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The Effect of Polyphenols in Olive Oil on Heart Disease Risk Factors: A Randomized Trial

María-Isabel Covas, MSc, PhD; Kristiina Nyyssönen, MSc, PhD; Henrik E. Poulsen, MD, PhD; Jari Kaikkonen, MSc, PhD; Hans-Joachim F. Zunft, MD, PhD; Holger Kiesewetter, MD, PhD; Antonio Gaddi, MD, PhD; Rafael de la Torre, MSc, PhD; Jaakko Mursu, MSc; Hans Bäumler, MSc, PhD; Simona Nascetti, MD, PhD; Jukka T. Salonen, MD, PhD; Montserrat Fitó, MD, PhD; Jyrki Virtanen, MSc; Jaume Marrugat, MD, PhD, EUROLIVE Study Group
[+] Article and Author Information

From the Municipal Institute for Medical Research, Barcelona, Spain; University of Kuopio and Oy Jurilab, Kuopio, Finland; Rigshospitalet, University Hospital, Copenhagen, Denmark; German Institute of Human Nutrition, Postdam-Rehbruecke, Germany; Charité-University of Medicine of Berlin, Berlin, Germany; and Centro per lo Studio dell'Arteriosclerosi e delle Malattie Dismetaboliche “GC Descovich,” Policlinico S. Orsola-Malpighi, Bologna, Italy.


Acknowledgments: The authors thank the EUROLIVE Investigators: R. Elosua, J.S. Vila, H. Schroder, and M. Farré-Albaladejo, Municipal Institute for Medical Research (IMIM), Barcelona, Spain, for methodologic and statistical assistance, performing diet record analyses, and management assistance; S. Voutilainen, T. Rissanen, T.P. Tuomainen, and V.P. Valkonen, Research Institute of Public Health, Kuopio University, Kuopio, Finland, for management and technical assistance; S. D'Addato, E. Grandi, S. Linarello, Z. Sangiorgio, and A. Fiorito, Policlinico S. Orsola-Malpighi, Bologna, Italy, for technical assistance and performing diet record analyses; T. Vilppo, Oy Jurilab, Kuopio, Finland, for performing oxidative and antioxidative biomarkers; and M.C. López-Sabater, K. De la Torre, and R.M. Lamuela-Raventós, Barcelona University, Barcelona, Spain, for the olive oil analyses.

Grant Support: By grant QLK1-CT-2001-00287 from the Commission of the European Communities Quality of Life and Management of Living Resources program.

Potential Financial Conflicts of Interest: None disclosed.

Requests for Single Reprints: María-Isabel Covas, PhD, Lipids and Cardiovascular Epidemiology Unit, Municipal Institute for Medical Research (IMIM), Carrer Dr. Aiguader, 80, 08003 Barcelona, Spain; e-mail, mcovas@imim.es.

Current Author Addresses: Drs. Covas, Fitó, and Marrugat: Lipids and Cardiovascular Epidemiology Unit, Municipal Institute for Medical Research (IMIM), Carrer Dr. Aiguader, 80, 08003 Barcelona, Spain.

Dr. Nyyssönen, Mr. Mursu, and Mr. Virtanen: Research Institute of Public Health, University of Kuopio, Harjulantie 1B, 70211 Kuopio, Finland.

Dr. Poulsen: Department of Clinical Pharmacology, Rigshospitalet, University Hospital Copenhagen, 20 Tagensvej, 2200 Copenhagen, Denmark.

Drs. Kaikkonen and Salonen: Oy Jurilab, Neulaniementie 2L 12, 70210 Kuopio, Finland.

Dr. Zunft: German Institute of Human Nutrition (DIFE), Arthur-Scheunert-Allee, 114-116, 14558 Postdam-Rehbruecke, Germany.

Drs. Kiesewetter and Bäumler: Charité-University of Medicine of Berlin, Schumannstr, 20/21, 10117 Berlin, Germany.

Drs. Gaddi and Nascetti: Dipartimento di Medicina Clinica e Biotecnologia Applicata, Policlinico S. Orsola-Malpighi, Via Massarenti, 9, 40138 Bologna, Italy.

Dr. de la Torre: Pharmacology Research Unit, Municipal Institute for Medical Research (IMIM), Carrer Dr. Aiguader, 80, 08003 Barcelona, Spain.

Author Contributions: Conception and design: M.-I. Covas, K. Nyyssönen, H.E. Poulsen, H.-J.F. Zunft, H. Kiesewetter, A. Gaddi, J.T. Salonen, J. Marrugat.

Analysis and interpretation of the data: M.-I. Covas, J. Kaikkonen, H. Kiesewetter, R. de la Torre, J. Mursu, J. Marrugat.

Drafting of the article: M.-I. Covas, R. de la Torre, J. Marrugat.

Critical revision of the article for important intellectual content: K. Nyyssönen, H.E. Poulsen, J. Kaikkonen, H.-J.F. Zunft, H. Kiesewetter, A. Gaddi, J. Mursu, H. Bäumler, S. Nascetti, J.T. Salonen, M. Fitó, J. Virtanen, J. Marrugat.

Final approval of the article: M.-I. Covas, K. Nyyssönen, H.E. Poulsen, J. Kaikkonen, H.-J.F. Zunft, A. Gaddi, R. de la Torre, H. Bäumler, S. Nascetti, J.T. Salonen, M. Fitó, J. Marrugat.

Provision of study materials or patients: K. Nyyssönen, H.E. Poulsen, A. Gaddi, S. Nascetti, M. Fitó, J. Marrugat.

Obtaining of funding: M.-I. Covas, K. Nyyssönen, J. Kaikkonen, H.-J.F. Zunft, H. Kiesewetter, J.T. Salonen, J. Marrugat.

Administrative, technical, or logistic support: J. Mursu, H. Bäumler, J. Virtanen.

Collection and assembly of data: K. Nyyssönen, J. Kaikkonen, H.-J.F. Zunft, H. Bäumler, S. Nascetti, M. Fitó, J. Virtanen.


Ann Intern Med. 2006;145(5):333-341. doi:10.7326/0003-4819-145-5-200609050-00006
Text Size: A A A

A daily 25-mL dose of all types of olive oil, similar to the daily consumption recommended by the U.S. Food and Drug Administration (5), reduced lipid cardiovascular risk factors and improved glutathione antioxidant status (7). Daily consumption of high- and medium-polyphenol olive oil decreased oxidative damage on lipids. Consumption of olive oil with high phenolic content provided the greatest benefits by increasing HDL cholesterol levels and reducing the oxidative damage on lipids.

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Figures

Grahic Jump Location
Figure 1.
Study flow diagram.

Sequence of olive oil administration: 1) high-, medium-, and low-polyphenol olive oil; 2) medium-, low-, and high-polyphenol olive oil; and 3) low-, high-, and medium-polyphenol olive oil.

Grahic Jump Location
Grahic Jump Location
Figure 2.
Changes from preintervention periods (mean percentage and upper 95% CI limit) in urinary tyrosol and hydroxytyrosol excretion as the function of the phenolic content of the olive oil administered.

P < 0.001 for linear trend. *P < 0.05 vs. low-polyphenol olive oil. †P < 0.05 vs. medium-polyphenol olive oil.

Grahic Jump Location

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References

Letters

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Comments

Submit a Comment
questioning dosage
Posted on September 7, 2006
James B Roufs
Nutritionist
Conflict of Interest: None Declared

Are the polyphenol contents correct? 25 ml of the three compositions translate into basically 0, 4, and 9 mg of pp ingested daily daily from the 25 ml olive oil. This would appear to be very low dose.

Please advise and thank you for your time...much appreciated!

Jim

Conflict of Interest:

Work in dietary supplement industry as consultant

Do interactions of olive oil-derived polyphenols and iron produce an antioxidant effect in vivo?
Posted on September 27, 2006
Luca Mascitelli
Comando Brigata alpina Julia
Conflict of Interest: None Declared

TO THE EDITOR "“ Covas et al (1) found that consumption of polyphenol- rich olive oil raised high density lipoprotein (HDL) levels and lowered levels of oxidative stress markers and oxidized low density lipoprotein. We suggest that some of the involved mechanisms might be related to interactions of endogenous iron with polyphenols absorbed from olive oil. The polyphenols may augment the antioxidant activity of endogenous iron binding antioxidants (2). Use of phlebotomy to achieve modest lowering of stored iron level (3) or induction of near iron deficiency (4) is associated with increased HDL concentration. Polyphenol-rich olive oil may acutely augment the reactive iron- neutralizing activity of endogenous iron binding capacity. In prolonged use, olive oil-derived polyphenols are associated with progressive loss of iron stores (5). Lowering the availability of reactive iron in vivo either by decreasing stored iron level or by acute iron chelation may improve antioxidant activity and raise HDL levels by closely related mechanisms (6).

Luca Mascitelli, MD Comando Brigata alpina "Julia" 33100 Udine, Italy

Francesca Pezzetta, MD Ospedale di San Vito al Tagliamento 33078 San Vito al Tagliamento, Italy

Jerome L. Sullivan, MD, PhD Burnett College of Biomedical Sciences University of Central Florida 32816 Orlando, Florida, USA

REFERENCES

1. Covas MI, Nyyssönen K, Poulsen HE et al. for the EUROLIVE Study Group. The effect of polyphenols in olive oil on heart disease risk factors: a randomized trial. Ann Intern Med. 2006; 145: 333-41.

2. Medina I, Tombo I, Satue-Gracia MT, German JB, Frankel EN. Effects of Natural Phenolic Compounds on the Antioxidant Activity of Lactoferrin in Liposomes and Oil-in-Water Emulsions. J Agric Food Chem. 2002; 50: 2392 -9.

3. van Jaarsveld H, Pool GF. Beneficial effects of blood donation on high density lipoprotein concentration and the oxidative potential of low density lipoprotein. Atherosclerosis. 2002; 161: 395-402.

4. Facchini FS, Saylor KL. Effect of iron depletion on cardiovascular risk factors: studies in carbohydrate-intolerant patients. Ann N Y Acad Sci. 2002; 967:342-51.

5. Facchini FS, Saylor KL. A low-iron-available, polyphenol-enriched, carbohydrate-restricted diet to slow progression of diabetic nephropathy. Diabetes. 2003; 52:1204-9.

6. Sullivan J. Is stored iron safe? J Lab Clin Med. 2004; 144: 280-4.

Conflict of Interest:

None declared

Can Polyphenols Protect Against Endotelial Dysfunction in Coronary Artery Disease?
Posted on October 3, 2006
Viola Vargova
Postgraduate Researcher,Faculty of Medicine,Safaric University,Kosice,Slovakia
Conflict of Interest: None Declared

Sir,

Numerous studies have indicated that olive oil intake may be inversely associated with risk of coronary artery disease (CAD) and cancer mortality. The beneficial effects of olive oil could be due to monounsaturated fatty acids (MUFA) or polyphenols which are rich in the extravirgin olive oil. We appreciate very much the study by Covas et al(1), showing that extravirgin olive oil with high phenolic content had greater beneficial effects compared to oil with lowest content of fenolics but with same amount of MUFA, on high density lipoprotein cholesterol(HDL- C),total cholesterol/HDL-C ratio and oxidative stress.However,it is difficult to completely rule out that these beneficial effects may be due to independent effects of MUFA rather than phenolics.Many studies have demonstrated the beneficial effects of antioxidant vitamins E,C and beta carotene on risk of CAD risk factors. However, when these antioxidants were administred to test their effects in randomized controlled intervention trials, there was no significant reduction in total cardiac events and mortality. Therefore, the results of this study may be interesting but do not provide a solution that longterm administration of extravirgin olive oil would also decrease the mortality or would provide better quality of life.

The results of treatment of post myocardial infarction patients with various oils have been conflicting.While fish oil and canola oils have been reported to be protective( 2,3) againts cardiac events and mortality, more recent trials reported no beneficial effects with fish oil and ALA rich oils.( 4,5).However, in these studies Mediterranean diet along with oils was not emphasised to be necessary for lack of benefit. It seems that the exact function of dietary nutrients and various mechanisms of pathogenesis of complications in CAD are still unknown.Administration of single meal rich in refined starches and glucose causes increased production of superoxide anion and free fatty acids(FFA) which are damaging to endothelium resulting into endothelial dysfunction which is a risk factor of atherothrombosis(6-8). Apart from these adverse effects, energy rich large meal enhances the generation of ATP in the mitochondria in conjuction with increased production of free radicals, inside the mitochondrial cell membrane, where they accumulate and damage the mitochondria. The mitochondria is protected by the coenzyme Q10, which is powerful free radical scavenger. However, if there is a deficiency of coemzyme Q10 and other antioxidants vitamin E and C, extensive damage can occur to endothelium, myocardium, plateletes and beta cells of pancrease.

There is an increased release of proinflamatory cytokines, tumor necrosis factor- alpha, IL-6, IL-18 and IL-2 along with rise in FFA and hyperglycemia which further damage the endothelium resulting into coronary trombosis and cardiac events(6-8). Increased availabilityof phenolics, MUFA and ù "“3 fatty acids via increased intake of extravirgin olive oil, along with mustard or canola oil(2,3) may repair these defects, leading to improved endothelial function, and decreased release of proinflammatory cytokines which may be protective against complications in patients with high risk of cardiac events. We would greatly appreaciate the opinion of authors on our view point.Email,icn2005@sancharnet.in

REFERENCES:

1.Covas MI,Nyysonen K,Poulsen HE et al.The effect of polyphenols in olive oil on heart disease risk factors.a randomized,controlled trial.Ann Intern Med 2006;145:333-341.

2..De Lorgeril M, Salen P, Martin JL,Monjaud I, Delaye J, Mamelle N. Mediterranean diet, traditional risk factors and the rate of cardiovascular complications after myocardial infarction .Final report of the Lyon Diet Heart Study. Circulation 1999;99:779-785.

3.Singh RB, Niaz MA, Sharma JP,Kumar R,Rastogi V,Moshiri M.Randomized, double blind,placebo controlled trial of fish oil and mustard oil in patients with suspected acute myocardial infarction:the Indian Experiment of Infarct Survival-4. Cardiovasc Durg Ther 1997;11:485-91.

4.Nilsen DW,Albraktsen G,Landmark K et al.Effects of a high dose concentrate of n-3 fatty acids or corn oil introduced early after an acute myocardial infarction in serum triglycerol and HDL cholesterol.Am J Clin Nutr 2001,74:50-56.

5.Burr ML,Fehly AM,Gilbert JF et al.Lack of benefit of dietary advice to men with angina;results of a controlled trial.Eur J Clin Nutr 2003;57;193- 200.

6.Esposito K,Glugliano D.Diet and inflammation:a link to metabolic and cardiovascular diseases.Euro Heart J,2006,27:15-20.

7.Vogel RA.Eating,vascular biology,and atherosclerosis:a lot to chew on.Euro Heart J,2006,27:13-14.

8.Singh RB,Pella D,DeMeester F.What to eat and chew in acute myocardial infarction. Eur Heart J 2006,27:1628-29.

Conflict of Interest:

None declared

Differential Effect of Olive Oil
Posted on October 16, 2006
Bruce L. Ring
Caritas Good Samaritan Med Center
Conflict of Interest: None Declared

Though post hoc analysis often raises more questions than answers, was there any trend to a greater beneficial effect of virgin olive oil on those individuals who had the most adverse lipid profiles at baseline? Bruce L. Ring, M.D. Caritas Good Samaritan Medical Center, Brockton, MA

Conflict of Interest:

None declared

Polyphenolic content in olive oil and bioactivity
Posted on November 7, 2006
María Isabel Covas
Institut Municipal d´Investigació Mèdica (IMIM), Barcelona , Spain
Conflict of Interest: None Declared
The polyphenolic content of the olive oils described is correct, as well as the estimated (0, 4, and 9 mg/day) intake from 25 mL/day of olive oils. The antioxidant activity of hydroxytyrosol, the major olive oil phenolic compound, has been reported to be 5 times greater than that of vitamin E (1). The recommended Dietary Allowance (RDA) for vitamin E is 15 mg/day. Thus, 9 mg/day of olive oil phenolic compounds do not seem to be a very low dose to achieve protective effects.

References

1.Aruoma OI, Deiana M, Jenner A, Halliwell B, Kaur H, Banni S, et al. J Agric Food Chem 1998; 46: 5181-7.

2. Institute of Medicine , Food and Nutrition board. Dietary Reference Intakes: Vitamin C, vitamin E, selenium, and carotenoids. National Academy Press, Washington, DC. 2000

Polyphenols from olive oil an iron metabolism
Posted on November 7, 2006
María Isabel Covas
Institut MUnicipal d´Investigació Mèdica (IMIM), Barcelona
Conflict of Interest: None Declared

We agree with Mascitelli and Sullivan that an interaction between polyphenols from olive oil and iron metabolism could, at least in part, explain the reduction on oxidative lipid damage observed in the EUROLIVE study. However, a reduction of iron absorption by polyphenols seems at present to be the most probable mechanism for the interaction. In vivo changes in the iron-ascorbate-oxygen-radical generating system are not yet well defined (1) whereas the inhibition of non-heme iron absorption by dietary polyphenols, i.e from tea, is well known (2). The potential effect of low iron status, such as that induced by blood donation, on LDL oxidation markers is still under debate (3). Although in humans iron depletion by blood donations elevates HDL cholesterol (4), in an experimental study in hypercholesterolemic rats the excess of iron, not its depletion, increased HDL-C (5). The suggestion by Mascitelli and Sullivan that the lowering of the availability of reactive iron in vivo either by decreasing stored iron level or by acute iron chelation, may improve antioxidant activity and raise HDL levels by closely related mechanisms is neither supported nor can be dismissed on the basis of our presented findings. The interaction between polyphenols from olive oil, iron absorption, and oxidative stress merits further investigation.

References

1 Van Jaarsveld H, Pool GF. Beneficial effects of blood donation on high density lipoprotein concentration and the oxidative potential of low density lipoprotein. Atherosclerosis 2002; 161: 395-402.

2. Mennen LI, Walker R, Bennetau-Pelissero C, and Saclbert A. Risk and safety of polyphenol consumption .

3. Van Hoydonck PGA, Schouten EG, Hoppenbrowers KPM, Temme EHM. Is blood donation induced low iron status associated with favourable levels of oxLDL, s-ICAM, s-VCAM and vWF antigen in healthy men? Atherosclerosis 2004; 172:321-327.

4. Nyyssönen K, Salonen R, Korpela H, Salonen JT. Elevation of serum high density lipoprotein cholesterol concentration due to lowering of body iron stores by blood letting. Eur J Lab Med 1994;2:113-115.

5. Turbino-Ribeiro SML, Silva ME, Chianca DA, de Paula H, Cardoso LM, Colombari E, Pedrosa ML. Iron overload in hypercholesterolemic rats affects iron homeostasis and serum lipids but not blood pressure. J Nutr 2003;133:15-20.

Conflict of Interest:

None declared

Olive Oil--Effect on Other Disease Risk Factors
Posted on October 24, 2006
James A Craner
University of Nevada School of Medicine, Las Vegas
Conflict of Interest: None Declared

To the Editor:

The randomized trial of olive oils on heart disease risk factors (1) concludes that daily supplements of 25 ml of extra-virgin olive oil improves cardiac risk factors. However, the authors do not appear to have consider or measured a serious side effect, namely the increase in body fat and weight gain that olive oil will cause.

Like all other plant-derived oils, olive oil is pure (100%) fat. 25 ml (1. 7 Tbsp) of olive oil (extra virgin or otherwise) contains 23.7 grams of fat, which is the equivalent of 213 kcal (2). Daily consumption of this amount of oil (fat) for just one year with no other change in dietary intake or calorie expenditure (exercise) would cause 8.64 kg (19.0 lbs) of additional weight gain each year [25 ml/day x 365 days/yr x 14 g fat/Tbsp x 1 Tbsp/14.79 ml x 1 kg/1000 g].

The volunteers in this study, who are reported as being in "good health," have an average baseline body mass index of 24 kg/m2 (perhaps from eating so much olive oil in their diets), which is borderline overweight. Assuming an average European adult male height of 175 cm (5 feet, 9 inches)(3), and assuming no other compensatory dietary or exercise modifications, a weight gain of 8.64 kg (19.0 lbs) of fat each year just from these supplements would impact body mass index (BMI) as shown in Table 1, and as illustrated in Figure 1.

In just 2.5 years, over half of these "healthy" volunteers will become obese, i.e., BMI>30 kg/m2. By 10 years, the average man continuing daily olive oil supplementation would be conservatively expected to weigh over 350 pounds!

Obesity is well established as the principal cause of or major risk factor for development of adult-onset diabetes mellitus, hypertension, and metabolic syndrome"”all of which are paradoxically secondary risk factors for CAD. Various types of cancer (prostate, colon, uterus, breast, esophagus), gallstones, gout, osteoarthritis of the knees and hips, obstructive sleep apnea, and non-alcoholic steatohepatitis, are major chronic diseases caused by or highly associated with obesity(4). Obesity is associated with over US $13 billion for disease care among workers in the United States alone (5).

To offset this massive weight gain, each person taking a daily olive oil supplement would need to increase his exercise by 213 kcal per day, which would require nearly doubling the baseline level of activity (mean 231 kcal per day) described in the study. The probability of overweight or obese individuals permanently losing clinically significant amounts of weight through increased physical activity is low (6). Furthermore, to achieve this questionably significant biochemical effect, participants were instructed to consume a diet intentionally devoid of anti-oxidant-containing vegetables, fruits and legumes"”the foundation of an optimally healthy diet, not merely for prevention of CAD but for prevention of all chronic diseases (7).

Is the net "benefit" of lowering LDL cholesterol an average of -0.58 mg/dl or increasing HDL cholesterol by 1.74 mg/dl"”both clinically trivial results, albeit statistically " significant""”really worth the individual and societal price of promoting obesity? There are obvious, deleterious, long-term clinical and public health ramifications of this and similar research agendas that appear intended to promote more consumption of European olive oil (8). Olive oil is not a healthy food, no matter what its level of virginity or microconstituents.

James Craner, MD, MPH, FACOEM, FACP Private Practice, Occupational Medicine/Internal Medicine, Reno/Las Vegas, NV Assistant Clinical Professor, University of Nevada School of Medicine, Las Vegas

References:

1. Covas MI, Nyyssonen K, Poulsen HE, et al. The effect of polyphenols in olive oil on heart disease risk factors. Ann Int Med 2006;145:333-341.

2. Pennington JAT. Food Values of Portions Commonly Used (15th Ed.). Harper & Row, New York, 1989.

3. Cavelaars, AEJM, Kunst, AE, Geurts, JJM, et al. Persistent variations in average height between countries and between socio-economic groups: an overview of 10 European countries. Annf Human Biology 27(4),407 - 421.

4. Calle EE, Thun MJ, Petrelli JM, et al. Body-mass index and mortality in a prospective cohort of U.S. adults. N Engl J Med 1999;341:1097-105.

5. Hertz RP, Unger AN, McDonald M, et al. The impact of obesity on work limitations and cardiovascular risk factors in the U.S. workforce. J Occup Environ Med 2004;46:1196-1203.

6. Shaw K, O'Rourke P, Del Mar C, Kenardy J. Psychological interventions for overweight or obesity. Cochrane Database of Systematic Reviews 2005, Issue 2. Art. No.: CD003818. DOI: 10.1002/14651858.CD003818.pub2.

7. Byers T, Nestle M, McTiernan A, et al. American Cancer Society guidelines on nutrition and physical activity for cancer prevention: reducing the risk of cancer with healthy food choices and physical activity. CA Cancer J Clin 2002;52:92"“119.

8. Estruch R, Martinez-Gonzalez MA, Corella D, et al. Effects of a Mediterranean-style diet on cardiovascular risk factors: a randomized trial. Ann Int Med 2006;145:1-11.

Table 1

BaselineYr 1Yr 2Yr 3Yr 4Yr 5Yr 10
Weight (lbs)163182201220239258353
Height (in)69696969696969
BMI (kg/m2)*24.126.929.732.535.338.151.9
% increase from baseline0%12%23%35%47%58%116%

*To convert from lbs/in2 to kg/m2, multiply by 703

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Summary for Patients

The Effect of Virgin and Refined Olive Oils on Heart Disease Risk Factors

The summary below is from the full report titled “The Effect of Polyphenols in Olive Oil on Heart Disease Risk Factors. A Randomized Trial.” It is in the 5 September 2006 issue of Annals of Internal Medicine (volume 145, pages 333-341). The authors are M.-I. Covas, K. Nyyssönen, H.E. Poulsen, J. Kaikkonen, H.-J.F. Zunft, H. Kiesewetter, A. Gaddi, R. de la Torre, J. Mursu, H. Bäumler, S. Nascetti, J.T. Salonen, M. Fitó, J. Virtanen, and J. Marrugat, for the EUROLIVE Study Group.

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