Hyperlipidemias: Catapano AL

Grigore L, Norata GD, Catapano AL. · Department of Pharmacological Sciences, University of Milan, Milan, Italy. · Vasc Health Risk Manag. · Pubmed #18561502 links to  free full text

Abstract: Although widely used in lipid lowering therapy, HMG CoA reductase inhibitors (even when administered at high doses) are frequently insufficient to achieve guideline-recommended LDL-C goals for many patients with hypercholesterolemia in everyday clinical practice. Many patients do not achieve LDL-C goal on the initial dose of statin and the majority of these patients does not reach their goal after 6 months. As a consequence, a wide therapeutic gap exists between target LDL-C levels and those typically achieved in clinical practice. A recent and more effective therapeutic hypocholesterolemic strategy is to treat the two main sources of cholesterol simultaneously (production of cholesterol, mainly in the liver, and absorption of cholesterol in the intestine) with a complementary mechanism of action, by co-administering ezetimibe, a novel agent inhibiting cholesterol absorption, with a statin, which inhibits cholesterol production in the liver. Ezetimibe can be effectively and safely co-administered with any dose of any statin and, compared with the single inhibition of cholesterol production, afforded by statins alone, provides consistently greater reductions in LDL-C through dual inhibition of both cholesterol production and absorption. We summarize the pivotal role of both the liver and intestine in the overall balance of cholesterol in the body and describe the clinical impact and relevance of using ezetimibe either alone or co-administered with statins in controlling elevated levels of plasma LDL cholesterol.

Catapano AL. · Center for the Study of Atherosclerosis and Laboratory of Lipoprotein Metabolism, Department of Pharmacological Sciences, University of Milan, Milan, Italy. · Fundam Clin Pharmacol. · Pubmed #18001316 No free full text.

Abstract: The recent discoveries on the concerted role of several mechanisms involved in regulating the balance of body cholesterol highlight the role of intestinal absorption. Selective modulators of intestinal cholesterol absorption are available that offer a new pharmacologic approach to the modulation of total body cholesterol homeostasis and to a more effective reduction of low-density-lipoprotein cholesterol.

Catapano AL, Catapano L, Fellin R. · Dipartimento di Scienze Farmacologiche, Centro per lo Studio dell'Aterosclerosi, Università degli Studi, Milano. · Ital Heart J Suppl. · Pubmed #15615349 No free full text.

Abstract: A number of clinical studies clearly demonstrate the efficacy of hypocholesterolemic treatment in reducing incident cardiovascular events. The benefit appears to be proportional to the reduction of LDL cholesterol. Recent guidelines suggest an even more stringent target of 70 mg/dl for LDL cholesterol in high-risk subjects. Statins represent a very effective treatment of hypercholesterolemia, and the co-administration of drugs with complementary mechanisms of action, may represent an additional pharmacological tool in clinical practice to achieve the suggested targets for LDL lowering. In this short review we address the most recent discoveries in the physiological pathways of cholesterol absorption and identify the concept of dual inhibition as a therapeutic paradigm that may help in reaching the LDL cholesterol targets in clinical practice.

Norata GD, Catapano AL. · Department of Pharmacological Sciences, University of Milano, Milano, Italy. · Nutr Metab Cardiovasc Dis. · Pubmed #15053163 No free full text.

Abstract: AIM: Dietary cholesterol absorption, endogenous cholesterol synthesis and biliary cholesterol excretion regulate whole body cholesterol balance as a result of biotransformation into bile acids or direct cholesterol excretion. Recent studies have significantly advanced our understanding of intestinal sterol absorption at molecular level. This review concentrates on two major issues: the mechanisms of sterol absorption, and the currently available or experimental drugs that affect this pathway. DATA SYNTHESIS: Nuclear hormone receptors, such as the liver X, farnesoid X and retinoid X receptors, regulate the absorption of dietary sterols by modulating the transcription of several genes involved in cholesterol metabolism, The ABC proteins transport dietary cholesterol from enterocytes back to the intestinal lumen, thus limiting the amount of absorbed cholesterol. By means of the same mechanism, ABC transporters also provide an efficient barrier against the absorption of plant sterols. Phytosterols, bile acid sequestrants, ezetimibe and ACAT inhibitors are possible means of affecting these pathways. CONCLUSION: In addition to providing an insight into the molecular mechanisms of sterol absorption, these recent findings may lead to new therapeutic options for the treatment of hypercholesterolemia. This is particularly true in the case of patients at high risk of coronary artery disease requiring aggressive lipid-lowering therapy combining a statin with drugs affecting cholesterol absorption in order to ensure the optimal management of dyslipidemia.

Bernini F, Catapano AL. · Dipartimento di Scienze Farmacologiche, Biologiche e Chimiche Applicate, Università degli Studi, Campus Universiario, 43100 Parma. · Ital Heart J. · Pubmed #14983744 No free full text.

Abstract: The development of more active and safe new 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors (statins) will increase the armamentarium of therapeutic tools available to the physicians for antiatherosclerotic therapies. Rosuvastatin presents a promising pharmacological profile: high affinity for the enzyme, a relative high hydrophilicity, selective hepatic uptake and activity, minimal cytochrome P450-mediated metabolism. Clinically the drug displays the highest lipid-lowering efficacy in the class with a safety profile similar to the other statins. Drug interaction potential is reduced. Rosuvastatin effectively decreases triglycerides, triglyceride-rich lipoproteins, non-HDL cholesterol, and increases HDL cholesterol. All together these properties will favor the achievement of therapeutic goals in the treated patients.

Bolego C, Poli A, Cignarella A, Catapano AL, Paoletti R. · Nutrition Foundation of Italy, Via S Pietro all'Orto 17, 20121 Milan, Italy. · Cardiovasc Drugs Ther. · Pubmed #12374904 No free full text.

Abstract: Rosuvastatin (ZD4522) and pitavastatin (NK-104) are novel HMG-CoA reductase inhibitors with a peculiar pharmacological profile. In particular, they show a high potency in decreasing LDL-C and their catabolism is not mediated by the cytochrome P-450 3A4, thus reducing the potential for drug-drug interaction and improving the management of blood cholesterol. As the magnitude of LDL-C reduction is directly associated with the decrease in the incidence of myocardial infarction and mortality for CAD, statins with increased LDL-C lowering potency may ensure the achievement of target LDL-C levels and offer a more aggressive cholesterol control, further improving CAD morbidity and mortality.

Norata GD, Grigore L, Raselli S, Redaelli L, Hamsten A, Maggi F, Eriksson P, Catapano AL. · Department of Pharmacological Sciences, University of Milan,Via Balzaretti 9, 20133 Milan, Italy. · Atherosclerosis. · Pubmed #17055512 No free full text.

Abstract: OBJECTIVE: Triglyceride-rich lipoproteins (TGRLs) are a cardiovascular risk factor and induce endothelial dysfunction. In the present study, we investigated the effects of post-prandial TGRLs from type IV hyperlipidemic subjects on endothelial activation addressing the effects of the lipoproteins on intracellular pathways and gene expression. METHODS: Thirty fasted hypertriglyceridemic patients were given an oral fat load (OFL) and blood samples were collected before the OFL (T0) and 2, 4, 6 and 8h thereafter. Endothelial function, determined as flow-mediated dilatation of the brachial artery, was assessed at the same time points. TGRLs were isolated at T0 and T4 (PP-TGRL) for in vitro studies. RESULTS: Compared with TGRLs, PP-TGRLs induced to a larger extent phosphorylation of p38 MAPK, CREB and IKB-alpha in human endothelial cells and increased the DNA binding activity of CREB, NFAT and NF-kappaB. Furthermore, PP-TRGLs upregulated the expression of several pro-inflammatory genes including vascular cell adhesion molecule-1 (VCAM-1), PECAM-1, ELAM-1, intercellular adhesion molecule-1 (ICAM-1), P-selectin, MCP-1, interleukin-6 (IL-6), TLR-4, CD40, ADAMTS1 and PAI-1. CONCLUSION: These effects may relate to the severe impairment of endothelial function seen during the post-prandial phase in hypertriglyceridemic patients.

Zoppo A, Maggi FM, Catapano AL. · Centro per lo Studio dell'Aterosclerosi, University of Milan, Italy. · Atherosclerosis. · Pubmed #10487482 No free full text.

Abstract: The role of plasma triglycerides as a risk factor for cardiovascular disease is still under scrutiny. While recent studies have shown that postprandial triglyceridemia is an independent risk factor, normalization of fasting plasma triglycerides through modification of nutritional habits remains the primary approach in the treatment of hypertriglyceridemia. To address the issue of whether a satisfactory dietary regimen results in the control of postprandial lipemia, 53 type IV hypertriglyceridemic patients underwent an hypolipidemic diet for 3 months. All patients had a reduction of fasting lipid parameters (average TG: from 516+/-208 to 229+/-99 mg/dl; total cholesterol (Chol): from 261+/-42 to 213+/-40 mg/dl and HDL Chol: from 33+/-9 to 38+/-8 mg/dl). Taking plasma TG < or =200 mg/dl as the target for dietary intervention 26 patients were classified as 'responders' while the remaining 27 were 'non responders'. Even if fasting total TG, total Chol, HDL and LDL Chol were normal, both responders and non responders (P<0.0001) showed an exaggerated postprandial response to an oral fat load as compared to controls (20 normolipidemic subjects). Also when 10 responders and 10 controls, all male, were matched for plasma TG (129+/-43 versus 121+/-41 mg/dl) and other lipid parameters, a statistically significant difference between the two groups was observed at the time of each of the postprandial tests (P<0.0001) and for the area under the curve. The fact that the post prandial response is poorly modified by a dietary regimen, that effectively reduces plasma fasting TG, suggests that commonly used dietary regimens fail to restore a normal postprandial metabolism. Whether the cardiovascular risk for these patients is reduced after diet remains, therefore, to be addressed.

Signori E, Rinaldi M, Fioretti D, Iurescia S, Seripa D, Perrone G, Norata GD, Catapano AL, Fazio VM. · Institute of Neurobiology and Molecular Medicine, CNR-ARTOV, 00133 Rome, Italy. · Biochem Biophys Res Commun. · Pubmed #17662693 No free full text.

Abstract: Apolipoprotein E, a key regulator in cholesterol-rich lipoprotein metabolism, is considered a strong candidate for treating hypercholesterolemia and cardiovascular disease. Inherited deficiency of this protein results in type III hyperlipoproteinemia in humans. ApoE-knockout mice, which develop spontaneous hypercholesterolemia, are an excellent model of human atherosclerosis. Here we investigated the therapeutic effects of a plasmid vector encoding human APOE3 sequence intramuscularly injected in hypercholesterolemic newborn mice at the ages of 5 and 14 days. We further explored the possibility of inducing tolerance in newborns when injected early. Our data show that direct i.m. naked DNA injection reduces severe hypercholesterolemia in newborn mice. Moreover, when naked DNA is administrated early, no immune response is generated against the human APOE, allowing repeated administrations. Neonatal therapies are important for the treatment of many genetic childhood diseases where early administration is required to prevent developmental damage. We propose the use of direct i.m. naked gene transfer in newborns to prevent long-term damages arising from hypercholesterolemic conditions.

Mikhailidis DP, Sibbring GC, Ballantyne CM, Davies GM, Catapano AL. · Department of Clinical Biochemistry (Vascular Disease Prevention Clinics), Royal Free Hospital, Royal Free and University College School of Medicine, London, UK. <> · Curr Med Res Opin. · Pubmed #17659159 No free full text.

Abstract: OBJECTIVE: To review and analyse the evidence for the cholesterol-lowering effect of ezetimibe in adult patients with hypercholesterolaemia who are not at low-density lipoprotein cholesterol (LDL-C) goal on statin monotherapy. RESEARCH DESIGN: Systematic review and meta-analysis. METHODS: MEDLINE and EMBASE were searched to identify ezetimibe randomised controlled trials (RCTs) published between January 1993 and December 2005. The meta-analysis combined data from RCTs, with a minimum treatment duration of 6 weeks, that compared treatment with ezetimibe 10 mg/day or placebo added to current statin therapy. The difference between treatments was analysed for four co-primary outcomes: mean percentage change from baseline in total cholesterol (TC), LDL-C, and high-density lipoprotein cholesterol (HDL-C), and number of patients achieving LDL-C treatment goal. Meta-analysis results are presented for a modified version of the inverse variance random effects model. RESULTS: Five RCTs involving a total of 5039 patients were included in the meta-analysis. The weighted mean difference (WMD) between treatments significantly favoured the ezetimibe/statin combination over placebo/statin for TC (-16.1% (-17.3, -14.8); p < 0.0001), LDL-C (-23.6% (-25.6, -21.7); p < 0.0001) and HDL-C (1.7% (0.9, 2.5); p < 0.0001). The relative risk of reaching the LDL-C treatment goal was significantly higher for patients on ezetimibe/statin relative to those on placebo/statin (3.4 (2.0, 5.6); p < 0.0001). In pre-defined sub-group analyses of studies in patients with coronary heart disease, the WMD between treatments remained significantly in favour of ezetimibe/statin (p < 0.0001) for TC and LDL-C but was no longer significant for HDL-C. Elevations in creatine kinase, alanine aminotransferase or aspartate aminotransferase that were considered as an adverse effect did not differ significantly between treatments. CONCLUSIONS: The meta-analysis we performed included only five studies and was restricted to analysis of the changes in cholesterol levels relative to baseline. However, the results suggest that ezetimibe co-administered with ongoing statin therapy provides significant additional lipid-lowering in patients not at LDL-C goal on statin therapy alone, allowing more patients to reach their LDL-C goal.

Catapano AL, Davidson MH, Ballantyne CM, Brady WE, Gazzara RA, Tomassini JE, Tershakovec AM. · University of Milan, Milan, Italy. · Curr Med Res Opin. · Pubmed #17022864 No free full text.

Abstract: OBJECTIVE: To assess the lipid-altering efficacy and safety of ezetimibe/simvastatin single tablet product compared with rosuvastatin at the approved usual starting, next highest, and maximum doses. RESEARCH DESIGN AND METHODS: Double-blind, multicenter, 6-week, parallel-group study in hypercholesterolemic patients (n = 2959). Patients were randomized based on stratification by low-density lipoprotein cholesterol (LDL-C) levels to ezetimibe/simvastatin or rosuvastatin, respectively, at the usual starting (10/20 or 10 mg/day), the next highest (10/40 or 20 mg/day), and maximum doses (10/80 or 40 mg/day). RESULTS: At all doses and across doses, ezetimibe/simvastatin reduced LDL-C levels significantly more (52-61%) than rosuvastatin (46-57%; p < or = 0.001). Significantly greater percentages of all patients (p < 0.001) and high risk patients (p < or = 0.005) attained LDL-C levels < 70 mg/dL (1.8 mmol/L) following ezetimibe/simvastatin treatment compared with rosuvastatin at the prespecified doses and across doses. Ezetimibe/simvastatin also produced significantly greater reductions in total cholesterol (p < 0.001), non-high-density lipoprotein cholesterol (p < 0.001), lipid ratios (p < or = 0.003), and apolipoprotein B (p < 0.05). Reductions in triglycerides were significantly greater with ezetimibe/simvastatin than rosuvastatin at the usual starting (p = 0.004) and next highest (p = 0.006) doses, and across all doses (p < 0.001). Increases in high-density lipoprotein cholesterol, and decreases in high sensitivity C reactive protein (hsCRP) were similar between treatment groups. Safety profiles were comparable for both treatments; however, the percent of patients with proteinuria was significantly higher following rosuvastatin treatment than ezetimibe/simvastatin, respectively at 10 mg versus 10/20 mg/day (p = 0.004) and 40 mg versus 10/80 mg/day (p < 0.001). CONCLUSION: Ezetimibe/simvastatin was more effective than rosuvastatin in LDL-C lowering, and provided greater or comparable improvements in other lipid measures and hsCRP at the approved usual starting, next highest, and maximum doses in hypercholesterolemic patients. Although the doses compared in this study were not equivalent on a milligram basis, the results provide clinically relevant information regarding the use of these drugs for initial therapy and for subsequent use at higher doses when appropriate. Both treatments were generally well-tolerated; however, this study was not powered nor of sufficient duration to assess the prevalence of rare clinical adverse effects. Overall, ezetimibe/simvastatin offers an effective and tolerable treatment option for lipid management. An assessment of its full clinical benefit awaits evaluation in longer-term clinical studies.

Filippi A, Tragni E, Bignamini AA, Sessa E, Merlini G, Brignoli O, Mazzaglia G, Catapano AL. · Italian College of General Practitioners, Florence, Italy. · Eur J Cardiovasc Prev Rehabil. · Pubmed #15785302 No free full text.

Abstract: BACKGROUND: Stroke represents worldwide the second and seventh cause of death and invalidity, respectively. Patients with ischaemic stroke or transitory ischaemic attack (TIA) are at high risk of recurrence, therefore requiring intensive treatment. Hypercholesterolaemia is a modifiable risk factor for stroke. The general practitioners attitude towards detection and treatment of dyslipidaemia among patients with stroke or TIA in Italy is unknown; we therefore aimed to address this issue taking advantage of the database of The Italian College of General Practitioners. METHODS: Prevalence of the monitored factors (lipid levels, statin prescription, and lipid level control with hypolipidaemic agents prescription) were analysed on a patient population of 465 061. RESULTS: A total of 2555 (49% women and 51% men) patients with a diagnosis of stroke and 2755 patients (52% women and 48% men) with a diagnosis of TIA were included in the study. Total plasma cholesterol (TC) was reported in more than 60% of the patients and low-density lipoprotein cholesterol (LDLc) and high-density lipoprotein cholesterol (HDLc) in less than half. Total plasma cholesterol and LDLc were controlled in 70.3 and 72.8% of the patients, respectively. The percentage of controlled patients decreased to 64% when both LDLc and TC were considered. Statins and fibrates were prescribed in a small proportion of patients (16.9 and 3.5%, respectively). An acceptable control of blood lipids was achieved in a majority of those patients (60.2%). However a relatively large number of patients (646) with high plasma lipids remained untreated. CONCLUSIONS: Monitoring and intervention strategies on plasma lipid levels in patients with a diagnosis of stroke or TIA need to be improved.

Maggi FM, Raselli S, Grigore L, Redaelli L, Fantappiè S, Catapano AL. · Department of Pharmacological Sciences, University of Milan, 20133 Milan, Italy. · J Clin Endocrinol Metab. · Pubmed #15181082 links to  free full text

Abstract: The objective of this work was to study whether changes in remnant lipoprotein (RLP) plasma levels during the postprandial phase relate to alterations of the endothelial function. Fasted patients (15 moderately dyslipidemic men) were given an oral fat load (OFL), and blood samples were collected before the OFL ingestion (T0) and 2, 4, 6, and 8 h (T2, T4, T6, T8) thereafter. Endothelial function, determined as flow-mediated dilatation (FMD) of the brachial artery, was assessed at the same time points. Triglyceridemia peaked between T4 (5.48 +/- 0.64 mmol/liter) and T6 (5.34 +/- 0.89 mmol/liter) and decreased at 8 h (4.36 +/- 0.87 mmol/liter) after the OFL. FMD decreased significantly 6 h after the OFL consumption (from 16.03 +/- 1.32% to 11.53 +/- 1.42%, P < 0.01). Cholesterol in RLPs increased steadily up to 6 h and decreased at 8 h (T0 0.53 +/- 0.10, T6 0.81 +/- 0.11, T8 0.73 +/- 0.13 mmol/liter). Fasting levels of triglycerides and cholesterol-RLPs (C-RLPs) correlated significantly with FMD at baseline. The decrease in endothelial function at 6 h also significantly correlated with the area under the curve of triglycerides (R = 0.53, P = 0.04). Postprandial C-RLPs (area under the curve), however, showed the best correlation with the decrease of FMD (R = 0.63, P = 0.012). The correlation persisted in a multivariate analysis. We concluded that C-RLPs contribute significantly to the endothelial dysfunction occurring during the postprandial lipemia.

Tragni E, Catapano AL, Bertelli A, Poli A. · Servizio di Epidemiologia e Farmacologia Preventiva (SEFAP), Dipartimento di Scienze Farmacologiche, Università degli Studi, Via Balzaretti, 9 20133 Milano. · Ital Heart J. · Pubmed #14983746 No free full text.

Abstract: BACKGROUND: Currently available guidelines suggest that hypolipidemic drugs should be used in subjects at high risk for coronary heart disease (CHD). Very often, however, physicians fail to comply with the targets (total or LDL cholesterol) that are proposed by the Consensus Panels. The aim of this survey was to evaluate the efficacy of a hypocholesterolemic treatment in achieving the therapeutic target according to Adult Treatment Panel II guidelines in a sample of general practitioners from Lombardy, a region of northern Italy. METHODS: Eighty-five general practitioners reported in a standardized manner data on the presence of major and minor coronary risk factors from at least 15 patients from their database for a total of 1275 patients. Treatment targets for LDL cholesterol were 100 mg/dl in patients with existing cardiovascular disease (class I), 130 mg/dl for patients with > or = 2 CHD risk factors (class II), and 160 mg/dl for the others (class III). Results on the efficacy of the therapy were divided into the following categories: 1) to target, 2) failure to reach the target by < or = 30 mg/dl, 3) failure to reach the target by > 30 mg/dl. Data were analyzed by means of the CSS statistical software. RESULTS: Overall 58.2% of the patients were males and the average age of the population was 59.2 +/- 10.1 years; 20.4% were diabetics, 34.5% smokers, 48.8% hypertensives, 16.9% had a previous myocardial infarction, 14.9% were suffering of stable angina, and 8.1% had undergone coronary artery bypass grafting and/or coronary angioplasty. Moreover 33.9% had a positive family history for CHD. Class I patients were 31.7% of the population, class II 52.9%, and class III 15.4%. Plasma lipid levels before treatment were on average 294 +/- 37 mg/dl for total cholesterol, 211 +/- 37 mg/dl for LDL cholesterol, 45 +/- 16 mg/dl for HDL cholesterol, and 195 +/- 104 mg/dl for plasma triglycerides. Of the patients 78.8% received dietary counseling, while 94.7% received hypolipidemic treatment (89.9% were only on statins). The average post-treatment value for total cholesterol was 225 +/- 33 mg/dl (-23%), LDL cholesterol 145 +/- 34 mg/dl (-31%), HDL cholesterol 50 +/- 15 (+15%), and plasma triglycerides 151 +/- 55 (-17%). When patients were stratified according to their LDL cholesterol target, 29.9% were on target, 34.0% missed it by < or = 30 mg/dl, and 36.1% by > 30 mg/dl. In class I only 14.9% achieved the target, in class II 31.2%, in class III 61.8%. CONCLUSIONS: These data show that general practitioners do not aim at an aggressive lipid lowering in patients at high risk, perhaps because of the limited knowledge of the need for modulating treatment according to the global CHD risk.

Wilson CJ, Priore Oliva C, Maggi F, Catapano AL, Calandra S. · Metabolic Service, Starship Children's Hospital, Auckland, New Zealand. · Ann Neurol. · Pubmed #12783430 No free full text.

Abstract: An infant presented with massive hyperchylomicronemia and a severe encephalopathy. MRI showed marked lipid deposition throughout the brain. Despite the normalization of the biochemistry, there was little clinical improvement, and at 18 months of age she has severe developmental delay, a strikingly abnormal MRI. Apolipoprotein C-II, the lipoprotein on chylomicrons responsible for the activation of lipoprotein lipase, was not detectable in blood. Analysis of the APO C-II gene revealed a novel homozygous point mutation, 1118C-->A. Subsequently, another sibling has been born with the same homozygous mutation and similar biochemistry but, perhaps because of early treatment, a normal neurological outcome.

Catapano AL, Poli A, Tragni E. · Istituto di Scienze Farmacologiche, Centro Studi Aterosclerosi Università degli Studi Via Balzaretti, 9, 20133 Milano. · Cardiologia. · Pubmed #12497838 No free full text.

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Pirillo A, Zhu W, Norata GD, Zanelli T, Barberi L, Roma P, Catapano AL. · Institute of Pharmacological Sciences, University of Milano, Italy. · Clin Chem Lab Med. · Pubmed #10834403 No free full text.

Abstract: Endothelium is an early target of pro-atherosclerotic events, which may result in functional and morphological perturbations. Oxidized low density lipoproteins, an atherogenic factor with strong cytotoxicity, may potentially contribute to altered endothelial function through the activation of a stress response, which would rescue cells to full vitality, or, conversely, by leading to cell death. Evidence is presented here for the ability of chemically oxidized low density lipoproteins to induce the synthesis of the inducible form of heat shock protein 70 in cultured human endothelial cells, and for the association of epitopes of these modified lipoproteins with apoptotic endothelial cells in aortic sections from hypercholesterolemic rabbits.

Norata GD, Catapano AL. · No affiliation provided · Circ Res. · Pubmed #17431191 links to  free full text

This publication has no abstract.