Background— In this prospective follow-up study, the effect of myocardial fibrosis on myocardial performance in symptomatic severe aortic stenosis was investigated, and the impact of fibrosis on clinical outcome after aortic valve replacement (AVR) was estimated. Methods and Results— Fifty-eight consecutive patients with isolated symptomatic severe aortic stenosis underwent extensive baseline characterization before AVR. Standard and tissue Doppler echocardiography and cardiac magnetic resonance imaging (late-enhancement imaging for replacement fibrosis) were performed at baseline and 9 months after AVR. Endomyocardial biopsies were obtained intraoperatively to determine the degree of myocardial fibrosis. Patients were analyzed according to the severity of interstitial fibrosis in cardiac biopsies (severe, n=21; mild, n=15; none, n=22). The extent of histologically determined cardiac fibrosis at baseline correlated closely with New York Heart Association functional class and markers of longitudinal systolic function (all P <0.001) but not global ejection fraction or aortic valve area. Nine months after AVR, the degree of late enhancement remained unchanged, implying that AVR failed to reduce the degree of replacement fibrosis. Patients with no fibrosis experienced a marked improvement in New York Heart Association class from 2.8±0.4 to 1.4±0.5 ( P <0.001). Only parameters of longitudinal systolic function predicted this functional improvement. Four patients with severe fibrosis died during follow-up, but no patient from the other groups died. Conclusions— Myocardial fibrosis is an important morphological substrate of postoperative clinical outcome in patients with severe aortic stenosis and was not reversible after AVR over the 9 months of follow-up examined in this study. Because markers of longitudinal systolic function appear to indicate sensitively both the severity of myocardial fibrosis and the clinical outcome, they may prove valuable for preoperative risk assessment in patients with aortic stenosis.

Background— Enzyme replacement therapy with recombinant α-galactosidase A reduces left ventricular hypertrophy and improves regional myocardial function in patients with Fabry disease during short-term treatment. Whether enzyme replacement therapy is effective in all stages of Fabry cardiomyopathy during long-term follow-up is unknown. Methods and Results— We studied 32 Fabry patients over a period of 3 years regarding disease progression and clinical outcome under enzyme replacement therapy. Regional myocardial fibrosis was assessed by magnetic resonance imaging late-enhancement technique. Echocardiographic myocardial mass was calculated with the Devereux formula, and myocardial function was quantified by ultrasonic strain-rate imaging. In addition, exercise capacity was measured by bicycle stress test. All measurements were repeated at yearly intervals. At baseline, 9 patients demonstrated at least 2 fibrotic left ventricular segments (severe myocardial fibrosis), 11 had 1 left ventricular segment affected (mild fibrosis), and 12 were without fibrosis. In patients without fibrosis, enzyme replacement therapy resulted in a significant reduction in left ventricular mass (238±42 g at baseline, 202±46 g at 3 years; P for trend <0.001), an improvement in myocardial function (systolic radial strain rate, 2.3±0.4 and 2.9±0.6 seconds −1 , respectively; P for trend=0.045), and a higher exercise capacity obtained by bicycle stress exercise (106±14 and 122±26 W, respectively; P for trend=0.014). In contrast, patients with mild or severe fibrosis showed a minor reduction in left ventricular hypertrophy and no improvement in myocardial function or exercise capacity. Conclusions— These data suggest that treatment of Fabry cardiomyopathy with recombinant α-galactosidase A should best be started before myocardial fibrosis has developed to achieve long-term improvement in myocardial morphology and function and exercise capacity.

ObjectiveThe long-term effects of enzyme-replacement therapy (ERT) in Fabry disease are unknown. Thus, the aim of this study was to determine whether ERT in patients with advanced Fabry disease affects progression towards ‘hard’ clinical end-points in comparison with the natural course of the disease.MethodsA total of 40 patients with genetically proven Fabry disease (mean age 40 ± 9 years; n = 9 women) were treated prospectively with ERT for 6 years. In addition, 40 subjects from the Fabry Registry, matched for age, sex, chronic kidney disease stage and previous transient ischaemic attack (TIA), served as a comparison group. The main outcome was a composite of stroke, end-stage renal disease (ESRD) and death. Secondary outcomes included changes in myocardial left ventricular (LV) wall thickness and replacement fibrosis, change in glomerular filtration rate (GFR), new TIA and change in neuropathic pain.ResultsDuring a median follow-up of 6.0 years (bottom and top quartiles: 5.1, 7.2), 15 events occurred in 13 patients (n = 7 deaths, n = 4 cases of ESRD and n = 4 strokes). Sudden death occurred (n = 6) only in patients with documented ventricular tachycardia and myocardial replacement fibrosis. The annual progression of myocardial LV fibrosis in the entire cohort was 0.6 ± 0.7%. As a result, posterior end-diastolic wall thinning was observed (baseline, 13.2 ± 2.0 mm; follow-up, 11.4 ± 2.1 mm; P < 0.01). GFR decreased by 2.3 ± 4.6 mL min−1 per year. Three patients experienced a TIA. The major clinical symptom was neuropathic pain (n = 37), and this symptom improved in 25 patients. The event rate was not different between the ERT group and the untreated (natural history) group of the Fabry Registry.ConclusionDespite ERT, clinically meaningful events including sudden cardiac death continue to develop in patients with advanced Fabry disease.

Mitral annular plane systolic excursion (MAPSE) has been suggested as a parameter for left ventricular (LV) function. This review describes the current clinical application and potential implications of routinely using MAPSE in patients with various cardiovascular diseases. Reduced MAPSE reflects impaired longitudinal function and thus provides complementary information to ejection fraction (EF), which represents the global result of both longitudinal and circumferential contraction. Reduced long-axis deformation results from dysfunctional or stressed longitudinal myofibres due to endo- (and potentially epi-) cardial ischaemia, fibrosis, or increased wall stress. In patients with aortic stenosis, reduced MAPSE is suggestive of subendocardial fibrosis. Moreover, reduced MAPSE could be used as a sensitive early marker of LV systolic dysfunction in hypertensive patients with normal EF, where compensatory increased circumferential deformation might mask the reduced longitudinal deformation. In addition, reduced MAPSE was associated with poor prognosis in patients with heart failure, atrial fibrillation and post-myocardial infarction as well as in patients with severe aortic stenosis undergoing aortic valve replacement. Despite of the routine use of newer and more refined echocardiographic technologies nowadays, such as strain-rate imaging, speckle-tracking imaging, and 3D echocardiography, the use of MAPSE measurement is still especially helpful to evaluate LV systolic function in case of poor sonographic windows, since good imaging quality is required for most of the modern echocardiographic techniques with the exception of tissue Doppler imaging.

Recent experiments on blinking quantum dots, weak turbulence in liquid crystals, and nanoelectrodes reveal the fundamental connection between 1/f noise and power law intermittency. The nonstationarity of the process implies that the power spectrum is random--a manifestation of weak ergodicity breaking. Here, we obtain the universal distribution of the power spectrum, which can be used to identify intermittency as the source of the noise. We solve in this case an outstanding paradox on the nonintegrability of 1/f noise and the violation of Parseval's theorem. We explain why there is no physical low-frequency cutoff and therefore why it cannot be found in experiments.

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.

PurposeIn this work we present a dual-phase diffusion tensor imaging (DTI) technique that incorporates a correction scheme for the cardiac material strain, based on 3D myocardial tagging.Methods In vivo dual-phase cardiac DTI with a stimulated echo approach and 3D tagging was performed in 10 healthy volunteers. The time course of material strain was estimated from the tagging data and used to correct for strain effects in the diffusion weighted acquisition. Mean diffusivity, fractional anisotropy, helix, transverse and sheet angles were calculated and compared between systole and diastole, with and without strain correction. Data acquired at the systolic sweet spot, where the effects of strain are eliminated, served as a reference.ResultsThe impact of strain correction on helix angle was small. However, large differences were observed in the transverse and sheet angle values, with and without strain correction. The standard deviation of systolic transverse angles was significantly reduced from 35.9±3.9° to 27.8°±3.5° (p<0.001) upon strain-correction indicating more coherent fiber tracks after correction. Myocyte aggregate structure was aligned more longitudinally in systole compared to diastole as reflected by an increased transmural range of helix angles (71.8°±3.9° systole vs. 55.6°±5.6°, p<0.001 diastole). While diastolic sheet angle histograms had dominant counts at high sheet angle values, systolic histograms showed lower sheet angle values indicating a reorientation of myocyte sheets during contraction.ConclusionAn approach for dual-phase cardiac DTI with correction for material strain has been successfully implemented. This technique allows assessing dynamic changes in myofiber architecture between systole and diastole, and emphasizes the need for strain correction when sheet architecture in the heart is imaged with a stimulated echo approach.

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. (Circ Cardiovasc Imaging. 2013;6:1066-1072.)