Early detection of organ involvement in Fabry disease by biomarker assessment in conjunction with LGE cardiac MRI: results from the SOPHIA study.

BACKGROUND: Initiation of enzyme replacement therapy (ERT) early in the Fabry disease course may facilitate better outcomes than in patients with advanced disease. Early diagnosis is often hindered by the heterogeneous nature of signs and symptoms, and by the presentation of atypical phenotypes. METHODS: The Sophisticated Assessment of Disease Burden in Patients with Fabry Disease study (SOPHIA; ClinicalTrials.gov, NCT01210196) evaluated clinical and diagnostic assessments for early detection of Fabry-related organ pathology in ERT-naïve patients with mild FD symptoms. Assessments included cardiac magnetic resonance imaging with late gadolinium enhancement (LGE-CMR), echocardiography, 24-h Holter electrocardiography, and biomarkers of FD and fibrosis. RESULTS: 35 patients with mean (SD) baseline age of 45.0 (10.2) years were included and assessed at baseline, 12 months, and (optionally) at 24 months. At baseline, LGE-CMR and elevated procollagen III N-terminal propeptide, sphingosine-1-phosphate, and globotriaosylsphingosine were the most prevalent indicators of early Fabry-related pathology. LGE was already present in 58.8% of patients with normal left ventricular mass index. 15.2% of patients showed grade 1 diastolic dysfunction. QRS duration increased from baseline to last observation, particularly in patients with severe baseline fibrosis. Fibrosis progressed from baseline to last observation, especially in patients with baseline LGE ≥ 2.50 mL (3.65 [1.14] mL vs 6.74 [1.10] mL). Statistically significant correlations were found between LGE volume and high-sensitivity troponin T, and between LGE volume and fragments of urinary collagen alpha-1 (I), (III), and (VII), and collagen alpha-3 (V). CONCLUSIONS: Fibrosis may become apparent before left ventricular hypertrophy occurs. LGE-CMR imaging is superior to conventional echocardiography for detecting early cardiomyopathy in FD and, in conjunction with biomarker tests, may help detect early organ involvement in mild FD.

Effect of combined systolic and diastolic functional parameter assessment for differentiation of cardiac amyloidosis from other causes of concentric left ventricular hypertrophy.

BACKGROUND: Differentiation of cardiac amyloidosis (CA) from other causes of concentric left ventricular hypertrophy remains a clinical challenge, especially in patients with preserved ejection fraction at the early disease stages. METHODS AND RESULTS: Consecutive hypertrophic patients with CA, isolated arterial hypertension, Fabry disease, and Friedreich ataxia (n=25 per group) were investigated; 25 healthy volunteers served as a control group. Standard echocardiography was performed, and segmental longitudinal peak systolic strain (LSsys) in the septum was assessed by 2-dimensional speckle tracking imaging. Indices of left ventricular hypertrophy and ejection fraction were similar among all patient groups. Deceleration time of early filling was significantly lower in patients with CA (147±46 milliseconds) compared with those with isolated arterial hypertension, Fabry disease, or control subjects (all P<0.0125). Septal basal LSsys (-6±2%) was significantly lower in patients with CA compared with those with isolated arterial hypertension (-14±6%), Fabry disease (-12±5%), Friedreich ataxia (-16±2%), or control subjects (-17±3%; all P<0.001), whereas septal apical LSsys was similar among all patient groups and control subjects (all P>0.05). A data-driven cutoff value for the ratio of septal apical to basal LSsys ratio >2.1 differentiated CA from other causes of left ventricular hypertrophy (sensitivity, 88%; specificity, 85%; positive predictive value, 67%; negative predictive value, 96%). The prevalence of septal apical to basal LSsys ratio >2.1 plus deceleration time of early filling <200 milliseconds was 88% in CA but 0% in all other groups. CONCLUSIONS: A systolic septal longitudinal base-to-apex strain gradient (septal apical to basal LSsys ratio >2.1), combined with a shortened diastolic deceleration time of early filling (deceleration time of early filling <200 milliseconds), aids in differentiating CA from other causes of concentric left ventricular hypertrophy.

Methods for assessment of left ventricular systolic function in technically difficult patients with poor imaging quality.

The assessment of left ventricular (LV) systolic function is often the most important information obtained during clinical echocardiography. Although LV systolic function may be visually estimated in many patients with or without contrast opacification, technically difficult patients may require alternative methods for evaluating LV systolic function. In this review, the authors describe several surrogate echocardiographic methods that might be helpful for the evaluation of LV systolic function in patients with poor image quality, including endocardial border delineation by contrast agents, mitral annular plane systolic excursion, mitral annular velocity derived from tissue Doppler, systolic time intervals, mitral regurgitation-derived LV dP/dt, and estimation of cardiac output by Doppler echocardiography. After a short introduction to the various issues involved, the authors propose a method for suitable measurement. In addition, indications and clinical implications, as well as limitations, of the different methods are discussed.

Differences in Fabry cardiomyopathy between female and male patients: consequences for diagnostic assessment.

OBJECTIVES: We hypothesized that Fabry cardiomyopathy in female patients might differ substantially from that in male patients and sought to prove this hypothesis in a large cohort consisting of 104 patients with Fabry disease. BACKGROUND: Fabry cardiomyopathy in male patients is characterized by left ventricular (LV) hypertrophy, impaired myocardial function, and subsequent progressive myocardial fibrosis. In contrast, the occurrence of these 3 cardiomyopathic hallmarks in female patients remains unknown. METHODS: In 104 patients (58 females, age 42 ± 16 years; 46 males, age 42 ± 13 years) with genetically proven Fabry disease, LV hypertrophy, regional myocardial deformation and myocardial fibrosis were assessed by standard echocardiography, strain rate imaging, and cardiac magnetic resonance (CMR) imaging-guided late enhancement (LE). RESULTS: In men, end-diastolic left ventricular wall thickness (LVWT) ranged from 6 to 19.5 mm (LV mass CMR 55 to 200 g/m(2)), and LE was never seen with LVWT <12 mm (LV mass <99 g/m(2)). In contrast in female patients, LVWT ranged from 5 to 15.5 mm, LV mass ranged from 39 to 146 g/m(2), and LE was already detectable with an LVWT of 9 mm (LV mass 56 g/m(2)). When LV mass was examined in CMR, LE was detected in 23% of the female patients without hypertrophy (n=9), whereas LE was never seen in male patients with normal LV mass. LE was always associated with low systolic strain rate, but the severity of impairment was independent of LVWT in female patients (lateral strain rate in patients with LV hypertrophy with LE -0.7 ± 0.2 s(-1); patients without LV hypertrophy with LE -0.8 ± 0.2 s(-1); p=0.45). CONCLUSIONS: In contrast to male patients, the loss of myocardial function and the development of fibrosis do not necessarily require myocardial hypertrophy in female patients with Fabry disease. Thus, in contrast to actual recommendations, initial cardiac staging and monitoring should be based on LV hypertrophy and on replacement fibrosis in female patients with Fabry disease.

Hemodynamic assessment of severe aortic stenosis: MRI evaluation of dynamic changes of vena contracta.

PURPOSE: Direct magnetic resonance imaging (MRI) planimetry of the maximal systolic aortic valve area does not consider temporal variations of the opening area during the ejection period. We evaluated an MRI-based methodology for the assessment of valvular dynamics in patients with severe aortic stenosis by measuring the systolic variability of the valvular blood stream, that is, the "vena contracta." MATERIALS AND METHODS: With institutional review board approval, we examined 22 patients (13 male, 9 female; mean age, 68 ±10 years) with severe aortic stenosis using 1.5 T MRI and a standardized scanning protocol consisting of gradient-echo phase-contrast velocity imaging and steady-state free precession-cine MRI before and after valve replacement therapy. Temporal changes of the aortic valve area, represented by systolic variations of the area of poststenotic turbulent flow at its smallest convergence, that is, the proximal vena contracta, were determined by MRI and quantified by a calculated parameter of temporal valve dynamics (T). T was defined as the period which the aortic valve spent over its maximal opening area (>85%) during systole. MRI was also used to determine left ventricular hypertrophy before (LVMI) and its regression (LVMR) after valve replacement. Findings were compared with transthoracic echocardiography and cardiac catheterization. RESULTS: All patients had an echocardiographic effective orifice area, EOATTE, of <1.0 cm2. The comparison of T to LVMI and LVMR revealed significant correlations (LVMI: r = -0.62; P = 0.002; LVMR: r = 0.62; P = 0.002). Further significant correlations with aortic stenosis severity were observed in the comparison with manual planimetry, invasive measurements, and echocardiographic valve areas, as well as with pressure gradients. CONCLUSIONS: MRI can measure systolic variations of the aortic valve area. Quantitative parameters of the hemodynamic relevance of valve dynamics obtained by this method correlate with established parameters of aortic stenosis severity and LVMR.

Assessment of the contractile reserve in patients with intermediate coronary lesions: a strain rate imaging study validated by invasive myocardial fractional flow reserve.

AIMS: The present study aims to compare the change of left ventricular deformation during dobutamine stress echocardiography (DSE) with the reference standard of invasive myocardial fractional flow reserve (FFR) to assess the haemodynamic significance of intermediate coronary lesions. METHODS AND RESULTS: In 30 patients with an intermediate coronary artery stenosis in one epicardial coronary artery, FFR measurements were performed during coronary catheterization. In case of an FFR < 0.75 after intracoronary adenosine administration, the stenosis was considered significant, indicating ischaemia. In addition, during DSE, peak systolic strain rate and systolic strain of the region of interest (supplied by the stenotic vessel) and of a non-ischaemic remote region were assessed at baseline and at peak stress. Thirteen patients had an FFR >or= 0.75, indicating normal flow reserve (non-ischaemic group). The remaining 17 patients with an FFR < 0.75 comprised the ischaemic group. At baseline DSE, mean values of strain rate (-1.2 +/- 0.3 s(-1)) and strain (-17 +/- 8%) were not significantly different between both groups. In the ischaemic group, in the target region, strain at peak stress decreased to - 10 +/- 8%, whereas strain rate remained unchanged. In contrast, in the non-ischaemic group, strain at peak stress remained unchanged (-18 +/- 7%), whereas strain rate increased to - 2.5 +/- 1.1 s(-1). The receiver operating characteristic curve analysis revealed the change in strain rate as the best parameter to detect ischaemia, with a sensitivity of 89% and a specificity of 86%. In the remote region, in both groups, strain rate (-1.4 +/- 0.4 s(-1)) and strain values (-20 +/- 7%) were not significantly different at baseline, and strain rate doubled and strain remained unchanged at DSE peak stress. CONCLUSION: Non-invasive evaluation of regional deformation, using strain rate imaging during DSE, predicted the relevance of intermediate coronary stenosis. In this context, strain rate is superior to strain measurements for the quantification of the contractile reserve.