Screening for Fabry Disease by Urinary Globotriaosylceramide Isoforms Measurement in Patients with Left Ventricular Hypertrophy.

BACKGROUND: Left ventricular hypertrophy (LVH) is a frequent echocardiographic feature in Fabry disease (FD) and in severe cases may be confused with hypertrophic cardiomyopathy (HCM) of other origin. The prevalence of FD in patients primarily diagnosed with HCM varies considerably in screening and case finding studies, respectively. In a significant proportion of patients, presenting with only mild or moderate LVH and unspecific clinical signs FD may remain undiagnosed. Urinary Gb3 isoforms have been shown to detect FD in both, women and men. We examined whether this non-invasive method would help to identify new FD cases in a non-selected cohort of patients with various degree of LVH. METHODS AND RESULTS: Consecutive patients older than 18 years with a diastolic interventricular septal wall thickness of ≥12mm determined by echocardiography were included. Referral diagnosis was documented and spot urine was collected. Gb3 was measured by mass spectroscopy. Subjects with an elevated Gb3-24:18 ratio were clinically examined for signs of FD, α-galactosidase-A activity in leukocytes was determined and GLA-mutation-analysis was performed. We examined 2596 patients. In 99 subjects urinary Gb3 isoforms excretion were elevated. In these patients no new cases of FD were identified by extended FD assessment. In two of three patients formerly diagnosed with FD Gb3-24:18 ratio was elevated and would have led to further diagnostic evaluation. CONCLUSION: Measurement of urinary Gb3 isoforms in a non-selected cohort with LVH was unable to identify new cases of FD. False positive results may be prevented by more restricted inclusion criteria and may improve diagnostic accuracy of this method.

Natural history of very severe aortic stenosis.

BACKGROUND: We sought to assess the outcome of asymptomatic patients with very severe aortic stenosis. METHODS AND RESULTS: We prospectively followed 116 consecutive asymptomatic patients (57 women; age, 67 + or - 16 years) with very severe isolated aortic stenosis defined by a peak aortic jet velocity (AV-Vel) > or = 5.0 m/s (average AV-Vel, 5.37 + or - 0.35 m/s; valve area, 0.63 + or - 0.12 cm(2)). During a median follow-up of 41 months (interquartile range, 26 to 63 months), 96 events occurred (indication for aortic valve replacement, 90; cardiac deaths, 6). Event-free survival was 64%, 36%, 25%, 12%, and 3% at 1, 2, 3, 4, and 6 years, respectively. AV-Vel but not aortic valve area was shown to independently affect event-free survival. Patients with an AV-Vel > or = 5.5 m/s had an event-free survival of 44%, 25%, 11%, and 4% at 1, 2, 3, and 4 years, respectively, compared with 76%, 43%, 33%, and 17% for patients with an AV-Vel between 5.0 and 5.5 m/s (P<0.0001). Six cardiac deaths occurred in previously asymptomatic patients (sudden death, 1; congestive heart failure, 4; myocardial infarction, 1). Patients with an initial AV-Vel > or = 5.5 m/s had a higher likelihood (52%) of severe symptom onset (New York Heart Association or Canadian Cardiovascular Society class >II) than those with an AV-Vel between 5.0 and 5.5 m/s (27%; P=0.03). CONCLUSIONS: Despite being asymptomatic, patients with very severe aortic stenosis have a poor prognosis with a high event rate and a risk of rapid functional deterioration. Early elective valve replacement surgery should therefore be considered in these patients.

The endocardial binary appearance ('binary sign') is an unreliable marker for echocardiographic detection of Fabry disease in patients with left ventricular hypertrophy.

AIMS: The binary sign, a binary appearance of the left ventricular endocardial border, was suggested to be an echocardiographic hallmark in diagnosing Fabry disease, a hereditary, lysosomal storage disorder. The aim of the present study was to examine the reliability of the binary sign as a screening tool to identify patients with Fabry disease. METHODS AND RESULTS: In total 309 subjects with an interventricular septum (IVS) thickness of ≥12 mm were investigated, of which 14 had a confirmed diagnosis of Fabry disease. Urinary globotriaosylceramide testing was used to rule out Fabry disease in the control group. From all patients echocardiographic images of the apical four-chamber view were analysed offline by a blinded observer. A binary sign was seen in 63 patients (20%), 4 had Fabry disease and 59 belonged to the control group. Although the proportion of binary signs in patients with Fabry disease was higher (29%) compared with the control group (20%) this difference was not statistically significant. The sensitivity and specificity were 28% (95% confidence interval (CI): 12-65%) and 80% (95% CI: 76-85%), respectively. In a logistic regression model adjusted for age, sex and presence of Fabry disease, the occurrence of a binary sign was highly dependent on the IVS thickness (odds ratio: 1.21; 95% CI: 1.1-1.35; P<0.001). CONCLUSION: The endocardial binary appearance is associated with the degree of septal hypertrophy but cannot adequately distinguish between patients with Fabry disease and patients with other causes of left ventricular hypertrophy.

Publisher Correction: Re-estimation improved the performance of two Framingham cardiovascular risk equations and the Pooled Cohort equations: A nationwide registry analysis.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Re-estimation improved the performance of two Framingham cardiovascular risk equations and the Pooled Cohort equations: A nationwide registry analysis.

Equations predicting the risk of occurrence of cardiovascular disease (CVD) are used in primary care to identify high-risk individuals among the general population. To improve the predictive performance of such equations, we updated the Framingham general CVD 1991 and 2008 equations and the Pooled Cohort equations for atherosclerotic CVD within five years in a contemporary cohort of individuals who participated in the Austrian health-screening program from 2009-2014. The cohort comprised 1.7 M individuals aged 30-79 without documented CVD history. CVD was defined by hospitalization or death from cardiovascular cause. Using baseline and follow-up data, we recalibrated and re-estimated the equations. We evaluated the gain in discrimination and calibration and assessed explained variation. A five-year general CVD risk of 4.61% was observed. As expected, discrimination c-statistics increased only slightly and ranged from 0.73-0.79. The two original Framingham equations overestimated the CVD risk, whereas the original Pooled Cohort equations underestimated it. Re-estimation improved calibration of all equations adequately, especially for high-risk individuals. Half of the individuals were reclassified into another risk category using the re-estimated equations. Predictors in the re-estimated Framingham equations explained 7.37% of the variation, whereas the Pooled Cohort equations explained 5.81%. Age was the most important predictor.

Comparison of Early Surgical or Transcatheter Aortic Valve Replacement Versus Conservative Management in Low-Flow, Low-Gradient Aortic Stenosis Using Inverse Probability of Treatment Weighting: Results From the TOPAS Prospective Observational Cohort Study.

Background No randomized comparison of early (ie, ≤3 months) aortic valve replacement (AVR) versus conservative management or of transcatheter AVR (TAVR) versus surgical AVR has been conducted in patients with low-flow, low-gradient (LFLG) aortic stenosis (AS). Methods and Results A total of 481 consecutive patients (75±10 years; 71% men) with LFLG AS (aortic valve area ≤0.6 cm2/m2 and mean gradient <40 mm Hg), 72% with classic LFLG and 28% with paradoxical LFLG, were prospectively recruited in the multicenter TOPAS (True or Pseudo Severe Aortic Stenosis) study. True-severe AS or pseudo-severe AS was adjudicated by flow-independent criteria. During follow-up (median [IQR] 36 [11-60] months), 220 patients died. Using inverse probability of treatment weighting to address the bias of nonrandom treatment assignment, early AVR (n=272) was associated with a major overall survival benefit (hazard ratio [HR], 0.34 [95% CI, 0.24-0.50]; P<0.001). This benefit was observed in patients with true-severe AS but also with pseudo-severe AS (HR, 0.38 [95% CI, 0.18-0.81]; P=0.01), and in classic (HR, 0.33 [95% CI, 0.22-0.49]; P<0.001) and paradoxical LFLG AS (HR, 0.42 [95% CI, 0.20-0.92]; P=0.03). Compared with conservative management in the conventional multivariate model, trans femoral TAVR was associated with the best survival (HR, 0.23 [95% CI, 0.12-0.43]; P<0.001), followed by surgical AVR (HR, 0.36 [95% CI, 0.23-0.56]; P<0.001) and alternative-access TAVR (HR, 0.51 [95% CI, 0.31-0.82]; P=0.007). In the inverse probability of treatment weighting model, trans femoral TAVR appeared to be superior to surgical AVR (HR [95% CI] 0.28 [0.11-0.72]; P=0.008) with regard to survival. Conclusions In this large prospective observational study of LFLG AS, early AVR appeared to confer a major survival benefit in both classic and paradoxical LFLG AS. This benefit seems to extend to the subgroup with pseudo-severe AS. Our findings suggest that TAVR using femoral access might be the best strategy in these patients. Registration URL: https://www.clinicaltrials.gov; Unique identifier: NCT01835028.

Predictors of outcomes in low-flow, low-gradient aortic stenosis: results of the multicenter TOPAS Study.

BACKGROUND: Patients with low-flow, low-gradient aortic stenosis have a poor prognosis with conservative therapy but a high operative mortality if treated surgically. Recently, we proposed a new index of aortic stenosis severity derived from dobutamine stress echocardiography, the projected aortic valve area at a normal transvalvular flow rate, as superior to other conventional indices to differentiate true-severe from pseudosevere aortic stenosis. The objective of this study was to identify the determinants of survival, functional status, and change in left ventricular ejection fraction during follow-up of patients with low-flow, low-gradient aortic stenosis. METHODS AND RESULTS: One hundred one patients with low-flow, low-gradient aortic stenosis (aortic valve area

External validation of two Framingham cardiovascular risk equations and the Pooled Cohort equations: A nationwide registry analysis.

BACKGROUND: Cardiovascular prevention guidelines advocate the use of statistical risk equations to predict individual cardiovascular risk. However, predictive accuracy and clinical value of existing equations may differ in populations other than the one used for their development. Using baseline and follow-up data of the Austrian health-screening program, we assessed discrimination, calibration, and clinical utility of three widely recommended equations-the Framingham 1991 and 2008 general cardiovascular disease (CVD) equations, and the Pooled Cohort equations predicting atherosclerotic CVD. METHODS: The validation cohort comprised 1.7 M individuals aged 30-79, without documented CVD history who participated in the program from 2009 to 2014. CVD events were defined by a cardiovascular cause of hospitalization or death. RESULTS: The observed five-year general CVD risk was 4.66%. Discrimination c-indices (0.72-0.78) were slightly lower than those reported for the development cohorts. C-indices for women were always higher than for men. CVD risk was overestimated by the Framingham 2008 equation, but underestimated by the Pooled Cohort equations. The Framingham 1991 equation was well-calibrated, especially for individuals up to 64 years. If applied to recommend health interventions at a predicted five-year risk between 5 and 10%, the equations were clinically useful with their net benefits, weighting true positives against false positives, ranging from 0.13 to 3.43%. CONCLUSION: The equations can discriminate high-risk from low-risk individuals, but predictive accuracy (especially for high-risk individuals) might be improved by recalibration. The Framingham 1991 equation yielded the most accurate predictions.

B-type natriuretic peptide in low-flow, low-gradient aortic stenosis: relationship to hemodynamics and clinical outcome: results from the Multicenter Truly or Pseudo-Severe Aortic Stenosis (TOPAS) study.

BACKGROUND: The prognostic value of B-type natriuretic peptide (BNP) is unknown in low-flow, low-gradient aortic stenosis (AS). We sought to evaluate the relationship between AS and rest, stress hemodynamics, and clinical outcome. METHODS AND RESULTS: BNP was measured in 69 patients with low-flow AS (indexed effective orifice area < 0.6 cm2/m2, mean gradient < or = 40 mm Hg, left ventricular ejection fraction < or = 40%). All patients underwent dobutamine stress echocardiography and were classified as truly severe or pseudosevere AS by their projected effective orifice area at normal flow rate of 250 mL/s (effective orifice area < or = 1.0 cm2 or > 1.0 cm2). BNP was inversely related to ejection fraction at rest (Spearman correlation coefficient r(s)=-0.59, P<0.0001) and at peak stress (r(s)=-0.51, P<0.0001), effective orifice area at rest (r(s)=-0.50, P<0.0001) and at peak stress (r(s)=-0.46, P=0.0002), and mean transvalvular flow (r(s)=-0.31, P=0.01). BNP was directly related to valvular resistance (r(s)=0.42, P=0.0006) and wall motion score index (r(s)=0.36, P=0.004). BNP was higher in 29 patients with truly severe AS versus 40 with pseudosevere AS (median, 743 pg/mL [Q1, 471; Q3, 1356] versus 394 pg/mL [Q1, 191 to Q3, 906], P=0.012). BNP was a strong predictor of outcome. In the total cohort, cumulative 1-year survival of patients with BNP > or = 550 pg/mL was only 47+/-9% versus 97+/-3% with BNP < 550 (P<0.0001). In 29 patients who underwent valve replacement, postoperative 1-year survival was also markedly lower in patients with BNP > or = 550 pg/mL (53+/-13% versus 92+/-7%). CONCLUSIONS: BNP is significantly higher in truly severe than pseudosevere low-gradient AS and predicts survival of the whole cohort and in patients undergoing valve replacement.