Case Vignette

A 49-year-old male marathon runner presents with progressive exertional dyspnea and corollary reductions in his running pace over a 6-month period. His traditional atherosclerotic risk factor profile is notable for medically treated dyslipidemia and a family history of premature coronary artery disease (CAD). He undergoes a maximal effort-limited exercise test on the treadmill that demonstrates a functional capacity well in excess of age/gender predicted peak value but reproduces his presenting symptoms. In conjunction with his presenting dyspnea, he is noted to have 1-2mm horizontal ST-segment depressions across the precordial leads of his exercise ECG that emerge near peak exercise and resolve 2-3 minutes into the recovery. He undergoes a conventional coronary angiography, which reveals a focal 60-70% stenosis by visual assessment in the proximal-LAD. The lesion was further characterized by fractional flow reserve (FFR), which yielded a value of 0.82. Relying on data from the FAME (Fractional Flow Reserve Versus Angiography for Multivessel Evaluation) trials,^4,5 from which an FFR cut-point for revascularization of 0.80 was established, intervention was deferred. The patient was advised that his CAD was not "severe enough" to justify an intervention and medical management with a beta-blocker, long acting nitrate preparation, and aspirin was initiated. Both the beta-blocker and nitrate produced significant undesirable side effects leading to non-compliance and were ultimately discontinued by the patient. He presented 8 months later after he was successfully resuscitated from a cardiac arrest that occurred 100 meters before the finish line of a large city marathon. Repeat coronary angiography demonstrated no evidence of plaque rupture, no new lesions, and stable LAD disease both by visual angiography and repeat FFR.

Although routine vigorous exercise promotes favorable changes in atherosclerotic vascular risk factors, no degree of exercise confers complete immunity from CAD. CAD may develop among aging competitive athletes,¹ and is an important cause of sudden cardiac death.^2,3 Effective clinical management of athletes with CAD, much like non-athletic patients, requires a strategy that integrates lifestyle modification, pharmacotherapy, and coronary revascularization. Most athletes with CAD, whether diagnosed in the context of symptoms, abnormal findings during functional testing, or through the increasing popular use of "screening" computed tomography scanning will undergo conventional coronary angiography during their evaluation. Conventional coronary angiography facilitates definitive determination of coronary anatomy and provides an opportunity for simultaneous percutaneous revascularization. The decision to proceed with percutaneous coronary revascularization in competitive athletes requires consideration of medical therapy options and a determination of coronary lesion severity. For the latter, visual inspection of coronary anatomy is sometimes coupled with invasive coronary physiologic assessment.

Invasive coronary physiologic assessment in the cardiac catheterization laboratory has emerged as a powerful tool to guide coronary revascularization decisions. Measurement of FFR and more recently the instantaneous-wave free ratio (iFR), to assess the functional significance of angiographically intermediate coronary stenoses, has been shown to improve clinical outcomes,^4-7 and is now standard of care.⁸ FFR is a ratio that quantifies the difference between the proximal and distal blood pressure surrounding a focal coronary stenosis and therefore provides a quantitative assessment of stenosis severity.⁹ For example, an FFR of 0.82 obtained across a proximal stenosis of the left anterior descending artery indicates an 18% reduction in blood flow distal to the stenosis under pharmacologically induced hyperemic conditions. Accordingly, FFR provides insight into the supply component of the myocardial ischemia supply/demand relationship.

Measurement of FFR or the iFR, an increasingly popular alternative which obviates the need for adenosine-induced hyperemia, is typically performed when angiographic lesion severity is visually indeterminate and the decision to proceed with revascularization must be made. The use of FFR/iFR in this context relies on clinical cut-points or binary "lines in the sand" which differentiate adequate versus inadequate blood supply. Current recommendations for FFR/iFR cut-points have emerged from careful analysis of clinical trial and registry data,^4-7 with emphasis on hard outcomes including mortality and the need for future revascularization. In essence, FFR and iFR cut-points were chosen to reflect a lesion severity at which the risk-benefit balance of percutaneous intervention favored intervention rather than conservative management among the populations enrolled in these trials. In the case of the pivotal FAME 1 and FAME 2 trials,^4,5 the study cohorts were a predominately older male population with a median age of about 65 years old and, in the former, all had multi-vessel CAD with at least two lesions with > 50% luminal narrowing. As is often the case in clinical sports cardiology, it is prudent to consider whether care patterns that have emerged from clinical trials are universally appropriate for use among competitive athletes.

Was the FFR data on the patient presented in this case a false negative result and thus the prior decision to forgo percutaneous intervention an error? This question cannot be answered by the available clinical trial data and underscores the challenges of applying invasive coronary physiologic assessment in patients who were unrepresented in the derivation literature. An important assumption when applying FFR (and iFR) cut-points is that they reflect the ischemic threshold of the population studied, below which coronary supply is insufficient to meet myocardial demands. However, endurance athletes have a unique supply/demand relationship whereby they routinely far exceed the myocardial oxygen demand of the typical study patient during the course of their training and competition. Therefore, it is conceivable that even at FFR (and iFR) values above the traditional cut-points, endurance athletes with stable CAD will experience myocardial demand ischemia. Demand ischemia during endurance exercise is not trivial and was identified to be the leading cause of sudden cardiac arrest among older marathon runners in the Race Associated Cardiac Arrest Registry (RACER).³ This suggests that the risk of "stable CAD" may not be the same in endurance athletes as in their less active counterparts.

With stakes this high and an uncertainty regarding the precise role of invasive coronary physiologic assessment in competitive athletes, clinicians should be cautious in their interpretation of borderline values. In these circumstances, functional data from carefully conducted maximal effort exercise stress testing should be obtained before coronary angiography whenever possible and should be considered during the revascularization decision-making process. Among competitive athletes with documented evidence of ischemia during prior functional testing, revascularization of seemingly indeterminate lesions may be a preferred option over medical therapy as suggested by a recent European consensus statement.¹⁰ Furthermore, it valuable to engage the athletic patient in a shared-decision making discussion about medical therapy versus revascularization prior to catheterization as both strategies have distinct pros and cons. Ultimately, more scientific investigation is needed to identify accurate FFR and iFR cut-points which reflect the true risk/benefit balance of percutaneous revascularization in competitive athletes with CAD. Until then, cardiologists will be most effective when they evaluate each revascularization decision in the context of the individual athlete, by integrating clinical history and ancillary testing, to reach a plan that is aligned with the patient's optimal care goals.

References

1. Morrison BN, McKinney J, Isserow S, et al. Assessment of cardiovascular risk and preparticipation screening protocols in masters athletes: the Masters Athlete Screening Study (MASS): a cross-sectional study. BMJ Open Sport Exerc Med 2018;4:e000370.
2. Mittleman MA, Maclure M, Tofler GH, Sherwood JB, Goldberg RJ, Muller JE. Triggering of acute myocardial infarction by heavy physical exertion. Protection against triggering by regular exertion. Determinants of Myocardial Infarction Onset Study Investigators. N Engl J Med 1993;329:1677-83.
3. Kim JH, Malhotra R, Chiampas G, et al. Cardiac arrest during long-distance running races. N Engl J Med 2012;366:130-40.
4. Tonino PA, De Bruyne B, Pijls NH, et al. Fractional flow reserve versus angiography for guiding percutaneous coronary intervention. N Engl J Med 2009;360:213-24.
5. De Bruyne B, Fearon WF, Pijls NH, et al. Fractional flow reserve-guided PCI for stable coronary artery disease. N Engl J Med 2014;371:1208-17.
6. Davies JE, Sen S, Dehbi HM, et al. Use of the instantaneous wave-free ratio or fractional flow reserve in PCI. N Engl J Med 2017;376:1824-34.
7. Gotberg M, Christiansen EH, Gudmundsdottir IJ, et al. Instantaneous wave-free ratio versus fractional flow reserve to guide PCI. N Engl J Med 2017;376:1813-23.
8. Levine GN, Bates ER, Blankenship JC, et al. 2011 ACCF/AHA/SCAI guideline for percutaneous coronary intervention. A report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines and the Society for the Cardiovascular Angiography and Interventions. J Am Coll Cardiol 2011;58:e44-122.
9. Pijls NH, van Son JA, Kirkeeide RL, De Bruyne B, Gould KL. Experimental basis of determining maximum coronary, myocardial, and collateral blood flow by pressure measurements for assessing functional stenosis severity before and after percutaneous transluminal coronary angioplasty. Circulation 1993;87:1354-67.
10. Niebauer J, Borjesson M, Carre F, et al. Recommendations for participation in competitive sports of athletes with arterial hypertension: a position statement from the sports cardiology section of the European Association of Preventive Cardiology (EAPC). Eur Heart J 2018;39:3664-71.

Keywords: Sports, Athletes, Coronary Artery Disease, Coronary Angiography, Risk Factors, Aspirin, Adenosine, Hyperemia, Blood Pressure, Constriction, Pathologic, Coronary Stenosis, Percutaneous Coronary Intervention, Myocardial Ischemia, Running, Registries, Heart Arrest, Dyspnea, Dyslipidemias, Tomography, Electrocardiography, Cohort Studies

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