Cardiology

White Coat Hypertension: Are Doctors Bad for Your Blood Pressure?

March 20, 2013

By Lauren Foster

Faculty Peer Reviewed

Hypertension is a pervasive chronic disease affecting approximately 65 million adults in the United States, and a significant cause of morbidity and mortality [1]. Antihypertensives are widely prescribed due to their effectiveness in lowering blood pressure, thereby reducing the risk of cardiovascular events. However, the phenomenon of the “white coat effect” may be a complicating factor in the diagnosis and management of hypertensive patients. It is well established that a considerable number of people experience an elevation of their blood pressure in the office setting, and particularly when measured by a physician. The cause of this white coat hypertension, as well as its implications in the prognosis and treatment of hypertension, is still controversial.

The concept of white coat hypertension has existed for many years, with some of the first reports of blood pressure varying between a resting value and one taken by the physician written by Alam and Smirk in the 1930s [2]. Studies since then have continued to demonstrate the elevating effect of a physician’s office on blood pressure, with an estimated 20% prevalence of white coat hypertension in the general population [3]. The definition of white coat hypertension used in research continues to vary, however, producing a range of incidences from 14.7% to 59.6% [3]. Most studies characterize white coat hypertension as an office blood pressure of greater than 140/90 mmHg, with ambulatory blood pressures less than 135/85 [3]. The regular use of home blood pressure monitors and 24-hour ambulatory blood pressure monitoring (ABPM) has further demonstrated this discrepancy in clinical practice as well as in research.

White coat hypertension is hypothesized to be a result of anxiety and subsequent sympathic nervous system activation. Studies examining the presence of white coat hypertension among individuals with anxious traits have not found evidence of this association; rather it appears to be associated with a state of anxiety unique to the presence of a physician [5]. In a study by Gerin, Ogedegbe, and colleagues, ABPM measurements of patients’ blood pressure in a separate laboratory facility were compared to ABPM measurements in the waiting room of a physician’s office and a manual blood pressure performed by a physician in the examining room. Their results demonstrated a significant elevation of blood pressure on the day of the physician’s office visit, with a larger increase in previously diagnosed hypertensive patients, and no difference in blood pressure between the waiting room and the examining room [2]. This provides evidence for the notion that white coat hypertension is the result of a classically conditioned response to a physician’s office. That this occurred more often in patients with previously established hypertension may be due to an initial anxiety reaction as patients learn they have hypertension, which is further conditioned by the following office visits to check their blood pressure control [2].

The effect of isolated white coat hypertension on cardiovascular risk has been controversial. One study examining the target organ damage of hypertension in terms of left ventricular mass and carotid-femoral pulse wave velocity found a positive correlation with daytime blood pressure values, but not with those who had elevated office blood pressures alone [6]. A recent meta-analysis likewise showed that cardiovascular risk is not significantly different between white coat hypertension and normotension [7]. However, another study by Gustavsen and colleagues evaluating the rate of cardiovascular deaths and nonfatal events over a 10-year follow-up period found that patients with white coat hypertension and essential hypertension had similar event rates, but normotensive patients had significantly lower rates [8]. In contrast, a different study determined that the unadjusted rate of all-cause mortality in patients with white coat hypertension (4.4 deaths per 1,000 years of follow-up) was less than patients with sustained hypertension (10.2 deaths per 1,000 years of follow-up), and that this was clinically significant after adjusting for age, sex, smoking, and use of antihypertensive medication [9]. The effect of isolated white coat hypertension on cardiovascular risk still needs further investigation to determine the necessity of treating it with antihypertensives.

As hypertension is routinely diagnosed by the blood pressure measurements obtained by a physician in an office setting, it is likely that a significant portion of white coat hypertension is treated with antihypertensives. In the study by Gustavsen and colleagues, they noted that 60.3% of patients with white coat hypertension were treated with antihypertensives at some point during the 10-year follow-up [8]. In the Treatment of Hypertension Based on Home or Office Blood Pressure (THOP) trial, antihypertensive treatment was adjusted based on either self-measured home blood pressure values or conventional office measurements. At the end of the 6-month period, less intensive drug treatment was used for the home blood pressure group as opposed to those measured in an office, and more home blood pressure patients could permanently stop antihypertensive drug treatment (25.6% vs. 11.3%). However, those treated based on home blood pressure measurements had slightly higher blood pressures at the end of the trial than those treated in the office, which could potentially increase cardiovascular risk [10]. Evaluating whether a patient has sustained hypertension or white coat hypertension with normotensive ambulatory blood pressure using home devices or ABPM may help to identify those who do in fact require antihypertensive medications.

White coat hypertension may also play a role in cases of resistant hypertension. ABPM may be necessary to differentiate cases of true drug-resistant hypertension and those that are well controlled outside of the physician’s office in order to prevent overtreatment. One study found that when patients who were documented to have uncontrolled hypertension had their blood pressure monitored for 24 hours, only 69% were actually uncontrolled [11]. Studies have also looked for other ways to differentiate true resistant hypertension and white-coat resistant hypertension, and have determined that true resistant hypertension patients have excessive intake of salt and alcohol as well as higher renin values [12].

In clinical practice, white coat hypertension is likely a common confounding factor in the diagnosis and treatment of hypertension. Patients often insist that their blood pressure is much lower at home than at their office visit, and the anxiety of an appointment solely for a blood pressure check is likely a contributing factor. Shifts away from physician measurement of blood pressure or substitution with automatic blood pressure devices may help to counteract this phenomenon. Home blood pressure monitoring devices can be a useful tool in discerning whether a patient’s blood pressure is properly controlled on a current treatment regimen or if additional therapy is needed. Avoiding overtreatment of hypertension may also lower health care costs, although the cardiovascular risks of white coat hypertension must be further elucidated so that the importance of treating white coat hypertension can be determined. White coat hypertension is a real and ubiquitous phenomenon, and must be considered by physicians for all patients with elevated blood pressures.

Commentary by Dr. Stephen Kayode Williams

Attending Physician, Bellevue Primary Care Hypertension Clinic

Are doctors bad for your blood pressure? Yes! This is a timely discussion as we eagerly await updated national guidelines for the management of hypertension. How will JNC 8 address this issue that comes up at every visit to our primary care clinics? The latest US hypertension guidelines were published in 2003 [13]. The more recent 2011 UK guidelines are remarkable in stating that in order to confirm a new diagnosis of hypertension, ambulatory blood pressure monitoring (or alternatively home blood pressure monitoring) should demonstrate daytime blood pressures greater than or equal to 135/85 mmHg [14] . An exhaustive cost-effectiveness analysis performed for these guidelines came to the conclusion that, despite the expenses incurred with ambulatory blood pressure monitoring, there are vast cost savings that come with the prevention of an erroneous diagnosis of hypertension using office blood pressure readings alone. In this country, ambulatory blood pressure monitoring is not widely available in primary care. Stayed tuned to see how the upcoming hypertension guidelines address these clinical correlations.

Lauren Foster is a 4th year medical student at NYU School of Medicine

Peer reviewed by Stephen Kayode Williams, MD, MS, Bellevue Primary Care Hypersion Clinic

Image courtesy of Wikimedia Commons

References:

1. Fields LE, Burt VL, Cutler JA, Hughes J, Roccella EJ, Sorlie P. The burden of adult hypertension in the United States 1999 to 2000: a rising tide. Hypertension. 2004;44(4):398-404.  http://www.ncbi.nlm.nih.gov/pubmed/15326093

2. Gerin W, Ogedegbe G, Schwartz JE, et al. Assessment of the white-coat effect. J Hypertens. 2006;24(1):67-74.

3. Pickering TG. White coat hypertension. Curr Opin Nephrol Hypertens. 1996;5(2):192-198.  http://circ.ahajournals.org/content/98/18/1834.full

4. Verdecchia P, Schillaci G, Boldrini F, Zampi I, Porcellati C. Variability between current definitions of ‘normal’ ambulatory blood pressure. Implications in the assessment of white coat hypertension. Hypertension. 1992;20(4):555-562.

5. Ogedegbe G, Pickering TG, Clemow L, et al. The misdiagnosis of hypertension: the role of patient anxiety. Arch Intern Med. 2008;168(22):2459-2465. http://archinte.jamanetwork.com/article.aspx?articleid=773457

6. Silveira A, Mesquita A, Maldonado J, Silva JA, Polonia J. White coat effect in treated and untreated patients with high office blood pressure. Relationship with pulse wave velocity and left ventricular mass index. Rev Port Cardiol. 2002;21(5):517-530.

7. Pierdomenico SD, Cuccurullo F. Prognostic value of white-coat and masked hypertension diagnosed by ambulatory monitoring in initially untreated subjects: an updated meta analysis. Am J Hypertens. 2011;24(1):52-58.  http://ajh.oxfordjournals.org/content/24/1/52.abstract

8. Gustavsen PH, Høegholm A, Bang LE, Kristensen KS. White coat hypertension is a cardiovascular risk factor: a 10-year follow-up study. J Hum Hypertens. 2003;17(12):811-817.

9. Dawes MG, Bartlett G, Coats AJ, Juszczak E. Comparing the effects of white coat hypertension and sustained hypertension on mortality in a UK primary care setting. Ann Fam Med. 2008;6(5):390-396.  http://www.annfammed.org/content/6/5/390.full.pdf

10. Den Hond E, Staessen JA, Celis H, et al. Treatment of Hypertension Based on Home or Office Blood Pressure (THOP) Trial Investigators. Antihypertensive treatment based on home or office blood pressure–the THOP trial. Blood Press Monit. 2004;9(6):311-314.

11. Godwin M, Delva D, Seguin R, et al. Relationship between blood pressure measurements recorded on patients’ charts in family physicians’ offices and subsequent 24 hour ambulatory blood pressure monitoring. BMC Cardiovasc Disord. 2004;4:2.  http://www.biomedcentral.com/1471-2261/4/2/

12. Veglio F, Rabbia F, Riva P, et al. Ambulatory blood pressure monitoring and clinical characteristics of the true and white-coat resistant hypertension. Clin Exp Hypertens. 2001;23(3):203-211.

13. Chobanian AV, Bakris GL, Black HR, et al. The Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure: the JNC 7 report. JAMA. 2003;289:2560-2572.  http://www.ncbi.nlm.nih.gov/pubmed/12748199

14. Krause T, Lovibond K, Caulfield M, McCormack T, Williams B. Management of hypertension: summary of NICE guidance. BMJ. 2011;343:d4891.  http://www.bmj.com/content/343/bmj.d4891?tab=responses

From The Archives – Myths and Realities: Heart and Wine

September 27, 2012

Please enjoy this post from the archives dated August 26, 2010

By Aditya Mattoo, MD

Faculty Peer Reviewed

Not too long ago, a patient came to my clinic and said (I’m paraphrasing of course), “I never cared for alcohol, doctor, so I haven’t had much to drink since my college days. Maybe champagne or wine on the rare special occasion, but I keep hearing about how wine is good for your heart, so I am thinking I should start drinking regularly.” For years I have been telling patients don’t drink, don’t smoke, don’t do drugs, don’t eat fatty foods, exercise more, and lose weight. I have become quite accustomed to playing the role of “Dr. Buzzkill” with my patients (the actual name given to me by a patient). Yet, we have all heard about the potential benefit to light drinking. Still, I felt a little uneasy about telling someone to start drinking everyday. To ease my discomfort, I decided to review the data behind alcohol and cardiovascular mortality for the current installment of Myths and Realities.

Alcohol and its affects on cardiovascular disease has been studied as far back as 1904, when Dr. Richard Cabot published an article in JAMA attempting to draw a relationship between alcoholism and arteriosclerosis.[1] The recent reemergence of this discussion has been prompted by the observation that French people, although eating a diet relatively rich in saturated fats, had a relatively lower incidence of cardiovascular disease and mortality from cardiovascular events. This so called “French Paradox”, coined in 1992 by Dr. Serge Renaud, a scientist from Bordeaux University in France, has been attributed to the higher consumption of wine.

Several mechanisms for the protective effect of alcohol in cardiovascular disease have been proposed. For example, alcohol related antiatherogenic alterations in plasma lipoproteins, particularly elevations in high-density lipoprotein cholesterol, are thought to offer cardiovascular protection. Additionally, alcohol associated increased activity of endothelial-type nitric oxide synthase, leading to increased levels of nitric oxide and maintenance of blood vessel patency, has also been implicated. Finally, the potential anticoagulant and antiplatelet properties of polyphenols, found in wine, may contribute as well. Some studies have suggested that red wine, because of the disproportionately higher levels of polyphenols as compared to other forms of alcohol (i.e. white wine, liquor and beer), is more protective from a cardiovascular standpoint.

Many clinical studies over the last three decades have attempted to validate this phenomenon. In 1991, Rimm et al published a study of 51,529 male health professionals followed prospectively for two years.[2] A questionnaire was distributed at the beginning of the study asking about alcohol intake in the previous 10 years, along with coronary risk factors, diet, etc. Follow-up questionnaires asked about newly diagnosed coronary disease, and a statistically significant inverse relationship was seen, suggesting a lower incidence of coronary disease in men with increased alcohol consumption.

In 1995, a prospective study of cardiovascular mortality in middle-aged women was published by Fuchs et al.[3] In this study, a dietary questionnaire was sent to 85,709 nurses beginning in 1980 and continuing for a 12 year follow up period. A J-shaped relationship was observed, i.e., light-moderate drinking was associated with a decreased risk of death, however, heavier drinking was associated with an increased risk of death from other causes, particularly breast cancer and cirrhosis.

In 1997, Thun et al published a study following 490,000 men and women for nine years.[4] A similar questionnaire was used to assess alcohol consumption and then cause of death was observed. As one would expect, excessive alcohol consumption was associated with increased rates of death from cirrhosis, as well as cancers of the mouth, esophagus, pharynx, larynx and liver. In contrast, the risk of cardiovascular death was 30-40% lower in both men and women who reported one drink daily compared to nondrinkers.

Castelnuovo et al performed a meta-analysis reviewing 26 studies on the relationship of beer and wine and cardiovascular mortality.[5] Published in 2002, a total of 417,454 persons were studied and a 32% risk reduction of cardiovascular death with moderate wine consumption was observed, whereas a 22% risk reduction was observed with moderate beer consumption.

Finally, in April of this year, the Journal of the American College of Cardiology, published an article by Mukamal et al supporting this growing body of evidence that alcohol consumption prevents cardiovascular disease.[6] Data from the National Health Interview Survey, which surveyed approximately 245,000 U.S. adults annually between the years 1987 and 2000, showed that light and moderate drinkers had a 31% and 38%, respectively, lower risk of death due to heart disease than abstainers.

Overall, large epidemiological findings have consistently demonstrated a cardiovascular benefit of light alcohol consumption. Although no head-to-head prospective studies have been conducted to compare cardiovascular outcomes of different types of alcohol, the literature suggests that red wine seems to be the most protective. However, skeptics note that these studies do not take into account the different drinking patterns of wine, beer and hard liquor drinkers. Another potential confounder is lifestyle. Studies have shown that light, particularly wine, drinkers may have different demographics and behavior patterns as compared to the rest of the population. They have a tendency to eat healthier, exercise more and come from higher socioeconomic backgrounds (which may imply they have better access to medical care). The contribution of the direct effect of alcohol or the common lifestyle choices of light moderate drinkers is a difficult confounder to tease out from survey-based, uncontrolled data.

So bringing it all back home, how should you counsel your patients? Although detractors often complain that the data is largely based on patients answering questionnaires reliably, the literature is has reproduced the benefits of light alcohol consumption time and time again. Furthermore, there is an undeniable paucity of studies that demonstrate light drinking is harmful. Armed with this, Dr. Buzzkill would probably advise patients to have a glass of wine nightly with dinner. aybe now my patients will start calling me Dr. Feelgood.

Until the next installment of Myths and Realities–the first round is on me. Cheers!

Dr. Mattoo is a second year fellow in Nephrology, NYU Langone Medical Center

Peer reviewed by Barbara Porter, Section Editor, Myths and Realities, Clinical Correlations

Image courtesy of Wikimedia Commons.

References:

[1] Cabot, RC. The Relation of Alcohol to Arteriosclerosis. JAMA. 1904; 43(12):774-775.

[2] Rimm, EB. Prospective study of alcohol consumption and risk of coronary disease in men. The Lancet. 1991; 338(8765):464-468.

[3] Fuchs, CS. Alchohol consumption and mortality among women. NEJM. 1995; 332(19):1245–1250.

[4] Thun, MJ. Alcohol consumption and mortality among middle-aged and elderly U.S. adults. NEJM. 1997 Dec 11;337(24):1705-14.

[5] Di Castelnuovo, A. Meta-analysis of wine and beer consumption in relation to vascular risk. Circulation. 2002 June 18;105:2836-2844.

[6] Mukamal, KJ. Alcohol Consumption and Cardiovascular Mortality Among U.S. Adults, 1987 to 2002. J Am Coll Cardiol. 2010; 55:1328-1335.

Are Dentists Really Causing Infective Endocarditis?

August 29, 2012

By Jeffrey Krutoy, DDS

Faculty Peer Reviewed

Bacterial infective endocarditis is a potentially devastating disease, and while it may be an easy tradition to blame the dentist, recent research and new guidelines from the American Heart Association (AHA) indicate that it may not be so simple.

Infective endocarditis (IE), while relatively uncommon (with yearly incidence rates ranging from 2 to 6 cases per 100,000 people), results in high rates of morbidity and mortality even when treated.[1] For this reason, physicians have emphasized the importance of identifying the offending pathogens and sources of infection, with the goal of preventing new cases.  Many bacterial species, especially streptococci, staphylococci, and enterococci, are well known causes of endocarditis.  Prior to recent studies indicating increasing incidence of multidrug resistant staphylococcal IE, viridans streptococci have long been the most frequently noted microbes affecting heart valves in subacute infections. [2,3]

The knowledge that viridans streptococci are normal residents of the oral cavity led to the assumption that dental procedures are responsible for many cases of infective endocarditis.   For this reason, the first set of guidelines written in the 1950s  recommended antibiotic prophylaxis prior to dental procedures in an attempt to prevent cases of IE in susceptible individuals.  A recent overhaul of these guidelines has caused confusion among patients and medical practitioners alike.

The American Heart Association’s guidelines on antibiotic prophylaxis for IE have been updated many times since they first appeared in 1955.  By 1997, antibiotic premedication was recommended in all high- and moderate-risk cardiac patients.  These included people with congenital malformations, prosthetic valves, acquired valve disorders (eg, rheumatic heart disease), hypertrophic cardiomyopathy, and mitral valve prolapse with regurgitation (see Table 1).   It was suggested that patients stratified into these high and moderate risk categories should be prescribed prophylactic antibiotics prior to undergoing certain dental procedures known to cause bleeding.  The listed treatments included extractions, periodontal surgery and scaling, dental implant placement, and complicated endodontic (root canal) treatments.  Excluded were less invasive procedures such as standard restorative dentistry (crowns, bridges, fillings), local anesthesia injections, and most orthodontic work.[4] These guidelines were complicated for both patients and practitioners, and it was therefore not uncommon to note over-prescription of antibiotic prophylaxis to low-risk patients for even non-invasive procedures “just in case.”[5] As time passed, the quality of the evidence behind the recommendations came under increasing scrutiny.

Table 1 (From 1997 Guidelines) [4]
High Risk: Low Risk (no prophylaxis necessary):
Prosthetic Cardiac Valves Isolated secundum atrial septal defect
Cyanotic Congenital Heart Disease Surgical repair of atrial septal defect, ventricular septaldefect, or patent ductus arteriosus (without residua >6 mo)
History of Bacterial Endocarditis Previous coronary artery bypass graft surgery
Pulmonary Shunts (surgically created) MVP without valvular regurgitation
Moderate Risk: Physiological, functional, or innocent heart murmurs
Any other congenital cardiac abnormality Previous Kawasaki disease without valvular dysfunction
Hypertrophic Cardiomyopathy Cardiac pacemakers and implanted defibrillators
Mitral Valve Prolapse with regurgitation (or with thickened leaflets)
Acquired valve injuries (rheumatic heart disease)

The 2007 guidelines took a less aggressive, more evidence-based approach to endocarditis prophylaxis.  The AHA recognized that many of the previous guidelines were based on “expert opinion, clinical experience, and descriptive studies” rather than solid scientific evidence.  They acknowledged that even with perfect compliance using the most efficacious antibiotic, dental prophylaxis would be unlikely to prevent most cases of infectious endocarditis.  They recognized that unnecessary prophylaxis is potentially problematic for several other reasons: adverse medication reactions, antibiotic resistance, and cost.  For these reasons, the AHA narrowed the prophylaxis recommendations to include only those patients at highest risk for endocarditis (Table 2) when undergoing procedures during which bleeding is expected. [6]

Table 2 (From 2007 Guidelines) [6]
Highest Risk (only category recommended to continue receiving prophylaxis as per AHA)
Prosthetic cardiac valve or prosthetic material used for cardiac valve repair
Previous IE
Congenital heart disease (CHD)- Unrepaired cyanotic CHD, including palliative shunts and conduits- Completely repaired congenital heart defect with prosthetic material or device, whether placed by surgery or by catheter intervention, during the first 6 months after the procedure – Repaired CHD with residual defects at the site or adjacent to the site of a prosthetic patch or prosthetic device (which inhibit endothelialization)
Cardiac transplantation recipients who develop cardiac valvulopathy

Other organizations, such as the National Institute for Health and Clinical Excellence (NICE) in England went even further by publishing recommendations in 2008 that no antibiotics at all were recommended prior to any dental procedures.[7]  The same year, the Cochrane Collaboration found not only a lack of data to support dental prophylaxis, but also expressed uncertainty that dental procedures actually cause many cases of IE.[8]

A question arose: if it is not clear that dental procedures cause IE, why are oral bacteria often found in infected heart valves?  Numerous studies have been conducted in recent years to investigate the idea that transient bacteremia from daily hygiene activities such as tooth brushing and flossing causes endocarditis. In a randomized controlled trial published in Circulation by Lockhart and colleagues, researchers drew blood cultures from participants at 6 time points before, during, and after either tooth extraction or tooth brushing.[9]  They demonstrated bacteremia after extraction and, to a lesser extent, after tooth brushing.  This finding has an important implication: the average person brushes his or her teeth twice per day (and, realistically, flosses much less) but only visits the dentist twice per year, making the cumulative daily transient bacteremia riskier than almost any procedure performed during a single dental visit. [9-12]

Patients may be concerned about engaging in a daily hygiene ritual that may expose them to harm.  Good news comes in the form of other studies that reveal that dental plaque accumulation and gingival inflammation (bleeding gingiva while brushing) are related to an increased degree of bacteremia following daily oral health care.[13, 14] If a patient takes care of his or her dental and periodontal health, fewer bacteria are seeded into the bloodstream every day.

A few closing observations can be made.  First, solid evidence linking dental procedures to endocarditis is scarce and will likely remain so, as the low incidence of IE makes definitive research difficult to perform. Next, in light of current evidence and guidelines, the routine prescription of antibiotic prophylaxis to low-risk patients should be highly discouraged.  There is no such thing as a totally safe drug, and antibiotic resistance is a major concern.  Finally, and perhaps most important, emphasis should be placed on educating patients and improving oral health.

Jeffrey Krutoy, DDS is a 3rd year medical student at NYU School of Medicine

Peer reviewed by Robert Donnino, MD, Division of Cardiology, NYU Langone Medical Center

Image courtesy of Wikimedia Commons

References:

[1] Tleyjeh IM, Abdel-Latif A, Rahbi H, et al. A systematic review of population-based studies of infective endocarditis. Chest. 2007;132(3):1025-1035. http://journal.publications.chestnet.org/article.aspx?articleid=1085332

[2] Baddour LM, Wilson WR, Bayer AS, et al. AHA Scientific Statement: Infective Endocarditis. Diagnosis, antimicrobial therapy, and management of complications:

a statement for healthcare professionals from the Committee on Rheumatic Fever, Endocarditis, and Kawasaki Disease, Council on Cardiovascular Disease in the Young, and the Councils on Clinical Cardiology, Stroke, and Cardiovascular Surgery and Anesthesia, American Heart Association. Circulation. 2005; 111(23):e394-e434. http://www.ncbi.nlm.nih.gov/pubmed/15956145

[3] Karchmer AW. Infective endocarditis. In: Longo DL, Fauci AS, Kasper DL, Hauser SL, Jameson JL, Loscalzo J, eds. Harrison’s Principles of Internal Medicine. 18th ed. New York: McGraw-Hill; 2012:

[4] Dajani AS, Taubert KA, Wilson W, et al. Prevention of bacterial endocarditis: Recommendations by the American Heart Association. Circulation. 1997;96(1):358–366.

[5] Shaw D, Conway DI. Pascal’s Wager, infective endocarditis and the ‘‘no-lose’’ philosophy in medicine. Heart. 2010;96(1):15–18.

[6] Wilson W, Taubert KA, Gewitz M, et al. Prevention of infective endocarditis. Guidelines from the American Heart Association Rheumatic Fever, Endocarditis and Kawasaki Disease Committee, Council on Cardiovascular Disease in the Young, and the Council on Clinical Cardiology, Council on Cardiovascular Surgery and Anesthesia, and the Quality of Care and Outcomes Research Interdisciplinary Working Group. Circulation. 2007; 116(15):1736–1754.

[7]  National Institute for Health and Clinical Excellence. Prophylaxis against infective endocarditis: antimicrobial prophylaxis against infective endocarditis in adults and children undergoing interventional procedures. NICE Clinical Guideline No 64. London: National Institute for Health and Clinical Excellence. Published March 2008. Updated January 23, 2011.  http://guideline.gov/content.aspx?id=14323

[8]  Oliver R, Roberts G, Hooper L, Worthington HV. Antibiotics for the prophylaxis of bacterial endocarditis in dentistry. Cochrane Database Syst Rev. 2008; 4:CD003813.

[9] Lockhart PB, Brennan MT, Sasser HC, Fox PC, Paster BJ, Bahrani-Mougeot FK.  Bacteremia associated with toothbrushing and dental extraction. Circulation. 2008; 117(24):3118–3125. http://www.ncbi.nlm.nih.gov/pubmed/18541739

[10]  Lucas VS, Gafan G, Dewhurst S, Roberts GJ. Prevalence, intensity and nature of bacteraemia after toothbrushing. J Dent. 2008;36(7):481–487.

[11]  Crasta K, Daly CG, Mitchell D, Curtis B, Stewart D, Heitz-Mayfield LJ. Bacteraemia due to dental flossing. J Clin Periodontol. 2009;36(4)323–332.

[12]  Sakamoto H, Karakida K, Otsuru M, Aoki T, Hata Y, Aki A.  Antibiotic prevention of infective endocarditis due to oral procedures: myth, magic, or science? J Infect Chemother. 2007;13(4):189–195. http://www.ncbi.nlm.nih.gov/pubmed/17721679

[13]  Tomás I, Diz P, Tobías A, Scully C, Donos N. Periodontal health status and bacteraemia from daily oral activities: systematic review/meta-analysis. J Clin Periodontol. 2012;39(3):213–228. http://www.ncbi.nlm.nih.gov/pubmed/22092606

[14] Lockhart PB, Brennan MT, Thornhill M, et al. Poor oral hygiene as a risk factor for infective endocarditis-related bacteremia  J Am Dent Assoc. 2009;140(10):1238-1244.

Should We Measure Apolipoproteins to Evaluate Coronary Heart Disease Risk?

August 24, 2012

By Navya Nair, MD

Faculty Peer Reviewed

Coronary heart disease (CHD) is the major cause of mortality worldwide.[1] Lipoproteins play a major role in the development of this disease.[2] Current guidelines advocate that low-density lipoprotein (LDL) cholesterol should be the primary target for lipid lowering therapy.[3] However, there is a growing literature on the atherogenic potential of apolipoprotein B (apo B)-containing lipoproteins and the protective effect of apolipoprotein A-one (apo AI)-containing lipoproteins. Many studies suggest that these apolipoproteins be used as markers to evaluate risk of coronary heart disease.

What are apolipoproteins and why are they relevant?

Apolipoproteins are found on the surface of lipoproteins and regulate lipid metabolism. The two apolipoproteins that are of clinical interest are apo B and apo AI. Apo B is found on LDL particles and is responsible for the clearance of LDL cholesterol through the LDL receptor pathway. Overexpression of apo B in transgenic mice increases the levels of LDL, resulting in increased susceptibility to diet-induced atherosclerosis. Apo AI is the structural protein in high-density lipoprotein (HDL) particles. Apo AI also activates lecithin:cholesterol acyltransferase (LCAT), which esterifies free cholesterol on HDL particles. Mutations that lead to apo AI deficiency are characterized by low or absent levels of HDL.[4]

A review of the relevant literature

I. Apolipoprotein-related Mortality RISk (AMORIS) study

The AMORIS study investigated the use of apo B, apo AI, and the apo B:apo AI ratio at predicting fatal myocardial infarction (MI). The study followed 75 553 Swedish men and women from 1985 to 1996. The authors found that apo B and the apo B:apo AI ratio were both strongly predictive of increased risk of fatal MI in both men and women. Furthermore, they found that apo B was a stronger predictor of risk of fatal MI than LDL cholesterol. Apo AI was found to be protective for risk of fatal MI. The authors propose that apo B, apo AI, and apo B:apo AI be used in the evaluation of cardiovascular risk and that this is of greatest benefit in patients with dyslipidemia with normal or low LDL cholesterol.[5]

II. INTERHEART Study

The INTERHEART study compared the apolipoproteins and cholesterol as indices for risk of acute MI. INTERHEART was a standardized case-control study and included 12 461 cases and 14 637 age- and sex-matched controls in 52 countries. Results showed that a high apo B:apo AI ratio had the highest population attributable risk (54%) of acute MI when compared to LDL:HDL cholesterol ratio (37%) and total:HDL cholesterol ratio (32%), and this was a statistically significant difference (p<0.0001). The study concluded that non-fasting apo B:apo AI ratio was superior to any of the cholesterol ratios for estimation of risk of acute MI in all ethnic groups, in both sexes, and at all ages, and it should be introduced into worldwide clinical practice.[1]

III. Copenhagen General Population Study

The Copenhagen General Population study aimed to determine influence of normal food intake on lipid profiles in diabetic and nondiabetic individuals. It included 58 434 individuals, 2270 of whom had diabetes mellitus. The study showed that triglycerides increased and LDL cholesterol decreased after normal food intake in diabetics and nondiabetics. However, no statistically significant differences in postprandial apo B concentrations were found. The authors suggest that this finding may be useful for discussion during revisions of guidelines for lipid measurements in individuals with or without diabetes.[5a]

IV. Québec Cardiovascular Study

The Québec Cardiovascular Study included 2155 men who were followed for a period of 5 years for clinical signs of ischemic heart disease. Study findings showed that apo B was predictive of ischemic heart disease independent of triglycerides, HDL cholesterol, and total:HDL cholesterol ratio. Apo AI was less predictive of ischemic heart disease, and this association was eliminated when controlling for plasma lipid and lipoprotein levels. The authors suggest that apo B is an important tool in the assessment of ischemic heart disease in men because it may provide information that would not be obtained from the conventional lipid-lipoprotein profile.[6]

V. Prospective Epidemiological Study of Myocardial Infarction (PRIME)

PRIME was a prospective cohort study conducted in Northern Ireland and France that included 9711 men aged 50 to 59 years free of CHD and stroke at baseline and followed them for 10 years. The study aimed to compare the association of a large panel of lipids with the risk of incident coronary heart disease and ischemic stroke. The results showed that that apo B, apo AI, apo B:apo AI along with total cholesterol, HDL cholesterol, LDL cholesterol, non-HDL cholesterol, and triglycerides were all significantly predictive of future coronary heart disease. The trend was similar for ischemic stroke but with lower strength.[7]

VI. Atherosclerosis Risk in Communities (ARIC) Study

The ARIC study included 12 339 middle-aged participants free of coronary heart disease and followed them for 10 years to evaluate the value of baseline lipoprotein cholesterol levels, triglycerides, lipoprotein-a, apolipoproteins AI and B, and HDL density subfractions in predicting coronary heart disease. The results showed that LDL cholesterol, HDL cholesterol, triglycerides, and lipoprotein-a provided substantial prediction of coronary heart disease and that there was no enhancement in prediction with apolipoproteins.[8]

Smaller studies have shown that measurement of apolipoproteins can be useful in particular instances. A 2010 publication in Metabolic Syndrome Related Disorders showed that in hypertriglyceridemic metabolic syndrome patients, apo B and non-HDL cholesterol are better predictors of significant coronary stenosis than LDL cholesterol.[9] A 2011 publication in Diabetes Care showed that apo B and apo AI are better predictors of diabetic retinopathy than total cholesterol, LDL cholesterol, non-HDL cholesterol, and triglycerides.[10]

What does this mean for clinical practice?

Two large studies, AMORIS and INTERHEART, show that apolipoproteins are useful and even superior to LDL cholesterol in estimating risk of MI. It appears that the apoB:apoAI ratio is the most useful of the apolipoprotein values in predicting this risk. An advantage of using apo B instead of LDL is that apo B levels have been shown to remain stable despite food intake. Despite these promising results, other studies, such as the ARIC study, have shown that apolipoproteins are not useful at predicting CHD.

Despite the promising results on the utility of apolipoprotein levels in predicting CHD as described above, the current National Cholesterol Education Program Expert Panel on Detection, Evaluation, and Treatment of High Cholesterol in Adults (NCEP/ATP III) guidelines do not recommend measurement of apolipoproteins in clinical management.[3]

Apo B: NCEP/ATP III guidelines acknowledge that apo B is a strong predictor of coronary atherosclerosis and CHD events. However, they state that there is not enough evidence to justify apo B replacing LDL cholesterol as the preferred target of therapy.

In patients with hypertriglyceridemia, apo B is a better predictor of coronary heart disease than LDL cholesterol. Due to this difference, NCEP/ATP III guidelines set non-HDL cholesterol as a secondary target in patients with hypertriglyceridemia. The reason for this is that non-HDL cholesterol is significantly correlated with apo B and therefore can serve as a surrogate for it, as apo B measurements are not widely available in clinical practice.[3]

Apo AI: NCEP/ATP III guidelines state that, although low levels of apo AI are associated with increased risk of CHD, this relationship has not been shown to be independent of HDL cholesterol levels. Standardized methods for estimating apo AI are not routinely available and therefore it is not recommended to use apo AI in routine risk assessment of CHD.[3]

The American Diabetes Association (ADA) and American College of Cardiology Foundation (ACCF) consensus panel state that apo B may be a more useful predictor of cardiometabolic risk than LDL cholesterol and might be a more discriminating measure of the adequacy of lipid-lowering therapy. The ADA/ACCF consensus panel concludes that apo B should be measured in patients with cardiometabolic risk on pharmacologic treatment when LDL cholesterol is <130 mg/dl and non-HDL cholesterol is <160 mg/dl because it is a more sensitive index of residual cardiovascular disease. They state that apo B levels should be used to guide adjustments in therapy in these patients.[11]

In summary, apo B, although a strong predictor of coronary heart disease, is not currently recommended as the primary target of therapy by NCEP/ATP III guidelines. NCEP/ATP III guidelines recommend apo B as the secondary target of therapy in patients with hypertriglyceridemia, but because measurement of apo B is not widely available in clinical practice, non-HDL cholesterol should be used as a surrogate marker. NCEP/ATP III guidelines do not recommend assessment of apo AI, despite its value as a predictor of lower risk of CHD, because of its lack of independent association with CHD and lack of availability. ADA/ACCF consensus guidelines recommend measurement of apo B in patients with cardiometabolic risk on pharmacologic treatment whose LDL cholesterol is <130 mg/dl and non-HDL cholesterol is <160 mg/dl in order to determine residual cardiovascular disease and to titrate medications.

At this time, measurement of apolipoproteins is only recommended in specific situations as described above. With more studies investigating the utility of apolipoproteins at predicting CHD risk, it remains to be seen if future recommendations will call for using apolipoproteins as the primary markers for determining CHD risk and the primary target of therapy.

Commentary by Dr. Arthur Schwartzbard

We have since seen the publication of long-term follow-up of the Québec Heart Study, supporting the role of apo B-containing lipoproteins and their link to increased risk of cardiovascular disease. It is my expectation that more updated guidelines will support the measurement of apo B in assessing cardiometabolic risk. This is likely to be most valuable in patients with diabetes or elevated triglycerides. A subanalysis from the VA-HIT study also suggests some superiority of apo B to non-HDL, though more data are needed on this issue.

Dr. Navya Nair is a recent graduate of NYU School of Medicine

Peer reviewed by Arthur Schwartzbard, MD, Assistant Professor, Department of Medicine, Division of Cardiology, NYU Langone Medical Center

Image courtesy of Wikimedia Commons

References:

1. McQueen MJ, Hawken S, Wang X, et al. Lipids, lipoproteins, and apolipoproteins as risk markers of myocardial infarction in 52 countries (the INTERHEART study): a case-control study. Lancet. 2008;372:224–233.  http://www.ncbi.nlm.nih.gov/pubmed/18640459

2. Kappelle PJWH, Gansevoort RT, Hillege JL, Wolffenbuttel BHR, Dullaart RPF. Apolipoprotein B?A-I and total cholesterol?high-density lipoprotein cholesterol ratios both predict cardiovascular events in the general population independently of nonlipid risk factors, albuminuria and C-reactive protein. J Intern Med. 2010;269:232–242.  http://onlinelibrary.wiley.com/doi/10.1111/j.1365-2796.2010.02323.x/abstract

3. National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III). Third report of the National Cholesterol Education Program (NCEP) expert panel on detection, evaluation, and treatment of high blood cholesterol in adults (Adult Treatment Panel III) final report. Circulation 2002;106:3143–3421.

4. Mahley RW, Weisgraber KH, Bersot TP. Disorders of lipid metabolism. In: Kronenberg HM, Melmed S, Polonsky KS, Larsen PR, eds. Williams Textbook of Endocrinology.11th ed. Philadelphia, PA: Saunders Elsevier; 2008:1589-1631.

5. Walldius G, Jungner I, Holme I, Aastveit AH, Kolar W, Steiner E. High apolipoprotein B, low apolipoprotein A-I, and improvement in the prediction of fatal myocardial infarction (AMORIS study): a prospective study. Lancet. 2001;358 (9298):2026–2033.  http://www.ncbi.nlm.nih.gov/pubmed/11755609

5a. Langsted A, Nordestgaard BG. Nonfasting lipids, lipoproteins and apolipoproteins in individuals with and without diabetes: 58,434 individuals from the Copenhagen General Population Study. Clin Chem. 2010;579(3):482-489.

6. Lamarche B, Moorjani S, Lupien PJ, et al. Apolipoprotein A-I and B levels and the risk of ischemic heart disease during a five-year follow-up of men in the Québec cardiovascular study. Circulation. 1996;94(3):273-278.

7. Canouï-Poitrine F, Luc G, Bard JM, et al. Relative contribution of lipids and apolipoproteins to incident coronary heart disease and ischemic stroke: the PRIME Study. Cerebrovasc Dis. 2010;30(3):252–259. http://www.ncbi.nlm.nih.gov/pubmed/20664258

8. Sharrett AR, Ballantyne CM, Coady SA, et al. Coronary heart disease prediction from lipoprotein cholesterol levels, triglycerides, lipoprotein(a), apolipoproteins A-I and B, and HDL density subfractions: the Atherosclerosis Risk in Communities (ARIC) study. Circulation. 2001;104(10):1108-1113.

9. Boumaiza I, Omezzine A, Rejeb J, et al. Apolipoprotein B and non-high-density lipoprotein cholesterol are better risk markers for coronary artery disease than low-density lipoprotein cholesterol in hypertriglyceridemic metabolic syndrome patients. Metab Syndrome Relat Disord. 2010;8(6):515-522.

10. Sasongko MB, Wong TY, Ngyuen TT, et al. Serum apolipoprotein AI and B are stronger biomarkers of diabetic retinopathy than traditional lipids. Diabetes Care. 2011;34(2):474–479.  http://care.diabetesjournals.org/content/34/2/474.full.pdf

11. Brunzell JD, Davidson M, Furberg CD, et al. Lipoprotein management in patients with cardiometabolic risk: consensus conference report from the American Diabetes Association and the American College of Cardiology Foundation. J Am Coll Cardiol. 2008;51(15):1512-1524. http://www.ncbi.nlm.nih.gov/pubmed/18402913

Omega-3 Fatty Acids and Atherosclerosis

August 17, 2012

By Michael Malone

Faculty Peer Reviewed

Omega-3 long chain polyunsaturated fatty acids (PUFAs) have been popularized in recent years as beneficial nutrients with cardioprotective effects. Omega-3 PUFAs are so named because of a double bond between the 3rd and 4th carbon of the polycarbon chain. They are “poly-unsaturated” with hydrogen atoms, as their carbon chains contain multiple double bonds. Three omega-3 long chain PUFAs are typically discussed in the context of medical therapy, the first being alpha-linolenic acid (ALA). ALA is an essential precursor omega-3 that is converted by the body into eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA).[1] However, this conversion is not very efficient in humans.[2] Omega-3s are best obtained through the diet, but they are available as supplements as well.[1] Omega-3s are common in poultry and most famously found in fish such as salmon, herring, trout, and sardines. ALA is a component of many plant products such as flax seed oil and to a lesser extent canola and soy oils.[3] Increased consumption of omega-3 PUFAs increases their proportion in blood and tissue lipid pools.[4] Serum concentrations of omega-3s can be measured.

Treatment of Hypertriglyceridemia

Omega-3 PUFAs are widely used to treat hypertriglyceridemia, defined as a triglyceride level greater than 150 mg/dL. The NHANES 3 National Health and Nutrition Examination Survey determined that around 35% of men and 25% of women in the US have triglyceride levels over 150 mg/dL. Triglyceride levels greater than 500 mg/dL are associated with an increased risk of pancreatitis.[1] Triglycerides can be lowered through physical exercise, low-calorie diets, and limiting consumption of alcohol. Omega-3 PUFAs can lower triglycerides when used alone or in combination with niacin or fibrates. They can also be used in conjunction with statins, which have a mild ability to reduce triglyceride levels on their own.[3] When omega-3 supplementation was combined with a statin, non-HDL-C levels were reduced much more than on a statin alone. In addition, VLDL-C, triglycerides, and total cholesterol decreased and HDL-C increased–all by more significant amounts than with just a statin alone.[5] Of the 3 omega-3 PUFAs discussed, EPA and DHA have shown the greatest efficacy.[6] The mechanism by which omega-3 PUFAs lower triglycerides is still unknown, but they reduce the hepatic synthesis of VLDLs, which are almost entirely triglycerides, and accelerate lipoprotein lipase, which hydrolyzes triglycerides.[1] With prescription strength omega-3s, triglycerides can be lowered 30-40%.[5] Aggressively lowering LDL-C with statins has been shown to stabilize atherosclerotic plaques.[7]

Clinical Associations

While omega-3 PUFAs are approved for the treatment of hypertriglyceridemia, evidence suggests that they have many other biological activities. Low levels of omega-3 PUFAs have been associated with numerous diseases. One study found that obese children have lower omega-3 concentrations in their serum phospholipids than age-matched lean controls[2] while another found correlations between low omega-3 PUFAs and markers of metabolic syndrome.[8] Low levels of omega-3s were significantly associated with acute coronary syndrome. They were also independently correlated with the presence and degree of lumen occlusion of lipid-rich, atherosclerotic plaques.[9] In other studies, omega-3s were correlated with decreased risk of sudden death and non-fatal myocardial infarction.[4]

Role in Atherosclerotic Disease

The role of omega-3 PUFAs in the treatment of atherosclerosis is not as clear as its role in triglyceride therapy, but there is strong evidence to suggest clinical efficacy. As stated earlier, EPA and DHA have the greatest therapeutic effect and were the omega-3s most often studied. Omega-3 PUFAs influence gene transcription.[10] It is thought that when omega-3s incorporate into the cellular membrane, they disrupt cholesterol rafts, changing the fluidity of cell membranes.[11] This releases endothelial relaxing factors, like nitric oxide, decreasing vascular tone.[12] It has been shown that after 3 months of omega-3 supplementation in obese adolescents with demonstrated vascular inflammation, vasoconstrictive responses and endothelial function improved.[8]

In addition to changing the endothelial response, omega-3 PUFAs seem to modulate the inflammatory response through inhibition of cyclooxygenase-2 (COX-2). While this mechanism is unclear, omega-3 PUFAs incorporate directly into the plaque. Decreased COX-2 activity is associated with decreased release of matrix metalloproteinases (MMPs), which have been implicated in the thinning of the atherosclerotic plaque cap that makes the plaque more prone to rupture.[5] It has been demonstrated that when patients were treated with omega-3s prior to surgery, carotid artery plaques had decreased levels of RNA for MMPs 7,9, and 12.[4] The same study found that in the 3-week treatment period the plaques showed a decreased number of foam cells and T-cells and had less inflammation and increased stability. However, over the short, 3-week presurgical treatment period, there was no change in primary outcome.[4] In another placebo-controlled study, obese adolescents treated with EPA for one year had improved vascular function; reduced inflammation; and decreased levels of lymphocytes, monocytes, TNF-alpha, interleulin-1, and interleukin-6.[8]

COX-2 inhibition affects platelet aggregation as well. EPA has been shown to reduce platelet aggregation and may have a beneficial effect on certain cardiovascular thrombotic disorders.[13] These effects may be enhanced by reduction in serum lipid levels. Elevated postprandial triglycerides were shown to be associated with increased plasminogen activator 1 and factor 7, increasing thrombosis risk and CHD events.[1] By altering lipid levels and regulating inflammatory mediators, endothelial function, inflammation, plaque stability, and platelet aggregation, omega-3 PUFAs have demonstrated a multifaceted, protective effect against atherosclerosis.

The Omega-6/Omega-3 Ratio

Like omega-3s, omega-6 PUFAs are essential fatty acids. Omega-6s have a double bond, but at the 6-carbon location. Arachidonic acid and linoleic acid (not to be confused with the omega-3 ALA) are examples of omega-6 PUFAs. They are commonly found in vegetable oils. The omega-6/omega-3 ratio found in the Western diet is considered high, with a ratio of 15-20/1 rather than the 1/1 found in the diet of many animals and pre-industrial era humans.[10]

Both omega-3s and omega-6s influence gene expression, but in antagonistic ways.[10] While omega-3s inhibit COX-2 products, omega-6s can be metabolized to form eicosanoid metabolic products such as prostaglandins, thromboxanes, leukotrienes, hydroxy fatty acids, and lipoxins.[14] Thus, whereas omega-3s have anti-inflammatory properties, omega-6s are pro-thrombotic and pro-aggretory, causing inflammation, oxidation of LDL, and platelet aggregation. Increasing ratios of omega-6/omega-3 PUFAs in platelet phospholipids have been correlated with an increased death rate from cardiovascular disease.[10] However, many studies have shown that low omega-6 levels are not as clear a predictor of health as high omega-3 levels are, suggesting that adverse health effects associated with high omega-6/omega-3 ratios in the Western diet is more a function of decreased omega-3 intake than the excess consumption of omega-6s.[2]

Lovaza

In addition to omega-3 supplements that are commercially available, there is now an FDA-approved prescription omega-3 supplement available in the US. Lovaza (Pronova BioPharma ASA, Lysaker, Norway) is 38% DHA, 47% EPA, and 17% other fish oils (840 mg of DHA and EPA) and is approved to treat hypertriglyceridemia. Fish-oil supplements commonly have a fishy smell and aftertaste that can be bothersome to some individuals.[6] These pharmacological agents are well tolerated with statins,[5] which are often co-prescribed. There is some concern that omega-3s, due to their anticoagulant effects, may increase the risk of bleeding or of hemorrhagic stroke, especially when combined with other agents like aspirin or warfarin. However, multiple clinical trials do not suggest that a true increased bleeding risk exists with PUFAs, even in combination with other anticoagulants.[6] Lovaza (pronounced “lo-vay-za”) is currently only contraindicated in patients with hypersensitivity to its components and used cautiously in patients allergic to fish or shellfish.

Recommendations

The American Heart Association recommends that patients with or without heart disease eat a variety of fish at least twice a week, preferably fishes like salmon, herring, and trout that are high in omega-3 PUFAs. Patients with heart disease are advised to consume about 1 gram of EPA and DHA daily, preferably from food, but supplements are acceptable after consultation with a physician.[5] There are no clear benefits to a specific omega-6/omega-3 ratio, as long as omega-3 intake is kept high. There are also no significant side effects to increasing omega-3 content in the diet or in a pharmaceutical form.

Conclusion

The idea that disease biology can be fine-tuned by diet is powerful. The potential mechanisms by which omega-3 PUFAs benefit atherosclerosis include lowering triglyceride levels, improving the effects of statin therapy, improving endothelial function, blocking pro-inflammatory pathways, and impairing platelet aggregation though COX-2 inhibition. Omega-3 prophylaxis has already shown therapeutic effects both in patients with prior MI or atherosclerosis and in those at risk for these conditions.

Commentary by Dr. Arthur Schwartzbard

Recent randomized controlled trials of omega-3 supplementation have not consistently demonstrated a reduction in cardiovascular events. To date, these agents look most effective at reducing triglycerides, and Lovaza is FDA approved to reduce triglycerides in patients whose triglycerides exceed 500 mg/dL. These agents are also advised for patients who do not consume at least 1-2 servings of fish weekly. This class has also been useful in patients with HIV dyslipidemia with markedly elevated triglycerides. It is possible that some of the lack of cardiovascular event reduction may be due to the rise in LDL cholesterol that has been noted with many of these agents. A new preparation of fish oil has been recently shown to also reduce LDL, and is currently in phase 3 trials.

Michael Malone is a 3rd year medical student at NYU School of Medicine

Peer reviewed by Dr. Arthur Schwartzbard, MD, Assistant Professor, Department of Medicine, Division of Cardiology, NYU Langone Medical Center

Image courtesy of Wikimedia Commons

References:

1. Bays HE, Tighe AP, Sadovsky R, Davidson MH. Prescription omega-3 fatty acids and their lipid effects: physiologic mechanisms of action and clinical implications. Expert Rev Cardiovasc Ther. 2008;6(3):391-409. http://www.ncbi.nlm.nih.gov/pubmed/18327998

2. Deckelbaum RJ. n-6 and n-3 Fatty acids and atherosclerosis: ratios or amounts? Arterioscler Thromb Vasc Biol. 2010;30(12):2325-2326. http://www.ncbi.nlm.nih.gov/pubmed/21084701

3. O’Keefe JH, Carter MD, Lavie CJ. Primary and secondary prevention of cardiovascular diseases: a practical evidence-based approach. Mayo Clin Proc. 2009;84(8):741-757. http://www.ncbi.nlm.nih.gov/pubmed/19648392

4. Cawood AL, Ding R, Napper FL, et al. Eicosapentaenoic acid (EPA) from highly concentrated n-3 fatty acid ethyl esters is incorporated into advanced atherosclerotic plaques and higher plaque EPA is associated with decreased plaque inflammation and increased stability. Atherosclerosis. 2010;212(1):252-259. http://www.ncbi.nlm.nih.gov/pubmed/20542512

5. Bays HE, McKenney J, Maki KC, Doyle RT, Carter RN, Stein E. Effects of prescription omega-3-acid ethyl esters on non–high-density lipoprotein cholesterol when coadministered with escalating doses of atorvastatin. Mayo Clin Proc. 2010;85(2):122-128. http://www.ncbi.nlm.nih.gov/pubmed/20118387

6. Bays HE. Safety considerations with omega-3 fatty acid therapy. Am J Cardiol. 2007;99(6A):35C-43C. http://www.ncbi.nlm.nih.gov/pubmed/17368277

7. Kadoglou NP, Sailer N, Moumtzouoglou A, Kapelouzou A, Gerasimidis T, Liapis CD. Aggressive lipid-lowering is more effective than moderate lipid-lowering treatment in carotid plaque stabilization. J Vasc Surg. 2010;51(1):114-121. http://www.ncbi.nlm.nih.gov/pubmed/19837545

8. Dangardt F, Osika W, Chen Y, et al. Omega-3 fatty acid supplementation improves vascular function and reduces inflammation in obese adolescents. Atherosclerosis. 2010;212(2):580-585. http://www.ncbi.nlm.nih.gov/pubmed/20727522

9. Amano T, Matsubara T, Uetani T, et al. Impact of omega-3 polyunsaturated fatty acids on coronary plaque instability: an integrated backscatter intravascular ultrasound study. Atherosclerosis. 2011.;218(1):110-116. http://www.ncbi.nlm.nih.gov/pubmed/21684546

10. Simopoulos AP. The omega-6/omega-3 fatty acid ratio, genetic variation, and cardiovascular disease. Asia Pac J Clin Nutr. 2008;17 Suppl 1:131-134. http://www.ncbi.nlm.nih.gov/pubmed/18296320

11. Layne J, Majkova Z, Smart EJ, Toborek M, Hennig B. Caveolae: a regulatory platform for nutritional modulation of inflammatory diseases. J Nutr Biochem. 2011;22(9):807-811. http://www.ncbi.nlm.nih.gov/pubmed/21292468

12. Okuda Y, Kawashima K, Sawada T, et al. Eicosapentaenoic acid enhances nitric oxide production by cultured human endothelial cells. Biochem Biophys Res Commun. 1997;232(2):487-491. http://www.ncbi.nlm.nih.gov/pubmed/9125207

13. Hirai A, Terano T, Hamazaki T, et al. The effects of the oral administration of fish oil concentrate on the release and the metabolism of [14C]arachidonic acid and [14C]eicosapentaenoic acid by human platelets. Thromb Res. 1982;28(3):285-298. http://www.ncbi.nlm.nih.gov/pubmed/6294902

14. Simopoulos AP. The importance of the omega-6/omega-3 fatty acid ratio in cardiovascular disease and other chronic diseases. Exp Biol Med (Maywood). 2008;233(6):674-688. http://www.ncbi.nlm.nih.gov/pubmed/18408140.

15. American Heart Association. Vitamin and mineral supplements. http://www.heart.org/HEARTORG/GettingHealthy/NutritionCenter/Vitamin-and-Mineral-Supplements_UCM_306033_Article.jsp.  Updated September 24, 2011.  Accessed July 28, 2011.

Bystander CPR: How Much Does It Help?

July 18, 2012

By Andrew L. Weinstein

Faculty Peer Reviewed

You have just completed a certification course in basic life support and are competent at performing cardiopulmonary resuscitation (CPR) using chest compressions, a CPR mask, a bag-valve mask with impedance threshold device, and an automated external defibrillator (AED), all interventions recommended by the American Heart Association (AHA) to improve circulation following a sudden cardiac arrest.[1] On your way home from the training center you see a man collapse and rush over to find him unresponsive, not breathing, and pulseless. You immediately initiate the “chain of survival” by ordering someone nearby to call 911 and someone else to search for an AED. You begin chest compressions, but fearing this man may have communicable diseases and a CPR mask or bag-valve mask is not available, you refrain from performing mouth-to-mouth ventilation. The emergency medical service (EMS) personnel arrive 5 minutes later and take over the resuscitation effort. The scene clears and you wonder: how much did my actions help this man’s chances of survival? Did failure to deliver rescue breaths hurt these chances?

Each year over 300,000 Americans suffer an out-of-hospital cardiac arrest (OHCA), defined as a cessation of cardiac mechanical activity that occurs outside of the hospital and is confirmed by the absence of circulation signs.[2,3] Though an OHCA can occur from noncardiac causes such as trauma or drowning, the majority of such events have a primary cardiac cause and a poor 6.5% overall survival rate to hospital discharge.[2] For most of these victims the scenario described above is the best they can realistically hope for, as only 8.6% of OHCAs are witnessed by EMS.[4] In the remaining cases, initiation of the chain of survival depends on family members or strangers while the victim’s chances of survival falls 7-10% every minute without bystander CPR until defibrillation.[2] Considering that the median time delay between calling 911 and EMS arrival is 5.3 minutes,[4,5] it is vital that bystanders perform CPR as soon as possible.

Even when bystanders witness an OHCA, studies show that they perform CPR in the minority of cases. According to the Center for Disease Control and Prevention (CDC) surveillance data on victims of OHCA of presumed cardiac cause who received CPR in the prehospital setting between 2005 and 2010,[6] the overall survival rate to hospital discharge was 9.6%. Although 37.6% of OHCA events were witnessed by bystanders, only 43.8% of them performed CPR and increased survival rate to 11.2% compared with 7.0% in victims who did not receive CPR prior to EMS arrival (p<0.001). In other words, the CDC’s analysis showed bystander CPR to have a 37.5% relative risk reduction and a number needed to treat of 24. To put this effect into perspective, aspirin given to prevent major cardiovascular events has a number needed to treat of 253 in patients without clinical evidence of cardiovascular disease.[7]

Research indicates that the infrequent performance of bystander CPR is due, in large part, to a reluctance to perform mouth-to-mouth ventilation. In a 1995 survey, only 15% of 975 respondents reported a willingness to perform chest compressions with mouth-to-mouth ventilation on a stranger, whereas 68% responded that they would “definitely” perform chest compressions alone if it were offered as an effective alternate CPR technique.[8] Since then, many studies have examined survival rates between conventional CPR, which includes rescue breathing, and compression-only CPR, and concluded that omitting ventilations from the bystander sequence confers no negative impact.[1, 9-11] As a result, the AHA Guidelines now recommend that “laypersons should be encouraged to do compression-only CPR if they are unable or unwilling to provide rescue breaths” on the basis that provision of compression-only CPR is superior to no CPR.[7,9]

Lastly, it should be noted that in addition to bystander CPR, several other parameters have been identified as significant predictors of OHCA survival. They include the location of the cardiac arrest, the presenting arrest rhythm, who first applied the AED, and whether there was a return of spontaneous circulation (ROSC) in the field.[4-6,12] The CDC reported that 84.1% of OHCAs occurred in the home and had a survival rate of 7.0%, whereas OHCAs that occurred in public had a survival rate of 20.2%. Of the bystander-witnessed OHCAs, an AED was applied prior to EMS arrival in 3.7% of cases, wherein survival rate was 23.5%. If the victim was found in a shockable arrest rhythm, survival rate was 27.1%, and if ROSC on the field was achieved, survival rate was 26.3%. Although understanding the reasons for these varying OHCA survival rates is important, and is explored extensively in the literature,[6,12] it is beyond the scope of this discussion.

From a young age we hear the mantra, “CPR saves lives.” We see CPR instructional posters on the walls of eating establishments and resuscitation efforts in action movies and TV shows. Although the prognosis of OHCAs remains poor, bystander CPR has been found to contribute a 4.2% overall increase in survival to hospital discharge compared with calling 911 alone. However, studies show that only a minority of bystanders perform CPR, discouraged by the thought of performing mouth-to-mouth ventilations on a stranger. Perhaps if these onlookers had known that compression-only CPR may be as effective as conventional CPR, many lives could have been saved. Now that compression-only CPR is recommended by the AHA guidelines, hopefully more bystanders will embrace the opportunity to help an OHCA victim’s chances of survival.

Andrew L. Weinstein is a 3rd year medical student at NYU School of Medicine

Peer reviewed by Dr. Kevin Felner, MD, Pulmonary, Critical Care, NYU Langone Medical Center

Image courtesy of Wikimedia Commons

References

1. Field JM, Hazinski MF, Sayre MR, et al. Part 1: executive summary: 2010 American Heart Association Guidelines for Cardiopulmonary Resuscitation and Emergency Cardiovascular Care. Circulation. 2010;122(18 Suppl 3):S640-656. http://circ.ahajournals.org/content/122/18_suppl_3/S640.long

2. Roger VL, Go AS, Lloyd-Jones DM, et al. Heart disease and stroke statistics–2011 update: a report from the American Heart Association. Circulation. 2011;123(4):e18–e209. http://circ.ahajournals.org/content/123/4/e18.long

3. Jacobs I, Nadkarni V, Bahr J, et al. Cardiac arrest and cardiopulmonary resuscitation outcome reports: update and simplification of the Utstein templates for resuscitation registries: a statement for healthcare professionals from a task force of the International Liaison Committee on Resuscitation (American Heart Association, European Resuscitation Council, Australian Resuscitation Council, New Zealand Resuscitation Council, Heart and Stroke Foundation of Canada, InterAmerican Heart Foundation, Resuscitation Councils of Southern Africa). Circulation. 2004;110(21):3385–3397. http://circ.ahajournals.org/content/110/21/3385.long

4. Weisfeldt ML, Everson-Steward S, Sitlani C, et al. Ventricular tachyarrhythmias after cardiac arrest in public versus at home. N Engl J Med. 2011;364:313-21. http://www.nejm.org/doi/full/10.1056/NEJMoa1010663

5. Weisfeldt ML, Sitlani CM, Ornato JP, et al. Survival after application of automatic external defibrillators before arrival of the emergency medical system: evaluation in the resuscitation outcomes consortium population of 21 million. J Am Coll Cardiol. 2010;55:1713-1720. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3008654/?tool=pubmed

6. McNally B, Robb R, Mehta M, et al. Out-of-hospital cardiac arrest surveillance – cardiac arrest registry to enhance survival, United States, October 1, 2005 – December 31, 2005. MMWR. 2011;60(SS08);1-19. http://www.cdc.gov/mmwr/preview/mmwrhtml/ss6008a1.htm

7. Berger JS, Lala A, Krantz MJ, Baker GS, Hiatt WR. Aspirin for the prevention of cardiovascular events in patients without clinical cardiovascular disease: A meta-analysis of randomized trials. Am Heart J. 2011;162(1):115-124.e2. http://www.ahjonline.com/article/S0002-8703(11)00272-9/fulltext

8. Locke CJ, Berg RA, Sanders AB, et al. Bystander cardiopulmonary resuscitation: concerns about mouth-to-mouth contact. Arch Intern Med. 1995;155:938–43.

9. Sayre MR, Berg RA, Cave DM, Page RL, Potts J, White RD; American Heart Association Emergency Cardiovascular Care Committee. Hands-only (compression-only) cardiopulmonary resuscitation: a call to action for bystander response to adults who experience out-of-hospital sudden cardiac arrest: a science advisory for the public from the American Heart Association Emergency Cardiovascular Care Committee. Circulation. 2008;117(16):2162-7. http://circ.ahajournals.org/content/117/16/2162.long

10. Hallstrom A, Cobb L, Johnson E, Copass M. Cardiopulmonary resuscitation by chest compression alone or with mouth-to-mouth ventilation. N Engl J Med. 2000;342:1546-1553. http://www.nejm.org/doi/full/10.1056/NEJM200005253422101

11. Rea TD, Fahrenbruch C, Culley L, et al. CPR with chest compressions alone or with rescue breathing. N Engl J Med. 2010;363:423-33. http://www.nejm.org/doi/full/10.1056/NEJMoa0908993

12. Sasson C, Rogers MAM, Dahl J, Kellermann AL. Predictors of survival from out-of-hospital cardiac arrest: a systematic review and meta-analysis. Circ Cardiovasc Qual Outcomes. 2010;3:63-81. http://circoutcomes.ahajournals.org/content/3/1/63.long

American College of Cardiology 2012

May 29, 2012

By Steven Sedlis, MD

The 2012 Scientific Sessions of the American College of Cardiology were held from March 24-27, 2012 in Chicago. This is always a great city for a conference —terrific restaurants, museums and parks—it almost makes you feel as though you are in New York. The McCormick Place Convention Center is another attraction—it is well laid out and easy to navigate. It allows participants to freely move from session to session spending time on what interests them most. The ACC meetings are also well designed with a good mix of science and education and not much scheduled during major trial presentations so attendees are able to hear the trial results without missing out on other presentations. Of course all major trials are now published online on the day of presentation so there is no real need to sit through the talks, but nevertheless it is exciting to hear trials presented by the principal investigators and the discussions between the investigators and the moderator and panel provide valuable insight and perspective. The late breaking trial results are available on http://www.cardiosource.org/News-Media/Meeting-Coverage/ACC/ACC-2012.aspx.

I know the fellows had a good time and made numerous presentations. Louai Razzouk won a prize for his poster presentation entitled “Is Minimal Luminal Area by Intravascular Ultrasound the Critical Determinant of Future MACE in Intermediate Lesions? Insights from PROSPECT”. Medical residents also had an opportunity to present. I was particularly proud of Nick Amoroso who presented ” Mean Platelet Volume is Significantly Associated With Survival Following Percutaneous Coronary Intervention and Coronary Artery Bypass Surgery” and handled the questions of the moderating panel with coolness and aplomb (by his own highly reliable account). Amita Singh had two presentations on triple anti-platelet therapy including cilostazol.

The ACC meetings featured a large number of educational offerings including many specifically linked to the American Board of Internal Medicine Maintenance of Certification program. I do need to renew my boards in interventional cardiology in 2019 so I decided to try a cath lab simulation module worth 10 points out of the 100 needed for recertification. I was particularly interested in the simulation because of my experiences with the Sim center at the VA and the new Sim center that just opened at Bellevue which we have been using for medical student teaching in cardiology. I have always been very skeptical about the educational value of simulations, even though the medical students seemed to be enjoying and learning from them. I was very pleasantly surprised by my experience with cath lab simulation at the ACC. I was told to insert a straight catheter and a straight wire (both very stiff and dangerous feeling) into a femoral sheath in a mannequin. When I felt a “click” I was told to press on the “fluoro” pedal and advance the catheters. Well, a J tipped wire appeared on the screen and I was able to select from a wide variety of catheter shapes and manipulate them into coronary arteries. I was particularly impressed with the coronary images obtained with varying camera angles. We always emphasize to the fellows the importance of obtaining appropriate views to make diagnoses and treat lesions safely—the simulator could let us teach this important lesion without exposing a real patient to excessive contrast and radiation. I then had to perform 4 simulated coronary interventions and ran into many of the complications that we are tested on in the interventional boards and that I lecture about to the fellows (it was helpful to my ego that the proctor explained that complications were programmed in and had nothing to do with my procedural manipulations or choice of balloons, wires, stents and medications ). I “dissected a left main”, “perforated a coronary artery with a guidewire” and “caused slow flow” with a stent expansion. It was reasonably realistic and was a fair test of my ability to recognize problems (it helps when the mannequin says “my chest is hurting”) and respond to them appropriately. I guess that simulations are here to stay and we will be increasingly using them at all levels of medical education.

The ACC meeting includes the Innovations in Intervention (I2) summit sponsored by the ACC and the Cardiology Research Foundation (CRF). This partnership is rather controversial because of the strong ties that CRF has with industry and the live case demonstrations at the I2 summit generate controversy as well. This year, several live cases featured the use of pressure wire for measurement of fractional flow reserve (FFR ) in clinical decision making. I was outraged when the operators decided to go ahead and stent lesions even when the FFR was well in the normal range. Promulgating bad practice and inappropriate use of technology before a wide audience of practitioners and fellows who will take these cases as license to ignore the evidence and make money treating stenoses that are better left alone is thoughtless at best—reprehensible actually. I was disappointed that the panel of experts moderating the live cases had a different response—they concluded that there is still uncertainty and difference of opinion over the value of physiologic assessment of lesions in the cath lab. I differ.

A number of late breaking interventional trials were presented during the I2 summit. BCIS1 ( Balloon-Pump Assisted Coronary Intervention Study) showed some intriguing hints of long term benefit with intra-aortic balloon pumping in patients undergoing elective high risk PCI. A total of 301 patients with LVEF < 30% undergoing PCI of lesions in vessels supplying > 40% of the myocardium were enrolled, 151 to IABP and 150 to conventional therapy. There was no difference in the primary endpoint of major adverse cardiac events (MACE) at 28 days between the IABP and conventional therapy arms (15.2% vs. 16.0%). Procedural complications were significantly lower in the IABP arm (1.3% vs. 10.7%, p < 0.001), although access site complications (3.3% vs. 0%, p = 0.06) and all bleeds (19.2% vs. 11.3%, p=0.06) tended to be more frequent in the IABP arm. All-cause mortality at 2 years (median 51 months) was significantly lower in the IABP arm at 2 years (27.8% vs. 38.7%, HR 0.66, 95% CI 0.44-0.98; p=0.039). Information on other outcomes at 2 years such as MI, cardiovascular death, and CVA was not available. This may reflect the play of chance, but it does support the notion that balloon pumping may be very useful in the setting of high risk PCI.

The INFUSE-AMI trial evaluated intracoronary abciximab and manual aspiration thrombectomy in the setting of anterior wall STEMI treated with PCI and bivalirudin. This trial seemed highly relevant to interventionalists at NYU all who use bivalirudin for PCI and very frequently perform manual clot aspiration. A total of 452 patients were randomized, 229 to aspiration thrombectomy and 223 to no aspiration thrombectomy, and 229 to intracoronary abciximab, and 223 to no abciximab. The primary outcome of infarct size at 30 days, as assessed by cardiac magnetic resonance imaging (MRI) was significantly lower in the abciximab arm, as compared with the no abciximab arm (15.1 vs. 17.9, p=0.03). There was no difference in infarct size with thrombectomy. None of the treatments were associated with improvement in blood flow and the study was under-powered for clinical end points. This study will not change clinical practice (at least not at NYU). The interventional community here is still waiting for the results of larger ongoing trials before giving up on thrombectomy.

Another trial of interest to NYU interventionalists who are increasingly using cilostazol post PCI for prevention of restenosis and stent thrombosis (think of Amita Singh’s presentations) was the HOST-ASSURE Randomized Trial that evaluated whether triple therapy with aspirin, clopidogrel 75 mg daily, and cilostazol would be noninferior for cardiovascular outcomes at 1 month when compared with dual antiplatelet therapy (DAPT) with aspirin and clopidogrel 150 mg daily. A total of 3,755 patients were randomized at 40 centers in South Korea: 1,879 to triple therapy and 1,876 to DAPT. The primary composite outcome of cardiac death, myocardial infarction (MI), stroke, stent thrombosis (ST), and PLATO (PLATelet inhibition and patient Outcomes) major bleeding was similar between the triple therapy and DAPT arms (1.2% vs. 1.4%, hazard ratio 0.85, 95% confidence interval 0.49-1.48; p < 0.001 for noninferiority, p = 0.57 for superiority). On-treatment platelet reactivity was better with cilostazol at 1 and 30 days following PCI. Cilostazol for 1 month may thus be a viable alternative to double-dose therapy with clopidogrel in patients undergoing DES PCI. Again, not practice changing, but more data indicating that cilostazol may be a safe and effective therapy post PCI (at least in Asian patients where most of the research has been done).

An interventional trial with important public policy implications was the CPORT-E trial which evaluated the safety of PCI done in hospitals without cardiac surgery on site. A total of 18,867 patients were enrolled at 60 centers, 14,149 to PCI at sites without on-site cardiac surgery, and 4,718 to sites with on-site cardiac surgery (72 were unassigned). The median procedure volume at these institutions was 150. Of the patients enrolled, 64% were undergoing PCI for acute coronary syndrome; 23% of the procedures were either urgent or emergent. There was an even distribution between patients with one-, two-, and three-vessel disease (roughly 28-34%); left main PCI was undertaken in 3% of the patients and saphenous vein graft PCI in about 9%. The primary endpoint of all-cause mortality at 6 weeks was noninferior between sites without and with on-site cardiac surgery (0.9% vs. 1.0%, p for noninferiority p = 0.004). At 9 months, rates of MACE (death, myocardial infarction, target vessel revascularization [TVR]) were noninferior (12.1% vs. 11.2%, p for noninferiority = 0.05). The VA has adopted the idea of performing PCI in centers with cardiac surgery on site and trials such as this one will surely lead to approval of small interventional labs throughout the country. Coronary intervention has matured, high volume is probably not a good measure of quality and a cardiac surgery program on site is not necessary for safe performance of PCI.

Cardiac surgery on site may not be needed for the safe performance of PCI, but consultation with a cardiac surgeon is certainly a good idea for patients with advanced 3 vessel coronary artery disease. The ASCERT study was an observational comparative effectiveness study comparing survival after PCI versus CABG. The investigators linked the American College of Cardiology Foundation National Cardiovascular Data Registry and the Society of Thoracic Surgeons Adult Cardiac Surgery Database to claims data from the Centers for Medicare and Medicaid Services for the years 2004 through 2008. Outcomes were compared with the use of propensity scores and inverse-probability-weighting adjustment to reduce treatment selection bias. Among patients 65 years of age or older who had two-vessel or three-vessel coronary artery disease without acute myocardial infarction, 86,244 underwent CABG and 103,549 underwent PCI. The median follow-up period was 2.67 years. At 1 year, there was no significant difference in adjusted mortality between the groups (6.24% in the CABG group as compared with 6.55% in the PCI group; risk ratio, 0.95; 95% confidence interval [CI], 0.90-1.00). At 4 years, there was lower mortality with CABG than with PCI (16.4% vs. 20.8%; risk ratio, 0.79; 95% CI, 0.76-0.82). Similar results were noted in multiple subgroups and with the use of several different analytic methods. Residual confounding was assessed by means of a sensitivity analysis. The authors of this study themselves acknowledge that no degree of statistical manipulation can fully acount for bias in such a study. There are unmeasured variables such as frailty that affect both the choice of revascularization options and survival. The growing feeling which is now incorporated into both the CABG and PCI guidelines is that neither randomized trials nor giant registry studies such as ASCERT can adequately guide therapy for individual patients. Rather, a heart team of experienced interventionalists and cardiac surgeons and often general cardiologists as well is best able to incorporate evidence from studies and individual patient characteristics and preferences to select the most appropriate treatment for patients with advanced coronary artery disease.

Well wouldn’t it be wonderful if we could wipe out atherosclerosis and get rid of both interventionalists and cardiac surgeons and all those trials they do (like the ones I have spent my professional career doing). The latest candidate for miracle drug is the monoclonal antibody to Proprotein Convertase Subtilisin/Kexin Type 9 Serine Protease (PCSK9). PCSK9 binds to and inactivates the hepatic LDL receptor raising serum LDL. The PCSK9 Inhibition in Patients With Primary Hypercholesterolemia on Atorvastatin trial randomized patients 1:1:1:1:1:1 to placebo every 2 weeks (Q2W); the novel anti PCSK9 blocker SAR236553 50, 100, or 150 mg Q2W; or SAR236553 200 or 300 mg every 4 weeks (Q4W) alternating with placebo to mimic Q2W dosing. Randomization was stratified according to atorvastatin dose, to evaluate any effect of background atorvastatin dose on the LDL-C lowering efficacy of SAR236553. Baseline LDL-C was about 125-130 mg/dl in the six arms. Decreases in LDL-C from baseline were: 39.6% with 50 mg Q2W, 64.2% with 100 mg Q2W, 72.4% with 150 mg Q2W dose, 43.2% with 200 mg Q4W, and 47.7% with 300 mg Q4W, versus 5.1% with placebo (p < 0.0001 for all comparisons vs. placebo). Target LDL-C ?100 mg/dl was significantly higher with SAR236553 than placebo (89-100% vs. 16%, p < 0.05). LDL-C reductions with SAR236553 were similar among atorvastatin doses. Changes in high-density lipoprotein cholesterol (HDL-C) were also noted: 6.7% vs. 4.1% vs. 5.5% vs. 6.3% vs. 8.5% vs. -1.0%, respectively (only 50 mg Q2W, 200 mg Q4W, and 300 mg Q4W demonstrated p < 0.05 as compared with placebo). Similarly, reductions in serum triglycerides were noted: 6.6% vs. 5.5% vs. 18.9% vs. 10.8% vs. 8.4% vs. -9.7%, respectively (only 150 mg Q2W had p < 0.05 when compared with placebo). The clinical value of these dramatic changes in lipid profiles will be evaluated in larger trials, but the audience seemed enthusiastic about the potential of the novel target for treatment .

Diet, exercise, chocolate,alcohol in moderation,a few carefully selected pills and injections seem to me to be appropriate methods of prevention. For some patients, however, more drastic methods may be needed. STAMPEDE compared intensive medical therapy to bariatric surgery in patients with type 2 DM who were either obese or overweight. Eligible patients were randomized in 1:1:1 fashion to either intensive medical therapy alone, intensive medical therapy + Roux-en-Y gastric bypass, or intensive medical therapy + sleeve gastrectomy. All patients received intensive medical therapy as defined by the American Diabetes Association (including lifestyle counseling, frequent home glucose monitoring). Use of newer diabetic medications was permitted. The goal was to achieve a glycated hemoglobin (HbA1c) of ?6%, or intolerance to medication. All bariatric procedures were performed by a single surgeon at the Cleveland Clinic, as per standard operating techniques. A total of 150 patients were randomized. However, eight patients withdrew consent and two missed follow-up appointments, resulting in 141 patients in the primary analysis. Of these, 41 received intensive medical therapy alone, 50 underwent gastric bypass, and 50 underwent sleeve gastrectomy. The primary endpoint of achieving HbA1c ?6% at 12 months was significantly higher in the gastric bypass and sleeve gastrectomy arms, as compared with the medical therapy arm (42% vs. 37% vs. 12%, p = 0.002 and p = 0.008, respectively). No difference was noted between the surgical arms (p = 0.59). Interestingly, all successfully treated patients in the gastric bypass arm did so without the use of any medications, whereas 28% in the sleeve gastrectomy arm required concomitant medications. Mean change in HbA1c at 12 months from baseline for intensive medical therapy, gastric bypass, and sleeve gastrectomy was -1.4% vs. -2.9% vs. -2.9%, p < 0.001 for both; mean change in body weight from baseline was -5.4 kg vs. -29.4 kg vs. -25.1 kg, p < 0.001 for both. There was a salutary effect on high-density lipoprotein cholesterol (HDL-C) (% change from baseline: 11.3% vs. 28.5% vs. 28.4%, p < 0.001 for both), triglycerides (% change from baseline: -14% vs. -44% vs. -42%, p = 0.002, p = 0.08, respectively), high-sensitivity C-reactive protein (hs-CRP) (% change from baseline: -33.2% vs. -84% vs. -80%, p < 0.001 for both), and number of antihypertensive and lipid-lowering medications required at 12 months as well. It is clear that bariatric surgery is the most effective therapy (by far) for morbid obesity. The beneficial effects observed in this short term study of less obese but diabetic patients raises many important questions. Are the benefits sustained? Is there a detriment to stopping statins in diabetic patients whose lipid profile improves with surgery? Are the results reproducible in the community? And if this really does turn out to be a valuable therapy, can our nation afford it? Healthy school lunches and gym classes at an early age seems like a better option to me.

Those were just a few of the late breaking trials. There were trials on stem cell therapy for heart failure, on CT angiography in the emergency department as an alternative to traditional evaluation with stress testing, on pacing for neurally mediated syncope with documented asystole and on late outcomes after trans catheter aortic valve replacement among other studies. None of the trials presented this year were truly landmark studies or will be immediately practice changing. But trials with implications for policy such as CPORT-E needed to be presented even though the results were not surprising. CPORT was very controversial when it was first designed and it shows how far the field of interventional cardiology has progressed over the last 10 years that we now accept without question that high quality PCI can be safely done in small community hospitals. That may not be good news for academic centers which would like to keep a monopoly on doing these kinds of procedures, but it probably is good news for patients, and that is the only measure that counts. Academic centers will be needed to develop and evaluate new treatments and to train practitioners to go out into the community and provide those treatments for the benefit of patients. ACC 2012 was an important part of that process and its contribution to the health and welfare of our nation will be felt in the coming year as the attendees return home, think critically about what they have seen, heard and read about at the meetings and apply their new found knowledge to patient care. 

Dr. Steven Sedlis is an associate professsor, Department of Medicine, NYU Langone Medical Center

Image courtesy of Wikimedia Commons

Nothing QT (Cute) about it: rethinking the use of the QT interval to evaluate risk of drug induced arrhythmias

April 27, 2012

By Aneesh Bapat, MD

Faculty Peer Reviewed

Perhaps it’s the French name, the curvaceous appearance on electrocardiogram (EKG), or its elusive and mysterious nature, but Torsades des pointes, a polymorphic ventricular arrhythmia, is certainly the sexiest of all ventricular arrhythmias. Very few physicians and scientists can explain its origin in an early afterdepolarization (EAD), and fewer still can explain its “twisting of the points” morphology on EKG. Despite its rare occurrence (only 761 cases reported to the WHO Drug Monitoring Center between 1983 and 1999)1, every medical student is taught that it is an arrhythmia caused by prolongation of the QT interval. The more savvy medical student will implicate the corrected QT interval (QTC) and recite a fancy formula with a square root sign to determine this value. Suffice to say, the mystic nature of torsades des pointes and the negative attitude towards QT prolongation have been closely intertwined over the years. While the most common culprits, such as cisapride, macrolides, terfenadine, and haloperidol[1] have become maligned for this reason, there are many more that do not even make it to the market because they prolong QT interval2. (A comprehensive list of QT prolonging drugs with associated arrhythmia risk can be found at <http://www.qtdrugs.org/>) Although our conceptions of a long QT interval have been inculcated repeatedly, there is growing evidence that QT interval prolongation may not be sufficient to predict risk of drug induced TdP, and that other, more sensitive and specific markers should be utilized.

The QT interval, which is the amount of time between the start of the QRS complex and the end of the T wave on EKG, is a marker of the amount of time required for ventricular tissue depolarization and repolarization. On a cellular basis, it is closely related to the duration of the cardiac myocyte action potential (AP). In pathological conditions, myocyte depolarization can even occur during phase 2 or 3 of the action potential, producing an EAD. These EADs can give rise to ectopic beats in the tissue, and produce arrhythmias such as TdP due to the R on T phenomenon. It is generally thought that EADs are caused by problems with myocyte repolarization- which would prolong QT interval- and thus QT prolongation has been linked to EAD mediated arrhythmias such as TdP. Drugs such as haloperidol have been shown to block the potassium channels responsible for AP repolarization, and as a result prolong QT interval. However, it has become more apparent in recent years that prolonged repolarization (or QT interval) is neither sufficient nor necessary to produce the EADs (or ectopic beats) that cause arrhythmias[3-6].

The EAD is an arrhythmogenic entity that has been implicated in a variety of abnormal rhythms, including ventricular tachycardias, such as TdP, ventricular fibrillation, and atrial arrhythmias. In the normal cardiac action potential, Na+ channel opening produces the inward current necessary for the initial upstroke of the action potential, L-type calcium channels produce a plateau caused by influx of calcium, and K+ channels produce an outward current to assure full repolarization. The simplistic explanation for EADs has always been that EADs occur when inward currents (Na+ and Ca2+) are greater than outward currents (K+). This explains why EADs can occur as a result of K+ current inhibition- as seen with the use of anti-arrhythmics such as sotalol, or in the presence of hypokalemia. The advantage of this simplistic viewpoint is just that- it is simple. However, it is far from comprehensive. In fact, there are cases where potassium current inhibition does not cause EADs, and others where potassium currents are augmented and EADs do occur[3,4,7]. The key to the genesis of EADs is not the duration or magnitude of the various currents that make the action potenatial, but rather the timing of channel openings8. The classic example to contradict the simplistic idea of EAD genesis is the antiarrhythmic drug amiodarone, which acts via potassium channel blockade and causes QT prolongation, but does not produce EADs or increase TdP risk7,9. Since the occurrence of EADs is not solely determined by the duration of the action potential, it follows that the risk of TdP is not solely determined by the QT interval.

Although much basic science and clinical research have brought into question the validity of using QT prolongation to determine TdP risk, the message has been lost in translation to the bedside. In the clinic or hospital setting, too much weight is put into the baseline QT interval when deciding whether a drug can be used. A recent clinical study has shown that the degree of QT prolongation does not correlate to the baseline QT interval10. Another study has proposed the use of the Tp-e (amount of time from peak to end of the T wave) or the Tp-e/QT ratio as indicators for arrhythmia risk, regardless of whether they occur in presence of long QT, short QT, or unchanged QT11. Yet another study proposes the use of three EKG criteria- T wave flattening, reverse use dependence of the QT interval, and instability of the T wave- to determine whether a drug is arrhythmogenic. This study cites a better sensitivity to arrhythmia risk and an earlier onset in changes as compared to QT prolongation. This set of criteria even stands tall in the face of the paradoxical situations of prolonged QT and decreased arrhythmia risk- as with amiodarone use7. When the day comes that QT prolongation is deemed unsatisfactory, better alternatives exist.

The study of arrhythmias has advanced significantly over the years, but unfortunately the clinical practice has lagged behind. The major shortcoming of arrhythmia treatment in the clinic has been tunnel vision. For example, in the landmark CAST trial, Na+ channel blockade was used to prevent post-MI premature ventricular complexes. However, the study had to be terminated because of increased mortality- which was partially a result of arrhythmias [3,12]. The lesson from that trial should have been that a multi-faceted problem involving a variety of players cannot be eliminated by targeting one of them. Unfortunately, a similar approach has been taken in using QT prolongation as a marker for TdP risk. The factors that influence arrhythmogenesis are far too numerous to focus on only one, and a new, more comprehensive approach should be considered.

Aneesh Bapat is a 4th year medical student at NYU Langone Medical Center

Peer reviewed by Neil Bernstein, MD, Departments of Medicine (Cardio Div) and Pediatrics, NYU Langone Medical Center

Image courtesy of Wikimedia Commons

References:

1. Darpo B. Spectrum of drugs prolonging QT interval and the incidence of torsades de pointes. European Heart Journal Supplements. 2001;3:K70-K80. Available at: http://eurheartjsupp.oupjournals.org/cgi/doi/10.1016/S1520-765X(01)90009-4.

2. Kannankeril P, Roden DM, Darbar D. Drug-Induced Long QT Syndrome. Journal of the American College of Cardiology. 2010;62(4):760 -781.

3. Weiss JN, Garfinkel A, Karagueuzian HS, Chen P-S, Qu Z. Early afterdepolarizations and cardiac arrhythmias. Heart rhythm?: the official journal of the Heart Rhythm Society. 2010;7(12):1891-9. Available at: http://www.ncbi.nlm.nih.gov/pubmed/20868774  [Accessed February 15, 2011].

4. Ding C. Predicting the degree of drug-induced QT prolongation and the risk for torsades de pointes. Heart rhythm?: the official journal of the Heart Rhythm Society. 2011. Available at: http://www.ncbi.nlm.nih.gov/pubmed/21699823  [Accessed August 25, 2011].

5. Couderc J-P, Lopes CM. Short and long QT syndromes: does QT length really matter? Journal of electrocardiology. 2010;43(5):396-9. Available at: http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=2928258&tool=pmcentrez&rendertype=abstract  [Accessed June 18, 2011].

6. Hondeghem LM. QT prolongation is an unreliable predictor of ventricular arrhythmia. Heart rhythm?: the official journal of the Heart Rhythm Society. 2008;5(8):1210-2. Available at: http://www.ncbi.nlm.nih.gov/pubmed/18675236  [Accessed September 7, 2011].

7. Shah RR, Hondeghem LM. Refining detection of drug-induced proarrhythmia: QT interval and TRIaD. Heart rhythm?: the official journal of the Heart Rhythm Society. 2005;2(7):758-72. Available at: http://www.ncbi.nlm.nih.gov/pubmed/15992736  [Accessed August 25, 2011].

8. Tran D, Sato D, Yochelis A, et al. Bifurcation and Chaos in a Model of Cardiac Early Afterdepolarizations. Physical Review Letters. 2009;102(25):1-4. Available at: http://link.aps.org/doi/10.1103/PhysRevLett.102.258103  [Accessed July 14, 2010].

9. Opstal JM van, Schoenmakers M, Verduyn SC, et al. Chronic Amiodarone Evokes No Torsade de Pointes Arrhythmias Despite QT Lengthening in an Animal Model of Acquired Long-QT Syndrome. Circulation. 2001;104(22):2722-2727. Available at: http://circ.ahajournals.org/cgi/doi/10.1161/hc4701.099579  [Accessed August 25, 2011].

10. Kannankeril PJ, Norris KJ, Carter S, Roden DM. Factors affecting the degree of QT prolongation with drug challenge in a large cohort of normal volunteers. Heart rhythm?: the official journal of the Heart Rhythm Society. 2011. Available at: http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=3154568&tool=pmcentrez&rendertype=abstract  [Accessed August 25, 2011].

11. Gupta P, Patel C, Patel H, et al. T(p-e)/QT ratio as an index of arrhythmogenesis. Journal of electrocardiology. 2008;41(6):567-74. Available at: http://www.ncbi.nlm.nih.gov/pubmed/18790499  [Accessed August 25, 2011].

12. Anon. Preliminary report: effect of encainide and flecainide on mortality in a randomized trial of arrhythmia suppression after myocardial infarction. The Cardiac Arrhythmia Suppression Trial (CAST) Investigators. The New England journal of medicine. 1989;321(6):406-12. Available at: http://www.ncbi.nlm.nih.gov/pubmed/2473403  [Accessed August 26, 2011].

From The Archives: How Does Alcohol Cause Cardiomyopathy?

April 19, 2012
Please enjoy this post from the archives dated November 4, 2009

Charles Levine

Faculty peer reviewed

Excessive consumption of ethanol (EtOH) has many deleterious effects on the human body. The heart is a target of damage from EtOH consumption, as chronic consumption of EtOH leads to decreased cardiac function and structural heart disease, including dilated cardiomyopathy.(1) The exact mechanism by which EtOH exerts its deleterious effects on the heart remains poorly understood and is an area of active research. This report will focus on some of the proposed mechanisms and some recent advances in the understanding of the pathogenesis of EtOH-induced cardiomyopathy.

The pathogenesis of alcoholic cardiomyopathy is likely multifactorial, and current evidence suggests a role for decreased excitation/contraction coupling, oxidative damage, and membrane destabilization in cardiac myocytes. However, the key initiating event is not known. Several theories have been put forth to explain the underlying pathogenesis of alcoholic cardiomyopathy. Two of the leading theories will be reviewed here.

The idea that apoptosis underlies the myocardial damage observed in alcoholic cardiomyopathy was first proposed in 2000 by Chen et al, based on the observation that several markers of apoptosis were observed to be elevated in many cardiac diseases.(2-4) A more recent study looked at the post-mortem hearts of 20 long-standing alcoholics and compared them to non-alcoholic controls and hearts from patients with hypertension but not alcoholism. Histological staining for apoptosis using terminal deoxynucleotidyl transferase d-UTP nick-end labeling (TUNEL), as well as staining for several markers of apoptosis, including Bcl-2 and activated caspase-3, revealed a significantly elevated level of apoptosis in the alcoholic and hypertensive hearts, as compared to control hearts.(5) The authors concluded that alcohol mediates its deleterious effects on the heart via induction of apoptosis. These studies failed, however, to identify any mechanistic connection between EtOH exposure and myocyte death.

Another theory has been termed the acetaldehyde toxicity theory by Cai et al.(6) The theory is based on the observation, made several decades ago in rats, that acute EtOH exposure can decrease cardiac contractility.(7) It was hypothesized then that the long-term effects of EtOH exposure on cardiac contractility could result from either chronic exposure to EtOH itself or from exposure to a toxic metabolite of EtOH, possibly acetaldehyde, which is metabolized from EtOH in the liver by the enzymes alcohol dehydrogenase and P450IIE1.(8)

To elucidate the exact effects of acetaldehyde on various cellular and physiological processes, Li and Ren recently conducted an elegant study using transgenic mice. These mice express a transgene coding for the human enzyme alcohol dehydrogenase.(9) By feeding these mice high levels of ethanol, they were able to simulate the high serum levels of acetaldehyde observed in human chronic alcoholics. The authors fed EtOH to transgenic and non-transgenic littermate control mice and analyzed these mice for insulin signaling in the heart, oxidative and endoplasmic reticulum (ER) stress in the heart, and overall cardiac function. Any differences between the two groups could then be attributed to increased exposure to acetaldehyde.

Interestingly, the authors found significant differences between the two groups of mice in all of the processes they tested. It had been known previously that chronic EtOH ingestion leads to impaired glucose tolerance and to cerebral dysfunction secondary to reduced insulin-receptor signaling. It was not clear, however, whether these effects were at all related to EtOH induced cardiomyopathy. This study provided evidence that these effects do indeed contribute to the pathogenesis of alcoholic cardiomyopathy. Chronic alcohol feeding led to glucose intolerance, dampened cardiac glucose uptake, cardiac hypertrophy, and contractile dysfunction in control mice. These effects were significantly exaggerated by the alcohol dehydrogenase transgene. Thus, acetaldehyde exposure directly mediates the toxicity of EtOH on the heart and may underlie the pathogenesis of alcohol-induced cardiomyopathy.

Although the above study did not directly address the role of acetaldehyde in the ER and oxidative stress, previous studies from Ren’s lab showed that acetaldehyde and ethanol both induced the generation of reactive oxygen species and resultant apoptosis in human cardiac myocytes.(10) This finding provides more evidence for the acetaldehyde toxicity theory, and in addition, explains some of the findings of Chen et al, mentioned above, that apoptosis underlies the pathogenesis of alcoholic cardiomyopathy. Thus, both theories of the pathogenesis of alcoholic cardiomyopathy can be seen as complementary, with the acetaldehyde toxicity theory underlying the ultimate apoptosis that may contribute significantly to cardiac dysfunction.

These studies provide a compelling explanation for the pathogenesis of alcoholic cardiomyopathy, but they do not offer an explanation for the reversibility of the disease observed clinically with EtOH abstinence. Several studies have demonstrated that even as little as 10 weeks of abstinence can improve cardiac function significantly in patients with alcoholic cardiomyopathy. (11-13) Given that the final cardiac insult from EtOH results in apoptosis, and that the cardiomyopathy can be reversible, perhaps myocyte regeneration from adult stem cells may play a significant role in restoration of cardiac function following abstinence from EtOH. This finding itself could be extremely exciting in the context of harnessing this reparative potential for the treatment of other cardiac diseases as well.

Charles Levine is a 4th year medical student at NYU School of Medicine.

Peer reviewed by Robert Donnino MD, NYU Division of Cardiology

 

References
1. McKenna CJ, Codd MB, McCann HJ, Sugrue DD. Alcohol consumption and idiopathic dilated cardiomyopathy: a case control study. Am Heart J. 1998;135(5 Pt 1):833-837.
2. Chen DB, Wang L, Wang PH. Insulin-like growth factor I retards apoptotic signaling induced by ethanol in cardiomyocytes. Life Sci. 2000;67(14):1683-1693.
3. Piano MR. Alcoholic cardiomyopathy: incidence, clinical characteristics, and pathophysiology. Chest. 2002;121(5):1638-1650.
4. Djoussé L, Gaziano JM. Alcohol consumption and heart failure: a systematic review. Curr Atheroscler Rep. 2008;10(2):117-120.
5. Fernández-Solà J, Fatjó, Sacanella E, et al. Evidence of apoptosis in alcoholic cardiomyopathy. Hum Pathol. 2006;37(8):1100-1110.
6. Cai L. Alcoholic cardiomyopathy: Acetaldehyde, insulin insensitization and ER stress. J Mol Cell Cardiol. 2008;44(6):979-982.
7. Rubin E, Urbano-Marquez A. Alcoholic cardiomyopathy. Alcohol Clin Exp Res. 1994; 18(1):111-114.
8. Oyama T, Isse T, Kagawa N, et al. Tissue-distribution of aldehyde dehydrogenase 2 and effects of the ALDH2 gene-disruption on the expression of enzymes involved in alcohol metabolism. Front Biosci. 2005;10:951-960.
9. Li SY, Gilbert SA, Li Q, Ren J. Aldehyde dehydrogenase-2 (ALDH2) ameliorates chronic alcohol ingestion-induced myocardial insulin resistance and endoplasmic reticulum stress. J Mol Cell Cardiol. 2009;47(2):247-255.
10. Guo R, Ma H, Gao F, Zhong L, Ren J. Metallothionein alleviates oxidative stress-induced endoplasmic reticulum stress and myocardial dysfunction. J Mol Cell Cardiol. 2009.
11. Masani F, Kato H, Sasagawa Y. [An echocardiographic study of alcoholic cardiomyopathy after total abstinence]. J Cardiol. 1990;20(3):627-634.
12. Agatston AS, Snow ME, Samet P. Regression of severe alcoholic cardiomyopathy after abstinence of 10 weeks. Alcohol Clin Exp Res. 1986;10(4):386-387.
13. Renault A, Mansourati J, Genet L, Blanc JJ. [Dilated cardiomyopathies in severe cardiac failure in chronic alcoholics: clinical course after complete withdrawal]. Rev Med Interne. 1993;14(10):942.

From The Archives: How to interpret troponins in renal disease?

March 15, 2012

Please enjoy this post from the archives first posted on October 21, 2009.

By Ivan Saraiva MD

Case: A 68-year-old man, with a history of stable angina and end-stage renal disease treated by hemodialysis for the past three years, presents to the hospital with leg swelling and shortness of breath. He also complains of intermittent chest pain unrelated to exertion. Physical exam reveals bilateral pitting lower extremity edema, pulmonary crackles, and an elevated jugular venous pressure. Initial electrocardiogram is notable for some nonspecific repolarization abnormalities. Troponin I levels drawn at 0, 6, and 12 hours after initial presentation are 0.03-ng/mL, 0.12-ng/mL, and 0.09-ng/mL, respectively. How should this patient be further evaluated and treated?

Many clinicians debate the usefulness of troponin and other biomarkers in patients with impaired renal function for several reasons. Often, patients admitted for non-cardiac problems will have incidentally elevated troponins. On the other hand, patients in heart failure may have positive troponins for any number of reasons, whether due to an acute ischemic myocardial insult or as a consequence of a chronic fluid-overloaded state. Some clinicians even question whether or not elevated troponins represent myocardial injury at all. In each of these cases, concomitant renal disease only further complicates the clinical picture.

Troponin (Tn) subtypes T, I, and C exist together as a protein complex bound to actin thin filaments in both skeletal and cardiac muscle. This complex regulates muscle contraction and relaxation via its interaction with actin and calcium ions released from the sarcoplasmic reticulum of the muscle cells. TnT and TnI have different isoforms in cardiac and striated muscle, which allows laboratory assays that can identify troponins specifically released from injured myocytes in the heart.

Several studies have explored the significance of elevated troponins in patients with concomitant renal disease [1-10]. Up to 80% of patients with low glomerular filtration rates (GFR), and in the absence of acute coronary syndromes or congestive heart failure, have positive values for TnT, regardless of whether or not they receive dialysis treatment. On the other hand, one large study that included more than 700 patients found the prevalence of TnI to be only 0.4-6% depending on the cut-off value chosen [3]. These results suggest that a positive TnT may represent a common and benign incidental finding in patients with impaired renal function, whereas a positive TnI occurs only in the setting of an acute coronary event. However, other studies have demonstrated consistent associations between elevated TnT and hard endpoints such as death and myocardial infarction [2,3,5,6]. Therefore, although chronic kidney disease appears to be nonspecifically associated with positive TnT values, the absolute TnT level may serve as a useful prognostic marker.

The etiology of the increased TnT in renal disease remains unclear. Recently, a few small, but well-designed, studies have attempted to clarify the association. Askoy et al. studied TnT levels in 62 patients with non-ischemic congestive heart failure. Elevated TnT values were associated with a low ejection fraction, severity of heart failure (NYHA class), and low GFR in the initial univariate analysis. However, after adjustment by regression analysis, only a low GFR remained significantly associated with a positive TnT [1]. Going in the same line of thought, Tsutamoto et al. performed a very elegant study measuring the transcardiac TnT gradient by measuring levels in both the aortic root and coronary sinus [10]. They classified 258 patients with congestive heart failure as having either normal or low GFR. Despite the finding of markedly elevated levels of TnT in the patients with low GFR compared to the patients with normal renal function, the transcardiac gradient appeared similar between the two groups. They concluded that the elevated TnT observed in patients with a low GFR occurs as a result of accumulation rather than increased myocardial injury.

In conclusion, evidence suggests that the kidneys clear TnT and thus baseline levels may indeed rise in the setting of a low GFR. Conversely, it appears that elevated TnI values represent myocardial injury in both patients with low GFR and other populations. Keep in mind however that several mechanisms of non-ischemic myocardial injury occur in the setting of renal disease, including fibrotic and infiltrative processes. These may independently result in an elevated TnI even in the absence of an acute ischemic myocardial insult [11]. Despite these conclusions, elevated TnT and TnI remain specific for heart disease and should never be treated as meaningless.

Based on the above discussion, the management of our case patient should proceed as follows. The differential diagnosis for his presentation must account for a fluid-overloaded state, chest discomfort, and positive TnI values. The patient may have suffered an acute coronary event, exacerbation of a chronic heart failure state, or worsening of his renal function leading to fluid-overload. All of these etiologies may account for his elevated troponin. Notably, this case used the values of TnI, the biomarker assumed to be less commonly accumulated in the setting of chronically impaired renal function. Thus, his positive TnI can be more confidently interpreted as specific for an acute myocardial injury. Furthermore, the patient’s TnI displays a peak followed by a downward trend, which increases the likelihood of an acute event and less likely represents a chronically elevated troponin due to renal disease alone.

Dr. Saraiva is a 2nd year internal medicine resident at NYU Medical Center.

Faculty peer reviewed by Robert Roswell MD, NYU Division of Cardiology

References:

1. Aksoy N, Ozer O, Sari I, Sucu M, Aksoy M, Geyikli I. Contribution of renal function impairment to unexplained troponin T elevations in congestive heart failure. Ren Fail 2009, 31(4):272-7.

2. Ammann P, Maggiorini M, Bertel O, Haenseler E, Joller-Jemelka HI, Oechslin E, Minder EI, Rickli H, Fehr T. Troponin as a risk factor for mortality in critically ill patients without acute coronary syndromes. J Am Coll Cardiol 2003, 41(11):2004-9.

3. Apple FS, Murakami MM, Pearce LA, Herzog CA. Predictive value of cardiac troponin I and T for subsequent death in end-stage renal disease. Circulation 2002, 106:2941-5.

4. Aviles RJ, Askari AT, Lindahl B, Wallentin L, Jia G, Ohman EM, Mahaffrey KW, Newby LK, Califf RM, Simoons ML, Topol EJ, Lauer MS. Troponin T levels in patients with acute coronary syndromes, with or without renal dysfunction. N Engl J Med 2002, 346(26):2047-52.

5. deFilippi C, Wasserman S, Rosanio S, Tiblier E, Sperger H, Tocchi M, Christenson R, Uretsky B, Smiley M, Gold J, Muniz H, Badalamenti J, Herzog C, Henrich W. Cardiac troponin T and C-reactive protein for predicting prognosis, coronary atherosclerosis, and cardiomyopathy in patients undergoing long-term hemodialysis. JAMA 2003, 290:353-9.

6. Frankel WL, Herold DA, Ziegler TW, Fitzgerald RL. Cardiac troponin T is elevated in asymptomatic patients with chronic renal failure. Am J Clin Pathol 1996, 106(1):118-23.

7. Jacobs LH, de Kerkhof JV, Mingels AM, Keijnen VW, der Sande FM, Wodzig WK, Kooman JP, van Dieijen-Visser MP. Haemodialysis patients longitudinally assessed by highly sensitive cardiac troponin T and commencial cardiac troponin T and cardiac troponin I assays. Ann Clin Biochem 2009, 46:283-90.

8. Mongeon F-P, Dorais M, Lorier JL, Froment D, Letendre E, Rinfret S. Effect of hemodialysis, coronary artery disease and diabetes on cardiac troponin T: a prospective survery over one year. Open cardiovasc med j 2009, 3:69-77.

9. Sutidze M, Kajrishvili M, Tsimakuridze M, Khachapuridze N, Sulakvelidze M. Factors associated with increased serum levels of specific markers of myocardial injury – cardiac troponins T and I in chronic haemodialysis patients. Georgian Med News 2009, 169:39-43.

10. Tsutamoto T, Kawahara C, Yamaji M, Nishiyama K, Fujii M, Yamamoto T, Horie M. Relationship between renal function and serum cardiac troponin T in patients with chronic heart failure. Eur J Heart Fail 2009, 11(7):653-8.

11. Schietinger BJ, Brammer GM, Wang H, Christopher JM, Kwon KW, Mangrum AJ, Mangrum JM, Kramer CM. Patterns of later gadolinium enhancement in chronic hemodialysis patients. J Am Coll Cardiol Img 2008, 1(4):450-6.

Cardiac Murmur Websites: An Internet Review of Common Cardiac Auscultation Websites

February 29, 2012

By Rachel Bond, MD

Faculty Peer Reviewed

In the field of medicine including the art of physical diagnosis, there is nothing more nerve provoking then having to master the art of cardiac auscultation. Imagine the concern of medical students, residents, internists and freshly starting cardiologists all alike who are asked by patients time and time again, “does my heart sound okay?!” With the advancement in technology and the rapid surge of echocardiogram usage, the use of a stethoscope has not been very provocative. However, being able to elicit a murmur remains key in any medical profession. Certain ways to go about learning how to identify murmurs remain arbitrary and based on experience. However, with the World Wide Web at our fingertips, there are a number of free websites that provide audio samples of murmurs and maneuvers to elicit them. Below is a list of a few of these websites with my very own synopsis.

To simplify the review, websites will be grouped into:

Highly recommended, recommended or not recommended based on my review; however, please feel free to explore all including websites at your own timely discretion.

Highly Recommended:

http://www.easyauscultation.com/?gclid=CKrG_s3Yg6oCFQPc4AodIDrm0g

This website has convincing heart sounds that are easily heard and can be listened to over and over to place in your memory bank. Under each sound file, there is a description of the murmur heard with specific maneuvers that can be performed. The website is driven by a complete course that includes common murmurs heard in the primary care setting as well as more advanced cardiac murmurs including congenital defects. Also included are sample lung sounds. This website also includes quizzes integrated within each course section which is a great way to test your knowledge and understanding. I would recommend this site as a good learning tool. The sound quality is heard best with the use of headphones. Also great is the fact it can be played on iphones or ipads as per the site (I did not try this).

http://www.blaufuss.org/

This is a relatively advanced cardiac auscultation site. It includes illustrations of the cardiac exam, including the relationship between the murmur and the carotid pulse. It also shows illustrations of the normal chambers of the heart and cardiac cycle for the different murmurs appreciated on the website. You can listen to the murmurs as many times as you may need to place it in your memory. It also gives great descriptions of the murmurs. I would recommend reading a physiology textbook or reviewing a simpler website prior to venturing here. There also is a quiz at the end to test your fund of knowledge that can be rather challenging. As such, this site is definitely for those already advanced in cardiac auscultation that need some brushing up.

Recommended:

http://depts.washington.edu/physdx/heart/history.html

This is a great website which includes a brief introduction of historical data, and a basic overview of the cardiac exam, including techniques to accentuate certain murmurs. With each sound file presented on the website, which are easily accessed and heard relatively well, there is a written description of what exactly is being heard. The sound quality can definitely be improved; however, it does seem to get the point of the sound of the murmur across.

http://www.cardiologysite.com/auscultation/html/index.html

This website has a great overview of not only cardiac auscultation, but also angiography for those interested in the cardiac field. With the multitude of things presented on this site, the auscultation part falls short of things the other sites include, such as descriptions of the murmurs heard. It does give good representations of the sounds of the murmurs. As such, if you are looking for a site that provides accurate sounding murmurs with little information on description and maneuvers that can be performed, this is a good site. As such, it would most likely be for the more advanced cardiac examiner or someone using a dual textbook or additional website.

www.youtube.com

This website has a number of videos and documentaries on cardiac auscultation and different murmurs with the ability to hear them and see the location the physician places the stethoscope. There are a number of videos to look up; however, it lacks a full description of the murmur heard and any written words.

Not Recommended:

http://www.wilkes.med.ucla.edu/inex.htm

This is one of the first websites we come across under the Google search engine. In fact, it’s one of the first websites I used during my medicine clerkship in medical school. There is a rather brief over view of the physiology of the heart that we typically learn way back in our basic science curriculum of medical school. This underlining physiology is meant to help us understand the cause of the murmurs themselves. The website includes information on the pulmonary system allowing us to get a feel of the entire cardiopulmonary system. There are also sample audio clips of the typical sounds each murmur comprises and pathologic lung sounds; however, the sound quality is poor and the clips are very short giving us little ability to place these sounds in our memory bank. There is a troubleshooting page to help improve the sound quality; however, this seems too complicated and with the time spent attempting to correct the sound quality, it seems it should/could be used to search for a better auscultation site.

http://filer.case.edu/dck3/heart/listen.html#Introduction

When you first arrive at this website, it appears promising. Initially giving you an overview as to why auscultation is an important craft to have in any medical field. It also explains where to place ones stethoscope (for the beginners) and different maneuvers’ that can be performed to bring out murmurs. As you venture further in to the website and evaluate the actual murmur sounds, it initially is great in that it gives you the sound of the murmur and a description of the murmur, as well as differentials as to why this murmur might be heard. However, you soon realize the website is incomplete; these descriptions are soon gone and only the murmur is heard which is a brief clip that sometimes works on the website or sometimes doesn’t. This website initially seemed like the perfect pick for the budding 2nd year medical student who would want to get a start on things prior to beginning their medical clerkships; however, it needs a few adjustments.

Dr. Rachel Bond is a 3rd year resident at NYU Langone Medical Center

Peer reviewed by Robert Donnino, MD , Cardiology Editor, Clinical Correlations

Image courtesy of Wikimedia Commons

The Diagonal Earlobe Crease: Historical Trivia or a Useful Sign of Coronary Artery Disease?

November 2, 2011

Nicholas Mark, MD & Sarah Buckley, MD

Faculty Peer Reviewed

Background

Publius Aelius Hadrianus, better known as Hadrian, emperor of Rome (117-138 CE), traveler, warrior, and lover of all things Greek, fell ill at the age of 60. He developed progressive edema and episodic epistaxis, fell into a depression soothed by rich food and drink, and succumbed to death within 2 years. The exact cause of Hadrian’s death–whether by heart failure, glomerulonephritis, or even hereditary hemorrhagic telangiectasia–has been a topic of debate among paleopathologists. It was not until 1980 that a crucial clue was found, memorialized in stone busts of the late emperor: he was sculpted with a deep diagonal crease in both earlobes. [1]

Since its first description by Frank in the New England Journal of Medicine in 1973[2], the presence of the diagonal earlobe crease (ELC) has been recognized as a marker of coronary artery disease (CAD). Subsequent studies confirmed the ELC (or Frank’s sign) as a predictor of CAD independent of age, cholesterol, blood pressure, or smoking status. On the other hand, several studies found no correlation between ELC and CAD and suggest that it is simply a marker of advancing age. Over 50 papers have been published regarding this physical diagnosis sign, and for almost 4 decades controversy has raged over its utility. Is the ELC a clinically useful predictor of CAD? In order to answer this question we performed a meta-analysis of all published studies evaluating the role of ELC as a predictor of CAD.

Methods

Published articles, abstracts, and letters were obtained using the search term “Ear Lobe Crease.” Raw data regarding prevalence of ELC and CAD were collected and analyzed to calculate sensitivity, specificity, and likelihood ratios (LR). Significance was determined using the Fisher exact test and Chi squared test (depending on the number of patients in the study), and P values and 95% confidence intervals (CI) were calculated.

Results

There was significant variation in the design of the studies, ranging from large population screening studies to smaller studies looking at patients undergoing angiography for suspected CAD. The majority of studies found that ELC was a statistically significant predictor of CAD: the results of 6 of the 22 studies analyzed were not significant, and the remaining 16 studies demonstrated varying degrees of predictive value, with likelihood ratios ranging from of 1.33 to 9.20 (see figure 1). Upon pooling all data, we found an overall sensitivity of 60.4% and specificity of 74.4%. We found that the presence of ELC has a LR of 2.37 (CI of 2.26 to 2.48) for predicting CAD. We analyzed the subset of studies that included only cardiac patients and found that the utility of ELC was lower in this group than in an unselected patient population (LR of 1.88 vs 2.44). Similarly, when the higher-risk diabetic population of the Fremantle Diabetes study was excluded, the LR was slightly higher.

Discussion

Frank suggested that the presence of “a prominent crease in a lobule portion of the auricle” may be indicative of small vessel pathology, possibly explaining the correlation with CAD.[1] Shoenfield and colleagues performed histological examination of earlobe creases and found substantial thickening of the arteriolar walls relative to controls without ELC.[25]

Many authors performed multivariate analysis to ascertain if ELC is truly an independent marker of CAD risk or just a surrogate for other known risk factors. Several studies found that though ELC correlates with CAD, it is independent of other CAD risk factors (hypertension, hyperlipidemia, diabetes, and smoking).[13,15].

Other studies reported that that the LR of bilateral ELC is higher than that of unilateral ELC [15], and that depth of the ELC portends a greater likelihood of CAD. It has also been proposed that the presence of additional factors, such as earlobe hair [17], could further increase the utility of the sign.

The utility of ELC may vary depending on several factors. Age appears to be a significant potential confounder, and indeed the incidence of ELC increases with age in every study. However, as expected, the incidence of CAD also increases with age, and it is unclear at what ages the utility of the sign is highest. Several studies performed subgroup analyses looking at the utility of the ELC in patients of different ages with conflicting results. In general, though, the studies found that the presence of ELC has some predictive value across all age ranges.

A few studies have reported negative results in the context of specific ethnic groups. Fisher and colleagues found no significant relationship between ELC and CAD in American Indians [11], and Rhoads and colleagues found no relationship in Japanese-Americans living in Hawaii.[8] Overall, the published incidence of ELC seems to vary significantly among different populations; the significance of this is not clear.

The utility of ELC may also be lower in patients who have a higher pretest probability of CAD, such as in the studies of patients undergoing angiograms for assessment of suspected CAD.[3,17,22] Furthermore, the Fremantle diabetes study suggested that among patients with one of the most important CAD risk factors, diabetes, there is no correlation between ELC and CAD.[21]

Given these limitations, what is the utility of ELC relative to the more established CAD risk factors such as diabetes, hypertension, hyperlipidemia, and smoking? Unlike the modifiable risk factors, which can be addressed by medical management, ELC is only a marker for coronary disease. A recent epidemiological study by Greenland and colleagues [26] and review by Weissler in JAMA [27] showed that the predictive value of these traditional risk factors for predicting CAD complications (MI or death) was quite low (LR ranging from 1.07 to 1.39). Though our meta-analysis looked at ELC as a predictor of CAD (rather than complications of CAD), we find that while the LR of ELC for predicting CAD is modest (LR of 2.37, CI of 2.13 – 2.88), it is significantly higher than that of traditional risk factors. Although we find that the presence of ELC is neither especially sensitive nor specific for CAD, when compared to other known risk factors it does appear to be useful. Thus, we propose that ELC may be a useful additional marker for identifying patients with CAD.

Perhaps if Hadrian were alive today, his sculptors would not have been the only ones to take note of his ears.

FIGURE ONE:

Drs. Nicholas Mark and Sarah Buckley are former students of NYU School of Medicine

Reviewed by Beno Oppenheimer, MD, Assistant Professor Medicine, Division Pulmonary/Critical Care, Course director Introduction to Bedside Diagnosis, NYU School of Medicine

Image courtesy of Wikimedia Commons (Hadrian, emperor of Rome)

References:

1. Petrakis NL. Diagonal earlobe creases, type A behavior and the death of Emperor Hadrian. West J Med. 1980;132(1):87–91. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1216678/

2. Frank ST. Aural sign of coronary-artery disease. N Engl J Med. 1973;289(6):327-328.

3. Lichstein E, Chadda KD, Naik D, Gupta PK. Diagonal ear-lobe crease: prevalence and implications as a coronary risk factor. N Engl J Med. 1974;290(11):615-616.

4. Mehta J, Hamby RI. Letter: Diagonal ear-lobe crease as a coronary risk factor. N Engl J Med. 1974. 291(5):260.

5. Christiansen JS, Mathiesen B, Andersen AR, Calberg H. Letter: Diagonal ear-lobe crease in coronary heart disease. N Engl J Med. 1975;293(6):308-309.

6. Sprague DH. Diagonal ear-lobe crease as an indicator of operative risk. Anesthesiology. 1976;45(3):362-364.

7. Doering C, Ruhsenberger C, Phillips DS. Ear lobe creases and heart disease. J Am Geriatr Soc. 1977;25(4):183-185.

8. Rhoads GG, Yano K. Ear-lobe crease and coronary-artery heart disease. Ann Intern Med. 1977;87(2):245.  http://www.ncbi.nlm.nih.gov/pubmed/889207

9. Kaukola S. The diagonal ear-lobe crease, a physical sign associated with coronary heart disease. Acta Med Scand Suppl. 1978;619:1-49.

10. Wermut W, Jaszczenko S, Ruszel A. Ear lobe crease as a risk factor in coronary disease. Wiad Lek. 1980;33(6):435-438.

11. Fisher JR. Sievers ML. Ear-lobe crease in American Indians. Ann Intern Med. 1980;93(3):512.

12. Kaukola S. The diagonal ear-lobe crease, heredity and coronary heart disease. Acta Med Scand Suppl. 1982;668:60-63.

13. Elliott WJ. Ear lobe crease and coronary artery disease. 1,000 patients and review of the literature. Am J Med. 1983;75(6):1024-1032.

14. Wagner RF Jr, Reinfeld HB, Wagner KD, et al. Ear-canal hair and the ear-lobe crease as predictors for coronary-artery disease. N Engl J Med. 1984;311(20):1317-1318.

15. Gu?iu I, el Rifai C, Mallozi M. Relation between diagonal ear lobe crease and ischemic chronic heart disease and the factors of coronary risk. Med Interne. 1986;24(2):111-116.

16. Gibson TC, Ashikaga T. The ear lobe crease sign and coronary artery disease in aortic stenosis. Clin Cardiol. 1986;9(8):388-390.

17. Verma SK, Khamesra R, Bordia A. Ear-lobe crease and ear-canal hair as predictors of coronary artery disease in Indian population. Indian J Chest Dis Allied Sci. 1988;30(3):189-196.

18. Kenny DJ, Gilligan D. Ear lobe crease and coronary artery disease in patients undergoing coronary arteriography. Cardiology. 1989;76(4):293-298.

19. Miri? D, Rumboldt Z, Pavi? M, Kuzmani? A, Bagatin J. The role of diagonal ear lobe crease in the clinical evaluation of coronary risk. Lijec Vjesn. 1990;112(7-8):206-207.

20. Moraes D, McCormack P, Tyrrell J, Feely J. Ear lobe crease and coronary heart disease. Ir Med J. 1992;85(4):131-132. http://www.ncbi.nlm.nih.gov/pubmed/1473944

21. Motamed M, Pelekoudas N. The predictive value of diagonal ear-lobe crease sign. Int J Clin Pract. 1998;52(5):305-306.  http://www.ncbi.nlm.nih.gov/pubmed/9796561

22. Davis TM, Balme M, Jackson D, Stuccio G, Bruce DG. The diagonal ear lobe crease (Frank’s sign) is not associated with coronary artery disease or retinopathy in type 2 diabetes: the Fremantle Diabetes Study. Aust N Z J Med. 2000;30(5):573-577.

23. Dytfeld D, Le?na J, Protasewicz A, Sarnowski W, Dyszkiewicz W, Paradowski S. Ear lobe crease as a factor of potential risk for coronary artery disease?–World news review and own research. Pol Arch Med Wewn. 2002;108(1):633-638.

24. Bahcelioglu M, Isik AF, Demirel B, Senol E, Aycan S. The diagonal ear-lobe crease. As sign of some diseases. Saudi Med J. 2005;26(6):947-951.

25. Shoenfeld Y, Mor R, Weinberger A, Avidor I, Pinkhas J. Diagonal ear lobe crease and coronary risk factors. J Am Geriatr Soc. 1980;28(4):184-187.

26. Greenland P, Knoll MD, Stamler J, et al. Major risk factors as antecedents of fatal and nonfatal coronary heart disease events. JAMA. 2003;290(7):891-897.

27. Weissler AM. Traditional risk factors for coronary heart disease. JAMA. 2004;291(3):299-300. http://jama.ama-assn.org/content/291/3/299.3