Inflammation in Fabry disease: stages, molecular pathways, and therapeutic implications.

Fabry disease, a multisystem X-linked disorder caused by mutations in the alpha-galactosidase gene. This leads to the accumulation of globotriaosylceramide (Gb3) and globotriaosylsphingosine (Lyso-Gb3), culminating in various clinical signs and symptoms that significantly impact quality of life. Although treatments such as enzyme replacement, oral chaperone, and emerging therapies like gene therapy exist; delayed diagnosis often curtails their effectiveness. Our review highlights the importance of delineating the stages of inflammation in Fabry disease to enhance the timing and efficacy of diagnosis and interventions, particularly before the progression to fibrosis, where treatment options are less effective. Inflammation is emerging as an important aspect of the pathogenesis of Fabry disease. This is thought to be predominantly mediated by the innate immune response, with growing evidence pointing towards the potential involvement of adaptive immune mechanisms that remain poorly understood. Highlighted by the fact that Fabry disease shares immune profiles with systemic autoinflammatory diseases, blurring the distinctions between these disorders and highlighting the need for a nuanced understanding of immune dynamics. This insight is crucial for developing targeted therapies and improving the administration of current treatments like enzyme replacement. Moreover, our review discusses the complex interplay between these inflammatory processes and current treatments, such as the challenges posed by anti-drug antibodies. These antibodies can attenuate the effectiveness of therapies, necessitating more refined approaches to mitigate their impact. By advancing our understanding of the molecular changes, inflammatory mediators and causative factors that drive inflammation in Fabry disease, we aim to clarify their role in the disease's progression. This improved understanding will help us see how these processes fit into the current landscape of Fabry disease. Additionally, it will guide the development of more effective diagnostic and therapeutic approaches, ultimately improving patient care.

Comparison between myocardial contrast echocardiography and single-photon emission computed tomography for predicting transmurality of acute myocardial infarction.

Contrast-enhanced cardiovascular magnetic resonance imaging (CMR) has been shown to accurately assess transmural extent of infarction, which is an excellent predictor of long-term improvement in contractile function. We assessed the relative accuracy of myocardial contrast echocardiography (MCE) and single-photon emission computed tomography (SPECT) to predict transmural extent of infarction after acute myocardial infarction. MCE, SPECT, and CMR were performed in 40 patients with acute myocardial infarction 7 to 10 days after thrombolysis. CMR was used to divide the transmural extent of infarction into 5 groups: 0%, 1% to 25%, 26% to 50%, 51% to 75%, and 76% to 100% in dysfunctional segments. MCE and SPECT were compared with assessment grades of transmural extent of infarction. There was a significant relation (p<0.0001) between decreasing contrast intensity as assessed qualitatively by MCE and increasing transmural extent of infarction on CMR as was the case for SPECT. The accuracy of MCE (77%) to predict>50% transmural extent of infarction (nonviable myocardium) was significantly (p=0.02) superior to that of SPECT (70%). Absence of uptake on MCE and SPECT virtually ruled out 25% transmural extent of infarction (84% vs 76%, p=0.03). MCE and SPECT correlate well with the transmural extent of infarction. However, MCE is significantly more accurate in predicting >50% of the transmural extent of infarction and more sensitive in identifying

Myocardial contrast echocardiography accurately reflects transmurality of myocardial necrosis and predicts contractile reserve after acute myocardial infarction.

BACKGROUND: Both myocardial contrast echocardiography (MCE) and cardiovascular magnetic resonance (CMR) can identify myocardial necrosis after acute myocardial infarction (AMI). However, transmural extent of infarction (TEI) correlates of myocardial perfusion by MCE after AMI are unknown. We sought to ascertain the ability of MCE to (1) predict TEI as defined by contrast-enhanced CMR and (2) to compare the relative accuracy of these techniques to predict contractile reserve late after AMI. METHODS: MCE and CMR were performed in 42 patients with AMI 7 to 10 days after thrombolysis. Contractile reserve with low-dose dobutamine was evaluated 12 weeks after revascularization. RESULTS: Both qualitative (myocardial contrast intensity) and quantitative MCE [peak contrast intensity, microbubble velocity (beta), and myocardial blood flow] showed a significant (P < .0001) inverse relationship with increasing TEI. However, beta was the single best predictor of TEI (P = .002). Both qualitative MCE and CMR predicted contractile reserve similarly (area under receiver operating characteristic curve were 0.84 and 0.80, respectively). Qualitative and quantitative MCE parameters as well as CMR correlated significantly with the degree of contractile reserve (P < .001). Multiple logistic regression analysis using clinical, electrocardiographic, MCE, and CMR parameters showed that both MCE (OR = 0.03, 95% CI 0.01-0.10, P < .001) and CMR (OR = 0.11, 95% CI 0.04-0.26, P < .001) are independent predictors of contractile reserve. The most discriminative quantitative parameters for prediction of contractile reserve were microbubble velocity (P < .001) and myocardial blood flow (P = .001) assessed by MCE. CONCLUSION: MCE reflects the transmural extent of AMI as assessed by CMR. Both techniques predict contractile reserve.

Cardiovascular magnetic resonance and the evaluation of heart failure.

Cardiovascular magnetic resonance (CMR) has established itself as probably the single best way of phenotyping the failing heart. It is the accepted gold standard for measuring cardiac function, volumes, and mass, but within the same scan session additional techniques are available for greater definition. Tissue characterization with the contrast agent gadolinium is well validated and allows the precise visualization and quantification of myocardial infarction. This can be used for viability assessment and to determine heart failure etiology. Dobutamine stress CMR and CMR perfusion hold advantages over conventional techniques. The new frontiers of CMR in heart failure hold the promise of unique insights quantifying myocardial iron, nonischemic fibrosis, microvascular perfusion, plaque characterization, and CMR-targeted intervention. The development and validation of these techniques represent major research challenges for the future. From a clinical perspective, an equal challenge is in increasing the availability of the modality for patients and physicians.

The pathologic basis of Q-wave and non-Q-wave myocardial infarction: a cardiovascular magnetic resonance study.

OBJECTIVES: The purpose of this study was to determine the pathologic basis of Q-wave (QW) and non-Q-wave (NQW) myocardial infarction (MI). BACKGROUND: The QW/NQW distinction remains in wide clinical use but the meaning of the difference remains controversial. We hypothesized that measurement of total MI size and transmural extent by late gadolinium enhancement cardiovascular magnetic resonance (CMR) would identify the pathologic basis of QWs. METHODS: A total of 100 consecutive patients with documented previous MI had electrocardiogram and CMR on the same day. Patients with acute MI within seven days were excluded. Left ventricular function and the size and transmural extent of MI were quantified in the three major arterial territories and correlated with the presence of QW. RESULTS: Subendocardial MI showed QW in 28%. Transmural MI showed NQW in 29%. Of all MIs, 48% were at some point transmural, and 99% of these were at some point non-transmural. As MI size and number of transmural segments increased, the probability of QW increased (anterior: total size chi-square = 53, p < 0.0001, transmural extent chi-square = 36, p < 0.0001; inferior: total size chi-square = 16, p = 0.001, transmural extent chi-square = 10, p = 0.001). These findings did not hold for lateral MI. In a multivariate model, the transmural extent of MI was not an independent predictor of QW when total size of MI was removed. The QW/NQW classification was a good test for size of MI (area under receiver operating characteristic curve: anterior 0.90, inferior 0.77). CONCLUSIONS: The QW/NQW distinction is useful, but it is determined by the total size rather than transmural extent of underlying MI.

The histologic basis of late gadolinium enhancement cardiovascular magnetic resonance in hypertrophic cardiomyopathy.

OBJECTIVES: We sought to identify the histologic basis of myocardial late gadolinium enhancement cardiovascular magnetic resonance (CMR) in hypertrophic cardiomyopathy (HCM). BACKGROUND: The histologic basis of late gadolinium CMR in patients with HCM is unknown. METHODS: A 28-year-old male patient with HCM and heart failure underwent late gadolinium enhancement CMR and, 49 days later, heart transplantation. The explanted heart was examined histologically for the extent of collagen and disarray, and the results were compared with a previous in vivo CMR scan. RESULTS: Overall, 19% of the myocardium was collagen, but the amount per segment varied widely (SD +/- 19, range 0% to 71%). Both disarray and collagen were more likely to be found in the mesocardium than in the endo- or epicardium. There was a significant relationship between the extent of late gadolinium enhancement and collagen (r = 0.7, p < 0.0001) but not myocardial disarray (p = 0.58). Segments containing >15% collagen were more likely to have late gadolinium enhancement. Regional wall motion was inversely related to the extent of myocardial collagen and late gadolinium enhancement but not disarray (p = 0.0003, 0.04, and NS, respectively). CONCLUSIONS: In this patient with HCM and heart failure, regions of myocardial late gadolinium enhancement by CMR represented regions of increased myocardial collagen but not disarray.

Gadolinium enhanced cardiovascular magnetic resonance in Anderson-Fabry disease. Evidence for a disease specific abnormality of the myocardial interstitium.

AIMS: Anderson-Fabry Disease (AFD), an X-linked disorder of sphingolipid metabolism, is a cause of idiopathic left ventricular hypertrophy but the mechanism of hypertrophy is poorly understood. Gadolinium enhanced cardiovascular magnetic resonance can detect focal myocardial fibrosis. We hypothesised that hyperenhancement would be present in AFD. METHODS AND RESULTS: Eighteen males (mean 43+/-14 years) and eight female heterozygotes (mean 48+/-12 years) with AFD underwent cine and late gadolinium cardiovascular magnetic resonance. Nine male (50%) had myocardial hyperenhancement ranging from 3.4% to 20.6% (mean 7.7+/-5.7%) of total myocardium; in males, percentage hyperenhancement related to LV mass index (r=0.78, P=0.0002) but not to ejection fraction or left ventricular volumes. Lesser hyperenhancement was also found in four (50%) heterozygous females (mean 4.6%). In 12 (92%) patients with abnormal gadolinium uptake, hyperenhancement occurred in the basal infero-lateral wall where, unlike myocardial infarction, it was not sub-endocardial. In two male patients with severe LVH (left ventricular hypertrophy) and systolic impairment there was additional hyperenhancement in other myocardial segments. CONCLUSIONS: These observations suggests that myocardial fibrosis occurs in AFD and may contribute to the hypertrophy and the natural history of the disease.

Myocardial scarring caused by left ventricular assist device (LVAD) insertion demonstrated by cardiovascular magnetic resonance.

We report three cases of dilated cardiomyopathy treated with left ventricular assist devices (LVAD), subsequently explanted. These mechanical devices are being increasingly used to support left ventricular function in the short and long term. We used cine and gadolinium-enhanced cardiovascular magnetic resonance (CMR) to examine the consequences of previous LVAD implantation. In all cases, there was apical akinesis and tethering on cine imaging. Early (< 5 minutes) imaging after gadolinium demonstrated apical hypo-enhancement, an avascular area of scar or thrombus, while late (> 10 minutes) imaging demonstrated transmural apical infarction which in one case extended into the inferior wall. The findings suggest that LVAD insertion may cause permanent myocardial fibrosis at the site of ventricular insertion, and the cases demonstrate the use of contrast-enhanced CMR in this scenario of iatrogenic ventricular scarring.

Toward clinical risk assessment in hypertrophic cardiomyopathy with gadolinium cardiovascular magnetic resonance.

OBJECTIVES: We sought to assess whether hyperenhancement by gadolinium cardiovascular magnetic resonance (CMR) occurs in hypertrophic cardiomyopathy (HCM) and correlates with the risk of heart failure and sudden death. BACKGROUND: The myocardial interstitium is abnormal in HCM at post-mortem. Focally increased interstitial myocardial space appears as hyperenhancement with gadolinium CMR. METHODS: In a blinded, prospective study, HCM patients were selected for the presence (n = 23) or absence (n = 30) of an increased clinical risk of sudden death and/or progressive adverse left ventricular (LV) remodeling. Gadolinium-enhanced CMR was performed. RESULTS: Myocardial hyperenhancement was found in 42 patients (79%), affecting 10.9% (range 0% to 48%) of the LV mass. There was a greater extent of hyperenhancement in patients with progressive disease (28.5% vs. 8.7%, p < 0.001) and in patients with two or more risk factors for sudden death (15.7% vs. 8.6%, p = 0.02). Improved discrimination was seen in patients >40 years old (29.6% vs. 6.7%, p < 0.001) for progressive disease and for patients <40 years old for risk factors for sudden death (15.7% vs. 2.1%, p = 0.002). Patients with diffuse rather than confluent enhancement had two or more risk factors for sudden death (87% vs. 33%, p = 0.01). CONCLUSIONS: Gadolinium CMR reveals myocardial hyperenhancement in HCM. The extent of hyperenhancement is associated with progressive ventricular dilation and markers of sudden death.

Right ventricular function in adults with repaired tetralogy of Fallot assessed with cardiovascular magnetic resonance imaging: detrimental role of right ventricular outflow aneurysms or akinesia and adverse right-to-left ventricular interaction.

OBJECTIVES: We examined the relationship among biventricular hemodynamics, pulmonary regurgitant fraction (PRF), right ventricular outflow tract (RVOT) aneurysm or akinesia, and baseline and surgical characteristics in adults with repaired tetralogy of Fallot (rTOF). BACKGROUND: The precise relationship of pulmonary regurgitation with biventricular hemodynamics has been hampered by limitations of right ventricular (RV) imaging. METHODS: We assessed 85 consecutive adults with rTOF and 26 matched healthy controls using cardiovascular magnetic resonance imaging. RESULTS: Patients had higher right ventricular end-diastolic volume index (RVEDVi) (p < 0.001), right ventricular end-systolic volume index (RVESVi) (p < 0.001), right ventricular mass index (RVMi) (p < 0.001), and lower right ventricular ejection fraction (RVEF) (p < 0.001) and left ventricular ejection fraction (LVEF) (p = 0.002) compared to controls. The PRF (range 0% to 55%) independently predicted RVEDVi (p < 0.01) and the latter predicted RVESVi (p < 0.01) and RVMi (p < 0.01). The RVOT aneurysm/akinesia was present in 48/85 (56.9%) of patients and predicted RV volumes (RVEDVi, p = 0.01, and RVESVi, p = 0.03). There was a negative effect of RVOT aneurysm/akinesia and RVMi on RVEF (p < 0.01 and p = 0.02, respectively). There was only a tendency among patients with transannular or RVOT patching toward RVOT aneurysm/akinesia (p = 0.09). The LVEF correlated with RVEF (r = 0.67, p < 0.001). CONCLUSIONS: Pulmonary regurgitation and RVOT aneurysm/akinesia were independently associated with RV dilation and the latter with RV hypertrophy late after rTOF. The RVOT aneurysm/akinesia was common but related only in part to RVOT or transannular patching. Both RV hypertrophy and RVOT aneurysm/akinesia were associated with lower RVEF. Left ventricular systolic dysfunction correlated with RV dysfunction, suggesting an unfavorable ventricular-ventricular interaction. Measures to maintain or restore pulmonary valve function and avoid RVOT aneurysm/akinesia are mandatory for preserving biventricular function late after rTOF.

Do results of the ENABLE (Endothelin Antagonist Bosentan for Lowering Cardiac Events in Heart Failure) study spell the end for non-selective endothelin antagonism in heart failure?

The last two decades have seen major advances in the treatment of chronic heart failure, primarily as a result of therapeutic manipulation of activated neurohormonal systems. Despite this progress, many patients still suffer significant morbidity and premature death. Antagonism of the biological effects of endothelin, a potent vasoconstrictor, represents a further potential target. To date, positive results from animal models of heart failure have not been translated into clinical practice, perhaps as a consequence of the high doses of drug used. The ENABLE (Endothelin Antagonist Bosentan for Lowering Cardiac Events in Heart Failure) study evaluated the effects of low dose bosentan, a non-selective endothelin receptor antagonist, in patients with severe heart failure (left ventricular ejection fraction <35%, New York Heart Association class IIIb-IV). A total of 1,613 patients were randomized to receive either bosentan (125 mg twice a day) or placebo. The preliminary results were presented at the 51st Annual Scientific Session of the American College of Cardiology (17-20 March 2002, Atlanta, GA, USA). The primary endpoint of all-cause mortality or hospitalization for heart failure was reached in 321/808 patients on placebo and 312/805 receiving bosentan. Treatment with bosentan appeared to confer an early risk of worsening heart failure necessitating hospitalization, as a consequence of fluid retention. It has been suggested that further studies using even lower doses of bosentan or more aggressive concomitant diuretic therapy may avoid this adverse effect. The results from the ENABLE study have, however, thrown further doubt on the potential benefits of non-specific endothelin receptor blockade in heart failure.

Initial experience with the intravascular contrast agent NC100150-injection (Clariscan) for breath-hold and navigator-gated magnetic resonance coronary artery imaging.

PURPOSE: To examine magnetic resonance coronary artery imaging after NC100150-Injection. MATERIALS AND METHODS: Breath-hold and navigator-gated images were acquired in five patients. RESULTS: Breath-hold image quality, coronary artery-fat SDNR, and coronary artery SNR improved. Respiratory artifacts due to reduced liver signal intensity degraded navigator-gated image quality. CONCLUSION: NC100150-Injection improves breath-hold coronary artery imaging. Navigator-gated acquisitions should use techniques that are insensitive to T2* effects.

Comparison of interstudy reproducibility of cardiovascular magnetic resonance with two-dimensional echocardiography in normal subjects and in patients with heart failure or left ventricular hypertrophy.

Fast breath-hold cardiovascular magnetic resonance (CMR) shows excellent results for interstudy reproducibility of left ventricular (LV) volumes, ejection fraction, and mass, which are thought to be superior to results of 2-dimensional echocardiography. However, there is no direct comparison of the interstudy reproducibility of both methods in the same subjects. A total of 60 subjects (normal volunteers [n = 20], or patients with heart failure [n = 20] or LV hypertrophy [n = 20]) underwent 2 CMRs and 2 echocardiographic studies for assessment of LV volumes, function, and mass. The interstudy reproducibility coefficient of variability was superior for CMR in all groups for all parameters. Statistical significance was reached for end-systolic volume (4.4% to 9.2% vs 13.7% to 20.3%, p <0.001), ejection fraction (2.4% to 7.3% vs 8.6% to 19.4%, p <0.001), and mass (2.8% to 4.8% vs 11.6% to 15.7% p <0.001), with a trend for end-diastolic volume (2.9% to 4.9% vs 5.5% to 10.5%, p = 0.17). The superior interstudy reproducibility resulted in considerably lower calculated sample sizes (reductions of 55% to 93%) required by CMR compared with echocardiography to show clinically relevant changes in LV dimensions and function. Thus, CMR has excellent interstudy reproducibility in normal, dilated, and hypertrophic hearts, and is superior to 2-dimensional echocardiography.

Assessment of reactive hyperaemia using real time zonal echo-planar flow imaging.

The measurement of limb blood flow at rest and during reactive hyperaemia has potential as a marker of vascular health and endothelial function because it is the stimulus that causes flow-mediated dilatation, commonly measured as brachial arterial reactivity. Because the flow increases are short lived, they represent a significant challenge for measurement by cardiovascular magnetic resonance. In this study we used a real time, single shot zonal echo-planar imaging method (ZEPI) to study reactive hyperaemia in the femoral artery of five healthy volunteers. Flow velocity was measured every 78 msec. Changes in peak forward flow velocity during systole (580 vs. 390 mm/sec, p < 0.01) and minimum flow velocity (160 vs. 100 mm/sec, p < 0.01) were shown. With progressing improvement in spatial resolution, this technique will allow the accurate noninvasive determination of total flow, flow profile, and peak velocities in real time.

Breath-hold FLASH and FISP cardiovascular MR imaging: left ventricular volume differences and reproducibility.

PURPOSE: To compare fast imaging with steady-state precession (FISP) and fast low-angle shot (FLASH) magnetic resonance acquisitions to quantify left ventricular volumes, mass, and function and to determine if the two techniques are comparable. MATERIALS AND METHODS: Left ventricular volume studies were performed in 10 patients with heart failure and in 10 healthy subjects by using FISP and FLASH imaging. Identical section positions were used for section-by-section contour comparisons. Manual analysis was performed by two experienced observers. The study was repeated on a different day and interobserver and interstudy reproducibility assessed. RESULTS: With FISP, end-diastolic volume was larger (healthy subjects: +18 mL [13%], P <.001; patients: +6 mL [3%], not significant), end-systolic volume larger (healthy subjects: +9 mL [17%], P =.001; patients: +8 mL [6%], P =.001) and left ventricular mass smaller (healthy subjects: -25 g (19%), P <.001; patients: -21 g (11%), P <.001). There were no significant differences in ejection fraction. Both sequences had excellent interstudy and interobserver reproducibility, with statistically better reproducibility for interstudy healthy-subject ejection fraction on FISP images (P =.05). Section-by-section analysis determined that at FISP, endocardial contours were drawn larger and the epicardial contours smaller than on FLASH images. FISP enabled better delineation of epicardial fat from myocardium, of blood-myocardium interface in areas of trabeculation or papillary muscles, and of the atrioventricular ring. CONCLUSION: FISP produces small but significantly higher left ventricular volume measurements, as compared with FLASH imaging. FLASH imaging and FISP have similar reproducibility.