the PTL of CAD supporting an extended role for coronary CTA. Strategies incorporating FFRCT may confer benefits in evaluating patients with stable chest pain.

Multimodality imaging of subclinical aortic atherosclerosis: relation of aortic stiffness to calcification and plaque in female twins.

Aortic stiffness, an important predictor of cardiovascular events, may relate to aortic calcification rather than noncalcified atherosclerotic plaque. The aim of this study was to determine the relation of aortic stiffness to aortic plaque and aortic calcification in asymptomatic postmenopausal women. One hundred female twins (mean age±standard deviation 64±7 years) underwent computed tomography and magnetic resonance imaging (black-blood sequence) of the aorta. The topographical relation of plaque on magnetic resonance images and calcification on computed tomography images was assessed on magnetic resonance/computed tomography fused images. Carotid-femoral pulse wave velocity was used as a measure of aortic stiffness. Aortic plaque was identified in 87% and calcification in 65% of subjects, both increased with age and were higher in the abdominal compared with thoracic aorta (P<0.0001). Plaque correlated with calcification (R=0.68; P<0.0001), but was also detected in 58% of women who had no calcification. Pulse wave velocity (adjusted for age and blood pressure) increased across quartiles of calcification (P<0.01) but not plaque score (P=0.56). Shared genetic factors accounted for >99% of the correlation (0.35) between PWV and calcification. In conclusion, there is a high prevalence of subclinical atherosclerosis within the aorta in asymptomatic middle-aged women. Aortic stiffening relates to aortic calcification, but not to atherosclerotic plaque burden, and the association of aortic stiffness with calcification is driven by common genes.

Effectiveness of alternative strategies to define index case phenotypes to aid genetic diagnosis of familial hypercholesterolaemia.

OBJECTIVE: To determine the utility of secondary stratification measures to improve the ascertainment of index cases of familial hypercholesterolaemia (FH). DESIGN: A retrospective study of genotyped index patients with Simon Broome (SB) FH. SETTING: University teaching hospital. PATIENTS: 204 patients aged 55±14 years; 36% had tendon xanthoma (TX), 21% had coronary heart disease (CHD), low-density lipoprotein cholesterol (LDL-C) was 6.20±2.24 mmol/l and 55% had genetic FH. INTERVENTIONS: The effects of different staging systems (SB vs Dutch criteria), presence of TX, use of LDL-C level, personal history of CHD and imaging evidence of atheroma by carotid intima-media thickness or coronary artery calcium score to identify genetic FH was explored. OUTCOME MEASURES: Changes in C-statistic and net reclassification index (NRI). RESULTS: SB criteria gave a C-statistic of 0.64 comprising C=0.65 in TX(+) and C=0.5 in TX(-) patients. Genetic FH was present in 75% of TX(+) compared with 44% in TX(-) patients. The Dutch criteria gave C=0.72. Addition of imaging criteria to prior CHD raised C=0.64 to C=0.65 in all patients with a NRI of 19% (p=0.06). In TX(-) patients imaging raised C=0.50 to C=0.65 with a NRI of 0.38 (p=0.001) and a weighted comparison index of 0.28, implying the detection of 14 more FH cases per thousand. CONCLUSIONS: Patients with tendon xanthoma (definite FH) should be genotyped. In patients with possible FH, the presence of a personal history of CHD or imaging evidence of increased atheroma offers the best method of identifying index patients likely to have monogenic FH.