Elevated Plasma Lipoprotein(a) and Coronary Heart Disease in Men Aged 55 Years and Younger

Bostom, Andrew G.; Cupples, L. Adrienne; Jenner, Jennifer L.; Ordovas, J. M.; Seman, Leo; Wilson, Peter W.F.; Schaefer, E. J.; Castelli, William P.

doi:10.1001/jama.1996.03540070040028

Cited by 299 publications

(46 citation statements)

References 60 publications

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“…An extensive body of laboratory evidence indicates a critical role of Lp(a) in the development of atherothrombotic diseases (Marcovina & Morrisett, 1995), which is con®rmed by most (Rosengren et al, 1990;Sigurdsson et al, 1992;Wald et al, 1994;Cremer et al, 1994;Bostom et al, 1994;Schaefer et al, 1994;Terres et al, 1995;Bostom et al, 1996), though not all Ridker et al, 1993;Alfthan et al, 1994;Ridker et al, 1995), prospective cohort studies. The circulating level of Lp(a) is largely under genetic control (Boerwinkle et al, 1992), and is unaffected by many interventions known to affect LDL metabolism, including most dietary interventions (Berglund, 1995).…”

Section: Introductionmentioning

confidence: 98%

Diterpenes from coffee beans decrease serum levels of lipoprotein(a) in humans: results from four randomised controlled trials

et al. 1997

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Objective: Un®ltered coffee raises serum LDL cholesterol in humans, owing to the presence of the diterpenes cafestol and kahweol. Norwegians with a chronic high intake of un®ltered coffee also had elevated serum levels of lipoprotein(a), an LDL-like particle which is insensitive toward dietary interventions. We now experimentally studied the in¯uence of coffee diterpenes on lipoprotein(a) levels. Design: Four randomised controlled trials. Subjects: Healthy, normolipidemic volunteers. Interventions: Coffee, coffee oil, and pure diterpenes for 4±24 weeks. Main outcome measures: The circulating level of lipoprotein(a). Results: In 22 subjects drinking ®ve to six strong cups of cafetiere coffee per day, the median fall in lipoprotein(a) was 1.5 mg/dL after two months (P 0.03), and 0.5 mg/dL after half a year (P b 0.05), relative to 24 ®lter coffee drinkers. Coffee oil doses equivalent to 10±20 cups of un®ltered coffee reduced lipoprotein(a) levels by up to 5.5 mg/dL (P`0.05) in two separate trials (n 12±16 per group). A puri®ed mixture of cafestol and kahweol, as well as cafestol alone, were also effective in reducing Lp(a) levels (n 10). Averaged over the four trials, each 10 mg/d of cafestol (plus kahweol)Ðthe amount present in two to three cups of cafetiere coffeeÐdecreased Lp(a) levels by 0.5 mg/dL or 4% from baseline values after four weeks (n 63). Conclusions: Coffee diterpenes are among the few dietary exceptions shown to in¯uence serum lipoprotein(a) levels. However, the Lp(a)-reducing potency of coffee diterpenes may subside in the long run, and their adverse side effects preclude their use as lipoprotein(a)-reducing agents.

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Section: Introductionmentioning

confidence: 98%

Diterpenes from coffee beans decrease serum levels of lipoprotein(a) in humans: results from four randomised controlled trials

et al. 1997

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“…The lipoprotein Lp(a) has been identified as a major risk factor for atherosclerosis (1)(2)(3). This lipoprotein is distinguished from LDL by the presence of apolipoprotein(a) (apo[a]), 1 which contains multiple copies of domains closely related to the fourth kringle of plasminogen, one domain related to the fifth kringle of plasminogen, and a region similar to the proteinase domain of plasminogen (4).…”

Section: Introductionmentioning

confidence: 99%

The atherogenic lipoprotein Lp(a) is internalized and degraded in a process mediated by the VLDL receptor.

Argraves¹,

Kozarsky²,

Fallon³

et al. 1997

J. Clin. Invest.

148

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Lp(a) is a major inherited risk factor associated with premature heart disease and stroke. The mechanism of Lp(a) atherogenicity has not been elucidated, but likely involves both its ability to influence plasminogen activation as well as its atherogenic potential as a lipoprotein particle after receptor-mediated uptake. We demonstrate that fibroblasts expressing the human VLDL receptor can mediate endocytosis of Lp(a), leading to its degradation within lysosomes.

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“…An elevated plasma concentration of the lipoprotein Lp(a) 1 causes focal deposition of Lp(a) in the vessel wall and represents a major independent risk factor for vascular diseases, including atherosclerosis, restenosis, and stroke (1)(2)(3)(4)(5)(6)(7)(8)(9)(10). Lp(a) consists of a low density lipoprotein particle covalently linked to the additional protein, apolipoprotein(a) (apo(a)) (11).…”

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confidence: 99%

Feedback Mechanism of Focal Vascular Lesion Formation in Transgenic Apolipoprotein(a) Mice

Lawn

Pearle

Kunz³

et al. 1996

Journal of Biological Chemistry

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Apolipoprotein(a) (apo(a)), the distinguishing protein of atherogenic lipoprotein(a), directs accumulation of the lipoprotein(a) particle to sites in the arterial wall where atherosclerotic lipid lesions develop in man and in transgenic mice expressing human apo(a). It has been proposed that focal apo(a) accumulation in the transgenic mouse vessel wall causes the observed severe local inhibition of transforming growth factor-␤ (TGF-␤) activity and the consequent activation of the smooth muscle cells, which subsequently accumulate lipid to form lesions if the mice are fed a high fat diet. We show that blocking formation of these vascular lesions by two independent mechanisms, tamoxifen treatment and increasing high density lipoprotein, also abolishes apo(a) accumulation, inhibition of TGF-␤ activity, and activation of smooth muscle cells. The data are consistent with a feedback mechanism in which an initial accumulation of apo(a) inhibits local TGF-␤ activity, leading to further accumulation of apo(a). Breaking the feedback loop prevents smooth muscle cell activation and therefore lipid lesion development.An elevated plasma concentration of the lipoprotein Lp(a) 1 causes focal deposition of Lp(a) in the vessel wall and represents a major independent risk factor for vascular diseases, including atherosclerosis, restenosis, and stroke (1-10). Lp(a) consists of a low density lipoprotein particle covalently linked to the additional protein, apolipoprotein(a) (apo(a)) (11). Plasma-derived Lp(a) accumulates in the vessel wall more readily than low density lipoprotein, reflecting the ability of its apo(a) component to bind to extracellular and cell surface targets (1, 2). The accumulation of Lp(a) occurs at focal sites in the vessel wall for reasons that are poorly understood, although several observations suggest that it occurs at sites of endothelial injury or dysfunction, where the "response to injury" hypothesis proposes that atherosclerotic lesions are initiated (12). For example, Lp(a) localizes in the vessel wall of rabbits where the endothelium has been physically injured by balloon catheter (13). In humans, Lp(a) is localized in atherosclerotic plaques and accumulates at sites of microvascular inflammation, where endothelial permeability is known to be increased (14). Once in the vessel wall, Lp(a) may further enhance initial endothelial dysfunction, as indicated by studies which show that high Lp(a) levels are associated with impaired endothelium-dependent vasodilation before atherosclerotic lesions are detectable by angiography (15,16).A potential mechanism by which apo(a) might promote endothelial dysfunction and atherogenesis is the inhibition of plasminogen activation, suggested by the sequence homology of apo(a) to plasminogen (17). Reduced plasmin activity would be expected to have two major atherogenic consequences, both of which have been confirmed in vivo. Reduced plasmin activity in the presence of apo(a) reduces clot lysis, which may stimulate lesion development by prolonging the lifetime of mural t...

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Elevated Plasma Lipoprotein(a) and Coronary Heart Disease in Men Aged 55 Years and Younger

Cited by 299 publications

References 60 publications

Diterpenes from coffee beans decrease serum levels of lipoprotein(a) in humans: results from four randomised controlled trials

Diterpenes from coffee beans decrease serum levels of lipoprotein(a) in humans: results from four randomised controlled trials

The atherogenic lipoprotein Lp(a) is internalized and degraded in a process mediated by the VLDL receptor.

Feedback Mechanism of Focal Vascular Lesion Formation in Transgenic Apolipoprotein(a) Mice

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