Anastasia Vamvakidou

Prognostic usefulness of contemporary stress echocardiography in patients with left bundle branch block and impact of contrast use in improving prediction of outcome.

Aims Patients with symptomatic left bundle branch block (LBBB) may have myocardial ischaemia due to both coronary artery disease and/or cardiomyopathy (microcirculatory abnormalities) and may have concomitant left ventricular (LV) dysfunction. We aimed to assess the feasibility and prognostic value of contemporary stress echocardiography (SE), which can uncover both pathophysiologies in LBBB patients in routine clinical practice, and also aimed to assess the additive value of contrast SE. Methods and results Accordingly, 190 consecutive patients (age 70.5 ± 11.3 years, LV ejection fraction = 50.1 ± 10%) with symptomatic LBBB who underwent SE over 6 years were assessed, of which 142 (75%) underwent contrast SE and 176 (92.6%) had diagnostic SE. Inducible ischaemia was present in 25 (14.2%) patients. During follow-up (35.4 ± 20.2 months) there were 32 deaths (18%) and 18 (10.2%) first cardiovascular (CV) events (acute myocardial infarction/mortality) in the 176 patients with diagnostic studies. Wall thickening score index at peak stress (WTSIpeak), which measures combined LV function and inducible ischaemia, was an independent predictor of mortality (HR = 3.78, 95% CI = 1.39-10.31, P = 0.01) and CV events (HR = 3.96, 95% CI = 1.1-14.3, P = 0.036). An abnormal SE (myocardial ischaemia and/or abnormal LV function) predicted an almost three-fold increase in all-cause mortality and CV events compared with normal SE. Amongst the confounders affecting assessment of wall thickening in LBBB and conventional prognostic variables, use of contrast was an independent predictor (P = 0.034) of WTSI1.16 (optimal predictor of mortality/CV outcome). Conclusion SE in patients with LBBB demonstrated high feasibility and the combination of LV systolic function and myocardial ischaemia provided important prognostic information. Contrast-enhanced SE improved the prediction of outcome.

Cost-effectiveness of a management strategy based on exercise echocardiography versus exercise electrocardiography in patients presenting with suspected angina during long term follow up: A randomized study

INTRODUCTION Exercise ECG (Ex-ECG) is advocated by guidelines for patients with low - intermediate probability of coronary artery disease (CAD). However, there are no randomized studies comparing Ex-ECG with exercise stress echocardiography (ESE) evaluating long term cost-effectiveness of each management strategy. METHODS Accordingly, 385 patients with no prior CAD and low-intermediate probability of CAD (mean pre-test probability 34%), were randomized to undergo either Ex-ECG (194 patients) or ESE (191 patients). The primary endpoint was clinical effectiveness defined as the positive predictive value (PPV) for the detection of CAD of each test. Cost-effectiveness was derived using the cumulative costs incurred by each diagnostic strategy during a mean of follow up of 3.0 years. RESULTS The PPV of ESE and Ex-ECG were 100% and 64% (p = 0.04) respectively for the detection of CAD. There were fewer clinic (31 vs 59, p < 0.01) and emergency visits (14 vs 30, p = 0.01) and lower number of hospital bed days (8 vs 29, p < 0.01) in the ESE arm, with fewer patients undergoing coronary angiography (13.4% vs 6.3%, p = 0.02). The overall cumulative mean costs per patient were £796 for Ex-ECG and £631 for ESE respectively (p = 0.04) equating to a >20% reduction in cost with an ESE strategy with no difference in the combined end-point of death, myocardial infarction, unplanned revascularization and hospitalization for chest pain between ESE and Ex-ECG (3.2% vs 3.7%, p = 0.38). CONCLUSION In patients with low to intermediate pretest probability of CAD and suspected angina, an ESE management strategy is cost-effective when compared with Ex-ECG during long term follow up.

Exercise echocardiography in asymptomatic severe aortic stenosis

A 77 year old female with asymptomatic severe aortic stenosis (AS) and normal LV systolic function was referred for exercise stress echocardiography (ESE) in order to assess whether she is truly asymptomatic and to risk-stratify her aortic valve disease. While she only developed minimal breathlessness after 4.2 min of Bruce protocol and no other high risk features (arrhythmias, SBP drop, mean Aortic gradient rise [20 mmHg) [1], it was noted that her stroke volume (SV/ indexed SVi) and flow rate (FR) at peak stress had dropped compared to the ones at rest (SVi rest = 45.7 ml/m, SVi stress = 27 ml/m, FR rest = 234 ml/s, FR stress = 203 ml/ s). SV can drop physiologically during exercise due to reduction in ejection time [2]. However the drop in FR remained unexplained. This could be due to stress-induced myocardial dysfunction originating from global ischaemia due to AS or from myocardial ischaemia due to associated significant coronary artery disease (CAD). The patient had contrast ESE in order to assess for exercise induced LV dysfunction. This showed significant Regional Wall Thickening Abnormality in the left anterior descending (LAD) territory involving 9 out of 17 segments. She therefore underwent a coronary angiogram which confirmed features of tight proximal LAD disease (Fig. 1). Patient was referred for aortic valve replacement (AVR) and coronary artery bypass grafting. The above case highlights two important points. First that careful assessment of FR during ESE is crucial as FR reflects cardiac output. Secondly that the risk stratification of patients with asymptomatic severe AS using ESE should include assessment of regional wall thickening which may help to clarify the cause of exercise induced LV systolic dysfunction. The latter could be the result of ischaemia due to CAD and is a bad prognostic marker in severe AS.

Long-Term Association of Dipyridamole Stress Myocardial Contrast Echocardiography versus Single-Photon Emission Computed Tomography with Clinical Outcomes in Patients with Known or Suspected Coronary Artery Disease

Background: Single‐photon emission computed tomography (SPECT) is a well‐established method to evaluate patients with coronary artery disease. Myocardial contrast echocardiography (MCE) is an imaging technique that allows the assessment of myocardial perfusion in real time. Previous research has shown that vasodilator MCE is superior to SPECT for the prediction of hard events. The aim of this study was to investigate the long‐term association of SPECT and MCE with clinical outcomes in patients with known or suspected coronary artery disease. Methods: Accordingly, 258 patients who underwent MCE and SPECT as part of multicenter studies performed prospectively were followed up for hard events (all‐cause mortality and nonfatal myocardial infarction). The mean age was 63.4 ± 5.5 years, 186 (72.1%) were men, and 32 (12.4%) had left ventricular systolic dysfunction. We calculated the ratio of the number of abnormal segments (at rest and/or stress) to the total number of segments expressed as MCE and SPECT indices. Results: Over a mean follow‐up period of 80.4 ± 6.1 months, 46 patients had hard events. MCE and SPECT indices were associated with all‐cause mortality on univariate analysis (P = .008 and P = .035, respectively) but only MCE index was independently associated with hard events (hazard ratio, 4.24; 95% CI, 1.27–14.15; P = .019), beyond clinical data and left ventricular function, and independently associated with hard cardiac events (hazard ratio, 4.78; 95% CI, 1.06–21.59; P = .042). Conclusions: MCE but not SPECT showed a long‐term association with outcome. These results thus favor the routine use of MCE in the long‐term assessment of patients with known or suspected coronary artery disease. HIGHLIGHTSMCE has better long‐term association with outcome than SPECT.MCE was associated with hard events independent of clinical prognostic markers.MCE was also independently associated with hard cardiac events.MCE, not SPECT, is associated with long‐term hard events in assessment of CAD.

STROKE VOLUME DETERMINED FLOW RESERVE DOES NOT PREDICT THE TRUE SEVERITY OF LOW-FLOW LOW-GRADIENT AORTIC STENOSIS AND IS NOT A ROBUST MARKER OF CONTRACTILE RESERVE IN PATIENTS UNDERGOING LOW-DOSE DOBUTAMINE ECHOCARDIOGRAPHY

Background: During low-dose dobutamine stress echocardiography in low-flow low-gradient aortic stenosis (LFLGAS), both the aortic stenosis severity and the presence of contractile reserve are conventionally assessed based on stroke volume flow reserve (SVFR) (stroke volume increase ≥20%). However

115 Diagnostic concordance and clinical outcomes in patients undergoing fractional flow reserve and stress echocardiography for the assessment of coronary stenosis of intermediate severity

Introduction The ischaemic consequences of a coronary artery stenosis can be assessed by invasive fractional flow reserve (FFR) or by non-invasive imaging. We sought to determine (i) the concordance between wall thickening assessment and FFR during clinically indicated stress echocardiography (SE) and FFR measurements and (ii) the predictors of hard events in these patients. Methods and Results 194 patients who underwent SE and invasive FFR measurements in close succession were analysed for diagnostic concordance and clinical outcomes. At the vessel level, the sensitivity, specificity, positive predictive value (PPV) and negative predictive value (NPV) of SE for identifying significant disease as assessed by FFR was 70%, 78%, 46% and 91% respectively. In patients with single vessel disease, the sensitivity, specificity, PPV and NPV were 86%, 66%, 38% and 95% respectively. The greatest discordance was seen in patients with wall thickening abnormalities (WTA) and negative FFR. During a follow up of 3.0±1.9 years there were 15 cardiovascular (CV) events. The number of wall segments with inducible WTAs emerged as the only independent predictor of CV events (HR 1.22 (1.05–1.43), p=0.01). FFR was not a predictor of outcome. There was a significant increase in event rate in patients with WTA/negative FFR and WTA/positive FFR, compared to patients with no WTA (p=0.04). However, no significant difference was seen between patients with WTA/negative FFR versus WTA/positive FFR (p=0.38) Conclusion In a patient population with significant CV risk factors, a normal SE effectively ruled out abnormal FFR. The greatest discordance was seen in patients with abnormal SE/normal FFR. In this group, patients had similar outcomes compared to those with abnormal SE/positive FFR but worse outcomes compared to patients with a normal SE. These findings have significant clinical implications.Abstract 115 Figure 1Abstract 115 Figure 2

107 The long term prognostic value of dipyridamole stress myocardial contrast echocardiography in comparison with single photon emission tomography in patients with known or suspected coronary artery disease

Background Single photon emission computed tomography (SPECT) is a well-established method to evaluate patients with coronary artery disease (CAD). Myocardial contrast echocardiography (MCE) is an imaging technique that allows assessment of myocardial perfusion in a real-time setting. Very short term prognostic study has shown that vasodilator MCE is superior to SPECT for the prediction of hard events. We sought to investigate the long term prognostic value of SPECT and MCE in the assessment of patients with known or suspected CAD. Methods We retrospectively followed-up patients with suspected or known CAD who were scheduled for coronary angiography and who also underwent MCE and SPECT at our institute, as part of multicentre studies performed between January 2002 and December 2009. Rest and vasodilator SPECT was performed after injection of 99mTc-sestamibi using the standard technique on separate days. Coronary Angiography (CA) was performed within thirty days of stress imaging. We calculated the ratio of the number of abnormal segments (at rest and/or stress) to the total number of segments expressed as% for both MCE and SPECT in order to obtain a uniform assessment of the total ischaemic and scar burden (MCE and SPECT indexes). This population was followed up in 2016 to obtain a long term prognostic value of MCE and SPECT for hard events, all-cause mortality and non-fatal myocardial infarction (NFMI). Results Of the 277 patients who were analysed, 262 followed up and 15 were lost to follow up (5.4%). The mean age was 63.4 years and 186 (71.8%) patients were male, 82 (31.7%) had diabetes, 180 (69.5%) hypertension, 189 (73%) dyslipidaemia, 26 (10%) family history of CAD (FHCAD) and 64 (24.7%) were smokers. Prior CAD (angina, known acute myocardial infarction (AMI) or coronary revascularisation) was present in 178 (68.7%) patients, left ventricular systolic dysfunction in 32 (12.4%) and chronic kidney disease in 16 (6.2%). Over a mean follow-up period of 80 months(6.6 years)±6 months, 18 patients suffered NFMI and 29 died (18% hard events, annualised hard events 2.7%). Both MCE and SPECT indexes were significant predictors on univariate analysis for all-cause mortality (p=0.008 and p=0.035 respectively), but MCE index was the only independent predictor for hard events (HR 3.711, 95% CI(1.13–12.14), p=0.03). Figure 1 demonstrates the Kaplan-Meier curve for the long-term prognostic value in all-cause mortality and NFMI of abnormal versus normal MCE. The annualised event rate for the abnormal MCE is 3.8% versus 1.0% for the normal MCE. Conclusion This is the first study to our knowledge that investigated the long-term prognostic value of SPECT and MCE in patients with suspected or known CAD. MCE was the only independent predictor of hard events. These results further support the routine use of MCE and not SPECT for the long-term prognostication of patients with known or suspected CAD.Abstract 107 Figure 1 Kaplan-Meier curve showing the long term prognostic value in predicting all cause-morality and NFMI for normal versus abnormal MCE

124 Stroke volume determined flow reserve does not predict the true severity of low-flow low-gradient aortic stenosis and is not a robust marker of contractile reserve in patients undergoing low-dose dobutamine echocardiography

Background During low-dose dobutamine stress echocardiography (LDDSE) in low-flow low-gradient aortic stenosis (LFLGAS), both the aortic stenosis (AS) severity and the presence of contractile reserve (CR) are conventionally assessed based on stroke volume flow reserve (SVFR), which is defined as stroke volume [SV] increase 20%. However frequent exaggerated chronotropic response to dobutamine with shortening left ventricular time result in SV drop. On the contrary, transvalvular flow rate (FR) (SV/ejection time) and left ventricular ejection fraction (LVEF) may increase. We aimed to assess the value of FR 200 ml/s (normal FR) and LVEF change in the identification of true severe AS (TSAS) and the assessment of CR respectively. Methods Accordingly 74 consecutive patients (mean age 78 years) with LFLGAS referred for LDDSE for determination of AS severity and CR underwent retrospective assessment of SV, FR, LVEF and standard echocardiographic parameters of AS severity (Table 1). The outcome assessed was all-cause mortality censored for aortic valve intervention. Results SVFR was present in 30 (40.5%) of the 74 patients whereas FR 200 ml/s was achieved in 60 (81.1%) (p<0.001). During the median follow-up of 316.5 days 28 (37.8%) deaths occurred. Amongst all standard echocardiographic predictors of AS severity at peak stress (aortic valve mean and peak gradient, peak velocity and area [AVA]) and clinical prognostic factors, AVA was an independent predictor of death (HR=0.1, 95%CI=0.02–0.7, p=0.03), and was therefore used to define TSAS (stress AVA 1.01cm2). TSAS was present in 47 (63.5%) patients of whom SVFR correctly identified 17 (36.2%) compared to 34 (72.3%) with FR 200 ml/s (p=0.001). In the 48 patients with LVEF 50%, amongst SV, FR and LVEF changes, only the latter was an independent predictor of death (HR=0.92, 95% CI=0.87–0.98, p=0.02) (Table 2). LVEF change of <5% was the best cut-off for the prediction of death (log rank p=0.004) and therefore for determination of CR (Figures 1-2). Increase in LVEF 5% had a significant impact on survival both on patients that underwent aortic valve intervention (log rank p=0.03) and those who underwent medical management (log rank p=0.01), as opposed to presence of SVFR (log rank p=0.234 and p=0.708 respectively). Conclusions During LDDSE in LFLGAS normalised FR, not SVFR, is a better determinant of TSAS, whereas assessment of LVEF change instead of SVFR determines CR.Abstract 124 Table 1 Patient echocardiographic characteristics Rest Stress p HR (bpm) 74.9±14.5 97.5±18.7 <0.001 LVEF (%) 43±15.7 53.5±18.5 <0.001 AVA (cm2) 0.77±0.13 0.92±0.2 <0.001 AVMG (mmHg) 25.7±6.7 35.3±10.9 <0.001 AVVmax (cm/sec) 328.1±43.3 384.8±52.5 <0.001 SV (ml) 56.6±14.1 64.4±16 <0.001 SVi (ml/m2) 32.3±8.2 36.8±9.7 <0.001 Flow Rate (ml/sec) 179.8±34.6 240.1±55.4 <0.001Abstract 124 Table 2 Univariable and multivariable analysis for prediction of all-cause mortality in patients with LVEF 50% Univariable Multivariable HR 95% CI p value HR 95% CI p value Age 1.002 0.9–1.1 0.96 Hypertension 0.9 0.3–2.5 0.85 Diabetes 0.9 0.3–2.6 0.88 Presence of ischaemia on stress echo 2.68 0.59–12.14 0.20 Change SV (ml) 0.99 0.9–1.04 0.67 Change FR (ml/sec) 0.99 0.98–1.004 0.19 Change LVEF (%) 0.92 0.87–0.98 0.02 0.92 0.87–0.98 0.02Abstract 124 Figure 1Abstract 124 Figure 2

132 Diagnostic Accuracy of Stress Echocardiography Compared with Invasive Coronary Angiography with Fractional Flow Reserve for The Diagnosis of Haemodynamically Significant Cad in Patients with Known or Suspected CAD

Introduction Haemodynamically significant coronary artery disease (CAD) is an important indication for revascularisation. Wall motion analysis during stress echocardiography (SE) is a noninvasive alternative to invasive fractional flow reserve (FFR) for evaluating hemodynamically significant CAD. We sought to determine the diagnostic accuracy of SE compared with invasive coronary angiography with FFR for the diagnosis of hemodynamically significant CAD. Methods and Results Between January 2008 and April 2015, all patients that underwent clinically indicated FFR measurements during invasive angiography and SE in close succession were analysed. Patients were excluded if tests were not done within 6 months of each other, or an intervening percutaneous coronary procedure or acute coronary syndrome occurred. 184 patients (mean age 66.5yrs, 59 (32%) female) were identified. The majority of patients underwent coronary angiography following SE. The prevalence of known CAD, diabetes and chronic kidney disease were 46%, 43% and 13% respectively, and 14 (8%) patients had previous coronary artery bypass surgery. Exercise SE was performed in 84 (46%) patients and Dobutamine SE in 100 (54%) patients. Contrast was used in 158 patients (86%). In 108 patients (59%), the SE was positive for inducible ischaemia. From 217 vessels analysed, the Left Anterior Descending Artery, Right Coronary Artery, Left Circumflex Artery and Left Main Coronary artery were involved in 120 (55%), 47 (22%), 30 (14%), 18 (8%) respectively, with 2 vessels being grafts. 46 FFR measurements were positive (21%) and 171 were negative (79%), using a cut off of≤ 0.80. At the vessel level, the sensitivity, specificity, positive predictive value (PPV) and negative predictive value (NPV) of SE for identifying significant disease as assessed by FFR was 70%, 77%, 45% and 90% respectively. In 73 patients, there was single vessel disease on angiography. At the vessel level, the sensitivity, specificity, PPV and NPV were 85%, 68%, 37% and 95%. Conclusion To date this is the largest study comparing SE and FFR for the assessment of the physiological significance of a coronary lesion, and reflects real world experience. SE demonstrates good diagnostic accuracy and excellent NPV for excluding flow-limiting disease. The low PPV is likely to represent the commencement of medical therapy following a positive SE, as well as referral bias (since only patients with positive SE underwent angiography) as well as the low prevalence of positive FFR measurements in this population. The presence of a haemodynamically significant stenosis can be accurately ruled out with SE.

Can severity of aortic stenosis be determined despite absent contractile reserve in low-flow low-gradient aortic stenosis?

A 79‐year‐old man presented with increasing breathlessness and his echocardiogram revealed severe left ventricular systolic dysfunction and low‐flow low‐gradient aortic stenosis. Low‐dose dobutamine stress echocardiography revealed the absence of contractile reserve (increase of stroke volume by ≥20% did not occur). The test would have therefore been inconclusive. However, the attainment of normal flow (FR≥200 mL/s) during dobutamine stress enabled the diagnosis of true severe aortic stenosis.