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    • Performing an ajmaline test in children is problematic for

    2019-06-15

    Performing an ajmaline test in children is problematic for 2 reasons. First, the test is apparently less sensitive in children than in adults. In fact, in 1 study, a repeat ajmaline challenge performed after puberty unmasked BrS in 23% of relatives with a previously negative drug test performed during childhood [64]. Second, the test is associated with greater risk than in adults. In 1 series, 10% of children undergoing the ajmaline test, including 3% of the asymptomatic subgroup, developed sustained VT [64,65]. Caution also should be exercised when performing a sodium blocker challenge in adults with a known pathogenic sodium channel mutation or in patients with prolonged PR intervals, pointing to a carrier of such a mutation [66].
    Differential diagnosis Other causes of ST-segment elevation should be excluded before establishing the diagnosis of BrS (Table 3). Artifacts secondary to low-pass filtering should be ruled out [67]. Circumstances that produce a type 1 Brugada-like ECG include right bundle branch block (RBBB), pectus excavatum, arrhythmogenic right ventricular cardiomyopathy (ARVC), and occlusion of the left anterior descendent artery or the conus branch of the right coronary artery, which supplies the RVOT (Table 3A). Discrimination between BrS and ARVC is particularly challenging. Although debate continues as to the extent to which structural abnormalities are present in BrS, most investigators consider BrS to be a channelopathy. Concealed structural abnormalities, such as histologic myocardial fibrosis of the RVOT, which may not become evident using conventional imaging techniques, have been proposed to account for or contribute to delayed conduction and ventricular arrhythmias in BrS. MRI and SM-164 manufacturer beam computed tomographic studies of BrS patients consistently show subtle abnormalities, including wall motion abnormalities and reduced contractile function of the RV and, to a lesser extent, of the LV, and dilation of the RVOT [68–71]. In the only study that discriminated between patients with and those without SCN5A mutations, no difference was observed in RVOT dimensions or RV ejection fraction between these patients. Slightly greater depressions of LV dimensions and ejection fraction were observed in patients with SCN5A mutations. Significant differences were observed in RV and LV dimensions and ejection fraction compared to healthy controls [72]. Cardiac dilation and reduced contractility in all of these studies were attributed to structural changes (fibrosis, fatty degeneration). However, as noted by van Hoorn et al. [72] virtually no signs of fibrosis or fatty degeneration could be detected, perhaps because the spatial resolution of the imaging used was too low to detect such subtle changes. Antzelevitch and colleagues have long suggested an alternative explanation [31,73,74]. Loss of the action potential (AP), which has been shown in experimental models to create the arrhythmogenic substrate in BrS, leads to contractile changes that could explain the wall motion abnormalities observed. The all-or-none repolarization at the end of phase 1 of the epicardial AP responsible for loss of the dome causes the calcium channel to inactivate very soon after it activates. As a consequence, calcium channel current is dramatically reduced, the cell becomes depleted of calcium, and contractile function ceases in those cells. This is expected to lead to wall motion abnormalities, particularly in the RVOT, dilation of the RVOT region, and reduced ejection fraction observed in patients with BrS. It has also been proposed that the loss of the AP dome, because it creates a hibernation-like state, may, over long periods of time, lead to mild structural changes, including intracellular lipid accumulation, vacuolization, and connexin 43 redistribution. These structural changes may, in turn, contribute to the arrhythmogenic substrate of BrS, although they are very different from those encountered in arrhythmogenic right ventricular cardiomyopathy/dysplasia (ARVC/D) [31,75]. This hypothesis would predict that some of the changes observed by recent studies may be the result of, rather than the cause of, the BrS phenotype [76].