Murat Sezer

Background: Angina and/or ischaemia with nonobstructive coronary arteries (ANOCA/INOCA) is common, particularly in women, and is most frequently attributable to coronary microvascular dysfunction (CMD), rather than representing a benign finding after exclusion of epicardial stenosis. Case Summary: A 55-year-old woman with cardiometabolic risk factors had recurrent angina and reversible ischaemia on stress single-photon emission computed tomography. Coronary angiography showed no obstructive disease. Doppler-based coronary function testing in the left anterior descending coronary artery demonstrated reduced coronary flow velocity reserve (1.99) with normal hyperaemic microvascular resistance (1.31 mmHg·s·cm−1), suggesting functional CMD. Wave intensity analysis showed high resting accelerating wave energy proportion without hyperaemic augmentation, and intracoronary electrocardiogram (ECG) during adenosine hyperaemia revealed ischaemic ST-segment shifts concordant with perfusion imaging. Discussion: Multimodal invasive assessment can phenotype the INOCA endotypes and provide real-time ischaemia confirmation. This case highlights the added value of combining intracoronary ECG with wave intensity analysis for real-time ischaemia verification in INOCA, supporting a shift from anatomical exclusion to integrated physiological diagnosis of CMD. Vasoreactivity testing was not performed; therefore, a coexisting vasospastic endotype was not excluded.

Background: Physiology‐guided coronary revascularization using fractional flow reserve (FFR) and/or instantaneous wave‐free ratio (iFR) improves outcomes compared with angiography alone. However, when FFR and iFR are measured simultaneously, discordance occurs in 15%–20% of lesions and is associated with heterogeneous clinical outcomes, while the underlying hemodynamic mechanisms are not fully captured by conventional pressure tracings. Reservoir–excess pressure analysis (REPA), which decomposes arterial pressure into reservoir pressure (Pr) and excess pressure (Pxs), and quantifies the diastolic rate constant (DRC), may offer additional pathophysiological insight into these differences. Elevated DRC and Pxs with reduced Pr may indicate systemic hyperperfusion accompanied by lower aortic compliance. Aims: The objective of this study was to characterize pressure‐derived hemodynamics (i.e., REPA) and identify mechanisms related to FFR/iFR discordance in coronary arteries with angiographically intermediate stenoses. Methods: This secondary analysis included 249 unique lesions with intermediate coronary artery stenoses (visually estimated diameter stenosis of 40%–70%) from 223 patients in the international, multicenter DEFINE‐FLOW study. FFR was defined as hyperemic Pd/Pa and iFR as resting Pd/Pa during the wave‐free period. Established thresholds (FFR ≤ 0.80 and iFR ≤ 0.89) were used to define concordant and discordant stenoses. REPA was performed on ensemble‐averaged proximal aortic pressure waveforms at rest to derive Pr, Pxs, and related parameters (Figure 2). Results: REPA parameters demonstrated distinct hemodynamic profiles across groups. FFR−/iFR+ cases showed significantly higher Pxs (7.53 [4.97, 10.12] mmHg) and DRC (3.00 [2.06, 3.52]) and lower IntPr/IntPxs (11.73 [9.57, 17.00]) compared with FFR+/iFR− (Pxs: 5.19 [4.21, 6.89] mmHg, DRC: 2.28 [1.69, 2.51], IntPr/IntPxs: 17.90 [14.23, 19.87]) and FFR−/iFR− (Pxs: 5.38 [4.03, 7.17] mmHg, DRC: 2.20 [1.67, 2.91], IntPr/IntPxs: 17.03 [12.76, 21.21]) cases. Notably, both Pxs and DRC values were highest and IntPr/IntPxs was lowest in FFR−/iFR+ cases. Pxs was an independent predictor of FFR−/iFR+ discordance among cases with FFR > 0.80; higher aortic Pxs was associated with lower iFR values and a greater likelihood of an abnormal iFR classification (OR: 1.230; 95% CI: 1.026–1.473; p = 0.025). In contrast, higher hAPV (OR: 1.187; 95% CI: 1.100–1.281; p < 0.001) and lower bAPV (OR: 0.751; 95% CI: 0.644–0.875; p < 0.001), which together reflect a higher CFR, were independent predictors of FFR+/iFR− discordance. Conclusions: Weaker proximal aortic reservoir function and higher aortic Pxs are associated with abnormal iFR in lesions with normal FFR, whereas higher CFR is associated with normal iFR in lesions with abnormal FFR. Systemic hemodynamics, including proximal aortic reservoir behavior, may provide additional mechanistic insight into altered coronary pressure hemodynamics and improve the pathophysiological understanding of FFR–iFR discordance that may affect revascularization decisions in chronic coronary syndromes.

Background: Clinical benefit of percutaneous coronary intervention (PCI) in chronic coronary syndromes (CCS) remains controversial. Coronary wave intensity analysis (WIA) provides mechanistic insights into cardiac–coronary coupling. Objectives: To assess peri-PCI WIA changes at rest and during hyperaemia, and to identify features associated with improvements in epicardial and microvascular resistance. Methods: Intracoronary Doppler and pressure measurements were analysed in 27 CCS patients undergoing elective PCI. Haemodynamics (fractional flow reserve (FFR), basal and hyperaemic stenosis resistance (bSR, hSR), coronary flow reserve (CFR), basal and hyperaemic microvascular resistance (bMR, hMR)) and WIA metrics (forward compression wave (FCW), backward compression wave (BCW), forward expansion wave (FEW), backward expansion wave (BEW), wave speed) were quantified at rest and hyperaemia. Results: PCI reduced bSR and hSR (p<0.001), increased FFR (0.58±0.18 to 0.87±0.09; p<0.001) and CFR (1.68±0.47 to 2.79±0.62; p<0.001), and lowered hMR (2.22 (1.67–3.10) to 1.49 (1.18–1.74); p<0.001). At rest, PCI increased FCW (40.3±48.9 to 89.3±64.8; p=0.022), FEW (24.5 (7.2–42.8) to 58.8 (24.0–93.1); p=0.001) and BEW (57.6±70.6 to 82.1±51.8; p=0.017). Hyperaemic backward wave peaks augmented significantly (BCW: 77.8±53.3 to 172.8±112.3; BEW: 60.5±47.5 to 126.7±66.2; both p<0.001). WIA time-to-peaks occurred earlier post-PCI. Reduced resting wave speed (41±21 to 25±10 m/s; p<0.001) correlated with hMR decreases (r=0.77; p<0.001). Increased resting BEW correlated with total vascular resistance reductions (hSR+hMR; r=−0.76; p<0.001). Conclusions: Elective PCI restores phasic cardiac–coronary coupling. Resting BEW and coronary wave speed provide complementary physiological endpoints reflecting microvascular and epicardial recovery, warranting larger prospective evaluation.

Currently, there is no established treatment for post-ischaemic reperfusion-related injury, namely reperfusion injury (RI), which paradoxically exacerbates microvascular and tissue damage in any reperfused ischaemic organ territory. During the ischaemic phase, the autoregulatory apparatus in a subtended organ region temporarily loses its pressure-regulating function because of the combined effects of drastically increased oxygen demand and ischaemic insult. Therefore, it cannot protect the hypoxically injured distal capillary bed from the detrimental effect of the sudden and uncontrolled pressure rise that occurs during the initial phase of reperfusion. This acute capillary barotrauma caused by abruptly initiated reperfusion at systemic pressure can be regarded as an iatrogenic trigger for subsequent damage in the reperfused organ territory. From this haemodynamic perspective, RI can be redefined as a ‘capillary hyperpressurization syndrome’, dictated by the ‘initial reperfusion pressure’. Accordingly, initiating reperfusion gently at lower pressures [pressure-controlled reperfusion (PCR)] and maintaining it at that level until protective autoregulatory myogenic control mechanisms recover may provide substantial benefit in limiting the progressive damage caused by post-ischaemic abrupt and full-pressure reperfusion. In this review, we revisit RI from this haemodynamic perspective and suggest that the same pathomechanism—namely, acute exposure of ischaemically injured microvascular endothelium to an uncontrolled pressure rise during the initial reperfusion phase—predominantly dictates post-reperfusion damage in the heart and in other organ ischaemia–reperfusion settings, where PCR techniques may help limit post-reperfusion damage.

Cerebral carbon dioxide (CO₂) vasoreactivity (CVR), defined as the dilatory capacity of cerebral vessels in response to CO₂, has pathophysiological importance and is clinically relevant. Reservoir-excess pressure analysis (REPA) of arterial blood pressure (ABP) waveforms, which estimates the pressure-buffering (reservoir) capacity of large arteries, provides contemporary insights beyond standard ABP measures by encompassing global arterial compliance and vascular tone. We examined the correlation between the systemic arterial reservoir behavior and CVR, as well as the coupling between peripheral and cerebrovascular hemodynamics. In 26 individuals, transcranial Doppler ultrasound (TCD) recordings of middle cerebral artery (MCA) flow velocity, simultaneous non-invasive ABP recordings and end-tidal CO₂ (etCO₂) were obtained at baseline and during intentional hyperventilation to lower CO₂. Reservoir-excess pressure parameters, including integral of reservoir pressure (IntPr) and diastolic rate constant (DRC) were extracted from ensemble-averaged ABP waveforms. CVR, defined as ΔMCA_V/ΔetCO2, and cerebrovascular resistance index (CVRi), defined as MAP/MCA_V, were calculated. Mean arterial pressure (MAP) was calculated as ABP averaged over the cardiac cycle. In participants in the below-mean CVR group, a lower DRC, reflecting slower diastolic decay, was associated with a higher CVRi (r = -0.445; p = 0.029). By contrast, in the above-mean CVR group, a lower DRC correlated with a lower CVRi (r = 0.807; p < 0.001), suggesting effective flow redistribution to support the brain when vasoreactivity is intact. REPA revealed subtle differences between the below- and above-mean CVR subgroups, despite comparable mean arterial, systolic, and diastolic blood pressures. The interplay between systemic arterial reservoir function and cerebral perfusion is modulated by the extent of CVR. When CVR is higher, increased peripheral vascular tone (reflected by a lower DRC) coincides with lower cerebrovascular resistance, which may contribute to effective redistribution of blood flow to preserve brain perfusion. In contrast, when vasoreactivity is lower, peripheral and cerebral vascular tone tend to rise in tandem, which may lead to reduced cerebral flow velocity and potentially compromised perfusion.

Revascularization decision for intermediate stenoses necessitates consideration of their hemodynamic impact. We report the use of distal coronary pressure (Pd) above proximal aortic pressure (Pa) during the early expansion period as a visual dichotomous marker (negative expansion resistance, NER) for rapid clinical decision-making. Simultaneous pressure and velocity signals were used to calculate instantaneous wave-free ratio (iFR), fractional flow reserve (FFR), hyperemic stenosis resistance (hSR), and to identify the NER. NER was defined as the Pd > Pa during the early-expansion period, which refers to early-decompression of coronary circulation marked by pressure decay (dP/dt < 0) coinciding the time-window of reduced ejection phase of systole to early diastole. Classification performance of NER was evaluated against iFR, FFR and hSR. Out of 475 lesions with mean diameter stenosis of 61% ± 16% from 388 patients with chronic coronary syndrome (CCS), 46%(217/475) exhibited the NER-phenomenon. Of these, 96% (209/217) had an iFR above 0.89(NPV = 0.96[95%CI 93–98] PPV = 0.47[95%CI 41–54]) indicating hemodynamically non-significant lesions. 94%(204/217) of the NER( +) lesions had an hSR below 0.80(NPV = 0.94 [95%CI 90–97] PPV = 0.36[95%CI 30–42]), and 88%(191/217) had an FFR above 0.80 (NPV = 0.88[95%CI 83–92] PPV = 0.53[95%CI 46–59]), indicating non-flow limiting lesions. Of 8 lesions with NER despite an abnormal iFR, only 1 had abnormal hSR, whereas 7 had normal hSR. Of 162 lesions with abnormal FFR, iFR identified 53 (33%) as ‘normal’ whereas NER was present in 26 (16%) of these cases.NER was associated with instantaneously stronger coronary decompression wave(8.0 ± 11.2 vs 5.5 ± 10.1 10.kW.m-2.s^-2 p:0.016) and higher flow acceleration(195 ± 204 vs 106 ± 182 cm.s^-2 p < 0.001). In conclusion, the NER, visually recognized by resting pressure tracings, rules out flow-limiting lesions in CCS with high certainty, offering a simple first-line evaluation for clinical decision-making, and warrants prospective clinical studies.