Cardiac dysfunction detected by CPET is a function of global ischemic burden given that the abnormalities in SV and HR are seen in symptomatic patients with both NO-CAD and O-CAD [7▪]. Men had the highest rate of revascularization in this study and their mean peak VO2 was 68% of predicted. ‘Balanced Ischemia’ seen in patients with diffuse O-CAD (triple vessel and left main disease) is a challenging condition for imaging-based stress testing to detect due to the nonregionalized nature of the ischemic burden. These patients are some of the highest risk patients and tend to have decreased peak VO2. Coronary angiogram should be considered in symptomatic patients with normal stress imaging and cardiac dysfunction with reduced peak VO2 (<70% of predicted) on CPET. Coronary CTA with FFR  may be the ideal next study in such individuals as patients in need of revascularization can be singled out and patients with NO-CAD can undergo exercise and medical therapy with close surveillance to ensure that peak VO2 and prognosis is improving over time. Continuous regular feedback with set goals for future peak VO2 values has the potential to improve patient adherence with lifestyle changes and medications. The effect of revascularization on peak VO2 would be an area of interest with the current paucity of information. The results of ORBITA, the only blinded, randomized placebo-controlled trial of PCI, show that in patients with angina and single vessel coronary stenosis, exercise capacity (measured by CPET) and symptoms were not improved significantly compared with placebo intervention [51▪▪]. In patients with multivessel CAD, one study comparing complete vs. incomplete revascularization with PCI in patients after MI did not show significant short-term differences on CPET between the two approaches . These data lend credence to the hypothesis that increasing peak VO2 is more likely a function of other mechanisms (including the microcirculation) rather than macrocirculation and that therapeutic interventions should move beyond the stenosis-centric frame to optimize outcomes.
In conclusion, there is a robust body of evidence demonstrating the clinical value of CPET in a number of patient populations, including those with cardiovascular disease. Key CPET variables hold powerful diagnostic and prognostic utility in patients with cardiovascular disease. CPET also holds considerable promise in gauging the response to a broad range of therapies, including pharmacologic, surgical and lifestyle interventions. Improving the CPET response, in particular peak VO2, may evolve into a primary treatment goal in patients with cardiovascular disease if future randomized trials support this approach.
Papers of particular interest, published within the annual period of review, have been highlighted as:
1▪. Guazzi M, Arena R, Halle M, et al. 2016 focused update: clinical recommendations for cardiopulmonary exercise testing
data assessment in specific patient populations. Circulation 2016; 133:e694–e711.
Most recent review article outlining the use of cardiopulmonary exercise testing (CPET) parameters for different clinical applications.
2▪. Foy AJ, Dhruva SS, Peterson B, et al. Coronary computed tomography angiography vs functional stress testing for patients with suspected coronary artery disease
: a systematic review and meta-analysis. JAMA Intern Med 2017; 177:1623–1631.
Most recent data summarizing the clinical impact of different testing strategies for stable coronary artery disease (CAD).
3. Hwang I-C, Choi SJ, Choi JE, et al. Comparison of mid- to long-term clinical outcomes between anatomical testing and usual care in patients with suspected coronary artery disease
: a meta-analysis of randomized trials. Clin Cardiol 2017; [Epub ahead of print].
4▪. Blankstein R, Bittencourt MS, Bhatt DL. Coronary CTA in the evaluation of stable chest pain: clear benefits, but not for all. J Am Coll Cardiol 2017; 69:1771–1773.
Editorial highlighting that most of the clinical gains with computed tomography angiography over functional testing likely come from enhanced utilization of preventive medications.
5. Chaudhry S, Arena R, Wasserman K, et al. Exercise-induced myocardial ischemia detected by cardiopulmonary exercise testing
. Am J Cardiol 2009; 103:615–619.
6. Upton MT, Rerych SK, Newman GE, et al. Detecting abnormalities in left ventricular function during exercise before angina and ST-segment depression. Circulation 1980; 62:341–349.
7▪. Chaudhry S, Kumar N, Behbahani H, et al. Abnormal heart-rate response during cardiopulmonary exercise testing
identifies cardiac dysfunction in symptomatic patients with nonobstructive coronary artery disease
. Int J Cardiol 2017; 228:114–121.
First article to describe abnormal acceleration of heart-rate response during late exercise in symptomatic patients with suspected CAD compared with a normal cohort. This abnormal compensatory response is physiologically indistinguishable between patients with obstructive and nonobstructive CAD (NO-CAD) and is consistent with undertreated atherosclerotic heart disease.
8. Belardinelli R, Lacalaprice F, Carle F, et al. Exercise-induced myocardial ischaemia detected by cardiopulmonary exercise testing
. Eur Heart J 2003; 24:1304–1313.
9. Belardinelli R, Lacalaprice F, Tiano L, et al. Cardiopulmonary exercise testing
is more accurate than ECG-stress testing in diagnosing myocardial ischemia in subjects with chest pain. Int J Cardiol 2014; 174:337–342.
10. Pinkstaff S, Peberdy MA, Kontos MC, et al. Usefulness of decrease in oxygen uptake efficiency slope to identify myocardial perfusion defects in men undergoing myocardial ischemic evaluation. Am J Cardiol 2010; 106:1534–1539.
11. Coeckelberghs E, Buys R, Goetschalckx K, et al. Prognostic value of the oxygen uptake efficiency slope and other exercise variables in patients with coronary artery disease
. Eur J Prev Cardiol 2016; 23:237–244.
12. Uliari S, Myers J, Bernardi E, et al. Oxygen uptake attenuation at ventilatory threshold in men with coronary artery disease
. J Cardiopulm Rehabil Prev 2016; 36:258–262.
13▪. Alzuhairi KSM, Soegaard PS, Ravkilde JR, et al. Long-term prognsis of nonst-elevation myocardial infarction patients with no obstructive coronary artery disease
is worse than patients with one- or two-vessel disease. Eur Heart J 2017; 38 (Suppl_1): ehx504.P4686-ehx4504.P4686.
Outcomes data showing that patients with non-ST elevation MI and NO-CAD have a comparable prognosis to patients with one-vessel or two-vessel disease and patients with diffuse atherosclerosis have worse prognosis than those with angiographically normal coronary arteries.
14. Jespersen L, Hvelplund A, Abildstrom SZ, et al. Stable angina pectoris with no obstructive coronary artery disease
is associated with increased risks of major adverse cardiovascular events. Eur Heart J 2012; 33:734–744.
15▪. Pizzi C, Xhyheri B, Costa GM, et al. Nonobstructive versus obstructive coronary artery disease
in acute coronary syndrome: a meta-analysis. J Am Heart Assoc 2016; 5:
Patients with NO-CAD are potentially undertreated and require more specific management.
16▪. Tavella R, Cutri N, Tucker G, et al. Natural history of patients with insignificant coronary artery disease
. Eur Heart J 2016; 2:117–124.
Symptomatic patients with NO-CAD often have persistent chest pain and impaired quality of life requiring novel strategies to improve health outcomes.
17▪. Williams MJA, Barr PR, Lee M, et al. Myocardial Infarction with non-obstructive coronary artery disease
: not a benign condition. Heart Lung Circ 2017; 26:S23.
Myocardial infarction without obstructive coronary disease is common (∼one in nine patients) and has an adverse outcome rate 12 times that of age and sex-matched patients without CAD.
18. Cassar A, Chareonthaitawee P, Rihal CS, et al. Lack of correlation between noninvasive stress tests and invasive coronary vasomotor dysfunction in patients with nonobstructive coronary artery disease
. Circ Cardiovasc Interv 2009; 2:237–244.
19▪. Mygind ND, Michelsen MM, Pena A, et al. Coronary microvascular function and cardiovascular risk factors in women with angina pectoris and no obstructive coronary artery disease
: The iPOWER Study. J Am Heart Assoc 2016; 5:e003064.
Impaired coronary flow reserve (CFR) is common in patients with angina and is independent of traditonal cardiovascular risk factors.
20. Rozanski A, Gransar H, Hayes SW, et al. Temporal trends in the frequency of inducible myocardial ischemia during cardiac stress testing: 1991 to 2009. J Am Coll Cardiol 2013; 61:1054–1065.
21. Shaw LJ, Mieres JH, Hendel RH, et al. Comparative effectiveness of exercise electrocardiography with or without myocardial perfusion single photon emission computed tomography in women with suspected coronary artery disease
: results from the What Is the Optimal Method for Ischemia Evaluation in Women (WOMEN) trial. Circulation 2011; 124:1239–1249.
22. Lee BK, Lim HS, Fearon WF, et al. Invasive evaluation of patients with angina in the absence of obstructive coronary artery disease
. Circulation 2015; 131:1054–1060.
23. Sara JD, Widmer RJ, Matsuzawa Y, et al. Prevalence of coronary microvascular dysfunction among patients with chest pain and nonobstructive coronary artery disease
. JACC Cardiovasc Interv 2015; 8:1445–1453.
24▪. Taqueti VR, Shaw LJ, Cook NR, et al. Excess cardiovascular risk in women relative to men referred for coronary angiography is associated with severely impaired coronary flow reserve, not obstructive disease. Circulation 2017; 135:566–577.
Impaired CFR in women identifies increased cardiovascular risk and is a potential target for future noninterventional therapeutics.
25▪. Gupta A, Taqueti VR, van de Hoef TP, et al. Integrated noninvasive physiological assessment of coronary circulatory function and impact on cardiovascular mortality in patients with stable coronary artery disease
. Circulation 2017; 10.1161/circulationaha.117.029992.
In patients that underwent cardiac PET scans, impaired CFR was a stronger predictor of cardiovascular mortality than maximal myocardial blood flow indicating that impaired coronary microcirculation is the main driver of cardiovascular events.
26▪▪. Christopoulos G, Bois J, Allison TG, et al. The impact of combined cardiopulmonary exercise testing
and SPECT myocardial perfusion imaging on downstream evaluation and management. J Nucl Cardiol 2017; [Epub ahead of print].
First combined modality study with CPET and MPI performed as one test. Diagnostic yield was enhanced by identification of nonischemic mechanism of exercise intolerance resulting in improved patient care. This study did not attempt to analyze inducible cardiac dysfunction from CAD on CPET, an analysis that would likely have reclassified a number of studies.
27▪▪. Ross R, Blair SN, Arena R, et al. Importance of assessing cardiorespiratory fitness in clinical practice: a case for fitness as a clinical vital sign: a scientific statement from the American Heart Association. Circulation 2016; 134:e653–e699.
Excellent review article highlighting extensive data in the literature that cardiorespiratory fitness (CRF) is a powerful clinical vital sign for all-cause mortality and accurately reclassifies risk for adverse outcomes independent of traditional cardiovascular risk factors. The underlying premise is that the addition of CRF for risk classification presents health professionals with unique opportunities to improve patient management and to encourage lifestyle-based strategies.
28. Khan H, Jaffar N, Rauramaa R, et al. Cardiorespiratory fitness and nonfatalcardiovascular events: a population-based follow-up study. Am Heart J 2016; 184:55–61.
29. Kavanagh T, Mertens DJ, Hamm LF, et al. Prediction of long-term prognosis in 12 169 men referred for cardiac rehabilitation. Circulation 2002; 106:666–671.
30. Kavanagh T, Mertens DJ, Hamm LF, et al. Peak oxygen intake and cardiac mortality in women referred for cardiac rehabilitation. J Am Coll Cardiol 2003; 42:2139–2143.
31. Fujimoto W, Oishi S, Kawai H. The prognostic significance of cardiopulmonary exercise testing
at discharge for the patients with acute myocardial infarction. J Card Fail 2016; 22:S174.
32. Coeckelberghs E, Buys R, Goetschalckx K, et al. Test-retest reliability of maximal and submaximal gas exchange variables in patients with coronary artery disease
. J Cardiopulm Rehabil Prev 2016; 36:263–269.
33▪. Anderson L, Oldridge N, Thompson DR, et al. Exercise-based cardiac rehabilitation for coronary heart disease: Cochrane systematic review and meta-analysis. J Am Coll Cardiol 2016; 67:1–12.
The study confirms that exercise-based cardiac rehabilitation reduces cardiovascular mortality and provides important data showing reductions in hospital admissions and improvements in quality of life that are consistent across patient and intervention types.
34. Aragam KG, Dai D, Neely ML, et al. Gaps in referral to cardiac rehabilitation of patients undergoing percutaneous coronary intervention in the United States. J Am Coll Cardiol 2015; 65:2079–2088.
35. Martin B-J, Arena R, Haykowsky M, et al. Cardiovascular fitness and mortality after contemporary cardiac rehabilitation. Mayo Clin Proc 2013; 88:455–463.
36▪. Boscheri A, Haller B, Christle J, et al. Physical exercise- mediated effects on left ventricular diastolic function outweigh other modifiable risk factors in coronary artery disease
patients. Eur Heart J 2017; 38 (Suppl_1): ehx493.P6036-ehx6493.P6036.
CAD patients who perform regular physical exercise at least 150 min/week have significantly better resting left ventricular diastolic function and peak volume of oxygen metabolized during exercise (VO2) independent of many traditional cardiovascular risk factors.
37▪. Simoes MV, Carvalho EEV, Crescencio JC, et al. Prospective controlled trial testing the effect of physical training over myocardial perfusion disturbance and quality of life in patients with primary microvascular angina: a pilot study. Eur Heart J 2017; 38 (Suppl_1): ehx504.P3428-ehx3504.P3428.
Physical training is associated with reduction of reversible ischemic myocardial perfusion defects in patients with microvascular angina. This positive effect was accompanied by significant improvement of the functional capacity and quality of life. The results of this pilot study indicate that physical training may constitute a relevant therapeutic strategy in this population.
38▪▪. Lindahl B, Baron T, Erlinge D, et al. Medical therapy for secondary prevention and long-term outcome in patients with myocardial infarction with nonobstructive coronary artery disease
. Circulation 2017; 135:1481–1489.
The long-term observational study in myocardial infarction with NO-CAD (MINOCA) patients indicates beneficial effects of treatment with statins and angiotensin-converting enzyme inhibitors/AT1 blockers on outcome in patients with MINOCA, a trend toward a positive effect of β-blocker treatment, and a neutral effect of dual antiplatelet therapy. Medical management is the mainstay for improving outcomes in patients with symptomatic NO-CAD just as it is in obstructive CAD.
39. Chaudhry S, Arena R, Wasserman K, et al. The utility of cardiopulmonary exercise testing
in the assessment of suspected microvascular ischemia. Int J Cardiol 2011; 148:e7–e9.
40. Tagliamonte E, Rigo F, Cirillo T, et al. Effects of ranolazine on noninvasive coronary flow reserve in patients with myocardial ischemia but without obstructive coronary artery disease
. Echocardiography 2015; 32:516–521.
41. Jürs A, Pedersen LR, Olsen RH, et al. Coronary microvascular function, insulin sensitivity and body composition in predicting exercise capacity in overweight patients with coronary artery disease
. BMC Cardiovasc Disord 2015; 15:159.
42. Beck DT, Martin JS, Casey DP, et al. Enhanced external counterpulsation improves endothelial function and exercise capacity in patients with ischaemic left ventricular dysfunction. Clin Exp Pharmacol Physiol 2014; 41:628–636.
43. Pauly DF, Johnson BD, Anderson RD, et al. In women with symptoms of cardiac ischemia, nonobstructive coronary arteries, and microvascular dysfunction, angiotensin-converting enzyme inhibition is associated with improved microvascular function: a double-blind randomized study from the National Heart, Lung and Blood Institute Women's Ischemia Syndrome Evaluation (WISE). Am Heart J 2011; 162:678–684.
44. Bhatia V, Bhatia R, Mathew B. Angiotensin receptor blockers in congestive heart failure: evidence, concerns, and controversies. Cardiol Rev 2005; 13:297–303.
45. Regensteiner JG, Bauer TA, Reusch JEB. Rosiglitazone improves exercise capacity in individuals with type 2 diabetes. Diabetes Care 2005; 28:2877–2883.
46. Pavia L, Orlando G, Myers J, et al. The effect of beta-blockade therapy on the response to exercise training in postmyocardial infarction patients. Clin Cardiol 1995; 18:716–720.
47. Wong AKF, Symon R, AlZadjali MA, et al. The effect of metformin on insulin resistance and exercise parameters in patients with heart failure. Eur J Heart Fail 2012; 14:1303–1310.
48. Edelmann F, Wachter R, Schmidt AG, et al. Effect of spironolactone on diastolic function and exercise capacity in patients with heart failure with preserved ejection fraction: the ALDO-DHF randomized controlled trial. JAMA 2013; 309:781–791.
49▪. Guazzi M, Bandera F, Ozemek C, et al. Cardiopulmonary exercise testing
: what is its value? J Am Coll Cardiol 2017; 70:1618–1636.
The review highlights modern CPET use as a single or combined test that allows the pathophysiological bases of exercise limitation to be translated into clinical practice.
50. Cook CM, Petraco R, Shun-Shin MJ, et al. Diagnostic accuracy of computed tomography-derived fractional flow reserve: a systematic review. JAMA Cardiol 2017; 2:803–810.
51▪▪. Al-Lamee R, Thompson D, Dehbi H-M, et al. Percutaneous coronary intervention in stable angina (ORBITA): a double-blind, randomised controlled trial. Lancet 2017; [Epub ahead of print].
First trial comparing percutaneous coronary intervention (PCI) with placebo (sham procedure) to relieve angina and increase exercise capacity in individuals with angina and single vessel disease with CPET as the primary endpoint. Surprisingly, the results revealed that CPI did not improve symptoms or increase exercise time or peak VO2 compared with placebo and called into question the clinical value of PCI in patients with single vessel disease. The results cannot be generalized to multivessel disease.
52. Zhao W, Bai J, Zhang F, et al. Impact of completeness of revascularization by coronary intervention on exercise capacity early after acute ST-elevation myocardial infarction. J Cardiothorac Surg 2014; 9:50.