Discussion
In this comparative study, we have provided a multimodal demonstration of the microvascular perfusion parameters in patients with Type-1 (Anginal episodes+no obstructive epicardial lesion+CFR<2.5+proven myocardial ischaemia) and Type-4 CMD (Post-PCI TIMI 3 flow+CFR<2.5)(figure 6). The study included coronary haemodynamic (flow and resistance), electrocardiographic (hyperemic ST segment shift) and coronary energy transfer (wave intensity) parameters for comparison.
Figure 6Visual abstract: differences between Type-1 and Type-4 CMD. APVB, average peak velocity basal; APVH, average peak velocity hyperemia; BMR, basal microvascular resistance; CFR, coronary flow reserve; CMD, coronary microvascular dysfunction; HMR, hyperemic microvascular resistance; ICECG, intracoronary ECG; INOCA, ischaemia in the setting of non-obstructed coronary arteries; PCI, percutaneous coronary intervention.
The CFR values were comparably low in both groups due to the definition of CMD. The ICECG, which is a highly sensitive19–23 and territory-specific24 25 tool to evaluate ischaemic electrical voltage changes in the downstream territory,20 21 showed similar hyperemic ST segment shift magnitudes. This findings indicate the presence of reversible myocardial ischaemia of microvascular origin at similar magnitude in both groups.
The ICECG is an established method to monitor the ischaemic changes beginning from the very early stages following PCI. It provides an opportunity to detect ischaemia much more conspicuously and conceivably sooner and better than the surface ECG. ICECG was used to predict myocardial viability, to assess severity of bifurcation lesions24 25 and ischaemic potential of epicardial coronary lesions26 and only very recently to assess presence and severity of microvascular dysfunction and ischaemia in INOCA patients (ClinicalTrials.gov ID NCT05471739). Notably, an independent relationship between hyperemic ST shift with a worse prognosis has been previously reported.27 Considering the fact that we have objectively proven the perfusion defects via myocardial perfusion scan (MPS) in the INOCA group as part of study protocol prior to haemodynamic measurements, the demonstrated relationships between ∆ST, CMD and perfusion defects suggest that the subsequent electrical heterogeneity between neighbouring myocardial territories occurs due to regional perfusion defects with microvascular origin in nonobstructed vessels with CMD. Mechanistically, several theories may be suggested to explain how hyperemic ST shift and this perfusion defects/ischaemia is associated. Adenosine may be exacerbating the perfusion heterogeneity28 leading to an increased electrical voltage potential gradient, which may be more overt between adjacent healthier (normal flow reserve) and diseased myocardial territories in terms of microcirculation. This may be a microvascular analogue of the transmural steal phenomenon. In line with this explanation, patchy hyperemic perfusion defects at microvascular bed has been previously reported in the setting of the hypertrophic cardiomyopathy without obstructive coronary artery disease (CAD).29 In the current study, mean hyperemic ST – shift (mV) in both groups were similar which implies the presence of same magnitude of reversible ischaemia in Type-1 and Type-4 CMD groups.
Consistent with the literature, while the impaired flow reserve (CFR) is mainly driven by post-occlusive relative hyperemia,30 which significantly amplifies resting coronary flow following PCI, in the Type-4 group. It was mainly driven by blunted hyperemic flow augmentation and inadequate resistance attenuation due to worse microvascular expansibility, reflected by higher HMR and lower BEW values indicating structural microvascular abnormality in the Type-1 CMD. Notably, Type-1 and Type-4 CMD groups showed different coronary wave intensity profiles. The mean BEW, BCW and FEW magnitudes were significantly smaller in Type-1 CMD, however, the mean FCW amplitudes were indifferent. Lower peak BEW values found in Type-1 group indicating a worse microvascular expansibility during diastole, together with the higher HMR may display the distinctive features of pathomechanisms in both groups, whereas, the similar mean ∆ST values highlighting the severity of resulting ischaemia is eventually indifferent. Nonetheless, Type-4 CMD occurs acutely as a functional consequence of reperfusion and tend to attenuate and normalise in follow-up30–32 whereas Type-1 CMD develops over years and constitutes a permanent and progressive entity.
Coronary microvascular haemodynamics in Type-4 CMD
CMD following elective coronary interventions is associated with a worse clinical outcome.3 Type-4 CMD involves a multifactorial process mainly driven by distal microembolisation and thrombus formation in capillary bed accompanied by a perivascular inflammatory process as well as the release of miscellanea of vasoactive substances and/or myocardial oedema developing in varying extents in the early hyperemic period.3 In acute phase, resting blood flow may temporarily increase contributing to lower CFR values, which may not recover immediately and last up to couple of months (persistent functional CMD).32 In severe cases, even periprocedural infarctions with remarkable periprocedural troponin increase may be seen.33 At long-term follow-up, periprocedural troponin elevation has been shown to be related with a 50% increased risk of subsequent major cardiac events and increased risk of re-PCI and death.27
Patients with Type-4 CMD showed evidence of ischaemia in downstream myocardium assessed by ICECG with comparable dynamic hyperemic ST shift to the Type-1 CMD group patients. Type-4 group was mainly characterised by increased baseline flow velocity (post-occlusive hyperemia) as expected. Post-PCI mean HMR value was also remarkably lower than that of CMD/INOCA group. This finding is also in line with the basic principle of coronary physiology and functional nature of the pathology. The microvascular resistance vessels are known to be pressure distensible and controlled by autoregulatory mechanisms. In maximally dilated coronary bed, coronary blood flow, hence the microvascular perfusion, is fully and linearly pressure-dependent.
Flow-limiting significant epicardial stenosis is compensated by an autoregulatory maximum vasodilation and resistance attenuation to sustain the blood flow. In this setting, treatment of a highly stenotic epicardial segment leads to an acute further basal flow augmentation by restoring distal perfusion pressure while the resistance is still low in Type-4 CMD group.34
Regarding the coronary arterial energy transfer characteristics, our Type-4 group had similar mean BEW peak magnitude to that of previously reported in patients with anginal complaints and positive functional test results without relevant epicardial stenoses (indicating that the symptoms are of a microvascular origin, ANOCA) reported by Broyd et al.17 This findings indicate the comparable impairment in microvascular expansibility in acute phase of Type-4 CMD following elective stenting and in patients with primary CMD (Type-1). Furthermore, in the setting of chronic obstructive CAD, attenuated BEW amplitudes in the acute phase were seen 30 min after a 1 min-long ballooning, which was performed to assess the impact of myocardial stunning, may be attributed to microvascular stunning.35 No continuous relationship between HMR and BEW could be observed in this study. However, lower HMR and higher BEW values observed in Type-4 in comparison with Type-1 CMD are consistent with the current physiological knowledge as Type-1 is mainly driven by the impaired vasodilatory capacity with higher minimal microvascular resistance and worse arteriolar expansibility, whereas the main reason of reduced flow reserve is relative hyperemia in Type-4 CMD in which microvascular resistance attenuation capacity at hyperemia is preserved.35
The BCW has been recently proposed to be a measure of myocardial viability in patients with heart failure secondary to ischaemic cardiomyopathy, where the greater amplitudes are related to a larger viable myocardial mass in the related territory.36 Although Type-1 group had smaller BCW amplitudes, lack of any gold standard methods for viability limits the interpretability of this wave in the present study. Likewise although significant, difference in the FEW magnitudes is of limited interpretability in our cohort as (1) the SD are relatively big, (2) the study was not designed hence equipped to investigate the meanings of WIA waveforms and (3) literature lacks of data and knowledge about this wave. Nonetheless, patients with Type-4 CMD with satisfactory TIMI 3 flow following PCI has similarly severe reversible ischaemia in related vessel-specific territory in comparison with patients with Type-1 CMD although the drivers largely differ in terms of coronary wave energy transfer features as well as haemodynamic characteristics.
Coronary microvascular haemodynamics in Type-1 CMD model (INOCA)
Presence of the ischaemia in the setting of non-obstructed coronary arteries (INOCA) is encountered in up to half of the patients undergoing angiography for anginal complaints.7 37 CMD comprises the major pathology in this group.38 These patients are typically characterised by blunted hyperemic flow velocity augmentation (lower CFR values). A specific subgroup of CMD with higher minimal microvascular resistance (HMR), named structural CMD, had distinctive macrostructural and microstructural alterations in addition to impaired microvascular functionality.39 40
Our study has included the IRVs identified through myocardial perfusion scan from patients with Type-1 CMD, which had similar hyperemic ST segment shift compared with post-elective PCI CMD (Type-4 CMD). Patients with CMD/INOCA with angiographically normal coronary arteries have comparable electrophysiological reversible ischaemia measures (∆ST) with post-PCI status, and these vessels had significantly higher HMR values compared with the Type-4 group. The significantly worse microvascular expansibility in our Type-1 CMD group with CFR <2.5 and perfusion scan proven ischaemia in comparison to previously reported values17 18 may suggest that patients with documented CFR <2.5 with objective ischaemia proof have worse microvascular expansibility in comparison with the ANOCA patients with positive functional test results alone.
On the other hand, significantly smaller in BCW intensities found in Type-1 CMD group should be approached cautiously since larger BCW values are associated with viability in the downstream myocardium36 but also they have been reported in patients with poorer microcirculation and CMD.6 This difference can probably be attributed to the dissimilarity in the context of studies. In a study measuring the intracoronary pressure and flow velocity data in the ischaemia-related artery (IRA) with the presence of a large infarct (=smaller, less contractile viable myocardium downstream) in comparison to healthy reference arteries, smaller BCW values in IRA are expected to be observed considering the difference in contractility between territories. On the other hand, a study involving CMD in the setting of INOCA may arguably display relatively augmented microvascular compression waves in comparison to a healthy reference group.
These findings of the present study, which had comparatively analysed Type-1 and Type-4 CMD groups utilising ICECG, IC Doppler and WIA parameters, collectively indicate that, CMD induced reversible ischaemia is as severe as that of acutely seen following elective PCI in the setting of chronic CAD, although the drivers may be different and the microvascular milieu is more severely affected in Type-1, as reflected by poorer microvascular expansibility.
Limitations and strengths
The current analysis has several technical limitations alongside the small sample size. The PCI group had no information regarding preprocedural CMD and postprocedural troponin values. For the calculation of microvascular resistance and wave intensity, we have relied on the aortic pressure (Pa) in the absence of Pd, given that there were no epicardial stenoses angiographically and our recent unpublished observations on Pd–Pa relationships demonstrating very high cross-correlation coefficients even in the presence of very low FFR values. However, there were no post-stent Pd/Pa or FFR measurements to uncover small diffusely developing pressure gradients throughout the artery. Although, the potential low residual pressure gradients in the Post-PCI/CMD group with no visual residual disease could expectedly have no relevant impact on the previous observations, calculation with distal pressure measurements would be more reliable. Inclusion of postprocedural physiological/imaging-based assessment methods would provide valuable information about residual epicardial ischaemia. The present analysis, as a mechanistic single centre study, could demonstrate no difference in haemodynamic characteristics with respect to sex and epicardial vessel in the entire group. Due to the small sample size, further analysis in CMD versus No-CMD cases in this regard could not be performed. Considering the previously reported differences in the literature,41 however, further studies should take the impact of these confounders into account. On the other hand, our study included only CMD/INOCA patients with MPS-documented evident-ischaemia and studied the IRVs, which forms a well-defined and evidence based CMD-vessel group rather than considering only impaired surrogate haemodynamic indices.