Lipoprotein(a) and Oxidized Phospholipids Promote Valve Calcification in Patients With Aortic Stenosis

Zheng, Kang; Tsimikas, Sotirios; Pawade, Tania; Kroon, Jeffrey; Jenkins, William; Doris, Mhairi; White, Audrey; Timmers, Nyanza K. L. M.; Hjortnaes, Jesper; Rogers, Maximillian A.; Aikawa, Elena; Arsenault, Benoît J.; Witztum, Joseph L.; Newby, David E.; Koschinsky, Marlys L.; Fayad, Zahi A.; Stroes, Erik S.G.; Boekholdt, S. Matthijs; Dweck, Marc R

doi:10.1016/j.jacc.2019.01.070

Cited by 229 publications

(210 citation statements)

References 25 publications

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“…These mice scored a 49% lower AV pressure gradient (as a measure for AV functioning) compared to their Ldlr /− -counterparts, lower total calcium content, and all Ldlr −/− /E06-scFc survived where almost half of the Ldlr /− -group did not survive [22]. Together with the in vitro OxPL-data of Zheng et al [31], these data imply a causal relation between OxPL-signaling and the progression of AS and that targeting OxPLs offers an interesting approach to treat the progression of AVS.…”

Section: Future Perspectivesupporting

confidence: 58%

“…Constructs containing a mutation in the LBS lack the ability to bind OxPLs and were unable to increase IL6, BMP2 and RUNX2 gene expression compared to their r-apo(a) counterparts carrying OxPL. These data support the pivotal role of OxPLs in mediating Lp(a)-induced calcification of VICs [31]. To further unravel this OxPL-mediated calcification, Bouchareb et al proposed a mechanism by which Lp(a) and its associated OxPLs induce calcification in human VICs through signaling via lysophosphatidic receptor (LPAR).…”

Section: Pathophysiology Of Lp(a)-induced Avsmentioning

confidence: 66%

“…During the follow-up visit after one year, patients in the top Lp(a) tertile were characterized by increased aortic valve calcification on the subsequent CT, more rapid echocardiographic progression, and most importantly: An increased incidence of AVR and death [31]. In short, there is strong evidence to support that Lp(a) plays a key role in the development AVS.…”

Section: Relevance Of Lp(a) In Avsmentioning

confidence: 99%

“…In vitro, Lp(a) incubation of human derived VICs for one week leads to increased gene expression of IL6, BMP2 and RUNX2. These osteogenic effects were attenuated once VICs were co-incubated with the E06 monoclonal antibody against OxPLs [31]. The role of OxPLs on Lp(a) was further substantiated using recombinant apo(a) (r-apo(a)) constructs with different lysine binding sites (LBS) to bind OxPLs.…”

Section: Pathophysiology Of Lp(a)-induced Avsmentioning

confidence: 99%

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Lipoprotein(a) as Orchestrator of Calcific Aortic Valve Stenosis

et al. 2019

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Aortic valve stenosis (AVS) is the most prevalent valvular heart disease in the Western World with exponentially increased incidence with age. If left untreated, the yearly mortality rates increase up to 25%. Currently, no effective pharmacological interventions have been established to treat or prevent AVS. The only treatment modality so far is surgical or transcatheter aortic valve replacement (AVR). Lipoprotein(a) [Lp(a)] has been implicated as a pivotal player in the pathophysiology of calcification of the valves. Patients with elevated levels of Lp(a) have a higher risk of hospitalization or mortality due to the presence of AVS. Multiple studies indicated Lp(a) as a likely causal and independent risk factor for AVS. This review discusses the most important findings and mechanisms related to Lp(a) and AVS in detail. During the progression of AVS, Lp(a) enters the aortic valve tissue at damaged sites of the valves. Subsequently, autotaxin converts lysophosphatidylcholine in lysophosphatidic acid (LysoPA) which in turn acts as a ligand for the LysoPA receptor. This triggers a nuclear factor-κB cascade leading to increased transcripts of interleukin 6, bone morphogenetic protein 2, and runt-related transcription factor 2. This progresses to the actual calcification of the valves through production of alkaline phosphatase and calcium depositions. Furthermore, this review briefly mentions potentially interesting therapies that may play a role in the treatment or prevention of AVS in the near future.

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Section: Future Perspectivesupporting

confidence: 58%

Section: Pathophysiology Of Lp(a)-induced Avsmentioning

confidence: 66%

Section: Relevance Of Lp(a) In Avsmentioning

confidence: 99%

Section: Pathophysiology Of Lp(a)-induced Avsmentioning

confidence: 99%

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Lipoprotein(a) as Orchestrator of Calcific Aortic Valve Stenosis

et al. 2019

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“…Calcification is the main contributor to aortic valve stenosis [4] and, in fact, stenosis constitutes the final stage of calcific aortic valve disease (CAVD), a tightly regulated process that resembles intimal artery calcification [5]. At the molecular level, damages to the valvular endothelium allow the infiltration of lipids which, upon oxidation [6,7], can promote an inflammatory process characterised by the formation of cellular infiltrates consisting mostly of macrophages, that is associated with remodelling of the tissue [8,9]. Cellular crosstalk involving extracellular vesicles such as exosomes is known to be crucial for the development of any type of cardiovascular calcification [10], and their production by the different cell types within the valve is thus concomitant to CAVD [11].…”

Section: Introductionmentioning

confidence: 99%

Correlation of Micro-Computed Tomography Assessment of Valvular Mineralisation with Histopathological and Immunohistochemical Features of Calcific Aortic Valve Disease

Solache-Berrocal

Barral-Varela

Areces-Rodríguez

et al. 2019

JCM

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Aortic valve stenosis is a serious disease with increasing prevalence in developed countries. Research aimed at uncovering the molecular mechanisms behind its main cause, aortic valve calcification, is thus crucial for the development of future therapies. It is frequently difficult to measure the extent of mineralisation in soft tissues and some methods require the destruction of the sample. Micro-computed tomography (µCT), a non-destructive technique, was used to quantify the density and volume of calcium deposits on cusps from 57 explanted aortic valves. Conventional and immunostaining techniques were used to characterise valve tissue degeneration and the inflammatory and osteogenic stage with several markers. Although most of the analysed cusps came from severe stenosis patients, the µCT parameter bone volume/tissue volume ratio distinguished several degrees of mineralisation that correlated with the degree of structural change in the tissue and the amount of macrophage infiltration as determined by CD68 immunohistochemistry. Interestingly, exosomal markers CD63 and Alix co-localised with macrophage infiltration surrounding calcium deposits, suggesting that those vesicles could be produced at least in part by these immune cells. In conclusion, we have shown that the ex vivo assessment of aortic valve mineralisation with µCT reflects the molecular and cellular changes in pathological valves during progression towards stenosis. Thus, our results give additional validity to quantitative µCT as a convenient laboratory tool for basic research on this type of cardiovascular calcification.

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Calcific Aortic Stenosis

Otto,

Newby,

Hillis

2024

JAMA

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ImportanceCalcific aortic stenosis (AS) restricts the aortic valve opening during systole due to calcification and fibrosis of either a congenital bicuspid or a normal trileaflet aortic valve. In the US, AS affects 1% to 2% of adults older than 65 years and approximately 12% of adults older than 75 years. Worldwide, AS leads to more than 100 000 deaths annually.ObservationsCalcific AS is characterized by aortic valve leaflet lipid infiltration and inflammation with subsequent fibrosis and calcification. Symptoms due to severe AS, such as exercise intolerance, exertional dyspnea, and syncope, are associated with a 1-year mortality rate of up to 50% without aortic valve replacement. Echocardiography can detect AS and measure the severity of aortic valve dysfunction. Although progression rates vary, once aortic velocity is higher than 2 m/s, progression to severe AS occurs typically within 10 years. Severe AS is defined by an aortic velocity 4 m/s or higher, a mean gradient 40 mm Hg or higher, or a valve area less than or equal to 1.0 cm2. Management of mild to moderate AS and asymptomatic severe AS consists of patient education about the typical progression of disease; clinical and echocardiographic surveillance at intervals of 3 to 5 years for mild AS, 1 to 2 years for moderate AS, and 6 to 12 months for severe AS; and treatment of hypertension, hyperlipidemia, and cigarette smoking as indicated. When a patient with severe AS develops symptoms, surgical aortic valve replacement (SAVR) or transcatheter aortic valve implantation (TAVI) is recommended, which restores an average life expectancy; in patients aged older than 70 years with a low surgical risk, 10-year all-cause mortality was 62.7% with TAVI and 64.0% with SAVR. TAVI is associated with decreased length of hospitalization, more rapid return to normal activities, and less pain compared with SAVR. However, evidence supporting TAVI for patients aged younger than 65 years and long-term outcomes of TAVI are less well defined than for SAVR. For patients with symptomatic severe AS, the 2020 American College of Cardiology/American Heart Association guideline recommends SAVR for individuals aged 65 years and younger, SAVR or TAVI for those aged 66 to 79 years, and TAVI for individuals aged 80 years and older or those with an estimated surgical mortality of 8% or higher.ConclusionsCalcific AS is a common chronic progressive condition among older adults and is diagnosed via echocardiography. Symptomatic patients with severe AS have a mortality rate of up to 50% after 1 year, but treatment with SAVR or TAVI reduces mortality to that of age-matched control patients. The type and timing of valve replacement should be built on evidence-based guidelines, shared decision-making, and involvement of a multidisciplinary heart valve team.

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Lipoprotein(a) and Oxidized Phospholipids Promote Valve Calcification in Patients With Aortic Stenosis

Cited by 229 publications

References 25 publications

Lipoprotein(a) as Orchestrator of Calcific Aortic Valve Stenosis

Lipoprotein(a) as Orchestrator of Calcific Aortic Valve Stenosis

Correlation of Micro-Computed Tomography Assessment of Valvular Mineralisation with Histopathological and Immunohistochemical Features of Calcific Aortic Valve Disease

Calcific Aortic Stenosis

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