Cholesterol Reduction in Cardiovascular Disease — Clinical Benefits and Possible Mechanisms

Levine, Glenn N.; Keaney, John F.; Vita, Joseph A.

doi:10.1056/nejm199502233320807

Cited by 636 publications

(266 citation statements)

References 117 publications

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“…Thirty-day follow-up was obtained for all patients. Forty-five patients had a cardiovascular event, including cardiac death (3 patients), myocardial infarction (12), unstable angina (1), ischemic ventricular fibrillation (1), stroke (3), and elevated troponin I (25). Two patients died of noncardiac causes (1 of sepsis on postoperative day 26 and 1 with a ruptured abdominal aortic aneurysm 28 days after femoralpopliteal bypass).…”

Section: Study Patientsmentioning

confidence: 99%

“…24 Loss of the vasodilator, antithrombotic, and anti-inflammatory properties of the endothelium likely contributes to these events. 25 Several prior studies addressed the question of whether study of endothelial function in a peripheral artery also provides prognostic information about cardiac events. Perticone and colleagues 7 examined endothelial function in forearm microvesRelation between endothelial function and event-free survival after vascular surgery.…”

Section: Gokce Et Al Endothelial Dysfunction and Cardiac Eventsmentioning

confidence: 99%

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Risk Stratification for Postoperative Cardiovascular Events via Noninvasive Assessment of Endothelial Function

et al. 2002

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Background-Brachial artery endothelial function is impaired in individuals with atherosclerosis and coronary risk factors and improves with risk reduction therapy. However, the predictive value of brachial artery endothelial dysfunction for future cardiovascular events is unknown. Methods and Results-We preoperatively examined brachial artery vasodilation using ultrasound in 187 patients undergoing vascular surgery. Patients were prospectively followed for 30 days after surgery. Forty-five patients had a postoperative event, including cardiac death (3), myocardial infarction (12), unstable angina/ischemic ventricular fibrillation (2), stroke (3), or elevated troponin I, reflecting myocardial necrosis (25). Preoperative endotheliumdependent flow-mediated dilation was significantly lower in patients with an event (4.9Ϯ3.1%) than in those without an event (7.3Ϯ5%; PϽ0.001), whereas endothelium-independent vasodilation to nitroglycerin was similar in both groups. In a Cox proportional-hazards model, the independent predictors of events were age (Pϭ0.001), renal insufficiency (Pϭ0.03), noncarotid surgery (Pϭ0.05), and lower brachial artery flow-mediated dilation (Pϭ0.007). If troponin I elevation was not considered an event, low flow-mediated dilation remained an independent predictor of risk (odds ratio 9.0, 95% CI 1.2 to 68; Pϭ0.03). When a flow-mediated dilation cutpoint of 8.1% was used, endothelial function had a sensitivity of 95%, specificity of 37%, and negative predictive value of 98% for events. Conclusions-Impaired brachial artery endothelial function independently predicts postoperative cardiac events, which supports a role for endothelial dysfunction in the pathogenesis of cardiovascular disease. The strong negative predictive value of preserved endothelial function raises the possibility that assessment of brachial artery flow-mediated dilation will be useful in the management of patients undergoing vascular surgery.

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Section: Study Patientsmentioning

confidence: 99%

Section: Gokce Et Al Endothelial Dysfunction and Cardiac Eventsmentioning

confidence: 99%

Risk Stratification for Postoperative Cardiovascular Events via Noninvasive Assessment of Endothelial Function

et al. 2002

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“…Impaired endothelium-derived NO bioactivity is a common feature of many vascular diseases (8 -10) that is thought to contribute to their clinical manifestations (11,12).…”

Section: Ascorbic Acid Enhances No Bioactivity In Patients With Vascumentioning

confidence: 99%

Ascorbic Acid Enhances Endothelial Nitric-oxide Synthase Activity by Increasing Intracellular Tetrahydrobiopterin

Huang¹,

Vita²,

Venema³

et al. 2000

Journal of Biological Chemistry

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Ascorbic acid enhances NO bioactivity in patients with vascular disease through unclear mechanism(s).We investigated the role of intracellular ascorbic acid in endothelium-derived NO bioactivity. Incubation of porcine aortic endothelial cells (PAECs) with ascorbic acid produced time-and dose-dependent intracellular ascorbic acid accumulation that enhanced NO bioactivity by 70% measured as A23187-induced cGMP accumulation. This effect was due to enhanced NO production because ascorbate stimulated both PAEC nitrogen oxide (NO 2 ؊ ؉ NO 3 Ϫ ) production and L-arginine to L-citrulline conversion by 59 and 72%, respectively, without altering the cGMP response to authentic NO. Ascorbic acid also stimulated the catalytic activity of eNOS derived from either PAEC membrane fractions or baculovirus-infected Sf9 cells. Ascorbic acid enhanced bovine eNOS V max by ϳ50% without altering the K m for L-arginine. The effect of ascorbate was tetrahydrobiopterin (BH 4 )-dependent, because ascorbate was ineffective with BH 4 concentrations >10 M or in PAECs treated with sepiapterin to increase intracellular BH 4 . The effect of ascorbic acid was also specific because A23187-stimulated cGMP accumulation in PAECs was insensitive to intracellular glutathione manipulation and only ascorbic acid, not glutathione, increased the intracellular concentration of BH 4 . These data suggest that ascorbic acid enhances NO bioactivity in a BH 4 -dependent manner by increasing intracellular BH 4 content.Nitric oxide is produced from L-arginine in the vascular endothelium by the endothelial isoform of nitric-oxide synthase (NOS).1 Endothelial production of NO is crucial in the control of vascular tone (1), arterial pressure (2-4), smooth muscle cell proliferation (5, 6), and platelet adhesion to the endothelial surface (7). Impaired endothelium-derived NO bioactivity is a common feature of many vascular diseases (8 -10) that is thought to contribute to their clinical manifestations (11,12).The action of NO is particularly sensitive to the local availability of superoxide. Both endothelial elaboration of NO and arterial relaxation in response to nitrovasodilators are dependent upon intact copper-zinc superoxide dismutase (SOD) activity (13,14). Animal models of hypercholesterolemia (15, 16) and hypertension (17) demonstrate an excess vascular superoxide flux that is linked to reduced NO bioactivity. Conversely, increasing vascular SOD activity enhances NO-mediated arterial relaxation in experimental models of atherosclerosis (18,19) and hypertension (17). Thus, scavenging superoxide has important implications for NO bioactivity under both normal and pathologic conditions. Ascorbic acid also efficiently scavenges superoxide (20) and numerous studies in a host of pathologic conditions such as diabetes (21), hypercholesterolemia (22), smoking (23), and hypertension (24) indicate that NO bioactivity is improved by parenteral ascorbic acid at supraphysiologic concentrations (ϳ10 mM). We have observed enhanced NO bioactivity in atherosclerotic patients aft...

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“…14,15 The 3-hydroxy-3-methylglutaryl CoA (HMG-CoA) reductase inhibitors, statins, have successfully been used in the prevention and treatment of cardiovascular diseases for many years. 16,17 They inhibit the HMG-CoA reductase, the rate limiting enzyme of the mevalonate pathway, 18 and thereby deplete cells of cholesterol and its downstream precursors. Beside the cholesterol lowering effect, statins also exert other beneficial effects that are now summarized as pleiotropic effects.…”

mentioning

confidence: 99%

Double impact on p‐glycoprotein by statins enhances doxorubicin cytotoxicity in human neuroblastoma cells

Sieczkowski

Lehner

Ambros³

et al. 2009

Intl Journal of Cancer

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The development of multidrug resistance (MDR) is a major problem during cancer treatment. Drug efflux via ATP-binding cassette (ABC) transporters is the main mechanism responsible for resistance to chemotherapeutics. We have recently observed that statins enhance susceptibility to doxorubicin-induced apoptosis in human rhabdomyosarcoma cells, which is now also observed in human SH-SY5Y neuroblastoma cells. We have therefore investigated the ABC transporter activity to confirm a possible inhibition by statins in SH-SY5Y cells. Indeed, simvastatin directly inhibited dye transport at equimolar concentrations of the ABC transporter inhibitor, verapamil. Making use of the fluorescence behavior of doxorubicin the accumulation of anthracycline was monitored in real-time confocal microscopy. The intracellular doxorubicin accumulation was immediately enhanced by statins in SH-SY5Y cells and also in a MYCN-amplified neuroblastoma cell line STA-NB-10. The heavily glycosylated P-glycoprotein (ABCB1, P-gp) transporter appeared as a 180-and 140-kDa species. Atorvastatin and simvastatin reduced the 180-kDa form of P-gp, but not verapamil. Thereby the fully glycosylated species is shifted to the core glycosylated species (140 kDa), which was only seen at statin exposure times longer than 24 hr. The functional importance of glycosylation of the transporter was highlighted by exogenous application of N-glycosidase F, which was sufficient to enhance doxorubicin accumulation. Hence, these novel findings of statins' dual impact on P-gp have clinical implications. The enhanced intracellular accumulation of chemotherapeutics or other ABC transporter substrates in the presence of statins may represent a novel concept to overcome MDR in cancer therapy and improve drug safety.Neuroblastoma is the most common solid tumor in early childhood. About 55% of patients older than 1 year already have metastases at the time of diagnosis and therefore have a poor survival rate despite intensive therapy. 1 In $20% of the neuroblastoma a MYCN oncogene amplification occurs, which is the most unfavorable prognostic factor. 2,3 The MYCN amplification is the best established clinical and biological marker, which allows determination of the prognosis of the tumor, with numerous reports confirming the association with rapid tumor progression, advanced clinical stage and poor outcome. 3,4 Studies have shown that the expression of the multidrug resistance-associated protein 1 (MRP1, ABCC1) in neuroblastoma also correlates with poor clinical outcome and prognosis. 5,6 Recently, a prospective study has provided further evidence that high levels of MRP1 expression are strongly associated with MYCN oncogene amplification and predictive of poor outcome. 7 ATP-binding cassette (ABC) transporters, also termed multidrug resistance (MDR) proteins, play an important role in the efflux of many drugs. 8,9 Moreover, these ABC transporters are overexpressed in a wide range of tumors, for example, colon, kidney, adrenocortical or hepatocellular carcinomas, and thereby conf...

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Cholesterol Reduction in Cardiovascular Disease — Clinical Benefits and Possible Mechanisms

Cited by 636 publications

References 117 publications

Risk Stratification for Postoperative Cardiovascular Events via Noninvasive Assessment of Endothelial Function

Risk Stratification for Postoperative Cardiovascular Events via Noninvasive Assessment of Endothelial Function

Ascorbic Acid Enhances Endothelial Nitric-oxide Synthase Activity by Increasing Intracellular Tetrahydrobiopterin

Double impact on p‐glycoprotein by statins enhances doxorubicin cytotoxicity in human neuroblastoma cells

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