DEBATE ARTICLE Evaluating left ventricular systolic dysfunction: Stress echocardiography Edgar Argulian, MD MPH,a and Farooq A. Chaudhry, MD, FACP, FACC, FASE, FAHAb a

Mount Sinai St Luke’s Hospital, New York, NY ´ e and Henry R. Kravis Zena and Michael A. Wiener Cardiovascular Institute and Marie-Jose Center for Cardiovascular Health, Icahn School of Medicine at Mount Sinai, New York b

Received Jan 31, 2015; accepted Feb 1, 2015 doi:10.1007/s12350-015-0116-5

Dyspnea is a common complaint in clinical practice. It has been shown to be a strong predictor of mortality in patients referred for stress testing to evaluate the cardiac reasons for symptoms.1 Echocardiography and commonly stress echocardiography are high-yield initial tests in evaluation of patients with unexplained dyspnea. In one study, stress echocardiography provided a potential explanation for dyspnea in [50% of referred patients2; this study did not include assessment of post-exercise diastolic function or novel techniques to assess myocardial mechanics which may provide incremental diagnostic information.3 The patient in question presents with chronic exertional dyspnea (8 months duration) without chest pain. She has strong cardiovascular risk factors (type 2 diabetes mellitus and hypertension). Her QRS complex duration is presumably narrow. Baseline echocardiogram shows mildly enlarged left ventricle and moderate systolic left ventricular dysfunction with diffuse hypokinesis (left ventricular ejection fraction of 35%). There is no significant valvular abnormality, right ventricular function is preserved, and estimated resting pulmonary artery systolic pressure is borderline (35 mm Hg). Resting echocardiogram can provide important clues to the cause of the left ventricular systolic dysfunction and may further assist in risk stratification. Presence of regional wall motion abnormalities concordant with coronary distribution and echo-bright areas of myocardial thinning may help with differential diagnosis but absence of these findings in this patient does

Funding None. Reprint requests: Edgar Argulian MD MPH, Mount Sinai St Lukeo´s Hospital, 1111 Amsterdam Ave, New York, NY; edgar_argulian@ J Nucl Cardiol 2015;22:957–60. 1071-3581/$34.00 Copyright Ó 2015 American Society of Nuclear Cardiology.

not rule out ischemic cardiomyopathy. Additional resting echocardiographic information that should be obtained in this patient includes estimated resting left ventricular filling pressures and global longitudinal strain. In parallel with initiating guideline-directed medical therapy, the important question is how to proceed with work-up for the cause of her systolic left ventricular dysfunction in a way that is accurate, safe, cost-effective, and prognostically relevant. We believe stress echocardiography is the best initial test for this patient. It is difficult to argue that stress echocardiography is an efficient, safe, and cost-effective modality. Since this patient has decreased baseline left ventricular ejection fraction, we would proceed with dobutamine echocardiography although exercise echocardiography has also been studied in these settings.4 Assuming the patient is already in the echo laboratory to get the resting images dobutamine infusion will take additional 30-40 minutes. The test is portable, non-invasive, and it is not associated with radiation exposure (in this middle-aged woman) or contrast exposure (in this diabetic patient). Since diagnostic ultrasound has no known adverse health effects, the risks are associated with the stress testing itself, not echocardiographic imaging. Overall, the life-threatening complications of dobutamine infusion are rare (1 in 557 patients in a large international registry of stress echocardiography).5 The cost of stress echocardiography is low compared to alternative modalities. In a modern cohort of patients referred for stress echocardiography for dyspnea without chest pain (like seen in this patient), the prevalence of ischemia was low (10%) although it was higher in patients with known coronary artery disease and baseline wall motion abnormalities.2 Dobutamine echocardiography can provide several important pieces of information for this patient including presence of contractile reserve and presence, 957


Argulian and Chaudhry Echocardiography debate

severity, and extent of ischemia. Low-dose dobutamine infusion helps determine contractile reserve suggestive of viable myocardium in affected segments. At higher dobutamine doses, the viable segments may continue to improve (monophasic response) or may demonstrate decrease in contractility (biphasic response) which is suggestive of ischemia. Prior studies have assessed the accuracy of dobutamine stress echocardiography in patients with systolic left ventricular dysfunction. One study assessed the global left ventricular wall motion score index during dobutamine infusion in patients with systolic left ventricular dysfunction.6 Patients with ischemic cardiomyopathy demonstrated predominantly a biphasic response (improved in contractility with lowdose dobutamine and deterioration with high-dose dobutamine), whereas patients with non-ischemic cardiomyopathy demonstrated predominantly a monophasic response (continuous improvement with higher doses of dobutamine). Based on the study results, dobutamine echocardiography had a sensitivity of 83% and specificity of 71% in detecting significant coronary artery disease (C50% stenosis). Importantly, the sensitivity increased proportionately with the severity of coronary artery disease reaching 100% for multivessel disease.6 In another study, although there was no difference in the number of akinetic segments at rest in patients with ischemic and non-ischemic cardiomyopathy, the former had more akinetic and less normal segments at peak dose.7 Six or more akinetic segments carried sensitivity of 80% and specificity of 96% for ischemic cardiomyopathy.7 Based on retrospective studies, the presence of inotropic contractile reserve with low-dose dobutamine infusion has been shown to carry prognostic information in patients with ischemic and non-ischemic cardiomyopathy.8,9 Also, it is a potential predictor of response to beta-blocker therapy and cardiac resynchronization therapy.10 Although many would quote Surgical Treatment for Ischemic Heart Failure (STICH) trial to argue that presence of viability has no differential survival benefit between revascularization and medical therapy arms, one should acknowledge several limitations of STICH viability substudy.11 Most importantly, only a subset of patients from STICH trial underwent viability assessment at the discretion of the treating physician; therefore, the benefits of randomization were lost and selection bias was possibly introduced.11 In the current era, objective information on contractile reserve can be obtained using speckle-tracking strain analysis as opposed to visual estimation.12 Finally, attainment of the age-predicted heart rate during dobutamine echocardiography also carries prognostic information. A metaanalysis of 11,542 patients undergoing stress echocardiography (both exercise and dobutamine) demonstrated

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a higher risk of cardiovascular events in patients who did not attain 85% of maximal age-predicted heart rate.13 One should keep in mind that the studies addressing the diagnostic accuracy of stress test modalities are mostly single center and commonly affected by angiographic referral bias.14 Also, technical factors and nonuniform definition of ‘positive’ stress testing should be considered in interpreting the existing evidence. In recent analysis, exclusion of patients with prior myocardial infarction significantly increased the sensitivity of dobutamine echocardiography.15 On the other end, specificity was lower when patients with resting wall motion abnormalities were included in the study (0.81 vs 0.88, P \ .10).15 In general, dobutamine echocardiography may have a higher combination of sensitivity and specificity for detection of flow-limiting stenosis compared to myocardial perfusion imaging.16 But the purpose of testing in this patient is not solely to identify the presence of coronary artery disease since she is already a candidate for initial aggressive medical therapy. Moreover, mere presence of coronary artery disease without establishing functional significance is not enough for diagnosing ischemic cardiomyopathy.17 Finally, there are no convincing benefits of routine revascularization for outcome improvement in patients with stable coronary artery disease.18 This applies to patients with systolic left ventricular dysfunction as studied in STICH trial although the number of patients with moderate-to-severe ischemia was too small to derive any meaningful conclusion.19 The important reasons for testing in this patient would include (1) identifying features that may indicate high-risk anatomy and (2) determining prognosis. One of the most valuable aspects of dobutamine echocardiography is effective risk stratification both in patients with and without left ventricular systolic dysfunction.20,21 This has been shown in multiple studies including prospective muticenter studies.22 Therefore, stress echocardiography can serve as an effective gatekeeper for coronary angiography and revascularization in the current era.23 Importantly, the predictive value of stress echocardiography extends beyond coronary artery disease.20 In a large series, 1477 consecutive patients with abnormal stress echocardiogram were followed for an average of 2.4 years.24 Among study subjects, 997 patients (67.5%) had angiographically significant coronary artery disease (defined as [50% stenoses), whereas 480 (32.5%) had ‘false-positive’ results (defined as \50% stenoses or normal coronary arteries). In multivariate analysis, characteristics associated with all-cause mortality included age, ability to exercise, resting systolic left ventricular dysfunction, and markedly abnormal stress echocardiography, while presence of angiographically significant coronary artery disease was not

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Argulian and Chaudhry Echocardiography debate


Figure 1. Patient management based on stress echocardiography findings.

predictive of mortality with hazard ratio of 1.05 (95% confidence interval 0.86-1.31). The study suggests that mere presence of coronary stenosis or coronary artery disease is a poor gold standard for defining false or true positivity of stress echocardiography.24 Another study explored the causes of ‘false positive’ echocardiograms manifesting as abnormal left ventricular contractile response to exercise.25 In this study, reduced resting left ventricular longitudinal function (estimated by mitral annular velocities) but not measures of microvascular dysfunction predicted abnormal stress response. This contrasts with myocardial perfusion imaging which can identify patients with no obstructive coronary artery disease but presence of ischemia. In one study these patients had higher rates of hospitalization for angina but no increase in mortality.26 Therefore, the ability of dobutamine echocardiography to evaluate latent or obvious myocardial dysfunction provides incremental

prognostic information beyond the presence of coronary stenosis. In conclusion, we suggest stress echocardiography as the best initial test for this patient (Figure 1). We believe it can guide the decision making and proper treatment in effective and cost-efficient manner. Disclosures The authors have indicated that they have no financial conflict of interest.

References 1. Argulian E, Agarwal V, Bangalore S, Chatterjee S, Makani H, Rozanski A, et al. Meta-analysis of prognostic implications of dyspnea versus chest pain in patients referred for stress testing. Am J Cardiol 2014;113:559-64.


Argulian and Chaudhry Echocardiography debate

2. Argulian E, Halpern DG, Agarwal V, Agarwal SK, Chaudhry FA. Predictors of ischemia in patients referred for evaluation of exertional dyspnea: A stress echocardiography study. J Am Soc Echocardiogr 2013;26:72-6. 3. Oh JK, Kane GC. Diastolic stress echocardiography: The time has come for its integration into clinical practice. J Am Soc Echocardiogr 2014;27:1060-3. 4. Peteiro J, Bouzas-Mosquera A, Pazos P, Broullon FJ, CastroBeiras A. Prognostic value of exercise echocardiography in patients with left ventricular systolic dysfunction and known or suspected coronary artery disease. Am Heart J 2010;160:301-7. 5. Varga A, Garcia MA, Picano E. Safety of stress echocardiography (from the International Stress Echo Complication Registry). Am J Cardiol 2006;98:541-3. 6. Sharp SM, Sawada SG, Segar DS, Ryan T, Kovacs R, Fineberg NS, et al. Dobutamine stress echocardiography: Detection of coronary artery disease in patients with dilated cardiomyopathy. J Am Coll Cardiol 1994;24:934-9. 7. Vigna C, Russo A, De Rito V, Perna GP, Testa M, Lombardo A, et al. Regional wall motion analysis by dobutamine stress echocardiography to distinguish between ischemic and nonischemic dilated cardiomyopathy. Am Heart J 1996;131:537-43. 8. Pratali L, Picano E, Otasevic P, Vigna C, Palinkas A, Cortigiani L, et al. Prognostic significance of the dobutamine echocardiography test in idiopathic dilated cardiomyopathy. Am J Cardiol 2001;88:1374-8. 9. Allman KC, Shaw LJ, Hachamovitch R, Udelson JE. Myocardial viability testing and impact of revascularization on prognosis in patients with coronary artery disease and left ventricular dysfunction: A meta-analysis. J Am Coll Cardiol 2002;39:1151-8. 10. Bangalore S, Hematpour K, Chaudhry FA. Dobutamine stress echocardiography: Does it predict response to beta-blockers in patients with heart failure? Curr Heart Fail Rep 2006;3:96-102. 11. Bonow RO, Maurer G, Lee KL, Holly TA, Binkley PF, DesvigneNickens P, et al. Myocardial viability and survival in ischemic left ventricular dysfunction. N Engl J Med 2011;364:1617-25. 12. Matsumoto K, Tanaka H, Kaneko A, Ryo K, Fukuda Y, Tatsumi K, et al. Contractile reserve assessed by three-dimensional global circumferential strain as a predictor of cardiovascular events in patients with idiopathic dilated cardiomyopathy. J Am Soc Echocardiogr 2012;25:1299-308. 13. Makani H, Bangalore S, Halpern D, Makwana HG, Chaudhry FA. Cardiac outcomes with submaximal normal stress echocardiography: A meta-analysis. J Am Coll Cardiol 2012;60:1393-401. 14. Arbab-Zadeh A. Stress testing and non-invasive coronary angiography in patients with suspected coronary artery disease: Time for a new paradigm. Heart Int 2012;7:e2. 15. Geleijnse ML, Krenning BJ, van Dalen BM, Nemes A, Soliman OI, Bosch JG, et al. Factors affecting sensitivity and specificity of

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diagnostic testing: Dobutamine stress echocardiography. J Am Soc Echocardiogr 2009;22:1199-208. Kim C, Kwok YS, Heagerty P, Redberg R. Pharmacologic stress testing for coronary disease diagnosis: A meta-analysis. Am Heart J 2001;142:934-44. Repetto A, Dal Bello B, Pasotti M, Agozzino M, Vigano M, Klersy C, et al. Coronary atherosclerosis in end-stage idiopathic dilated cardiomyopathy: An innocent bystander? Eur Heart J 2005;26:1519-27. Phillips LM, Hachamovitch R, Berman DS, Iskandrian AE, Min JK, Picard MH, et al. Lessons learned from MPI and physiologic testing in randomized trials of stable ischemic heart disease: COURAGE, BARI 2D, FAME, and ISCHEMIA. J Nucl Cardiol 2013;20:969-75. Panza JA, Holly TA, Asch FM, She L, Pellikka PA, Velazquez EJ, et al. Inducible myocardial ischemia and outcomes in patients with coronary artery disease and left ventricular dysfunction. J Am Coll Cardiol 2013;61:1860-70. Marwick TH, Case C, Sawada S, Rimmerman C, Brenneman P, Kovacs R, et al. Prediction of mortality using dobutamine echocardiography. J Am Coll Cardiol 2001;37:754-60. Smart SC, Dionisopoulos PN, Knickelbine TA, Schuchard T, Sagar KB. Dobutamine-atropine stress echocardiography for risk stratification in patients with chronic left ventricular dysfunction. J Am Coll Cardiol 1999;33:512-21. Sicari R, Pasanisi E, Venneri L, Landi P, Cortigiani L, Picano E. Stress echo results predict mortality: A large-scale multicenter prospective international study. J Am Coll Cardiol 2003;41:58995. Yao SS, Bangalore S, Chaudhry FA. Prognostic implications of stress echocardiography and impact on patient outcomes: An effective gatekeeper for coronary angiography and revascularization. J Am Soc Echocardiogr 2010;23:832-9. From AM, Kane G, Bruce C, Pellikka PA, Scott C, McCully RB. Characteristics and outcomes of patients with abnormal stress echocardiograms and angiographically mild coronary artery disease (\50% stenoses) or normal coronary arteries. J Am Soc Echocardiogr 2010;23:207-14. Nasis A, Moir S, Meredith IT, Barton TL, Nerlekar N, Wong DT, et al. Abnormal left ventricular contractile response to exercise in the absence of obstructive coronary artery disease is associated with resting left ventricular long-axis dysfunction. J Am Soc Echocardiogr 2014;28:95-105. Johnson BD, Shaw LJ, Buchthal SD, Bairey Merz CN, Kim HW, Scott KN, et al. Prognosis in women with myocardial ischemia in the absence of obstructive coronary disease: Results from the National Institutes of Health-National Heart, Lung, and Blood Institute-Sponsored Women’s Ischemia Syndrome Evaluation (WISE). Circulation 2004;109:2993-9.

Evaluating left ventricular systolic dysfunction: Stress echocardiography.

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