Angiotensin receptor blockers and ß blockers in Marfan syndrome: an individual patient data meta-analysis of randomised trials.

BACKGROUND: Angiotensin receptor blockers (ARBs) and ß blockers are widely used in the treatment of Marfan syndrome to try to reduce the rate of progressive aortic root enlargement characteristic of this condition, but their separate and joint effects are uncertain. We aimed to determine these effects in a collaborative individual patient data meta-analysis of randomised trials of these treatments. METHODS: In this meta-analysis, we identified relevant trials of patients with Marfan syndrome by systematically searching MEDLINE, Embase, and CENTRAL from database inception to Nov 2, 2021. Trials were eligible if they involved a randomised comparison of an ARB versus control or an ARB versus ß blocker. We used individual patient data from patients with no prior aortic surgery to estimate the effects of: ARB versus control (placebo or open control); ARB versus ß blocker; and indirectly, ß blocker versus control. The primary endpoint was the annual rate of change of body surface area-adjusted aortic root dimension Z score, measured at the sinuses of Valsalva. FINDINGS: We identified ten potentially eligible trials including 1836 patients from our search, from which seven trials and 1442 patients were eligible for inclusion in our main analyses. Four trials involving 676 eligible participants compared ARB with control. During a median follow-up of 3 years, allocation to ARB approximately halved the annual rate of change in the aortic root Z score (mean annual increase 0·07 [SE 0·02] ARB vs 0·13 [SE 0·02] control; absolute difference -0·07 [95% CI -0·12 to -0·01]; p=0·012). Prespecified secondary subgroup analyses showed that the effects of ARB were particularly large in those with pathogenic variants in fibrillin-1, compared with those without such variants (heterogeneity p=0·0050), and there was no evidence to suggest that the effect of ARB varied with ß-blocker use (heterogeneity p=0·54). Three trials involving 766 eligible participants compared ARBs with ß blockers. During a median follow-up of 3 years, the annual change in the aortic root Z score was similar in the two groups (annual increase -0·08 [SE 0·03] in ARB groups vs -0·11 [SE 0·02] in ß-blocker groups; absolute difference 0·03 [95% CI -0·05 to 0·10]; p=0·48). Thus, indirectly, the difference in the annual change in the aortic root Z score between ß blockers and control was -0·09 (95% CI -0·18 to 0·00; p=0·042). INTERPRETATION: In people with Marfan syndrome and no previous aortic surgery, ARBs reduced the rate of increase of the aortic root Z score by about one half, including among those taking a ß blocker. The effects of ß blockers were similar to those of ARBs. Assuming additivity, combination therapy with both ARBs and ß blockers from the time of diagnosis would provide even greater reductions in the rate of aortic enlargement than either treatment alone, which, if maintained over a number of years, would be expected to lead to a delay in the need for aortic surgery. FUNDING: Marfan Foundation, the Oxford British Heart Foundation Centre for Research Excellence, and the UK Medical Research Council.

Unsuspected somatic mosaicism for FBN1 gene contributes to Marfan syndrome.

PURPOSE: Individuals with mosaic pathogenic variants in the FBN1 gene are mainly described in the course of familial screening. In the literature, almost all these mosaic individuals are asymptomatic. In this study, we report the experience of our team on more than 5,000 Marfan syndrome (MFS) probands. METHODS: Next-generation sequencing (NGS) capture technology allowed us to identify five cases of MFS probands who harbored a mosaic pathogenic variant in the FBN1 gene. RESULTS: These five sporadic mosaic probands displayed classical features usually seen in Marfan syndrome. Combined with the results of the literature, these rare findings concerned both single-nucleotide variants and copy-number variations. CONCLUSION: This underestimated finding should not be overlooked in the molecular diagnosis of MFS patients and warrants an adaptation of the parameters used in bioinformatics analyses. The five present cases of symptomatic MFS probands harboring a mosaic FBN1 pathogenic variant reinforce the fact that apparently asymptomatic mosaic parents should have a complete clinical examination and a regular cardiovascular follow-up. We advise that individuals with a typical MFS for whom no single-nucleotide pathogenic variant or exon deletion/duplication was identified should be tested by NGS capture panel with an adapted variant calling analysis.

Clinical relevance of genotype-phenotype correlations beyond vascular events in a cohort study of 1500 Marfan syndrome patients with FBN1 pathogenic variants.

PURPOSE: Marfan syndrome (MFS) is a connective tissue disorder in which several systems are affected with great phenotypic variability. Although known to be associated with pathogenic variants in the FBN1 gene, few genotype-phenotype correlations have been found in proband studies only. METHODS: In 1,575 consecutive MFS probands and relatives from the most comprehensive database worldwide, we established survival curves and sought genotype-phenotype correlations. RESULTS: A risk chart could be established with clinical and genetic data. Premature termination codon variants were not only associated with a shorter life expectancy and a high lifelong risk of aortic event, but also with the highest risk of severe scoliosis and a lower risk for ectopia lentis (EL) surgery. In-frame variants could be subdivided according to their impact on the cysteine content of fibrillin-1 with a global higher severity for cysteine loss variants and the highest frequency of EL surgery for cysteine addition variants. CONCLUSION: This study shows that FBN1 genotype-phenotype correlations exist for both aortic and extra-aortic features. It can be used for optimal risk stratification of patients with a great importance for genetic counseling and personalized medicine. This also provides additional data for the overall understanding of the role of fibrillin-1 in various organs.

Pathogenic variants in THSD4, encoding the ADAMTS-like 6 protein, predispose to inherited thoracic aortic aneurysm.

PURPOSE: Thoracic aortic aneurysm and dissection (TAAD) is a life-threatening disease with often unrecognized inherited forms. We sought to identify novel pathogenic variants associated with autosomal dominant inheritance of TAAD. METHODS: We analyzed exome sequencing data from 35 French TAAD families and performed next-generation sequencing capture panel of genes in 1114 unrelated TAAD patients. Functional effects of pathogenic variants identified were validated in cell, tissue, and mouse models. RESULTS: We identified five functional variants in THSD4 of which two heterozygous variants lead to a premature termination codon. THSD4 encodes ADAMTSL6 (member of the ADAMTS/L superfamily), a microfibril-associated protein that promotes fibrillin-1 matrix assembly. The THSD4 variants studied lead to haploinsufficiency or impaired assembly of fibrillin-1 microfibrils. Thsd4+/- mice showed progressive dilation of the thoracic aorta. Histologic examination of aortic samples from a patient carrying a THSD4 variant and from Thsd4+/- mice, revealed typical medial degeneration and diffuse disruption of extracellular matrix. CONCLUSION: These findings highlight the role of ADAMTSL6 in aortic physiology and TAAD pathogenesis. They will improve TAAD management and help develop new targeted therapies.

Staged hybrid repair of type II thoracoabdominal aneurysms.

BACKGROUND: Open repair of type II thoracoabdominal aortic aneurysms (TAAAs) remains a challenging procedure. Staged procedures could decrease the incidence and severity of complications after complex aortic repair. In the present report, we have described a strategy using thoracic endovascular aortic repair (TEVAR) for proximal repair, followed by distal open repair. METHODS: From 2014 to 2018, 14 patients had undergone TEVAR, followed by distal open repair, for type II TAAAs. All patients should have a suitable proximal landing zone according to the current guidelines. In cases of chronic dissection, false lumen embolization was performed to achieve total exclusion. RESULTS: The mean patient age was 48 ± 15 years. Of the 14 patients, 5 had had Marfan syndrome (36%) and 6 had undergone previous aortic arch repair (43%). Ten patients had had a chronic dissection. The maximal aortic diameter was 73 ± 12 mm. The TEVAR technical success rate was 100%. The aortic length coverage was 211 ± 63 mm. The number of covered segmental arteries was 6 (range, 4-13). Two endoleaks were observed, one type Ib and one type II. The delay between TEVAR and open repair was 12 ± 8 weeks. Cerebrospinal fluid drainage was used in 13 patients. Six patients had undergone segmental artery reattachment during surgery. No spinal cord ischemic event was observed. One patient had died 5 weeks after open repair of multiple organ failure. During the 32 months of follow-up, no aortic-related deaths had occurred. No new aortic procedure was needed. The type Ib endoleak had resolved during open repair, and the type II TAAA had resolved spontaneously. The mean maximal thoracic aortic diameter had significantly decreased to 49 ± 8 mm (P < .0001). Aneurysmal shrinkage of ≥5 mm was observed in 13 patients (93%). CONCLUSIONS: Staged hybrid repair of type II TAAAs appears to be efficient, with low morbidity and mortality rates. This technique could improve postoperative outcomes after open repair, and TEVAR might have a role in ischemic preconditioning to protect against spinal cord ischemia.

Cardiovascular Magnetic Resonance May Avoid Unnecessary Coronary Angiography in Patients With Unexplained Left Ventricular Systolic Dysfunction: A Retrospective Diagnostic Pilot Study.

BACKGROUND: Coronary angiography (CA) is usually performed in patients with reduced left ventricular ejection fraction (LVEF) to search ischemic cardiomyopathy. Our aim was to examine the agreement between CA and cardiovascular magnetic resonance (CMR) imaging among a cohort of patients with unexplained reduced LVEF, and estimate what would have been the consequences of using CMR imaging as the first-line examination. METHODS: Three hundred five patients with unexplained reduced LVEF of ≤45% who underwent both CA and CMR imaging were retrospectively registered. Patients were classified as CMR+ or CMR- according to presence or absence of myocardial ischemic scar, and classified CA+ or CA- according to presence or absence of significant coronary artery disease. RESULTS: CMR+ (n = 89) included all 54 CA+ patients, except 2 with distal coronary artery disease in whom no revascularization was proposed. Among the 247 CA- patients, 15% were CMR+. CMR imaging had 96% sensitivity, 85% specificity, 99% negative predictive value, and 58% positive predictive value for detecting CA+ patients. Revascularization was performed in 6.5% of the patients (all CMR+). Performing CA only for CMR+ patients would have decreased the number of CAs by 71%. CONCLUSIONS: In reduced LVEF, performing CA only in CMR+ patients may significantly decrease the number of unnecessary CAs performed, without missing any patients requiring revascularization.

Genetic diversity and pathogenic variants as possible predictors of severity in a French sample of nonsyndromic heritable thoracic aortic aneurysms and dissections (nshTAAD).

PURPOSE: Heritable thoracic aortic aneurysms and dissections (hTAAD) are life-threatening complications of well-known syndromic diseases or underdiagnosed nonsyndromic heritable forms (nshTAAD). Both have an autosomal dominant transmission and are genetically heterogeneous. Our objective was to describe the relevance of molecular diagnosis in these patients and the contribution of each gene in nshTAAD. METHODS: Two hundred twenty-six consecutive nshTAAD probands, either young (<45 years) sporadic or familial cases were included. A next-generation sequencing capture panel comprising 23 known disease-causing genes was performed. RESULTS: Class 4 or 5 variants were identified in 18% of the nshTAAD probands, while class 3 variants were found in 10% of them. The yield in familial cases was greater than in sporadic cases. SMAD3 and FBN1 genes were the major disease-causing genes. Unexpectedly, no premature termination codon variant was identified in the FBN1 gene. Furthermore, we report for the first time that aortic dissection or surgery occurred significantly more often and earlier in probands with a class 4 or 5 pathogenic variant. CONCLUSION: This study indicates that genetic screening using NGS is efficient in young and familial nshTAAD. The presence of a pathogenic variant has a possible predictive value, which needs to be further investigated because it may influence care.

False lumen embolization in chronic aortic dissection promotes thoracic aortic remodeling at midterm follow-up.

OBJECTIVE: Failure of thoracic endovascular aortic repair (TEVAR) in chronic aortic dissections can be partially explained by retrograde false lumen (FL) flow through distal re-entry tears. After implantation of a thoracic stent graft, FL thrombosis occurs in less than 50% of the cases. The objectives of this study were to describe the feasibility and outcomes of FL embolization in patients with chronic aortic dissections. METHODS: Between June 2015 and January 2018, 27 patients (mean age, 61 ± 14 years) with chronic aortic dissection underwent FL embolization as an adjunct during or after TEVAR placement procedure. Indications for embolization were (1) symptomatic chronic aortic dissections with pain or rapid growth of aortic diameter (≥5 mm/y) requiring rapid exclusion of the aneurysm, (2) aneurysmal dilatation with persistent FL retrograde flow after TEVAR, and (3) large FL aneurysms (≥55 mm) that might lead to persistent retrograde flow. Twenty patients presented with type B chronic aortic dissections (74.1%) and seven presented a residual type A chronic aortic dissections (25.9%). Eight patients had a previous aortic arch replacement (29.6%). Six patients had previous repair with TEVAR (22.2%). The delay between the onset of dissection and the first endovascular repair was 47 months (range, 3-144). Spinal fluid drainage was used in 74.1% of cases (20/27 patients). Embolization devices included coils and vascular plugs. RESULTS: The technical success rate was 100% (27/27). Complete spinal cord ischemia was observed in one patient (3.7%). There was one hospital death from pneumonia after zone 1 supra-aortic trunk debranching with TEVAR and embolization. After the index procedure, FL thrombosis was observed in 81.5% of patients (22/27) on late phase computed tomography angiography. Five patients required two or more embolization procedures, leading to a high rate of complete FL thrombosis (92.6%). One patient presented a type IB endoleak and one patient presented a type II endoleak. Radiologic follow-up was 20 ± 10 months. The maximum thoracic aortic diameter significantly decreased from 63 mm to 54 ± 10 mm (P < .001). CONCLUSIONS: Embolization of the FL of chronic aortic dissections is technically feasible with a low morbidity rate. The FL thrombosis is observed in the majority of case and promotes favorable thoracic aortic remodeling. Longer follow-up is needed to confirm these good results on the thoracic aorta and this technique may, therefore, improve the results of TEVAR in chronic aortic dissections.

Homozygous and compound heterozygous mutations in the FBN1 gene: unexpected findings in molecular diagnosis of Marfan syndrome.

BACKGROUND: Marfan syndrome (MFS) is an autosomal-dominant connective tissue disorder usually associated with heterozygous mutations in the gene encoding fibrillin-1 (FBN1). Homozygous and compound heterozygous cases are rare events and have been associated with a clinical severe presentation. OBJECTIVES: Report unexpected findings of homozygosity and compound heterozygosity in the course of molecular diagnosis of heterozygous MFS and compare the findings with published cases. METHODS AND RESULTS: In the context of molecular diagnosis of heterozygous MFS, systematic sequencing of the FBN1 gene was performed in 2500 probands referred nationwide. 1400 probands carried a heterozygous mutation in this gene. Unexpectedly, among them four homozygous cases (0.29%) and five compound heterozygous cases (0.36%) were identified (total: 0.64%). Interestingly, none of these cases carried two premature termination codon mutations in the FBN1 gene. Clinical features for these carriers and their families were gathered and compared. There was a large spectrum of severity of the disease in probands carrying two mutated FBN1 alleles, but none of them presented extremely severe manifestations of MFS in any system compared with carriers of only one mutated FBN1 allele. This observation is not in line with the severe clinical features reported in the literature for four homozygous and three compound heterozygous probands. CONCLUSION: Homozygotes and compound heterozygotes were unexpectedly identified in the course of molecular diagnosis of MFS. Contrary to previous reports, the presence of two mutated alleles was not associated with severe forms of MFS. Although homozygosity and compound heterozygosity are rarely found in molecular diagnosis, they should not be overlooked, especially among consanguineous families. However, no predictive evaluation of severity should be provided.

MFAP5 loss-of-function mutations underscore the involvement of matrix alteration in the pathogenesis of familial thoracic aortic aneurysms and dissections.

Thoracic aortic aneurysm and dissection (TAAD) is an autosomal-dominant disorder with major life-threatening complications. The disease displays great genetic heterogeneity with some forms allelic to Marfan and Loeys-Dietz syndrome, and an important number of cases still remain unexplained at the molecular level. Through whole-exome sequencing of affected members in a large TAAD-affected family, we identified the c.472C>T (p.Arg158(∗)) nonsense mutation in MFAP5 encoding the extracellular matrix component MAGP-2. This protein interacts with elastin fibers and the microfibrillar network. Mutation screening of 403 additional probands identified an additional missense mutation of MFAP5 (c.62G>T [p.Trp21Leu]) segregating with the disease in a second family. Functional analyses performed on both affected individual's cells and in vitro models showed that these two mutations caused pure or partial haploinsufficiency. Thus, alteration of MAGP-2, a component of microfibrils and elastic fibers, appears as an initiating mechanism of inherited TAAD.

Aortic stenosis and transthyretin cardiac amyloidosis: the chicken or the egg?

BACKGROUND: Aortic stenosis (AS) and transthyretin cardiac amyloidosis (TTR-CA) are both frequent in elderly. The combination of these two diseases has never been investigated. AIMS: To describe patients with concomitant AS and TTR-CA. METHODS: Six cardiologic French centres identified retrospectively cases of patients with severe or moderate AS associated with TTR-CA hospitalized during the last 6 years. RESULTS: Sixteen patients were included. Mean ± SD age was 79 ± 6 years, 81% were men. Sixty per cent were NYHA III-IV, 31% had carpal tunnel syndrome, and 56% had atrial fibrillation. Median (Q1;Q4) NT-proBNP was 4382 (2425;4730) pg/mL and 91% had elevated cardiac troponin level. Eighty-eight per cent had severe AS (n = 14/16), of whom 86% (n = 12) had low-gradient AS. Mean ± SD interventricular septum thickness was 18 ± 4 mm. Mean left ventricular ejection fraction and global LS were 50 ± 13% and -7 ± 4%, respectively. Diagnosis of TTR-CA was histologically proven in 38%, and was based on strong cardiac uptake of the tracer at biphosphonate scintigraphy in the rest. Eighty-one per cent had wild-type TTR-CA (n = 13), one had mutated Val122I and 19% did not had genetic test (n = 3). Valve replacement was surgical in 63% and via transcatheter in 13%. Median follow-up in survivors was 33 (16;65) months. Mortality was of 44% (n = 7) during the whole follow-up period. CONCLUSIONS: Combination of AS and TTR-CA may occur in elderly patients particularly those with a low-flow low-gradient AS pattern and carries bad prognosis. Diagnosis of TTR-CA in AS is relevant to discuss specific treatment and management.

Marfan Sartan: a randomized, double-blind, placebo-controlled trial.

AIMS: To evaluate the benefit of adding Losartan to baseline therapy in patients with Marfan syndrome (MFS). METHODS AND RESULTS: A double-blind, randomized, multi-centre, placebo-controlled, add on trial comparing Losartan (50 mg when <50 kg, 100 mg otherwise) vs. placebo in patients with MFS according to Ghent criteria, age >10 years old, and receiving standard therapy. 303 patients, mean age 29.9 years old, were randomized. The two groups were similar at baseline, 86% receiving ß-blocker therapy. The median follow-up was 3.5 years. The evolution of aortic diameter at the level of the sinuses of Valsalva was not modified by the adjunction of Losartan, with a mean increase in aortic diameter at the level of the sinuses of Valsalva of 0.44 mm/year (s.e. = 0.07) (-0.043 z/year, s.e. = 0.04) in patients receiving Losartan and 0.51 mm/year (s.e. = 0.06) (-0.01 z/year, s.e. = 0.03) in those receiving placebo (P = 0.36 for the comparison on slopes in millimeter per year and P = 0.69 for the comparison on slopes on z-scores). Patients receiving Losartan had a slight but significant decrease in systolic and diastolic blood pressure throughout the study (5 mmHg). During the study period, aortic surgery was performed in 28 patients (15 Losartan, 13 placebo), death occurred in 3 patients [0 Losartan, 3 placebo, sudden death (1) suicide (1) oesophagus cancer (1)]. CONCLUSION: Losartan was able to decrease blood pressure in patients with MFS but not to limit aortic dilatation during a 3-year period in patients >10 years old. ß-Blocker therapy alone should therefore remain the standard first line therapy in these patients.

Incidence, diagnostic methods, and evolution of left ventricular thrombus in patients with anterior myocardial infarction and low left ventricular ejection fraction: a prospective multicenter study.

BACKGROUND AND OBJECTIVES: We aimed to assess the incidence and evolution of left ventricular (LV) thrombi in a high-risk population of patients with LV systolic dysfunction after anterior myocardial infarction (ant-MI). We also compared the accuracy of transthoracic echocardiography (TTE) and cardiac magnetic resonance imaging with contrast-delayed enhancement (CMR-DE) in detecting LV thrombi. METHODS: We prospectively included 100 consecutive patients with LV ejection fraction (LVEF) <45% at the first TTE performed <7 days after ant-MI. A second evaluation with TTE and CMR-DE (by blinded examiners) was performed at 30 days. A third TTE and assessment of clinical status were performed between 6 and 12 months after ant-MI. RESULTS: Patients (males 71%; mean age 59.1 ± 12.1 years; mean LVEF 33.5% ± 6.0%) were included at a median of 5.5 days (interquartile range 25th-75th percentile 4.25-6.0 days) after ant-MI. Thrombi were detected among 26 (26%) patients at a median of 12.0 days after ant-MI (7 patients at 1-7 days after MI; 15 at 8-30 days; and 4 after day 30). Sensitivity and specificity for LV thrombi detection were 94.7% and 98.5%, respectively, for TTE as compared with CMR-DE. Most thrombi (n = 24; 92.3%) disappeared after triple antithrombotic therapy (vitamin K antagonist in addition to dual antiplatelet therapy). CONCLUSION: Left ventricular thrombus is a frequent complication after ant-MI with systolic dysfunction. When a search for thrombus is prespecified, the accuracy of TTE is high as compared with CMR-DE. The best antithrombotic strategy is not known.

Aortic event rate in the Marfan population: a cohort study.

BACKGROUND: Optimal management, including timing of surgery, remains debated in Marfan syndrome because of a lack of data on aortic risk associated with this disease. METHODS AND RESULTS: We used our database to evaluate aortic risk associated with standardized care. Patients who fulfilled the international criteria, had not had previous aortic surgery or dissection, and came to our center at least twice were included. Aortic measurements were made with echocardiography (every 2 years); patients were given systematic ß-blockade and advice about sports activities. Prophylactic aortic surgery was proposed when the maximal aortic diameter reached 50 mm. Seven hundred thirty-two patients with Marfan syndrome were followed up for a mean of 6.6 years. Five deaths and 2 dissections of the ascending aorta occurred during follow-up. Event rate (death/aortic dissection) was 0.17%/y. Risk rose with increasing aortic diameter measured within 2 years of the event: from 0.09%/y per year (95% confidence interval, 0.00-0.20) when the aortic diameter was <40 mm to 0.3% (95% confidence interval, 0.00-0.71) with diameters of 45 to 49 mm and 1.33% (95% confidence interval, 0.00-3.93) with diameters of 50 to 54 mm. The risk increased 4 times at diameters ≥50 mm. The annual risk dropped below 0.05% when the aortic diameter was <50 mm after exclusion of a neonatal patient, a woman who became pregnant against our recommendation, and a 72-year-old woman with previous myocardial infarction. CONCLUSIONS: Risk of sudden death or aortic dissection remains low in patients with Marfan syndrome and aortic diameter between 45 and 49 mm. Aortic diameter of 50 mm appears to be a reasonable threshold for prophylactic surgery.

Multicentre medicoeconomic evaluation of cardiac magnetic resonance imaging for predicting coronary artery disease in left ventricular dysfunction: The CAMAREC study design.

BACKGROUND: Cardiac magnetic resonance imaging may provide a non-invasive alternative to coronary angiography for differentiating between ischaemic and non-ischaemic cardiomyopathy in cases of unexplained reduced left ventricular ejection fraction. AIM: The CAMAREC study aims to evaluate the diagnostic accuracy of cardiac magnetic resonance imaging in predicting significant coronary artery disease in patients with reduced left ventricular ejection fraction, using coronary angiography as the gold standard for comparison. METHODS: CAMAREC is a prospective cohort study of 406 patients in 10 centres with newly diagnosed, unexplained left ventricular ejection fraction ≤ 45%. Cardiac magnetic resonance imaging and coronary angiography will be conducted within a 2-week interval, starting with cardiac magnetic resonance imaging; independent committees will review the results blindly. Primary outcome is sensitivity of detecting ischaemic scar on cardiac magnetic resonance imaging for predicting significant coronary artery disease on coronary angiography according to Felker's criteria. Secondary outcomes include specificity and positive and negative predictive values (with 95% confidence intervals) of cardiac magnetic resonance imaging for predicting significant coronary artery disease in patients with reduced left ventricular ejection fraction, kappa concordance coefficient between cardiac magnetic resonance imaging and coronary angiography for diagnosing the affected myocardial territory, and the impact of cardiac magnetic resonance imaging on revascularization decisions. Two ancillary studies will evaluate the incremental cost-effectiveness of using cardiac magnetic resonance imaging first versus coronary angiography first, and the sensitivity of pre- and postcontrast T1-mapping for predicting significant coronary artery disease in patients with reduced left ventricular ejection fraction. CONCLUSION: Our study protocol is designed to rigorously evaluate cardiac magnetic resonance imaging as a non-invasive alternative to coronary angiography in patients with unexplained reduced left ventricular ejection fraction. The results will have significant implications for patient management, and may support growing evidence for the clinical utility of cardiac magnetic resonance imaging.

Primary Non-Aortic Lesions Are Not Rare in Marfan Syndrome and Are Associated with Aortic Dissection Independently of Age.

PURPOSE: The study sought to estimate the prevalence of primary non-aortic lesions (PNAL) unrelated to extension of aortic dissection (AD) in a cohort of patients with Marfan syndrome (MFS). METHODS: Adult patients presenting with pathogenic FBN1 mutations and an available pan-aortic contrast-enhanced CTA in eight French MFS clinics from April to October 2018 were included. Clinical and radiological data, particularly the presence of aortic lesions and PNAL (including aneurysm and ectasia), were retrospectively analyzed. RESULTS: Out of 138 patients, 28 (20.3%) had PNAL. In total, 27 aneurysms in 13 patients and 41 ectasias in 19 patients were reported mainly in the subclavian, iliac, and vertebral segments. Four patients (31%) with aneurysms and none with ectasia required prophylactic intervention during follow-up (median: 46 months). In multivariate analysis, factors associated with PNAL were history of AD (OR = 3.9, 95%CI: 1.3-12.1, p = 0.018), history of previous descending aortic surgery (OR = 10.3, 95%CI: 2.2-48.3, p = 0.003) and age (per 10 years OR = 1.6, 95%CI: 1.1-2.4, p = 0.008). CONCLUSION: PNAL is not rare in MFS patients with evolutive aortic disease. Natural history may differ between aneurysms and ectasia, emphasizing the need for standardized definitions and systematic screening for PNAL.