Systems

By Steven Bolger

Peer Reviewed

Omega-3 fatty acids were first identified as a potential agent to prevent and treat cardiovascular disease through several epidemiologic studies of the Greenlandic Inuit in the 1970s suggesting that high consumption of fish oil was associated with a decreased risk of cardiovascular disease [1,2]. Fish oil contains two omega-3 fatty acids, eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), that have been shown to be beneficial in treating hypertriglyceridemia and in the secondary prevention of cardiac events [3-5].

The GISSI-Prevenzione trial, published in 1999, was one of the first multicenter, randomized controlled trials to explore the effect of supplementation with omega-3 fatty acids on patients with recent myocardial infarctions [5]. The trial included 11,324 patients with recent myocardial infarctions. They were randomized to receive daily supplementation with either a capsule containing EPA and DHA in a 1-to-2 ratio or a placebo capsule for 3.5 years, with death from any cause, non-fatal myocardial infarction, and stroke as the composite primary endpoint. The trial demonstrated that supplementation with omega-3 fatty acids resulted in a significant reduction in the primary endpoint, with a relative risk reduction of 10% compared to placebo. The results of this trial suggested that a reduction in sudden cardiac death could be responsible for the decrease in mortality, sparking investigation of the potential anti-arrhythmic properties of omega-3 fatty acids.

Omega-3 fatty acids have been shown to increase the threshold of depolarization of cardiac muscle required for action potential generation in animal models, resulting in a decrease in arrhythmias. A 1994 study using a canine model showed that infusion of a fish oil emulsion resulted in a significantly decreased incidence of ventricular fibrillation compared to a control infusion in response to exercise-induced ischemia [6]. Further studies in rat cardiomyocytes revealed that the mechanism responsible for the reduction in arrhythmias is inhibition of voltage-dependent sodium and L-type calcium channels [7-9]. By shifting the cell membrane potential to a more negative value, omega-3 fatty acids increase the threshold required to generate an action potential, preventing the initiation of arrhythmias.

Several randomized controlled trials have failed to demonstrate that omega-3 fatty acid supplementation results in a reduction in ventricular arrhythmias in patients with implantable cardioverter-defibrillators. A 2005 trial of 200 patients with implantable cardioverter-defibrillators and recent episodes of sustained ventricular tachycardia or ventricular fibrillation showed no reduction in the risk of arrhythmias with fish oil supplementation [10]. The results of this trial furthermore suggested a possible pro-arrhythmic effect of omega-3 fatty acids. A 2006 trial similarly failed to show a reduction in ventricular tachycardia, ventricular fibrillation, or all-cause mortality in 546 patients with implantable cardioverter-defibrillators who received supplementation with omega-3 fatty acids [11].

A 2005 randomized controlled trial of 402 patients with implantable cardioverter-defibrillators, however, demonstrated a trend towards benefit in patients receiving supplementation with omega-3 fatty acids [12]. The primary endpoint selected for the trial was time to first episode of ventricular tachycardia, ventricular fibrillation, or death from any cause. Though the results did not show a significant reduction in the primary endpoint, patients who received omega-3 fatty acid supplementation showed a trend towards a prolonged time to the first episode of these arrhythmias or death from any cause, with a risk reduction of 28% and p-value of 0.057. Furthermore, the risk reduction was significant when probable episodes of ventricular tachycardia and ventricular fibrillation were included in the analysis, with a risk reduction of 31%.

With conflicting results from several trials, a systematic review was performed in 2008 of 12 randomized controlled trials to synthesize clinical data on the effects of fish oil on mortality and arrhythmia prevention [13]. The primary outcomes were defined as the arrhythmic end points of appropriate implantable cardioverter-defibrillator intervention and sudden cardiac death. The results of the meta-analysis showed that fish oil supplementation did not have a significant effect on arrhythmias and all-cause mortality. The review did demonstrate a significant reduction in deaths from cardiac causes consistent with previous studies, including the GISSI-Prevenzione trial.

Fish Oil For Atrial Fibrillation Prevention

In addition to trials investigating ventricular arrhythmias in patients with implantable cardioverter-defibrillators, there have been several observational studies exploring the effect of fish oil on the incidence of atrial fibrillation, which have yielded conflicting results. The Danish Diet, Cancer, and Health Study, a prospective cohort study, found that consumption of omega-3 fatty acids from fish was not associated with a reduction in the risk of atrial fibrillation or flutter [14]. The cohort for this study included 47,949 individuals living in Denmark with a mean age of 56 years. The Rotterdam Study found that consumption of EPA and DHA was similarly not associated with a reduction in the risk of developing atrial fibrillation [15]. The cohort for this study included 5184 patients with a mean age of 67.4 years who lived in the Netherlands. A 12-year prospective, observational study by Mozaffarian and colleagues of 4815 patients over the age of 65, however, found that consumption of fish was associated with a 31% reduction in the risk of atrial fibrillation [16].

The mixed results between these studies may reflect differences in the baseline characteristics of the cohorts of the three studies. The Mozaffarian study placed an age restriction on the cohort of the study, resulting in a mean age of 72.8 years, compared to 56 years for the Danish Diet, Cancer, and Health Study and 67.4 years for the Rotterdam Study. The risk of atrial fibrillation increases with age; thus, the reduction in risk of atrial fibrillation in response to omega-3 fatty acid supplementation may only be appreciable in elderly populations at highest risk [17-18]. The assessment of dietary intake of omega-3 fatty acids also differed between the studies depending on the method of information collection. The Rotterdam study, for example, obtained information via a questionnaire and follow-up interview with a dietician, while the Mozaffarian study employed only a questionnaire.

The 2012 OPERA trial was the first randomized controlled trial to assess the effect of omega-3 fatty acid supplementation on atrial fibrillation [19]. The OPERA trial randomized 1516 patients with a mean age of 64 years who were scheduled for cardiac surgery to receive either a daily fish oil capsule or placebo for 3-5 days before the surgery and for 10 postoperative days or until discharge, whichever came first. The results of the trial showed that perioperative supplementation with fish oil did not reduce the risk of postoperative atrial fibrillation compared to the placebo.

Overall, the results of studies exploring the potential anti-arrhythmic effects of omega-3 fatty acids in reducing the risk of atrial fibrillation have been conflicting. A 2010 meta-analysis of 10 randomized controlled trials examining the role of omega-3 fatty acids in preventing atrial fibrillation found no evidence of significant effects of omega-3 fatty acids on atrial fibrillation prevention [20].

In conclusion, although omega-3 fatty acid supplementation has been shown to provide several potential cardiovascular benefits, trials have failed to consistently show that omega-3 fatty acids have significant anti-arrhythmic effects. The reasons for the inconsistent results are unknown, and perhaps may be related to patient selection, type of fish oil preparation, fish oil dose, or other factors. Meta-analyses of randomized controlled trials have not shown a reduction in either ventricular arrhythmias or atrial fibrillation. Additional studies are necessary to further characterize the role of fish oil in preventing arrhythmias.

Steven Bolger is a 3rd year medical student at NYU School of Medicine

Peer reviewed by Robert Donnino, MD, Cardiology Editor, Clinical Correlations,  NYU Langone Medical Center

 Image courtesy of Wikimedia Commons

References

1. Bang HO, Dyerberg J, Hjøorne N. The composition of food consumed by Greenland Eskimos. Acta Med Scand. 1976;200(1-2):69-73. http://onlinelibrary.wiley.com/doi/10.1111/j.0954-6820.1976.tb08198.x/pdf

2. Dyerberg J, Bang HO, Stoffersen E, Moncada S, Vane JR. Eicosapentaenoic acid and prevention of thrombosis and atherosclerosis? Lancet. 1978;2(8081):117-119. http://www.sciencedirect.com/science/article/pii/S0140673678915052#

3. Balk EM, Lichtenstein AH, Chung M, Kupelnick B, Chew P, Lau J. Effects of omega-3 fatty acids on serum markers of cardiovascular disease risk: a systematic review. Atherosclerosis. 2006;189(1):19-30. http://www.sciencedirect.com/science/article/pii/S0021915006000694

4. Harris WS. n-3 fatty acids and serum lipoproteins: human studies. Am J Clin Nutr. 1997;65(5 Suppl):1645S-1654S. http://ajcn.nutrition.org/content/65/5/1645S.long

5. GISSI-Prevenzione Investigators (Gruppo Italiano per lo Studio della Sopravvivenza nell’Infarto miocardico). Dietary supplementation with n-3 polyunsaturated fatty acids and vitamin E after myocardial infarction: results of the GISSI-Prevenzione trial. Lancet. 1999;354(9177):447-455. http://www.sciencedirect.com/science/article/pii/S0140673699070725

6. Billman GE, Hallaq H, Leaf A. Prevention of ischemia-induced ventricular fibrillation by omega 3 fatty acids. Proc Natl Acad Sci U S A. 1994;91(10):4427-4430. http://www.pnas.org/content/91/10/4427.long

7. Kang JX, Xiao YF, Leaf A. Free, long-chain, polyunsaturated fatty acids reduce membrane electrical excitability in neonatal rat cardiac myocytes. Proc Natl Acad Sci U S A. 1995;92(9):3997-4001. http://www.pnas.org/content/92/9/3997.long

8. Xiao YF, Kang JX, Morgan JP, Leaf A. Blocking effects of polyunsaturated fatty acids on Na+ channels of neonatal rat ventricular myocytes. Proc Natl Acad Sci U S A. 1995;92(24):11000-11004. http://www.pnas.org/content/92/24/11000.long

9. Xiao YF, Gomez AM, Morgan JP, Lederer WJ, Leaf A. Suppression of voltage-gated L-type Ca2+ currents by polyunsaturated fatty acids in adult and neonatal rat ventricular myocytes. Proc Natl Acad Sci U S A. 1997;94(8):4182-4187. http://www.pnas.org/content/94/8/4182.long

10. Raitt MH, Connor WE, Morris C, et al. Fish oil supplementation and risk of ventricular tachycardia and ventricular fibrillation in patients with implantable defibrillators: a randomized controlled trial. JAMA. 2005;293(23):2884-2891. http://jama.jamanetwork.com/article.aspx?articleid=201082

11. Brouwer IA, Zock PL, Camm AJ, et al; SOFA Study Group. Effect of fish oil on ventricular tachyarrhythmia and death in patients with implantable cardioverter defibrillators: the Study on Omega-3 Fatty Acids and Ventricular Arrhythmia (SOFA) randomized trial. JAMA. 2006;295(22):2613-2619. http://jama.jamanetwork.com/article.aspx?articleid=202999

12. Leaf A, Albert CM, Josephson M, et al. Prevention of fatal arrhythmias in high-risk subjects by fish oil n-3 fatty acid intake. Circulation. 2005;112(18):2762-2768. http://circ.ahajournals.org/content/112/18/2762.long

13. León H, Shibata MC, Sivakumaran S, Dorgan M, Chatterley T, Tsuyuki RT. Effect of fish oil on arrhythmias and mortality: systematic review. BMJ. 2008;337:a2931. http://www.bmj.com/content/337/bmj.a2931.long

14. Frost L, Vestergaard P. n-3 Fatty acids consumed from fish and risk of atrial fibrillation or flutter: the Danish Diet, Cancer, and Health Study. Am J Clin Nutr. 2005;81(1):50-54. http://ajcn.nutrition.org/content/81/1/50.long

15. Brouwer IA, Heeringa J, Geleijnse JM, Zock PL, Witteman JC. Intake of very long-chain n-3 fatty acids from fish and incidence of atrial fibrillation. The Rotterdam Study. Am Heart J. 2006;151(4):857-862. http://www.sciencedirect.com/science/article/pii/S000287030500757X

16. Mozaffarian D, Psaty BM, Rimm EB, et al. Fish intake and risk of incident atrial fibrillation. Circulation. 2004;110(4):368-373. http://circ.ahajournals.org/content/110/4/368.long

17. Psaty BM, Manolio TA, Kuller LH, et al. Incidence of and risk factors for atrial fibrillation in older adults. Circulation. 1997;96(7):2455-2461. http://circ.ahajournals.org/content/96/7/2455.long

18. Furberg CD, Psaty BM, Manolio TA, Gardin JM, Smith VE, Rautaharju PM. Prevalence of atrial fibrillation in elderly subjects (the Cardiovascular Health Study). Am J Cardiol. 1994;74(3):236-241. http://www.sciencedirect.com/science/article/pii/0002914994903638

19. Mozaffarian D, Marchioli R, Macchia A, et al; OPERA Investigators. Fish oil and postoperative atrial fibrillation: the Omega-3 Fatty Acids for Prevention of Post-operative Atrial Fibrillation (OPERA) randomized trial. JAMA. 2012;308(19):2001-2011. http://jama.jamanetwork.com/article.aspx?articleid=1389226

20. Liu T, Korantzopoulos P, Shehata M, Li G, Wang X, Kaul S. Prevention of atrial fibrillation with omega-3 fatty acids: a meta-analysis of randomised clinical trials. Heart. 2011;97(13):1034-1040. http://heart.bmj.com/content/97/13/1034.l

Cindy Fei, MD

Peer Reviewed

A 63-year-old woman with hypertension presents to your clinic for routine follow-up. She came across an online article regarding C-reactive protein and its purported link to heart disease, and she asks you whether she should be tested for it. She is an otherwise asymptomatic non-smoker without a family history of heart disease. Her only medication is hydrochlorothiazide. Her blood pressure measured in the office is 128/81 mmHg, her low-density lipoprotein is 110 mg/dL, and her high-density lipoprotein is 54 mg/dL. What do you tell her?

What is CRP?

C-reactive protein (CRP) is an acute-phase reactant produced by the liver in response to the inflammatory cytokines interleukin-6 and interferon. CRP primarily mediates the inflammatory response by binding to complement and damaged cell membranes, but it has also been noted to bind to low-density lipoprotein (LDL) [1]. Common stimuli of high CRP levels (conventionally defined as >3 mg/L) include infection, cancer, and surgery. CRP also increases to intermediate levels (1-3 mg/L) with age, obesity, smoking, gum disease, and related co-morbidities such as chronic lung disease, diabetes, and hypertension [2]. Interestingly, the variability of multiple CRP measurements in the same person over time exhibits stability comparable to blood pressure and cholesterol [3]. While early measurements of CRP only detected levels greater than 3 mg/L, later studies capitalized on the development of improved high-sensitivity CRP (hs-CRP) assays, which detect levels as low as 0.1 mg/L.

With respect to healthy adults, studies show a positive correlation between elevated CRP levels and development of coronary heart disease, independent of other risk factors. A meta-analysis of 54 observation studies characterized this relationship as a log-linear association when adjusted for age and sex [4]. A 2009 meta-analysis of 11 good-quality studies calculated a relative risk of 1.58 (confidence interval 1.37-1.83) for the development of coronary artery disease in the high versus low serum CRP groups. The studies all adjusted for Framingham risk factors beforehand. The corresponding risk ratio for the intermediate versus low serum CRP groups was 1.22 (confidence interval 1.11-1.33) [5]. This relationship persists in individuals with known cardiovascular disease, with higher CRP values portending a worse prognosis. For instance, stable coronary artery disease subjects with a fairly even distribution of low, intermediate, and high serum CRP categories showed a statistically significant increased risk of cardiovascular death, myocardial infarction, or stroke in the intermediate CRP group compared with low CRP group (adjusted hazard ratio of 1.39). The adjusted hazard ratio rose to 1.52 for high CRP group compared to the low CRP group [6].

Does CRP play a pathologic role in atherosclerosis?

Multiple studies demonstrate an association between elevated CRP and increased risk of heart disease, regardless of prior cardiovascular disease diagnosis. However, it is unclear if a causal mechanism governs this association. Do high CRP levels drive atherosclerosis, or are they simply a marker of disease? Atherosclerotic plaques stain positive for CRP, but the evidence for causality is less clear [1]. Proposed avenues for CRP-induced plaque build-up include monocyte adhesion and recruitment into the vessel walls, macrophage activation, and smooth muscle cell proliferation. Moreover, binding to LDL facilitates LDL oxidation and uptake by macrophages. CRP also interferes with endothelial nitric oxide synthase function and prostacyclin synthesis, leading to decreased vasodilation [7].

In addition, CRP’s classification as an acute-phase reactant and its subsequent association with inflammatory conditions offer numerous confounding variables. On one hand, lower CRP levels after statin therapy are associated with a lower risk of recurrent myocardial infarction or coronary fatalities, regardless of post-statin LDL levels [8]. Post hoc analyses of the PROVE-IT trial demonstrated that lower CRP was significantly and independently associated with slower progression of atherosclerosis as measured by intravascular ultrasound over 18 months [9,10]. This suggests a direct link between CRP and cardiovascular risk independent of LDL levels.

On the other hand, scenarios that attempt to directly influence or change CRP levels do not necessarily maintain this link. For example, murine models of atherosclerosis do not reliably show increased plaque build-up in transgenic mice designed to produce human CRP [7]. One mendelian randomization study from 2008 calculated whether naturally-occurring genetic polymorphisms in the CRP gene and subsequent variations in serum CRP levels could predict cardiovascular outcomes. Genetic variation was responsible for up to 64% change in CRP level, but this did not translate into a statistically significant increased odds ratio for ischemic heart disease. In contrast, different apolipoprotein E genotypes accounted for up to a 14% change in cholesterol level, with a statistically significant increased odds ratio of 1.29 for development of ischemic heart disease [11]. A later mendelian randomization study also did not find a statistically significant relationship between genetically-raised CRP levels and the development of heart disease [12].

How to Use CRP in Clinical Practice

To date, the main randomized clinical trial that examines CRP and cardiovascular risk is the JUPITER trial published in 2008. This trial evaluated rosuvastatin 20mg daily for primary prevention in healthy adults who demonstrated both LDL <130 and hs-CRP >2. The trial was stopped early at the first interim analysis because the statin’s benefit was clear. After a median of 1.9 years of follow-up, a statistically significant reduction in the primary outcome (a composite of heart attack, stroke, unstable angina, revascularization, or cardiovascular death) was found for the statin group as compared to placebo (hazard ratio 0.56, 95% confidence interval 0.46 to 0.59) [13]. This suggested a role for CRP in selecting additional patients who would benefit from statins. Although the trial only included patients with higher levels of hs-CRP, a post hoc analysis demonstrated a consistent association between higher baseline hs-CRP and increased frequency of the primary outcome [14]. Of note, the trial was criticized on the grounds of conflict of interest, as the principal investigator co-owns the patent for the hs-CRP blood test used in the study [15].

In 2003, the Centers for Disease Control and Prevention and the American Heart Association recommended against universal screening for cardiovascular risk with CRP. The document identified intermediate-risk patients as the population for which it is reasonable to measure hs-CRP twice, 2 weeks apart, for further risk stratification [16]. In healthy asymptomatic adults with an intermediate Framingham risk of 5-20%, the addition of CRP appropriately reclassified only 4.3% of subjects into the high-risk category, and only 3.6% into the low-risk category [17]. According to one model developed prior to the updated statin therapy guidelines, testing the CRP of 440 intermediate-risk patients without a coronary heart disease equivalent is needed in order to reclassify 23 individuals as high-risk. If those 23 subjects initiated statin therapy, then 1 cardiovascular event (myocardial infarction, stroke, or fatal coronary heart disease) would be averted. In effect, the number needed to “test” of 440 would avert 1 cardiovascular event over 10 years, assuming appropriate statin interventions based on the 2002 Adult Treatment Panel III guidelines [18]. However, studies that have compared the accuracy of CRP versus coronary artery calcium score and carotid intima-media thickness in reclassifying intermediate-risk patients found that coronary artery calcium score and carotid intima-media thickness both outperformed CRP [17].

More recent guidelines still fail to offer compelling indications for CRP utilization. In fact, the 2009 US Preventive Services Task Force stated that there was insufficient evidence for the use of hs-CRP for cardiovascular risk assessment [19]. Two simultaneously released guidelines in November 2013 from the American College of Cardiology/American Heart Association (ACC/AHA), on the topics of cholesterol and on cardiovascular risk assessment, discuss a possible role for hs-CRP in patients who do not fall into the outlined four major statin benefit groups or who have unclear risk even after quantitative risk assessment. The recommendation to consider hs-CRP use under these select circumstances is based on expert opinion only, and does not distinguish between CRP versus other novel risk factors such as coronary artery calcium score and ankle-brachial index [20,21]. The new guidelines also suggest hs-CRP >2 as the threshold for upgrading the level of cardiovascular risk for a patient.

Conclusion

In summary, existing evidence tentatively suggests that CRP is an independent risk factor for heart disease; however, in the absence of data examining universal CRP screening, hard clinical outcomes, mortality, or cost effectiveness, the current recommendations are to use CRP sparingly under select circumstances. In the clinic, CRP may be used as a tool for further risk stratification of intermediate-risk patients in order to select candidates who may benefit the most from additional interventions and therapies.

With regards to the clinical vignette, this patient does not fall into one of the 4 major statin benefit groups, as outlined in the newly released 2013 ACC/AHA guidelines. Her calculated 10-year risk of atherosclerotic cardiovascular disease is 6%, which does not reach the threshold of 7.5% for starting a statin. According to the 2013 ACC/AHA Guideline on the Assessment of Cardiovascular Risk document, expert opinion states that hs-CRP may have a role in determining whether to begin statin therapy. If her measured hs-CRP were greater than 2, one may consider upgrading her risk level and adding a statin for primary prevention, with the knowledge that this recommendation is based on very limited data. 

Commentary By Robert Donnino, MD  Assistant Professor of Medicine (Cardiology)

The use of hs-CRP for cardiovascular risk stratification remains highly controversial. Analysis of existing data suggests that CRP is, at best, a weak independent risk factor for clinical cardiovascular events. Without the inclusion of patients with CRP < 2 in the JUPITER trial (Ridker et al., reference 8 from above), it cannot be concluded that the CRP level of >2 conferred any increased risk, nor does it identify patients who would have received additional benefit with statin therapy. This has led many to question whether patients with CRP < 2 would have received similar benefits from statin therapy if they had been included in the trial.

As mentioned in this overview on CRP, data published from the MESA cohort showed CRP was not a very effective tool for reclassifying intermediate risk patients into higher or lower risk groups, reclassifying a total of only 8% of patients (Yeboah, et al; reference 17 from above). For comparison, coronary calcium score in that same cohort reclassified 66% of patients into higher or lower risk groups. Other studies have even lower reclassification ability for CRP. Thus, although supported by current guidelines and followed by some practitioners, I believe the data do not support the use of CRP as a risk stratification tool and that much more powerful stratification tools are available (i.e. coronary calcium score). For more in-depth analysis of CPR for cardiovascular risk, I would recommend the excellent review by Yousuf and colleages (reference 7 from above). Until we have more clarifying data, the role of CRP in clinical practice will remain controversial. 

Dr. Cindy Fei is an internist at NYU Langone Medical Center

Peer review by Robert Donnino, MD, Assistant Professor of Medicine (Cardiology), NYU Langone Medical Center

Image courtesy of Wikimedia Commons

References 

1. Scirica BM, Morrow DA. Is C-reactive protein an innocent bystander or proatherogenic culprit? The verdict is still out. Circulation 2006;113(17): 2128-2134.
2. Windgassen EB, Funtowicz L, Lunsford TN, Harris LA, Mulvagh SL. C-reactive protein and high-sensitivity C-reactive protein: an update for clinicians Postgrad Med 2011;123(1): 114-119. http://www.ncbi.nlm.nih.gov/pubmed/21293091
3. Danesh J, Wheeler JG, Hirschfield GM, et al. C-reactive protein and other circulating markers of inflammation in the prediction of coronary heart disease. NEJM 2004;350(14): 1387-1397.
4. Emerging Risk Factors Collaboration, Kaptoge S, Di Angelantonio E, et al. C-reactive protein concentration and risk of coronary heart disease, stroke, and mortality: an individual participant meta-analysis Lancet 2010;375(9709): 132-140. http://www.ncbi.nlm.nih.gov/pubmed/20031199
5. Buckley DI, Fu R, Freeman M, Rogers K, Helfand M. C-reactive protein as a risk factor for coronary heart disease: a systematic review and meta-analyses for the U.S. Preventive Services Task Force. Ann Intern Med 2009;151(7): 483-495. http://www.ncbi.nlm.nih.gov/pubmed/19805771
6. Sabatine MS, Morrow DA, Jablonski KA, et al. Prognostic significance of the Centers for Disease Control/American Heart Association high-sensitivity C-reactive protein cut points for cardiovascular and other outcomes in patients with stable coronary artery disease. Circulation 2007;115(12): 1528-1536. http://www.ncbi.nlm.nih.gov/pubmed/17372173
7. Yousuf O, Mohanty BD, Martin SS, et al. High-sensitivity C-reactive protein and cardiovascular disease: a resolute belief or an elusive link? J Am Coll Cardiol 2013;62(5): 397-408. http://www.ncbi.nlm.nih.gov/pubmed/23727085
8. Ridker PM, Cannon CP, Morrow D, et al. C-reactive protein levels and outcomes after statin therapy. NEJM 2005;352(1): 20-28. http://www.nejm.org/doi/full/10.1056/NEJMoa042378
9. Cannon CP, Braunwald E, McCabe CH, et al. Intensive versus moderate lipid lowering with statins after acute coronary syndromes. NEJM 2004;350(15): 1495-1504. http://www.nejm.org/doi/full/10.1056/NEJMoa040583
10. Nissen SE, Tuzcu EM, Schoenhagen P, et al. Statin therapy, LDL cholesterol, C-reactive protein, and coronary artery disease. NEJM 2005;352(1): 29-38. http://www.nejm.org/doi/full/10.1056/NEJMoa042000
11. Zacho J, Tybjaerg-Hansen A, Jensen JS, Grande P, Sillesen H, Nordestgaard BG. Genetically elevated C-reactive protein and ischemic vascular disease. NEJM 2008;359(18): 1897-1908. http://www.ncbi.nlm.nih.gov/pubmed/18971492
12. C Reactive Protein Coronary Heart Disease Genetics Collaboration (CCGC), Wensley F, Gao P, et al. Association between C reactive protein and coronary heart disease: mendelian randomisation analysis based on individual participant data. BMJ 2011;342:d548. http://www.ncbi.nlm.nih.gov/pubmed/21325005
13. Ridker PM, Danielson E, Fonseca FA, et al. Rosuvastatin to prevent vascular events in men and women with elevated C-reactive protein NEJM 2008;359(21): 2195-2207. http://www.nejm.org/doi/full/10.1056/NEJMoa0807646
14. Ridker PM, MacFadyen J, Libby P, Glynn RJ. Relation of baseline high-sensitivity C-reactive protein level to cardiovascular outcomes with rosuvastatin in the Justification for Use of statins in Prevention: an Intervention Trial Evaluating Rosuvastatin (JUPITER) Am J Cardiol 2010;106(2): 204-209. http://www.ncbi.nlm.nih.gov/pubmed/20599004
15. de Lorgeril M, Salen P, Abramson J, et al. Cholesterol lowering, cardiovascular diseases, and the rosuvastatin-JUPITER controversy: a critical reappraisal. Arch Intern Med 2010;170(12): 1032-1036. http://archinte.jamanetwork.com/article.aspx?articleid=416101
16. Pearson TA, Mensah GA, Alexander RW, et al. Markers of inflammation and cardiovascular disease: application to clinical and public health practice: A statement for healthcare professionals from the Centers for Disease Control and Prevention and the American Heart Association. Circulation 2003;107(3): 499-511.
17. Yeboah J, McClelland RL, Polonsky TS, et al. Comparison of novel risk markers for improvement in cardiovascular risk assessment in intermediate-risk individuals JAMA 2012;308(8): 788-795. http://jama.jamanetwork.com/article.aspx?articleid=1352110
18. Emerging Risk Factors Collaboration, Kaptoge S, Di Angelantonio E, et al. C-reactive protein, fibrinogen, and cardiovascular disease prediction NEJM 2012;367(14): 1310-1320. http://www.ncbi.nlm.nih.gov/pubmed/23034020
19. US Preventive Services Task Force. Using Nontraditional Risk Factors In Coronary Heart Disease Risk Assessment. Oct 2009. Accessed Nov 2013. http://www.uspreventiveservicestaskforce.org/uspstf/uspscoronaryhd.htm
20. Stone NJ, Robinson J, Lichtenstein AH, et al. 2013 ACC/AHA guideline on the treatment of blood cholesterol to reduce atherosclerotic cardiovascular risk in adults: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines. Circulation http://www.ncbi.nlm.nih.gov/pubmed/24222016
21. Goff DC Jr, Lloyd-Jones DM, Bennett G, et al. 2013 ACC/AHA guideline on the assessment of cardiovascular risk: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines. Circulation http://www.ncbi.nlm.nih.gov/pubmed/24222018

By Shannon Chiu, MD

Peer Reviewed

The annual incidence of infective endocarditis (IE) is estimated to be 3 to 9 cases per 100,000 persons in developed countries [1-2]. Neurologic complications are the most severe and frequent extracardiac complications of IE, affecting 15-20% of patients [3-4]. They consist of 1) ischemic infarction secondary to septic emboli from the valvular vegetation, which can eventually undergo hemorrhagic transformation; 2) focal vasculitis/cerebritis from septic emboli obstructing the vascular lumen, which can then develop into brain abscess or meningoencephalitis; 3) mycotic aneurysm secondary to inflammation from septic emboli penetrating the vessel wall [5]. Amongst these complications, stroke is the most common and is the presenting feature in 50-75% of patients [6]. To date, an ongoing debate amongst physicians is the appropriateness of anticoagulation in patients with IE and how to balance the risk of thromboembolism against that of hemorrhagic transformation of stroke.

Specific risk factors have been associated with increased risk of symptomatic embolic events. Embolic risk is especially high within the first 2 weeks after diagnosis, decreasing in frequency after initiation of antibiotics [7]. Size, location and mobility of vegetations are key predictors; in fact, surgery may be indicated for prevention of embolism with involvement of anterior mitral leaflet, vegetation size >10mm, or increasing size despite appropriate antibiotics [5,8]. Additional risk factors for embolism in IE include advanced age and S. aureus infection. Importantly, S. aureus prosthetic valve endocarditis is known to be associated with higher overall mortality and severe neurologic complications such as hemorrhagic stroke [3,9-10]. Mechanisms for intracranial hemorrhage (ICH) in patients with IE include hemorrhagic transformation (HT) of ischemic infarct, rupture of mycotic aneurysms, or erosion of septic arteritic vessels [11].

Currently, evidence regarding anticoagulants primarily stems from observational studies. One of the arguments against anticoagulation in IE is the fear of early ICH and HT of ischemic stroke. In Tornos et al.’s retrospective observational series of 56 patients with native and prosthetic S. aureus IE, mortality was higher in prosthetic valve IE than in native valve IE (p=.02; odds ration [OR], 4.23; 95% confidence interval [CI], 1.15-16.25) [12]. The authors inferred that part of this difference stemmed from the deleterious effect of anticoagulation leading to lethal neurologic damage as 90% of patients with prosthetic valve IE due to S. aureus were receiving oral anticoagulant treatment on admission (vs. no patient with native valve IE due to S. aureus was receiving such treatment). Meanwhile, in Heiro et al.’s retrospective study, a sub-analysis of 32 patients with S. aureus IE showed that 57% of patients receiving anticoagulant therapy died within 3 months of admission vs. 20% of those not receiving anticoagulant therapy, though the difference was not statistically significant (p=0.1) [9]. Garcia-Cabrera et al. conducted a retrospective analysis of 1,345 cases of left-sided IE, and likewise found that hemorrhagic complications were significantly associated with anticoagulant therapy that was primarily used in patients with mechanical valves (hazard ration [HR] 2.71, 95% CI 1.54-4.76, p=0.001) [13]. On this basis, these authors have recommended stopping anticoagulants as soon as diagnosis of IE is suspected, at least until past the septic phase of the disease. Despite these reported associations of poor outcome in S. aureus IE and detrimental effect of anticoagulant therapy in these patients, these results arose from nonrandomized retrospective studies without matched cohorts. Moreover, Tornos et al.’s study was primarily designed to compare native valve with prosthetic valve IE patients, and the sample size of those receiving anticoagulation was small (19 out of 56) [12]. Similarly, Heiro et al.’s study was of limited statistical power, as only 2 of the 4 patients with lethal S. aureus IE actually died of hemorrhagic conditions while taking anticoagulant therapy.

On the opposing end, more recent prospective studies show no significant association between anticoagulation and increased risk of hemorrhagic complications, and that ICH due to anticoagulation after IE-related stroke is overestimated. Rasmussen et al. conducted a prospective cohort study of 175 S. auerus IE patients, of which 70 patients (40%, 95% CI 33-47%) experienced major cerebral events during the course of the disease [14]. Stroke was the most common complication (34%, 95% CI 27-41%), but the incidence of cerebral hemorrhage was low (3%, 95% CI 0.5-6%). None of the patients who experienced cerebral hemorrhage were receiving anticoagulant treatment. In fact, Rasmussen et al. found that patients receiving anticoagulation were less likely to have experienced a major cerebral event at time of admission compared to those not receiving such treatment (15% vs 37%, p=0.009). The indication for anticoagulation for the majority of patients in this study was prosthetic heart valves. Anticoagulation at the time of admission was associated with a significant reduction in the number of major cerebral events in patients with native valve IE (0 vs. 39%, p=0.008); however, this was not evident in those with prosthetic valve IE. In-hospital mortality rate was 23% (95% CI 17-29%) with no significant difference between patients with or without anticoagulant therapy.

An added complication to the picture is the decision for cardiac surgery in patients with IE who suffer a neurologic event. Except for clinically severe ICH, neurologic complications are not a contraindication for surgical treatment [5]. The decision to perform cardiopulmonary bypass remains controversial, as the surgery can cause/aggravate cerebral damage in several ways, such as ICH related to heparinization during the procedure, and possible hemodynamic worsening of the ischemic infarction (e.g. additional embolism, hypoperfusion) [5,15]. The timing of the surgery is also hotly debated, and evidence supporting surgical intervention is of limited quality and primarily based on observational studies. However, when needed, cardiac surgery can be performed promptly after a silent cerebral embolism or transient ischemic attack, but must be postponed for at least 1 month following ICH [8].

Despite controversy over anticoagulant therapy, recommendations regarding antiplatelet therapy are more clear-cut: antiplatelets are not recommended for patients with IE. In a double-blind, placebo-controlled trial comparing aspirin 325mg with placebo for 4 weeks in 115 IE patients, there was no significant decrease in the incidence of embolic events (OR 1.62, 95% CI 0.68-3.86) [16]. In fact, there was a trend toward more bleeding in the aspirin group (OR 1.92, 95% CI 0.76-4.86); and aspirin had no effect on vegetation size. While there are conflicting findings from observation studies regarding the use of chronic antiplatelet treatment before IE, in terms risks of death and embolic events, current available evidence suggests that antiplatelet therapy is not indicated in IE [17-19]. Patients on antiplatelet therapy for other indications may continue taking it, in the absence of major bleeding.

So where does this leave us? According to the most recent European Society of Cardiology guidelines, there is no indication to start anticoagulation in patients with IE [8]. For those already receiving anticoagulant therapy, and in which IE is complicated by ischemic or non-hemorrhagic stroke, the oral anticoagulant agent should be replaced by unfractionated heparin for 2 weeks. For those with ICH complication, all anticoagulation should be stopped, except for those with prosthetic valve IE in which case the recommendation is to reinitiate unfractionated heparin “as soon as possible” (no specified time-frame given in guidelines). Critically, the European Society of Cardiology guidelines acknowledge the low level of evidence supporting these recommendations.

Anticoagulation is undoubtedly a double-edged sword. Whenever cerebrovascular complications of IE are suspected, there should be low threshold to perform diagnostic brain imaging to rule out cerebral hemorrhage, which would definitively justify discontinuation of anticoagulation and likely postpone planned cardiac surgery. Repeat echocardiography and neuroimaging play an important role in management of IE patients. At this time, the lack of robust information on anticoagulant therapy in IE stresses the need for more large randomized controlled trials.

Dr. Shannon Chiu is a 2nd year resident at NYU Langone Medical Center

Peer Reviewed by Albert Jung, MD, Internal Medicine, NYU Langone Medical Center

Image courtesy of Wikimedia Commons

References:

1. Correa de Sa DD, Tleyjeh IM, Anavekar NS, et al.; Epidemiological trends of infective endocarditis: a population-based study in Olmsted County, Minnesota. Mayo Clin Proc. 2010;85:422-426. http://www.mayoclinicproceedings.org/article/S0025-6196%2811%2960327-3/fulltext 
2. Duval X, Delahaye F, Alla F, et al.; Temporal trends in infective endocarditis in the context of prophylaxis guideline modifications: three successive population-based surveys. J Am Coll Cardiol. 2012;59:1968-1976. http://www.sciencedirect.com/science/article/pii/S0735109712009849
3. Thuny F, Avierinos JF, Tribouilloy C, et al.; Impact of cerebrovascular complications on mortality and neurologic outcome during infective endocarditis: a prospective multicentre study. Eur Heart J. 2007;28:1155-1161. http://eurheartj.oxfordjournals.org/content/28/9/1155.long 
4. Sonneville R, Mirabel M, Hajage D, et al.; Neurologic complications and outcomes of infective endocarditis in critically ill patients: the ENDOcardite en REAnimation prospective multicenter study. Crit Care Med. 2011;39:1474-1481. http://journals.lww.com/ccmjournal/Abstract/2011/06000/Neurologic_complications_and_outcomes_of_infective.35.aspx
5. Ferro JM, Fonesca C. Infective endocarditis. Handb Clin Neurol, Neurologic Aspects of Systemic Disease Part I. 2014;119:75-91. http://www.sciencedirect.com/science/article/pii/B9780702040863000072
6. Sila C. Anticoagulation should not be used in most patients with stroke with infective endocarditis. Stroke. 2011;42:1797-1798. stroke.ahajournals.org/content/42/6/1797.full.pdf
7. Snygg-Martin U, Gustafsson L, Rosengren L, et al.; Cerebrovascular complications in patients with left-sided infective endocarditis are common: a prospective study using magnetic resonance imaging and neurochemical brain damage markers. Clin Infect Dis. 2008;47:23-30.  http://cid.oxfordjournals.org/content/47/1/23.long
8. Habib G, Hoen B, Tornos P, et al.; The task force on the prevention, diagnosis, and treatment of infective endocarditis of the European Society of Cardiology (ESC). Eur Heart J. 2009;30:2369-2413. http://eurheartj.oxfordjournals.org/content/ehj/30/19/2369.full.pdf
9. Heiro M, Nikoskelainen J, Engblom E, et al.; Neurologic manifestations of infective endocarditis: A 17-Year Experience in a Teaching Hospital in Finland. Arch Intern Med. 2000;160:2781-2787. http://archinte.jamanetwork.com/article.aspx?articleid=485459
10. Di Salvo G, Habib G, Pergola V, et al.; Echocardiography predicts embolic events in infective endocarditis. J Am Coll Cardiol. 2001;37:1069-1076. http://www.sciencedirect.com/science/article/pii/S0735109700012067
11. Molina CA, Selim MH. Anticoagulation in patients with stroke with infective endocarditis: the sword of Damocles. Stroke. 2011;42:1799-1800. http://stroke.ahajournals.org/content/42/6/1799.full.pdf
12. Tornos P, Almirante B, Mirabet S, et al.; Infective endocarditis due to Staphylococcus aureus: deleterious effect of anticoagulant therapy. Arch Intern Med. 1999;159:473-475. http://archinte.jamanetwork.com/article.aspx?articleid=414876
13. Garcia-Cabrera E, Fernandez-Hidalgo N, Almirante B, et al.; Neurological complications of infective endocarditis: risk factors, outcome, and impact of cardiac surgery: a multicenter observational study. Circulation. 2013;127(23):2272-84. http://circ.ahajournals.org/content/127/23/2272.long
14. Rasmussen RV, Snygg-Martin U, Olaison L, et al.; Major cerebral events in Staphylococcus aureus infective endocarditis: is anticoagulant therapy safe? Cardiology. 2009;114:284-291. http://www.karger.com/Article/FullText/235579
15. Goldstein LB, Husseini NE. Neurology and cardiology: points of contact. Rev Esp Cardiol. 2011;64(4):319-27. http://www.sciencedirect.com/science/article/pii/S188558571100154X
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By Anjali Varma Desai, MD

Peer Reviewed

Mr. Q is a 55-year-old male smoker who presents with recurrent chest pain in the mornings over the past several months. The patient reports being awakened from sleep at approximately 5:00 a.m. each morning with the same diffuse chest “pressure.” The pain typically lasts on the order of minutes, resolves, and then recurs at five-minute intervals in the same fashion for a total duration of two hours. The pain always occurs at rest and is never precipitated by exertion or emotional stress. The chest pain is generally associated with a sense of palpitations and occasional dizziness and light-headedness. An exercise stress test showed good exercise capacity without ST segment changes, even at target heart rate. Given the history, a diagnosis of coronary artery spasm was suggested. The patient was given a trial of diltiazem therapy, with marked improvement in his chest pain episodes thereafter.

In his landmark article in 1959, Dr. Myron Prinzmetal described a distinct type of “variant angina,” termed Prinzmetal’s angina. This chest pain tended to occur at rest (i.e. was not associated with increased cardiac work), waxed and waned cyclically, occurred at the same time each day, and could be accompanied by arrhythmias including ventricular ectopy, ventricular tachycardia, ventricular fibrillation, and various forms of AV block [1]. The patient’s EKG during painful episodes typically showed ST segment elevations (occasionally accompanied by reciprocal ST depressions), whereas the EKG obtained after the pain had resolved showed resolution of these ST segment changes [1]. Prinzmetal postulated that this separate clinical entity was due to transient spasm (“increased tonus”) of a large arteriosclerotic artery, causing temporary transmural ischemia in the distribution supplied by that artery.

It is important to note that, although ST elevation would be diagnostic, it is frequently not observed in cases of coronary artery spasm. Rather, the diagnosis of coronary artery spasm should be suspected based on the timing of chest pain and the presence of syncope, arrhythmia or cardiac arrest.

It was subsequently demonstrated that such episodes of coronary artery spasm can occur not only in patients with underlying fixed coronary artery obstruction but also in patients whose coronary arteries are anatomically normal [2-7]. Selzer et al. actually compared the syndromes of coronary artery spasm between nine patients with anatomically normal coronary arteries and 20 patients with obstructive coronary lesions [8]. Selzer et al. found that the non-coronary artery disease (CAD) group of patients was more likely to have a long history of nonexertional angina without prior infarction, normal EKG at rest with ST elevations in the inferior leads, conduction disease, and bradyarrhythmias during episodes of arterial spasm. Conversely, the CAD group of patients was more likely to have prior “effort angina” and prior infarction, as well as ST elevation in the anterolateral leads, ventricular ectopy and ventricular tachyarrhythmias.

Castello et al. also compared the syndromes of coronary artery spasm in 77 patients with underlying CAD (fixed coronary stenosis greater than or equal to 50%) and 35 patients with normal or minimally diseased coronary arteries [4]. These authors found, similarly, that angina exclusively at rest tends to occur in patients with structurally normal coronary arteries and that these patients tended to have more diffuse coronary artery spasms affecting more than one artery. In contrast, patients with underlying CAD usually had more focal coronary artery spasms superimposed on their fixed stenotic lesions.

The question arises as to what could be triggering coronary artery spasm in patients with structurally normal coronary arteries? As Prinzmetal suggested, “the distinctive dissimilarities [between typical angina and variant angina] are due to profound physiological and chemical rather than anatomical differences” [1]. These physiological and chemical differences are multi-factorial. Kugiyama et al. demonstrated that there is a deficiency in endothelial nitric oxide (NO) bioactivity in Prinzmetal’s angina-prone arteries; this defect makes those arteries especially sensitive to the vasodilator effect of nitroglycerin and the vasoconstrictor effect of acetylcholine [9]. Miyao et al. used intravascular ultrasound to show that Prinzmetal’s angina patients had diffuse intimal thickening of their coronary arteries, despite an angiographically normal appearance. This intimal hyperplasia was thought to be mediated by deficient NO activity [10]. NO is involved in the regulation of basal vascular tone and helps to mediate flow-dependent vasodilation, as well as suppressing the production of endothelin-1 and angiotensin-II, both of which are powerful vasoconstrictors [11]. As a result of all of these effects, deficient endothelial NO activity predisposes to coronary artery spasm. Endothelial NO is made by the endothelial NOS (e-NOS) gene, which has been found to have many genetic polymorphisms associated with coronary artery spasm [11]. It is important to note, however, that endothelial NO synthase polymorphisms are found in only one-third of patients with coronary spasm; accordingly, other genes or factors are most likely involved [11].

In a review article, Kusama et al. [12] highlighted several additional pathophysiologic contributors to Prinzmetal’s angina, including enhanced vascular smooth muscle contractility mediated by the Rho/Rho-kinase pathway [13-14], elevated markers of oxidative stress [11,15], low-grade chronic inflammation [11], and cigarette smoking [11,15] in addition to genetic polymorphisms of endothelial NO synthase (NOS) [11,15]. Polymorpisms of various genes may explain the higher incidence of Prinzmetal’s angina in the Japanese population as compared to the Caucasian population [12].

As our understanding of the pathophysiology behind Prinzmetal’s angina has evolved, new ways of diagnosing Prinzmetal’s angina have emerged. These diagnostic maneuvers typically involve provoking episodes of Prinzmetal’s angina under controlled settings (e.g. during coronary angiography) with acetylcholine, ergonovine, hyperventilation, and cold pressor stress testing. Okumura et al. showed that intracoronary injection of acetylcholine could be reliably used to induce coronary artery spasm with 99% specificity [16], a conclusion further supported by Miwa et al. [17]. Ergonovine, an ergot alkaloid and alpha-agonist that causes vasoconstriction, can similarly be used to induce episodes of coronary artery spasm accompanied by the characteristic chest pain and EKG changes that occur during spontaneous episodes of Prinzmetal’s angina [18-19]. Song et al. suggested ergonovine echocardiography as an effective screening test for coronary artery spasm, even before coronary angiography, with a sensitivity of 91% and a specificity of 88% [20]. Subsequent studies found that this was indeed an effective, safe, and well-tolerated screening test for coronary artery spasm [21-22].

It is important to note that provocation of arterial spasm with acetylcholine or ergonovine confers a multitude of risks including arrhythmias, hypertension, hypotension, abdominal cramps, nausea, and vomiting [11]. More serious complications include ventricular fibrillation, myocardial infarction, and death [23,24]. Quantitative estimates of the risks incurred by such invasive testing are on the order of 1% [25,26]. In one study, serious major complications, such as sustained ventricular tachycardia, shock, and cardiac tamponade occurred in four out of 715 patients (0.56%) receiving provocative acetylcholine testing [25]. In another study, nine patients out of 921 (1%) had more minor complications (nonsustained ventricular tachycardia [n=1], fast paroxysmal atrial fibrillation [n=1], symptomatic bradycardia [n=6], and catheter-induced spasm [n=1]) after undergoing acetylcholine provocation testing [26]. While such invasive testing is generally considered a safe technique to assess coronary vasomotor dynamics, these maneuvers should only be performed by qualified physicians in carefully controlled settings, where the patient may be properly and quickly resuscitated as needed [11].

Testing a different diagnostic strategy, Hirano et al. noted that a diagnostic algorithm of hyperventilation for six minutes, followed by cold water pressor for two minutes under continuous EKG and echocardiographic monitoring had a 90% Sensitivity, 90% specificity, 95% positive predictive value, and 82% negative predictive value for diagnosing vasospastic angina [27]. The combination of respiratory alkalosis from the hyperventilation as well as the reflex sympathetic coronary vasoconstriction in response to the cold pressor test [28], together, helped to induce coronary artery spasm and diagnose Prinzmetal’s angina. More recently, Hwang et al. suggested that measuring the change in coronary flow velocity of the distal left anterior descending artery (LAD) via transthoracic echo during the cold pressor test may provide additional diagnostic utility, with a sensitivity of 93.5% and a specificity of 82.4% for diagnosing coronary artery spasm [29].

In an article published in JACC in 2013, the Japanese Coronary Spasm Association (JCSA) discussed a comprehensive clinical risk score to aid in prognostic stratification of patients with coronary artery spasm [30]. A multicenter registry study of 1429 patients, median age 66 years, with a median follow-up period of 32 months, was performed. The primary endpoint was defined as major adverse cardiac events (MACE), including cardiac death, nonfatal myocardial infarction, hospitalization due to unstable angina pectoris, heart failure, and appropriate ICD shocks during the follow-up period that began at the date of the diagnosis of coronary artery spasm. In particular, cardiac death, nonfatal myocardial infarction and ICD shocks were categorized as hard MACE. The secondary endpoint was all-cause mortality. The study identified seven predictors of MACE: history of out-of-hospital cardiac arrest (4 points), smoking, angina at rest alone, organic coronary stenosis, multivessel spasm (2 points each), ST segment elevation during angina and beta-blocker use (1 point each). Based on total score, three risk categories were defined: low risk (score of 0 to 2, which included 598 patients), intermediate risk (score of 3 to 5, which included 639 patients) and high risk (score of 6 or more, which included 192 patients). The incidences of major adverse cardiac events in the low-, intermediate-, and high-risk patients were 2.5%, 7.0%, and 13.0%, respectively (p<0.001). This scoring system, known as the JCSA risk score, may help provide a comprehensive risk assessment and prognostic stratification scheme for patients with coronary artery spasm.

In terms of treatment, calcium channel blockers (e.g. nifedipine, diltiazem and verapamil) are the mainstay of therapy for coronary artery spasm. The goal of such therapy is to prevent vasoconstriction and promote coronary artery vasodilation. In one study of 245 patients with coronary artery spasm who were followed for an average of 80.5 months, the use of a calcium cannel blocker therapy was an independent predictor of myocardial-infarct-free survival in patients with coronary artery spasm [31]. In another observational study of 300 patients with coronary artery spasm, calcium channel blockers were effective in alleviating symptoms in over 90-percent of patients [32]. The drugs were evaluated and ranked as follows: markedly effective, leading to complete elimination of angina attacks within 2 days; effective, leading to complete elimination of attacks after 2 days or a reduction in the number of attacks to less than half during the periods of drug administration in the hospital; ineffective, leading to no reduction to less than half during the periods of drug administration. Efficacy rates (including markedly effective as well as effective categories) for nifedipine, diltiazem and verapamil were 94.0%, 90.8%, and 85.7%, respectively. Rarely, cases are refractory to medical therapy and literature exists to support the effectiveness of surgical revascularization in these circumstances [33].

It is clear that the phenomenon of “variant angina” is a complicated, multifaceted product of forces that are not only anatomical, but also genetic, chemical, physiological and behavioral in nature. While endothelial nitric oxide bioactivity appears to play a critical role in this process, there are undoubtedly several other factors involved. Over time, our knowledge of the pathophysiology driving Prinzemetal’s angina will continue to expand, as will our diagnostic and therapeutic repertoire for this fascinating clinical entity.

Dr. Anjali Varma Desai is a 3rd year resident at NYU Langone Medical Center

Peer Reviewed by Harmony R. Reynolds, MD, Medicine (Cardio Div), NYU Langone Medical Center

References:

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2. Maseri A, Severi S, Nes MD, et al. “Variant” angina: one aspect of a continuous spectrum of vasospastic myocardial ischemia. Pathogenetic mechanisms, estimated incidence and clinical and coronary arteriographic findings in 138 patients. Am J Cardiol. Dec 1978;42(6):1019-35 http://www.ncbi.nlm.nih.gov/pubmed/727129

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8. Selzer A, Langston M, Ruggeroli C, et al: Clinical syndrome of variant angina with normal coronary arteriogram. N Engl J Med 1976; 295: 1343-1347. http://www.ncbi.nlm.nih.gov/pubmed/980080

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12. Kusama Y, Kodani E, Nakagomi A, et al. Variant angina and coronary artery spasm: the clinical spectrum, pathophysiology and management. J Nihon Med Sch. 2011;78(1):4-12. Review. http://www.researchgate.net/publication/50351691_Variant_angina_and_coronary_artery_spasm_the_clinical_spectrum_pathophysiology_and_management

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