Pediatric Cardiomyopathy Mestroni, Luisa, MD; Sweet, Mary E., BA; Taylor, Matthew R.G., MD, PhD
Journal of the American College of Cardiology,
02/2016, Letnik:
67, Številka:
5
Journal Article
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Using a combination of homozygosity mapping, whole exome sequencing, and candidate gene screening, the group identified homozygous premature stop codon mutations in ALPK3 and, from immunohistological ...observations of heart tissue, suggest potential mechanisms for further exploration. Expression studies in mouse embryos and adult tissues have shown that Alpk3, also known as Midori, is expressed in the fetal heart as well as the adult heart and skeletal muscle, and it localizes to the nucleus where it may regulate transcription (5). Because Alpk3-deficient mice exhibit indistinct intercalated discs, Alpk3 may be necessary for their proper formation (4).
Genetic Infiltrative Cardiomyopathies Sweet, Mary E; Mestroni, Luisa; Taylor, Matthew R G
Heart failure clinics,
04/2018, Letnik:
14, Številka:
2
Journal Article
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Infiltrative cardiomyopathies are characterized by abnormal accumulation or deposition of substances in cardiac tissue leading to cardiac dysfunction. These can be inherited, resulting from mutations ...in specific genes, which engender a diverse array of extracardiac features but overlapping cardiac phenotypes. This article provides an overview of each inherited infiltrative cardiomyopathy, describing the causative genes, the pathologic mechanisms involved, the resulting cardiac manifestations, and the therapies currently offered or being developed.
Intracellular Ca(2+) handling is abnormal in human heart failure. Studies have demonstrated that left ventricular assist device (LVAD) support reverses phenotypic alterations, suggesting that, in ...select patients, LVAD support may be a bridge to recovery. Few studies have related support duration to phenotypic recovery. We hypothesized that reversal of impaired sarcoendoplasmic reticulum (SR) Ca(2+) cycling following LVAD implantation is duration-dependent.
We used post-rest potentiation to assess SR function, and Western blot analysis to measure Ca(2+)-cycling proteins. Left ventricular tissue from 10 non-failing hearts, 8 failing hearts and 10 LVAD-supported hearts was analyzed. Support ranged from 7 to 334 days. The median duration, 115 days, divided patients into short- and long-term support groups.
Post-rest potentiation (PRP) response recovered after short-term LVAD support to a level (116.8 +/- 12.1%; n = 5) close to non-failing (123.4 +/- 12.0%; n = 10) hearts, but recovery after long-term support (23.5 +/- 7.0%; n = 5) remained closer to that of failing hearts (13.5 +/- 5.6%). We found a similar pattern of normalization for SR Ca(2+)-ATPase protein and the phospholamban/SR Ca(2+)-ATPase ratio (non-failing: 0.66 +/- 0.11; failing: 1.21 +/- 0.23; short-duration LVAD: 0.68 +/- 0.14; long-duration LVAD: 1.67 +/- 0.30; correlation p < 0.001; r = 0.93). The ratio also tended to correlate with the PRP response after unloading (p = 0.05; r = -0.65).
SR Ca(2+) handling improved during early LVAD support, but long-term support was associated with abnormal Ca(2+) cycling. These findings cast doubt on strategies designed to wean patients after complete unloading with an LVAD.
Summary A genetic etiology has been identified in 30% to 40% of dilated cardiomyopathy (DCM) patients, yet only 50% of these cases are associated with a known causative gene variant. Thus, in order ...to understand the pathophysiology of DCM, it is necessary to identify and characterize additional genes. In this study, whole exome sequencing in combination with segregation analysis was used to identify mutations in a novel gene, filamin C ( FLNC ), resulting in a cardiac-restricted DCM pathology. Here we provide functional data via zebrafish studies and protein analysis to support a model implicating FLNC haploinsufficiency as a mechanism of DCM.