In this pilot study in South Australian patients with INOCA, we explored different doses of low dose dobutamine stress echocardiography (5mcg/kg/min, 10mcg/kg/min and 20mcg/kg/min) and assessed the association between GLS derived contractile reserve and invasive coronary haemodynamic indices of CFR and HMR. We found that there were more GLS derived contractile reserve at 5mcg/kg/min of dobutamine infusion between normal and abnormal coronary haemodynamic indices which may suggest hibernating myocardium contractility recruitment during the infusion. It is possible that in this cohort of patients with INOCA who reported frequent, prolonged and often random episodes of spontaneous myocardial ischaemia (Table B) developed a resting hibernating state that was reversed at very low dose dobutamine. The consistent failure to have any response to higher doses of dobutamine indicated limited contractile reserve.
Furthermore, the inability to demonstrate a negative association between GLS and CFR or HMR at low dose dobutamine may be explained by an inability to be a stressor that induces sufficient myocardial ischaemia to alter GLS. Higher doses of dobutamine were not used in this study. Alternatively, the mechanism of inducing myocardial ischaemia in patients with this pathophysiology is not triggered by dobutamine.
Leung et al also demonstrated an impaired CR indicates coronary microvascular dysfunction with low-dose DSE derived LV CR via echocardiographic speckle tracking method to estimate IMR non-invasively.39 Coronary microvascular dysfunction and impaired myocardial contractile reserve was demonstrated in women with angina and no obstructive coronary artery disease by Michelsen et al but without invasively derived microvascular indices but with reduced coronary flow reserve on echocardiography. The GLS reserve was found to be significantly lower in women with CMD.53
The finding in our study is similar to the findings of Leung et al. The main difference is the slight increase in contractile reserve at a low dose of dobutamine of 5mcg/kg/min (a dose not used in the Leung study), but a blunted response at the higher doses of 10 and 20mcg/kg/min. Our hypothesis is that there is a degree of hibernating myocardium that is recruited initially but the expected demonstration of contractile reserve in normal myocardium is impaired in this cohort with microvascular dysfunction as demonstrated by Leung et al.
Recently, Rahman et al demonstrated that in patients with angina and no obstructive coronary artery disease, diminished coronary flow reserve characterizes a cohort with inducible ischemia and a maladaptive physiological response to exercise, during simultaneous coronary pressure and flow velocity measured using a dual sensor-tipped guidewire during rest, supine bicycle exercise, and adenosine-mediated hyperaemia.54
There is no robust simple and effective non-invasive assessment for vasospastic angina, except for abnormal ECG changes for myocardial ischaemia and an exclusion of obstructive coronary artery disease on coronary angiography.55,56 The dynamic nature of coronary artery spasm has made this challenging for non-invasive evaluation. As for microvascular angina, different modalities have been explored. These include transthoracic doppler echocardiography (TTDE), myocardial contrast echocardiography (MCE), positron emission tomography (PET) and cardiac magnetic resonance (CMR). TTDE assessing coronary blood flow velocity can be evaluated at baseline and during hyperaemia by pulsed-wave Doppler echocardiography, with the sample volume placed on the colour signal in the mid- or distal tract of the left anterior descending coronary artery (LAD). This technique requires extensive training and assessment is only confined to LAD but not other coronary arteries.21–25
MCE-derived myocardial blood flow and myocardial blood volume can be assessed through intravenously injected, echogenic, gas-filled microbubbles that are similar in size and rheological properties to red blood cells and are detected in the myocardium by high-intensity ultrasound pulses. Myocardial perfusion abnormalities during dipyridamole infusion in patients with otherwise normal wall motion seems to be a marker of CMD.26,27
CMR derived myocardial perfusion obtained through the first-pass kinetics of T1- enhancing extracellular gadolinium-based contrast media. The contrast medium, diffusing from the microvasculature into the interstitial space, results in an increase in signal intensity that is proportional to the perfusion and blood volume of the tissue, the extravascular compartment size, and capillary permeability. A delayed signal increase and persistently hypointense regions are indicative of reduced perfusion. This technique is promising but limited to local availability. A further validation study is underway for this group of patients conducted by the CorMicA CMR sub-study.28
PET provides accurate, and reproducible quantification of regional myocardial blood flow, by means of continuous monitoring of the radioactivity emitted by an intravenously administered tracer, in the circulation and the myocardium. Despite well validated with coronary microvascular dysfunction and utilised in CMD research, this technique is limited by ionizing radiation, expense and lack of availability.29
The utility of 2D speckle tracking was assessed in a study by Roushdy et al in 2017.57 In a prospective 80 patient cohort of patients with possible angina, speckle tracking at peak stress for global longitudinal strain during dobutamine stress echocardiography (DSE) showed an increased sensitivity of 77% and specificity of 84% in detecting ischemia due to obstructive epicardial coronary artery disease, Our study in patients with INOCA did not demonstrate the same result as for patients with obstructive coronary artery disease.
Further research to define a simple functional non-invasive protocol that may assist in the diagnosis of myocardial ischaemia for patients with angina with no obstructive coronary artery disease would have incremental value given the recent increasingly recognised condition, together with emerging endotypes specific stratified medical therapy.
Study Limitations
The interpretation of our study findings should be considered in the context of the following limitations. Firstly, speckle tracking has been known to be afterload-dependant and in some circumstances may not be reflective of myocardial contractility. Secondly, the echocardiographic acquisition was not conducted simultaneously with the invasive study, instead, within 2 weeks from initial assessment. Thirdly, there was no healthy control in our study cohort. Finally, the population size was small and indicates the need for further studies in a larger cohort of patients.