Intracoronary electrocardiogram detects coronary microvascular dysfunction and ischemia in patients with no obstructive coronary arteries disease.

BACKGROUND: Coronary microvascular dysfunction (CMD) is the leading cause of ischemia with no obstructive coronary arteries disease (INOCA) disease. Diagnosis of CMD relies on surrogate physiological indices without objective proof of ischemia. OBJECTIVES: Intracoronary electrocardiogram (icECG) derived hyperemic indices may accurately and objectively detect CMD and reversible ischemia in related territory. METHODS: INOCA patients with proven ischemia by myocardial perfusion scan (MPS) and completely normal coronary arteries underwent simultaneous intracoronary electrophysiological (icECG) and physiological (intracoronary Doppler) assessment in all 3 coronary arteries during rest and under adenosine induced hyperemia. RESULTS: Sixty vessels in 21 patients were included in the final analysis. All patients had at least one vessel with abnormal CFR. 41 vessels had CMD (CFR < 2.5), of which 26 had increased microvascular resistance (structural CMD, HMR > 1.9 mmHg.cm-1.s) and 15 vessels had CMD (CFR < 2.5) with normal microvascular resistance (functional CMD, HMR <= 1.9 mmHg.cm-1.s). Only one-third of the patients (n = 7) had impaired CFR < 2.5 in all 3 epicardial arteries. Absolute ST shift between hyperemia and rest (∆ST) has shown the best diagnostic performance for ischemia (cut-off 0.10 mV, sensitivity: 95%, specificity: 72%, accuracy: 80%, AUC: 0.860) outperforming physiological indices (CFR: 0.623 and HMR: 0.653 DeLong's test P = .0002). CONCLUSIONS: In INOCA patients, CMD involves coronary artery territories heterogeneously. icECG can accurately detect CMD causing perfusion abnormalities in patients with INOCA outperforming physiological CMD markers, by demonstrating actual ischemia instead of predicting the likelihood of inducible ischemia based on violated surrogate thresholds of blunted flow reserve or increased minimum microvascular resistance. CONDENSED ABSTRACT: In 21 INOCA patients with coronary microvascular dysfunction (CMD) and myocardial perfusion scan proved ischemia, hyperemic indices of intracoronary electrocardiogram (icECG) have accurately detected vessel-specific CMD and resulting perfusion abnormalities & ischemia, outperforming invasive hemodynamic indices. Absolute ST shift between hyperemia and rest (∆ST) has shown the best classification performance for ischemia in no Obstructive Coronary Arteries (AUC: 0.860) outperforming Doppler derived CMD indices (CFR: 0.623 and HMR: 0.653 DeLong's test P = .0002).icECG can be used to diagnose CMD causing perfusion defects by demonstrating actual reversible ischemia at vessel-level during the initial CAG session, obviating the need for further costly ischemia tests. CLINICALTRIALS: GOV: NCT05471739.

A novel method that can be used in both the diagnosis and treatment of peripheral arterial disease in diabetics: vibration-mediated dilation.

OBJECTIVE: The growing incidence of diabetes and the increasing life expectancy of the diabetic population worldwide has increased the number of diabetic vascular complications occurring in cardiology practice. As current treatment and prevention methods are less effective in this patient group, there is a need for new treatment methods in this area. Exercise, which reduces metabolic and vascular problems associated with diabetes, often becomes impossible, especially in advanced-stage patients who need exercise the most. Since exercise and flow-mediated dilation (FMD) are effective by stimulating mechanotransduction mechanisms on the endothelium, it can be expected that the same mechanisms could also be stimulated by direct vibration. METHODS: In order to test this hypothesis, in this study, a group of 20 type 2 diabetes patients (11 males, age 56.80 ± 11.05 years and diagnosed for 15.35 ± 8.61 years) were examined via the application of FMD and vibration-mediated dilation (VMD). We performed vibration for five minutes with 20-Hz frequency and 3-mm vertical amplitude, to the same side forearm, with a 30-minute interval. Using a 10-MHz linear echo probe, brachial artery diameter and flow velocities were recorded for 10 minutes before and at two-minute intervals after the FMD and VMD applications. Then brachial artery flow and resistance were calculated at each stage. RESULTS: In the first minute after FMD and VMD applications, brachial artery diameter and flow velocities increased significantly, and vascular resistance decreased significantly. None of the corresponding FMD or VMD parameters in the first minute was different. The artery diameters in the first minute after FMD and VMD were increased by 6.04 ± 5.29 and 5.49 ± 5.21%, respectively. At the tenth minute, these values decreased to 1.73 ± 3.21 and 2.05 ± 3.31%. In the FMD series, all parameters except brachial artery diameter returned to their baseline values after the fourth minute. After VMD, all parameters also decreased after the first minute, but the recovery was much slower. At each stage after the first minute, the VMD averages were higher than the baseline value and their corresponding FMD values. CONCLUSION: The results of this study indicated that vibration may be a powerful, long-lasting and feasible treatment option in patients with peripheral perfusion failure, developed due to diabetic macro- and microvascular complications.

Primary versus iatrogenic (post-PCI) coronary microvascular dysfunction: a wire-based multimodal comparison.

BACKGROUND: Although there are studies examining each one separately, there are no data in the literature comparing the magnitudes of the iatrogenic, percutaneous coronary intervention (PCI)-induced, microvascular dysfunction (Type-4 CMD) and coronary microvascular dysfunction (CMD) in the setting of ischaemia in non-obstructed coronary arteries (INOCA) (Type-1 CMD). OBJECTIVES: We aimed to compare the characteristics of Type-1 and Type-4 CMD subtypes using coronary haemodynamic (resistance and flow-related parameters), thermodynamic (wave energy-related parameters) and hyperemic ECG changes. METHODS: Coronary flow reserve (CFR) value of <2.5 was defined as CMD in both groups. Wire-based multimodal perfusion markers were comparatively analysed in 35 patients (21 INOCA/CMD and 14 CCS/PCI) enrolled in NCT05471739 study. RESULTS: Both groups had comparably blunted CFR values per definition (2.03±0.22 vs 2.11±0.37; p: 0.518) and similar hyperemic ST shift in intracoronary ECG (0.16±0.09 vs 0.18±0.07 mV; p: 0.537). While the Type-1 CMD was characterised with impaired hyperemic blood flow acceleration (46.52+12.83 vs 68.20+28.63 cm/s; p: 0.017) and attenuated diastolic microvascular decompression wave magnitudes (p=0.042) with higher hyperemic microvascular resistance (p<0.001), Type-4 CMD had blunted CFR mainly due to higher baseline flow velocity due to post-occlusive reactive hyperemia (33.6±13.7 vs 22.24±5.3 cm/s; p=0.003). CONCLUSIONS: The perturbations in the microvascular milieu seen in CMD in INOCA setting (Type-1 CMD) seem to be more prominent than that of seen following elective PCI (Type-4 CMD), although resulting reversible ischaemia is equally severe in the downstream myocardium.

Coronary microcirculation in nonculprit vessel territory in reperfused acute myocardial infarction.

BACKGROUND: There is an ongoing debate on the extension of reperfusion-related microvascular damage (MVD) throughout the remote noninfarcted myocardial regions in patients with ST-elevation myocardial infarction (STEMI) that undergo primary percutaneous intervention (pPCI). The aim of this study was to elucidate the impact of reperfusion on remote microcirculatory territory by analyzing hemodynamic alterations in the nonculprit-vessel in relation to reperfusion. METHODS: A total of 20 patients with STEMI undergoing pPCI were included. Peri-reperfusion temporal changes in hemodynamic parameters were obtained in angiographically normal nonculprit vessels before and 1-h after reopening of the culprit vessel. Intracoronary pressure and flow velocity data were compared using pairwise analyses (before and 1-h after reperfusion). RESULTS: In the non-culprit vessel, compared to the pre-reperfusion state, mean resting average peak velocity (33.4 ± 9.4 to 25.0 ± 4.9 cm/s, P < 0.001) and mean hyperemic average peak velocity (53.5 ± 14.4 to 42.1 ± 10.66 cm/s, P = 0.001) significantly decreased; whereas baseline (3.2 ± 1.0 to 4.0 ± 1.0 mmHg.cm-1.s, P < 0.001) and hyperemic microvascular resistance (HMR) (1.9 ± 0.6 to 2.4 ± 0.7 mmHg.cm-1.s, P < 0.001) and mean zero flow pressure (Pzf) values (32.5 ± 6.9 to 37.6 ± 8.3 mmHg, P = 0.003) significantly increased 1-h after reperfusion. In particular, the magnitude of changes in HMR and Pzf values following reperfusion were more prominent in patients with larger infarct size and with higher extent of MVD in the culprit vessel territory. CONCLUSION: Reperfusion-related microvascular injury extends to involve remote myocardial territory in relation to the magnitude of the adjacent infarction and infarct-zone MVD. (GUARD Clinical TrialsNCT02732080).

Gradual Versus Abrupt Reperfusion During Primary Percutaneous Coronary Interventions in ST-Segment-Elevation Myocardial Infarction (GUARD).

Background Intramyocardial edema and hemorrhage are key pathological mechanisms in the development of reperfusion-related microvascular damage in ST-segment-elevation myocardial infarction. These processes may be facilitated by abrupt restoration of intracoronary pressure and flow triggered by primary percutaneous coronary intervention. We investigated whether pressure-controlled reperfusion via gradual reopening of the infarct-related artery may limit microvascular injury in patients undergoing primary percutaneous coronary intervention. Methods and Results A total of 83 patients with ST-segment-elevation myocardial infarction were assessed for eligibility and 53 who did not meet inclusion criteria were excluded. The remaining 30 patients with totally occluded infarct-related artery were randomized to the pressure-controlled reperfusion with delayed stenting (PCRDS) group (n=15) or standard primary percutaneous coronary intervention with immediate stenting (IS) group (n=15) (intention-to-treat population). Data from 5 patients in each arm were unsuitable to be included in the final analysis. Finally, 20 patients undergoing primary percutaneous coronary intervention who were randomly assigned to either IS (n=10) or PCRDS (n=10) were included. In the PCRDS arm, a 1.5-mm balloon was used to achieve initial reperfusion with thrombolysis in myocardial infarction grade 3 flow and, subsequently, to control distal intracoronary pressure over a 30-minute monitoring period (MP) until stenting was performed. In both study groups, continuous assessment of coronary hemodynamics with intracoronary pressure and Doppler flow velocity was performed, with a final measurement of zero flow pressure (primary end point of the study) at the end of a 60-minute MP. There were no complications associated with IS or PCRDS. PCRDS effectively led to lower distal intracoronary pressures than IS over 30 minutes after reperfusion (71.2±9.37 mm Hg versus 90.13±12.09 mm Hg, P=0.001). Significant differences were noted between study arms in the microcirculatory response over MP. Microvascular perfusion progressively deteriorated in the IS group and at the end of MP, and hyperemic microvascular resistance was significantly higher in the IS arm as compared with the PCDRS arm (2.83±0.56 mm Hg.s.cm-1 versus 1.83±0.53 mm Hg.s.cm-1, P=0.001). The primary end point (zero flow pressure) was significantly lower in the PCRDS group than in the IS group (41.46±17.85 mm Hg versus 76.87±21.34 mm Hg, P=0.001). In the whole study group (n=20), reperfusion pressures measured at predefined stages in the early reperfusion period showed robust associations with zero flow pressure values measured at the end of the 1-hour MP (immediately after reperfusion: r=0.782, P<0.001; at the 10th minute: r=0.796, P<0.001; and at the 20th minute: r=0.702, P=0.001) and peak creatine kinase MB level (immediately after reperfusion: r=0.653, P=0.002; at the 10th minute: r=0.597, P=0.007; and at the 20th minute: r=0.538, P=0.017). Enzymatic myocardial infarction size was lower in the PCRDS group than in the IS group with peak troponin T (5395±2991 ng/mL versus 8874±1927 ng/mL, P=0.006) and creatine kinase MB (163.6±93.4 IU/L versus 542.2±227.4 IU/L, P<0.001). Conclusions In patients with ST-segment-elevation myocardial infarction, pressure-controlled reperfusion of the culprit vessel by means of gradual reopening of the occluded infarct-related artery (PCRDS) led to better-preserved coronary microvascular integrity and smaller myocardial infarction size, without an increase in procedural complications, compared with IS. Registration URL: https://www.clinicaltrials.gov; Unique identifier: NCT02732080.

Artificial intelligence-derived cardiac ageing is associated with cardiac events post-heart transplantation.

Aims: An artificial intelligence algorithm detecting age from 12-lead electrocardiogram (ECG) has been suggested to reflect 'physiological age'. An increased physiological age has been associated with a higher risk of cardiac mortality in the non-transplant population. We aimed to investigate the utility of this algorithm in patients who underwent heart transplantation (HTx). Methods and results: A total of 540 patients were studied. The average ECG ages within 1 year before and after HTx were used to represent pre- and post-HTx ECG ages. Major adverse cardiovascular event (MACE) was defined as any coronary revascularization, heart failure hospitalization, re-transplantation, and mortality. Recipient pre-transplant ECG age (mean 63 ± 11 years) correlated significantly with recipient chronological age (mean 49 ± 14 years, R = 0.63, P < 0.0001), while post-transplant ECG age (mean 54 ± 10 years) correlated with both the donor (mean 32 ± 13 years, R = 0.45, P < 0.0001) and the recipient ages (R = 0.38, P < 0.0001). During a median follow-up of 8.8 years, 307 patients experienced MACE. Patients with an increase in ECG age post-transplant showed an increased risk of MACE [hazard ratio (HR): 1.58, 95% confidence interval (CI): (1.24, 2.01), P = 0.0002], even after adjusting for potential confounders [HR: 1.58, 95% CI: (1.19, 2.10), P = 0.002]. Conclusion: Electrocardiogram age-derived cardiac ageing after transplantation is associated with a higher risk of MACE. This study suggests that physiological age change of the heart might be an important determinant of MACE risk post-HTx.

FcεR1-expressing nociceptors trigger allergic airway inflammation.

BACKGROUND: Lung nociceptor neurons amplify immune cell activity and mucus metaplasia in response to an inhaled allergen challenge in sensitized mice. OBJECTIVE: We sought to identify the cellular mechanisms by which these sensory neurons are activated subsequent to allergen exposure. METHODS: We used calcium microscopy and electrophysiologic recording to assess whether vagal neurons directly respond to the model allergen ovalbumin (OVA). Next, we generated the first nociceptor-specific FcεR1γ knockdown (TRPV1Cre::FcεR1γfl/fl) mice to assess whether this targeted invalidation would affect the severity of allergic inflammation in response to allergen challenges. RESULTS: Lung-innervating jugular nodose complex ganglion neurons express the high-affinity IgE receptor FcεR1, the levels of which increase in OVA-sensitized mice. FcεR1γ-expressing vagal nociceptor neurons respond directly to OVA complexed with IgE with depolarization, action potential firing, calcium influx, and neuropeptide release. Activation of vagal neurons by IgE-allergen immune complexes, through the release of substance P from their peripheral terminals, directly amplifies TH2 cell influx and polarization in the airways. Allergic airway inflammation is decreased in TRPV1Cre::FcεR1γfl/fl mice and in FcεR1α-/- mice into which bone marrow has been transplanted. Finally, increased in vivo circulating levels of IgE following allergen sensitization enhances the responsiveness of FcεR1 to immune complexes in both mouse jugular nodose complex ganglion neurons and human induced pluripotent stem cell-derived nociceptors. CONCLUSIONS: Allergen sensitization triggers a feedforward inflammatory loop between IgE-producing plasma cells, FcεR1-expressing vagal sensory neurons, and TH2 cells, which helps to both initiate and amplify allergic airway inflammation. These data highlight a novel target for reducing allergy, namely, FcεR1γ expressed by nociceptors.

The Interplay between Features of Plaque Vulnerability and Hemodynamic Relevance of Coronary Artery Stenoses.

Fractional flow reserve (FFR) may not be immune from hemodynamic perturbations caused by both vessel and lesion related factors. The aim of this study was to investigate the impact of plaque- and vessel wall-related features of vulnerability on the hemodynamic effect of intermediate coronary stenoses. Methods and Results: In this cross-sectional study, patients referred to catheterization laboratory for clinically indicated coronary angiography were prospectively screened for angiographically intermediate stenosis (50-80%). Seventy lesions from 60 patients were evaluated. Mean angiographic stenosis was 62.1 ± 16.3%. After having performed FFR assessment, intravascular ultrasound (IVUS) was performed over the FFR wire. Virtual histology IVUS was used to identify the plaque components and thin cap fibroatheroma (TCFA). TCFA was significantly more frequent (65 vs. 38%, p = 0.026), and necrotic core volume (26.15 ± 14.22 vs. 16.21 ± 8.93 mm3, p = 0.04) was significantly larger in the positively remodeled than non-remodeled vessels. Remodeling index correlated with necrotic core volume (r = 0.396, p = 0.001) and with FFR (r = -0. 419, p = 0.001). With respect to plaque components, only necrotic core area (r = -0.262, p = 0.038) and necrotic core volume (r = -0.272, p = 0.024) were independently associated with FFR. In the multivariable model, presence of TCFA was independently associated with significantly lower mean FFR value as compared to absence of TCFA (adjusted, 0.71 vs. 0.78, p = 0.034). Conclusion: The current study demonstrated that for a given stenosis geometry, features of plaque vulnerability such as necrotic core volume, TCFA, and positive remodeling may influence the hemodynamic relevance of intermediate coronary stenoses.

Reducing Aortic Barotrauma and Vascular Extracellular Matrix Degradation by Pacemaker-Mediated QRS Widening.

Background The extent of pressure-related damage might be related to acceleration rate of the applied pressure (peak dP/dt) in the vascular system. In this study, we sought to determine whether dP/dt applied to the aortic wall (aortic dP/dt) and in turn vascular extracellular matrix degradation can be mitigated via modulation of left ventricular (LV) contractility (LV dP/dt) by pacemaker-mediated desynchronization. Methods and Results First, in 34 patients, changes in aortic dP/dt values in 3 aortic segments in response to pacemaker-mediated stepwise QRS widening leading to gradual desynchronization of the LV contraction by means of steadily changed atrioventricular delay (AVD) with temporary dual-chamber pacing was examined before and after beta-blocker (15 mg IV metoprolol) administration. Second, serum matrix metalloproteinase-9 levels were measured in the 20 patients with permanent pacemaker while they were on sinus rhythm with normal QRS width and 3 weeks after wide QRS rhythm ensured by dual pacing, dual sensing, and dual response to sensing with short AVD. LV dP/dt substantially correlated with dP/dt measured in ascending (r=0.83), descending (r=0.89), and abdominal aorta (r=0.96). QRS width strongly correlated with dP/dt measured in ascending (r=-0.95), descending (r=-0.92), and abdominal (r=-0.96) aortic segments as well. In patients with permanent pacemaker, wide QRS rhythm led to a significant reduction in serum matrix metalloproteinase-9 levels (from 142.5±32.9 pg/mL to 87.5±32.4 pg/mL [P<0.001]) at the end of 3 weeks follow-up. Conclusions QRS prolongation by short AVD dual pacing, dual sensing, and dual response to sensing results in concomitant decreases in peak dP/dt values in the LV and in all aortic segments with or without background beta-blocker administration, which in turn led to a significant reduction in circulating matrix metalloproteinase-9 levels. Registration URL: https://www.clini​caltr​ials.gov; Unique identifier: NCT03665558.