The Freestyle Valve in Severe Necrotizing Aortic Root Endocarditis: Comorbidity Upon Outcome.

BACKGROUND: Treatment of severe necrotizing aortic root endocarditis (SNARE) carries a substantial perioperative risk. As an alternative to homografts, we assessed short-term outcome and future prognosis in patients undergoing root replacement using the Freestyle valve. METHODS: Between 2000 and 2018, a total of 45 patients (mean age 70.9 ± 8.3 years, 66% men) underwent aortic root replacement for SNARE using the Freestyle valve. Mean Society of Thoracic Surgeons mortality score and EuroScore II were 22.6% ± 17.1 and 29.3% ± 20.9, respectively. Prosthetic endocarditis was present in 70.1%, and aortic annulus patch repair was performed in 64% of the patients. Median follow-up was 3.6 years (range: 0.1-14.5) and was 100% complete. RESULTS: The 30-day mortality was 15.5%. During follow-up, there were no reoperations, while reinfection was suspected in one patient. Survival was significantly inferior to the general population with a standardized mortality ratio of 10.7 (95% confidence interval [CI]: 9.1-12.6) (p < 0.0001). In 30-day survivors and after correction for significant comorbidities in a Cox proportional hazards model, estimated survival probabilities at 1, 5, and 10 years were 98.7 (95% CI: 92.5-99.8%), 94.1 (77.9-98.5%), and 63.8 (28.4-85.2%). Estimated mean difference in survival probability was better for the general population after postoperative year 6, but within the 95% CI for no difference. CONCLUSION: Use of the Freestyle valve is reliable solution for the most complex cases with a low rate of reinfection. Early mortality is substantial and caused by the patient's condition and severity of the infection. Excess late mortality can be attributed to patient-specific comorbidities.

Next-generation sequencing of 32 genes associated with hereditary aortopathies and related disorders of connective tissue in a cohort of 199 patients.

PURPOSE: Heritable factors play an important etiologic role in connective tissue disorders (CTD) with vascular involvement, and a genetic diagnosis is getting increasingly important for gene-tailored, personalized patient management. METHODS: We analyzed 32 disease-associated genes by using targeted next-generation sequencing and exome sequencing in a clinically relevant cohort of 199 individuals. We classified and refined sequence variants according to their likelihood for pathogenicity. RESULTS: We identified 1 pathogenic variant (PV; in FBN1 or SMAD3) in 15 patients (7.5%) and ≥1 likely pathogenic variant (LPV; in COL3A1, FBN1, FBN2, LOX, MYH11, SMAD3, TGFBR1, or TGFBR2) in 19 individuals (9.6%), together resulting in 17.1% diagnostic yield. Thirteen PV/LPV were novel. Of PV/LPV-negative patients 47 (23.6%) showed ≥1 variant of uncertain significance (VUS). Twenty-five patients had concomitant variants. In-depth evaluation of reported/calculated variant classes resulted in reclassification of 19.8% of variants. CONCLUSION: Variant classification and refinement are essential for shaping mutational spectra of disease genes, thereby improving clinical sensitivity. Obligate stringent multigene analysis is a powerful tool for identifying genetic causes of clinically related CTDs. Nonetheless, the relatively high rate of PV/LPV/VUS-negative patients underscores the existence of yet unknown disease loci and/or oligogenic/polygenic inheritance.

The Value of Circulating Biomarkers in Bicuspid Aortic Valve-Associated Aortopathy.

Traditional risk stratification model of bicuspid aortic valve (BAV) aortopathy is based on measurement of maximal cross-sectional aortic diameter, definition of proximal aortic shape, and aortic stiffness/elasticity parameters. However, conventional imaging-based criteria are unable to provide reliable information regarding the risk stratification in BAV aortopathy, especially considering the heterogeneous nature of BAV disease. Given those limitations of conventional imaging, there is a growing clinical interest to use circulating biomarkers in the screening process for thoracic aortic aneurysms as well as in the risk-assessment algorithms. We aimed to systematically review currently available biomarkers, which may be of value to predict the natural evolution of aortopathy in individuals with BAV.

Evaluation of microribonucleic acids as potential biomarkers in the bicuspid aortic valve-associated aortopathy.

OBJECTIVES: We aimed to evaluate the impact of microRNAs to predict the bicuspid aortic valve (BAV)-associated aortopathy. METHODS: Sixty-three BAV patients (mean age 47 ± 11 years, 92% men) with root dilatation, who underwent aortic valve ± proximal aortic surgery (mean post-AVR follow-up 10.3 ± 6.9 years) were included. The BAV aortopathy entities were categorized in the 'less dilated' (aortic root <50 mm) and 'severely dilated' (aortic root ≥50 mm) aorta. Several microRNAs were assessed using polymerase chain reaction. End-points were the correlation between microRNAs and severity of aortopathy/prevalence of adverse aortic events. RESULTS: Circulating levels of miR-17 and miR-106a were strongly correlated (r = 0.84, P < 0.001). Our analysis yielded significantly higher values of miR-17 (delta Ct 2.09 ± 0.64 vs delta Ct 1.68 ± 0.64, P = 0.02) and miR-106a (delta Ct 5.88 ± 0.43 vs delta Ct 5.61 ± 0.60, P = 0.046) in BAV patients with the less dilated versus the severely dilated aorta. miR-17 (delta Ct 1.51 ± 0.73 vs delta Ct 2.00 ± 0.61, P = 0.02) and miR-106a (delta Ct 5.39 ± 0.69 vs delta Ct 5.85 ± 0.44, P = 0.007) were significantly downregulated in BAV patients who experienced adverse aortic events. CONCLUSIONS: Expression of circulating miR-17 and miR-106a in the BAV root phenotype patients correlates with the severity of aortopathy and the risk of adverse aortic events. MicroRNAs have the potential to serve as biomarkers in the BAV-associated aortopathy.

Percutaneous left atrial unloading to prevent pulmonary oedema and to facilitate ventricular recovery under extracorporeal membrane oxygenation therapy.

OBJECTIVES: Left-sided unloading during extracorporeal membrane oxygenation (ECMO) therapy is crucial to prevent pulmonary oedema and facilitate ventricular recovery. We present the case of a 55-year-old man under ECMO therapy with pre-existing left ventricular (LV) thrombus formation and in need of ventricular unloading. METHODS: We implanted a 21-Fr TandemHeart Protek Solo trans-septal cannula into the left atrium using a trans-septal approach via the femoral vein. The cannula was connected to the venous line of the ECMO circuit. A flow probe and a clamp to reduce flow, if necessary, were attached to the left atrium line. Left atrium flow was adjusted to 900 ml/min under transoesophageal echocardiography control to keep the atrial septum in the mid-line and to prevent suction of the inflow cannula. RESULTS: After 9 days, the patient was weaned step-wise from ECMO and the TandemHeart cannula, which was then explanted. The patient is in New York health Association Class II without neurological sequelae (Cerebral Performance Scale 1). After 3 months, the patient has fully recovered and is working daily. The LV function is still moderately impaired, and the size of the LV thrombus remains the same. The atrial septum shows no residual defect. CONCLUSIONS: Percutaneous trans-septal insertion of a TandemHeart cannula incorporated in an ECMO circuit for the prevention of pulmonary oedema and subsequent weaning from extracorporeal circulation was feasible and safe in a patient with cardiogenic shock and an LV thrombus.

Diagnostic accuracy study of routine echocardiography for bicuspid aortic valve: a retrospective study and meta-analysis.

BACKGROUND: Transthoracic echocardiography (TTE) is the standard procedure to distinguish tricuspid aortic valve (TAV) from bicuspid aortic valve (BAV). Published studies assessed the accuracy of TTE for BAV under ideal conditions. Conversely, we aimed at assessing accuracy of TTE for BAV under routine conditions. METHODS: This retrospective, cross-sectional study of 216 adults included 132 men aged 62±14 years. Of these, 108 had BAV and 108 were age-matched individuals with TAV. All diagnoses were confirmed at surgery. We assessed TTE in two patient groups. First, in the (I) group of all 216 individuals, where we assessed accuracy for BAV according to the original diagnoses as documented by the primary investigators during original TTE examination. Second, we assessed accuracy for BAV according to expert re-evaluation in (II) all 158 TTE with availability of original recordings. Third, we performed a meta-analysis of published results on the accuracy of TTE for BAV according to PRISMA standards. RESULTS: Sensitivity, specificity and accuracy of (I) primary investigators was 46.3%, 97.2, and 71.8% as compared to (II) expert re-evaluation with 59.7%, 93%, and 77.8%, respectively. Sensitivity was significantly higher at re-evaluation (P<0.001). TTE at a non-tertiary care center (P=0.012), presence of aortic aneurysm (P=0.001) and presence of severe aortic valve calcification (P=0.003) predicted an inaccurate diagnosis of BAV. Conversely, meta-analysis of published TTE studies identified a pooled sensitivity of 87.7% and a pooled specificity of 88.3% for BAV. CONCLUSIONS: The current study shows that TTE yields almost ideal diagnostic accuracy when ideal investigators examine ideal patients. However, the study also shows that TTE yields suboptimal diagnostic accuracy under routine conditions. TTE in non-tertiary care settings, concomitant aortic aneurysm, and presence of severe aortic valve calcification predict an inaccurate diagnosis of BAV.

Mitral valve prolapse syndrome and MASS phenotype: Stability of aortic dilatation but progression of mitral valve prolapse.

BACKGROUND: Mitral valve prolapse syndrome (MVPS) and MASS phenotype (MASS) are Marfan-like syndromes that exhibit aortic dilatation and mitral valve prolapse. Unlike in Marfan syndrome (MFS), the presence of ectopia lentis and aortic aneurysm preclude diagnosis of MVPS and MASS. However, it is unclear whether aortic dilatation and mitral valve prolapse remain stable in MVPS or MASS or whether they progress like in MFS. METHODS: This retrospective longitudinal observational study examines clinical characteristics and long-term prognosis of 44 adults with MVPS or MASS (18 men, 26 women aged 38 ± 17 years) as compared with 81 adults with Marfan syndrome (MFS) with similar age and sex distribution. The age at final contact was 42 ± 15 years with mean follow-up of 66 ± 49 months. RESULTS: At baseline, ectopia lentis and aortic sinus aneurysm were absent in MVPS and MASS, and systemic scores defined by the revised Ghent nosology were lower than in MFS (all P < .001). Unlike in MFS, no individual with MVPS and MASS developed aortic complications (P < .001). In contrast, the incidence of endocarditis (P = .292), heart failure (P = .644), and mitral valve surgery (P = .140) was similar in all syndromes. Cox regression analysis identified increased LV end-diastolic (P = .013), moderate MVR (P = .019) and flail MV leaflet (P = .017) as independent predictors of mitral valve surgery. CONCLUSIONS: The study provides evidence that MVPS and MASS are Marfan-like syndromes with stability of aortic dilatation but with progression of mitral valve prolapse. Echocardiographic characteristics of mitral valve disease rather than the type of syndrome, predict clinical progression of mitral valve prolapse.

Perspectives on the revised Ghent criteria for the diagnosis of Marfan syndrome.

Three international nosologies have been proposed for the diagnosis of Marfan syndrome (MFS): the Berlin nosology in 1988; the Ghent nosology in 1996 (Ghent-1); and the revised Ghent nosology in 2010 (Ghent-2). We reviewed the literature and discussed the challenges and concepts of diagnosing MFS in adults. Ghent-1 proposed more stringent clinical criteria, which led to the confirmation of MFS in only 32%-53% of patients formerly diagnosed with MFS according to the Berlin nosology. Conversely, both the Ghent-1 and Ghent-2 nosologies diagnosed MFS, and both yielded similar frequencies of MFS in persons with a causative FBN1 mutation (90% for Ghent-1 versus 92% for Ghent-2) and in persons not having a causative FBN1 mutation (15% versus 13%). Quality criteria for diagnostic methods include objectivity, reliability, and validity. However, the nosology-based diagnosis of MFS lacks a diagnostic reference standard and, hence, quality criteria such as sensitivity, specificity, or accuracy cannot be assessed. Medical utility of diagnosis implies congruency with the historical criteria of MFS, as well as with information about the etiology, pathogenesis, diagnostic triggers, prognostic triggers, and potential complications of MFS. In addition, social and psychological utilities of diagnostic criteria include acceptance by patients, patient organizations, clinicians and scientists, practicability, costs, and the reduction of anxiety. Since the utility of a diagnosis or exclusion of MFS is context-dependent, prioritization of utilities is a strategic decision in the process of nosology development. Screening tests for MFS should be used to identify persons with MFS. To confirm the diagnosis of MFS, Ghent-1 and Ghent-2 perform similarly, but Ghent-2 is easier to use. To maximize the utility of the diagnostic criteria of MFS, a fair and transparent process of nosology development is essential.

Overexpression of Gremlin-1 in patients with Loeys-Dietz syndrome: implications on pathophysiology and early disease detection.

BACKGROUNDS: The Loeys-Dietz syndrome (LDS) is an inherited connective tissue disorder caused by mutations in the transforming growth factor ß (TGF-ß) receptors TGFBR1 or TGFBR2. Most patients with LDS develop severe aortic aneurysms resulting in early need of surgical intervention. In order to gain further insight into the pathophysiology of the disorder, we investigated circulating outgrowth endothelial cells (OEC) from the peripheral blood of LDS patients from a cohort of 23 patients including 6 patients with novel TGF-ß receptor mutations. METHODS AND RESULTS: We performed gene expression profiling of OECs using microarray analysis followed by quantitative PCR for verification of gene expression. Compared to OECs of age- and sex-matched healthy controls, OECs isolated from three LDS patients displayed altered expression of several genes belonging to the TGF-ß pathway, especially those affecting bone morphogenic protein (BMP) signalling including BMP2, BMP4 and BMPR1A. Gene expression of BMP antagonist Gremlin-1 (GREM1) showed the most prominent up-regulation. This increase was confirmed at the protein level by immunoblotting of LDS-OECs. In immunohistochemistry, abundant Gremlin-1 protein expression could be verified in endothelial cells as well as smooth muscle cells within the arterial media. Furthermore, Gremlin-1 plasma levels of LDS patients were significantly elevated compared to healthy control subjects. CONCLUSIONS: These findings open new avenues in the understanding of the pathogenesis of Loeys-Dietz syndrome and the development of new diagnostic serological methods for early disease detection.

Total serum transforming growth factor-ß1 is elevated in the entire spectrum of genetic aortic syndromes.

BACKGROUND: Total serum transforming growth factor-beta 1 (tsTGF-ß1) is increased in patients with Marfan syndrome (MFS), but it has not been assessed in thoracic aortic aneurysm and dissection (TAAD), Loeys-Dietz syndrome (LDS), and bicuspid aortic valve disease (BAVD). HYPOTHESIS: tsTGF-ß1 is increased in genetic aortic syndromes including TAAD, LDS, MFS, and BAVD. METHODS: We measured tsTGF-ß1 and performed sequencing of the genes FBN1, TGFBR1, and TGFBR2 in 317 consecutive patients with suspected or known genetic aortic syndrome (167 men, 150 women; mean age 43 ± 14 years). TAAD was diagnosed in 20, LDS in 20, MFS in 128, and BAVD in 30 patients, and genetic aortic syndrome was excluded in 119 patients. RESULTS: Elevated tsTGF-ß1 levels were associated with causative gene mutations (P = 0.008), genetic aortic syndrome (P = 0.009), and sporadic occurrence of genetic aortic syndrome (P = 0.048), whereas only genetic aortic syndrome qualified as an independent predictor of tsTGF-ß1 (P = 0.001). The tsTGF-ß1 levels were elevated in FBN1 and NOTCH1 mutations vs patients without mutations (both P = 0.004), and in NOTCH1 mutations vs ACTA2/MYH11 mutations (P = 0.015). Similarly, tsTGF-ß1 levels were elevated in MFS (P = 0.003) and in BAVD (P = 0.006) vs patients without genetic aortic syndrome. In contrast to specific clinical features of MFS, FBN1 in-frame mutations (P = 0.019) were associated with increased tsTGF-ß1 levels. CONCLUSIONS: tsTGF-ß1 is elevated in the entire spectrum of genetic aortic syndromes. However, gradual differences in the increases of tsTGF-ß1 levels may mirror different degrees of alteration of tsTGF-ß1 signaling in different genetic aortic syndromes.

The main pulmonary artery in adults: a controlled multicenter study with assessment of echocardiographic reference values, and the frequency of dilatation and aneurysm in Marfan syndrome.

BACKGROUND: Echocardiographic upper normal limits of both main pulmonary artery (MPA) diameters (MPA-d) and ratio of MPA to aortic root diameter (MPA-r) are not defined in healthy adults. Accordingly, frequency of MPA dilatation based on echocardiography remains to be assessed in adults with Marfan syndrome (MFS). METHODS: We enrolled 123 normal adults (72 men, 52 women aged 42 ± 14 years) and 98 patients with MFS (42 men, 56 women aged 39 ± 14 years) in a retrospective cross-sectional observational controlled study in four tertiary care centers. We defined outcome measures including upper normal limits of MPA-d and MPA-r as 95 quantile of normal persons, MPA dilatation as diameters > upper normal limits, MPA aneurysm as diameters >4 cm, and indication for surgery as MPA diameters >6 cm. RESULTS: MPA diameters revealed normal distribution without correlation to age, sex, body weight, body height, body mass index and body surface area. The upper normal limit was 2.6 cm (95% confidence interval (CI) =2.44-2.76 cm) for MPA-d, and 1.05 (95% CI = .86-1.24) for MPA-r. MPA dilatation presented in 6 normal persons (4.9%) and in 68 MFS patients (69.4%; P < .001), MPA aneurysm presented only in MFS (15 patients; 15.3%; P < .001), and no patient required surgery. Mean MPA-r were increased in MFS (P < .001), but ratios >1.05 were equally frequent in 7 normal persons (5%) and in 8 MFS patients (10.5%; P = .161). MPA-r related to aortic root diameters (P = .042), reduced left ventricular ejection fraction (P = .006), and increased pulmonary artery systolic pressures (P = .040). No clinical manifestations of MFS and no FBN1 mutation characteristics related to MPA diameters. CONCLUSIONS: We established 2.6 cm for MPA-d and 1.05 for MPA-r as upper normal limits. MFS exhibits a high prevalence of MPA dilatation and aneurysm. However, patients may require MPA surgery only in scarce circumstances, most likely because formation of marked MPA aneurysm may require LV dysfunction and increased PASP.

FBN1 gene mutation characteristics and clinical features for the prediction of mitral valve disease progression.

BACKGROUND: Until today, FBN1 gene mutation characteristics were not compared with clinical features for the prediction of mitral valve disease progression. METHODS: Therefore, we conducted a study of 116 patients (53 men, 63 women aged 33 ± 15 years) with a causative FBN1 gene mutation and ≤ moderate mitral valve regurgitation at baseline. RESULTS: During 7.4 ± 6.8 years 30 patients developed progression of mitral valve regurgitation ≥ 1 grade (primary endpoint), and 26 patients required mitral valve surgery (secondary endpoint). Cox regression analysis identified an association of atrial fibrillation (hazard ratio (HR)=2.703; 95% confidence interval (CI) 1.013-7.211; P=.047), left ventricular ejection fraction (HR=.970; 95%CI .944-.997; P=.032), indexed end-diastolic left ventricular diameter (HR=15.165; 95%CI 4.498-51.128; P<.001), indexed left atrial diameter (HR=1.107; 95%CI 1.045-1.173; P=.001), tricuspid valve prolapse (HR=2.599; 95%CI 1.243-5.437; P=.011), posterior leaflet prolapse (HR=1.075; 95%CI 1.023-1.130; P=.009), and posterior leaflet thickening (HR=3.368; 95%CI 1.265-8.968; P=.015) with progression of mitral valve disease, whereas none of the FBN1 gene mutation characteristics were associated with progression of mitral valve disease. However, Cox regression analysis identified a marginal relationship of FBN1 gene mutations located both in a transforming-growth-factor beta-binding protein-like (TGFb-BP) domain (HR=3.453; 95%CI .982-12.143; P=.053), and in the calcium-binding epidermal growth factor-like (cbEGF) domain (HR=2.909; 95%CI .957-8.848; P=.060) with mitral valve surgery, a finding that was corroborated by Kaplan-Meier analysis (P=.014; and P=.041, respectively). CONCLUSION: Clinical features were better predictors of mitral valve disease progression than FBN1 gene mutation characteristics.

Ascending aortic aneurysm and aortic valve dysfunction in bicuspid aortic valve disease.

BACKGROUND: The relationship of aortic valve dysfunction and ascending aortic aneurysm is unclear in adults with bicuspid aortic valve disease. METHODS: We retrospectively studied 134 consecutive out-patients (98 men, 36 women aged 43 ± 18 years) with bicuspid aortic valve disease. To investigate the relationship of ascending aortic aneurysm and aortic valve dysfunction we exclusively considered severe pathologies that required treatment by surgical or percutaneous intervention. RESULTS: Of 134 patients, 39 had aortic valve dysfunction without concomitant ascending aortic aneurysm which had been treated previously with isolated valve surgery or percutaneous valvuloplasty comprising 25 patients with aortic stenosis (19%) and 14 patients with aortic regurgitation (10%). Conversely, 26 patients had ascending aortic aneurysm which had been treated previously with aortic surgery (19%). Of these, ascending aortic aneurysm was associated with severe aortic stenosis in 13 patients and with severe aortic regurgitation in 7 patients, whereas aneurysm was unrelated to severe aortic valve dysfunction in the remaining 6 patients including 2 without any degree of aortic valve dysfunction. The maximal aortic diameters were similar at the time of aortic surgery irrespective of presence of severe aortic valve dysfunction (P=.527). Other characteristics of patients with ascending aortic aneurysm were also similar irrespective of presence or type of aortic valve dysfunction. CONCLUSION: The majority of patients with bicuspid aortic valve disease exhibit ascending aortic aneurysm in conjunction with severe aortic valve dysfunction. However, in our study 6 of 134 (5%) of persons with bicuspid aortic valve disease developed ascending aortic aneurysm without aortic valve dysfunction.

Predictors of outcome of mitral valve prolapse in patients with the Marfan syndrome.

Mitral valve prolapse has a prevalence of 2% to 3% in the general population, with adverse outcomes such as mitral valve regurgitation (MVR), heart failure, and endocarditis. Predictors of outcomes are used in idiopathic mitral valve prolapse for the timing of surgery, but such predictors are unknown in Marfan syndrome. Therefore, a population-based cohort study of 112 patients (49 male, 63 female; mean age 34 ± 15 years) with classic Marfan syndrome and mitral valve prolapse with moderate or less MVR at baseline was conducted. During 4.6 ± 3.6 years of follow-up, progression of MVR was observed in 41 patients and valve-related events, which comprised mitral valve endocarditis (7 events), heart failure (5 events), and mitral valve surgery (25 events), were observed in 31 patients. Multivariate Cox proportional-hazards regression analysis identified a flail mitral leaflet (hazard ratio [HR] 3.262, 95% confidence interval [CI] 1.406 to 7.566, p = 0.006) and increased indexed end-systolic left ventricular diameters (HR 1.113, 95% CI 1.043 to 1.188, p = 0.001) as independent predictors of progression of MVR. Similarly, mitral valve-related events were independently predicted by a flail mitral leaflet (HR 5.343, 95% CI 2.229 to 12.808, p <0.001), and mild (HR 14.336, 95% CI 1.873 to 109.755, p = 0.01) or moderate (HR 16.849, 95% CI 2.205 to 128.76, p = 0.006) degree of MVR. Conversely, aortic dilatation, dural ectasia, and sporadic mode of inheritance were not associated with outcome. In conclusion, the same clinical determinants that predict outcomes in idiopathic mitral valve prolapse also predict outcomes in mitral valve prolapse associated with Marfan syndrome.