Longitudinal Evaluation and Assessment of Cardiovascular Disease in Patients With Homozygous Familial Hypercholesterolemia

Kolansky, Daniel M.; Cuchel, Marina; Clark, Bernard J.; Paridon, Stephen; McCrindle, Brian W.; Wiegers, Susan E.; Araujo, Luis I.; Vohra, Yogesh; Defesche, Joep C.; Wilson, James M.; Rader, Daniel J.

doi:10.1016/j.amjcard.2008.07.035

Cited by 159 publications

(130 citation statements)

References 21 publications

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“…This absence of valvular calcification or stenosis in RFH swine was unlikely to be a result of insufficient animal age. RFH swine develop atherosclerosis on a similar developmental time frame as humans with HoFH (ie, by mid‐late adolescence for both of these groups41, 42); meanwhile, the adult age of the RFH swine studied herein is well past the porcine equivalent of the average age of CAVD diagnosis in humans with HoFH (17.9 years) 41. Limited histological examination of elderly RFH pigs (Figure S5) also did not show any progression of valvular pathology beyond what was present by 2 to 3 yo.…”

Section: Discussionmentioning

confidence: 99%

“…This may have been attributable to the young age of the swine (<6 months old), or this animal model may be intrinsically limited to experiencing only mild valvular disease. Meanwhile, the RFH swine used in the current study were equivalent to middle‐aged adults, meaning that animal age is unlikely to be the reason for the absence of more‐advanced valvular disease in this work, given that the CAVD diagnosis in humans with HoFH is typically made by the teenage years 41. Thus, our analysis of RFH swine is supportive of the hypothesis that additional stimulation beyond hypercholesterolemia is needed to develop advanced CAVD, which is also likely the case with humans.…”

Section: Discussionmentioning

confidence: 99%

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Development of Aortic Valve Disease in Familial Hypercholesterolemic Swine: Implications for Elucidating Disease Etiology

Porras

Shanmuganayagam

Meudt

et al. 2015

JAHA

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BackgroundFamilial hypercholesterolemia (FH) is a prevalent hereditary disease associated with increased atherosclerosis and calcific aortic valve disease (CAVD). However, in both FH and non‐FH individuals, the role of hypercholesterolemia in the development of CAVD is poorly understood. This study used Rapacz FH (RFH) swine, an established model of human FH, to investigate the role of hypercholesterolemia alone in the initiation and progression of CAVD. The valves of RFH swine have not previously been examined.Methods and ResultsAortic valve leaflets were isolated from wild‐type (0.25‐ and 1‐year‐old) and RFH (0.25‐, 1‐, 2‐, and 3‐year‐old) swine. Adult RFH animals exhibited numerous hallmarks of early CAVD. Significant leaflet thickening was found in adult RFH swine, accompanied by extensive extracellular matrix remodeling, including proteoglycan enrichment, collagen disorganization, and elastin fragmentation. Increased lipid oxidation and infiltration of macrophages were also evident in adult RFH swine. Intracardiac echocardiography revealed mild aortic valve sclerosis in some of the adult RFH animals, but unimpaired valve function. Microarray analysis of valves from adult versus juvenile RFH animals revealed significant upregulation of inflammation‐related genes, as well as several commonalities with atherosclerosis and overlap with human CAVD.ConclusionsAdult RFH swine exhibited several hallmarks of early human CAVD, suggesting potential for these animals to help elucidate CAVD etiology in both FH and non‐FH individuals. The development of advanced atherosclerotic lesions, but only early‐stage CAVD, in RFH swine supports the hypothesis of an initial shared disease process, with additional stimulation necessary for further progression of CAVD.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Development of Aortic Valve Disease in Familial Hypercholesterolemic Swine: Implications for Elucidating Disease Etiology

Porras

Shanmuganayagam

Meudt

et al. 2015

JAHA

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“…Recently, the FDA licensed two therapeutics for homozygous familial hypercholesterolemia, a serious condition that leads to early cardiovascular morbidity and mortality. 28 Although the literature describes this condition as occurring in one in one million persons, 29 manufacturers of these therapeutics believe that as many as 3,000 Americans might currently be affected. 30 Pre-licensure clinical trial data suggest various hepatotoxicity events could be associated with both therapeutics as a consequence of their mechanism of action, which increases hepatic fat.…”

Section: S I M U L a T E D E X A M P L E -H O M O Z Y G O U S F A M Imentioning

confidence: 99%

Orphan Therapies: Making Best Use of Postmarket Data

2014

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BACKGROUND: Postmarket surveillance of the comparative safety and efficacy of orphan therapeutics is challenging, particularly when multiple therapeutics are licensed for the same orphan indication. To make best use of product-specific registry data collected to fulfill regulatory requirements, we propose the creation of a distributed electronic health data network among registries. Such a network could support sequential statistical analyses designed to detect early warnings of excess risks. We use a simulated example to explore the circumstances under which a distributed network may prove advantageous. METHODS: We perform sample size calculations for sequential and non-sequential statistical studies aimed at comparing the incidence of hepatotoxicity following initiation of two newly licensed therapies for homozygous familial hypercholesterolemia. We calculate the sample size savings ratio, or the proportion of sample size saved if one conducted a sequential study as compared to a non-sequential study. Then, using models to describe the adoption and utilization of these therapies, we simulate when these sample sizes are attainable in calendar years. We then calculate the analytic calendar time savings ratio, analogous to the sample size savings ratio. We repeat these analyses for numerous scenarios. KEY RESULTS: Sequential analyses detect effect sizes earlier or at the same time as non-sequential analyses. The most substantial potential savings occur when the market share is more imbalanced (i.e., 90 % for therapy A) and the effect size is closest to the null hypothesis. However, due to low exposure prevalence, these savings are difficult to realize within the 30-year time frame of this simulation for scenarios in which the outcome of interest occurs at or more frequently than one event/ 100 person-years. CONCLUSIONS: We illustrate a process to assess whether sequential statistical analyses of registry data performed via distributed networks may prove a worthwhile infrastructure investment for pharmacovigilance.

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“…Более тяже-лое течение имеют «рецептор-негативные» пациенты по сравнению с «рецептор-дефектными» [3,12].…”

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“…Резко ускоряется процесс формирования атеросклеротических бляшек, что приводит к стено-зированию сосудистого русла коронарных, сонных, ренальных артерий, при этом риск раннего развития ишемической болезни сердца примерно в 20 раз выше, чем в общей популяции [3,4,11]. При гистологиче-ском исследовании коронарных артерий детей с го-мозиготной семейной гиперхолестеринемией атеро-склеротические изменения соответствуют конечным стадиям атеросклеротического процесса [3,12].…”

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Modern Approaches to the Treatment of Homozygous Familial Hypercholesterolemia

Леонтьева¹

2017

Ross. vestn. perinatol. pediatr.

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Longitudinal Evaluation and Assessment of Cardiovascular Disease in Patients With Homozygous Familial Hypercholesterolemia

Cited by 159 publications

References 21 publications

Development of Aortic Valve Disease in Familial Hypercholesterolemic Swine: Implications for Elucidating Disease Etiology

Development of Aortic Valve Disease in Familial Hypercholesterolemic Swine: Implications for Elucidating Disease Etiology

Orphan Therapies: Making Best Use of Postmarket Data

Modern Approaches to the Treatment of Homozygous Familial Hypercholesterolemia

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