Coronary Endothelium‐Dependent Vasomotor Function After Drug‐Eluting Stent and Bioresorbable Scaffold Implantation

Background Early generation drug‐eluting stents (DESs) showed a high grade of coronary endothelial dysfunction that was attributed to lack of stent reendothelialization. Endothelium‐dependent vasomotor response of current DESs and bioresorbable scaffolds (BRSs) remains unknown. This study sought to assess the device‐related endothelial function of current devices and to correlate neointima healing with endothelial function. Methods and Results A total of 206 patients from 4 randomized trials treated with the durable‐polymer everolimus‐eluting Xience (n=44), bioresorbable‐polymer sirolimus‐eluting Orsiro (n=35), polymer‐free biolimus‐eluting Biofreedom (n=24), bioactive endothelial‐progenitor cell‐capturing sirolimus‐eluting Combo DES (n=25), polymer‐based everolimus‐eluting Absorb (n=44), and Mg‐based sirolimus‐eluting Magmaris BRS (n=34) underwent endothelium‐dependent vasomotor tests and optical coherence tomography imaging, as per protocol, at follow‐up. Crude vasomotor responses of distal segments to low‐dose acetylcholine (10 −6 mol/L) were different between groups: bioresorbablepolymer DEShad the worst (−8.4%±12.6%) and durable‐polymer DES had the most physiologic (−0.4%±11.8%; P =0.014). High‐dose acetylcholine (10 −4 mol/L) showed similar responses between groups (ranging from −10.8%±11.6% to −18.1%±15.4%; P =0.229). Device healing was different between devices. Uncovered struts ranged from 6.3%±7.1% (bioresorbable‐polymer DES) to 2.5%±4.5% (bioactive DES; P =0.056). In multivariate models, endothelium‐dependent vasomotor response was associated with age, bioresorbable‐polymer DES, and angiographic lumen loss, but not with strut coverage nor plaque type. Endothelial dysfunction (defined as ≥4% vasoconstriction) was observed in 46.6% of patients with low‐dose and 68.9% with high‐dose acetylcholine, without differences between groups. Conclusions At follow‐up, endothelial dysfunction was frequently observed in distal segments treated with current stents without remarkable differences between devices. Although neointima healing was different between devices, poor healing was not associated with endothelial dysfunction.

Sex-dependent impact of coronary microvascular dysfunction on long-term clinical outcomes in patients with no-obstructive coronary artery disease

Background Coronary vasomotor response is different between males and females. However, the prognostic impact of this difference in coronary physiologic indices has not been characterized in patients with no obstructive coronary artery disease (NOCAD). Purpose We aimed to investigate the sex-specific differences of coronary vasomotor function in response to adenosine in a large cohort of patients with NOCAD and its impact on long-term clinical outcomes Methods We included 668 NOCAD patients who underwent invasive coronary vasoreactivity testing using intracoronary incremental doses of adenosine (18–72 μg) with available follow-up data. Indices of coronary vasomotor response were compared between males and females, and their prognostic impact on major adverse cardiovascular events (MACE: death, myocardial infarction, revascularization, and stroke) were analyzed based on sex. Results Females (N=461, mean age 54±12 years) had lower baseline microvascular resistance (BMR) and higher baseline average peak velocity (APV) than males (N=207, mean age 53±13 years), while hyperemic microvascular resistance (HMR) and hyperemic APV were similar between males and females. Consequently, coronary flow reserve (CFR: hyperemic/baseline APV) and resistive reserve ratio (RRR: BMR/HMR) were lower in females than males (Figure 1A). Lower CFR and RRR, as well as lower BMR and higher baseline APV were associated with MACE only in males, but not in females. Higher HMR was the only predictor for MACE in females (Figure 1B). Conclusions Sex-specific differences in coronary vasomotor response to adenosine may provide different prognostic values between males and females. FUNDunding Acknowledgement Type of funding sources: None.

P2Y11 Agonism Prevents Hypoxia/Reoxygenation- and Angiotensin II-Induced Vascular Dysfunction and Intimal Hyperplasia Development

Vascular dysfunction in cardiovascular diseases includes vasomotor response impairments, endothelial cells (ECs) activation, and smooth muscle cells (SMCs) proliferation and migration to the intima. This results in intimal hyperplasia and vessel failure. We previously reported that activation of the P2Y11 receptor (P2Y11R) in human dendritic cells, cardiofibroblasts and cardiomyocytes was protective against hypoxia/reoxygenation (HR) lesions. In this study, we investigated the role of P2Y11R signaling in vascular dysfunction. P2Y11R activity was modulated using its pharmacological agonist NF546 and antagonist NF340. Rat aortic rings were exposed to angiotensin II (AngII) and evaluated for their vasomotor response. The P2Y11R agonist NF546 reduced AngII-induced vascular dysfunction by promoting EC-dependent vasorelaxation, through an increased nitric oxide (NO) bioavailability and reduced AngII-induced H2O2 release; these effects were prevented by the use of the P2Y11R antagonist NF340. Human vascular SMCs and ECs were subjected to AngII or H/R simulation in vitro. P2Y11R agonist modulated vasoactive factors in human ECs, that is, endothelial nitric oxide synthase (eNOS) and endothelin-1, reduced SMC proliferation and prevented the switch towards a synthetic phenotype. H/R and AngII increased ECs secretome-induced SMC proliferation, an effect prevented by P2Y11R activation. Thus, our data suggest that P2Y11R activation may protect blood vessels from HR-/AngII-induced injury and reduce vascular dysfunctions. These results open the way for new vasculoprotective interventions.

Conceptualizing conduction as a pliant vasomotor response: impact of Ca2+ fluxes and Ca2+ sensitization

Conducted vasomotor responses depend on electrical spread in the vascular wall and its translation into vasomotor responses. Our computational investigation highlights how the regulatory state of the contractile apparatus can shape conduction without interfering with the underlying electrical spread. Contractile machinery is regulated, e.g., by regional endocrine or mechanical signals. We further illustrate how regional contractile regulation can work cooperatively with electrical spread to optimize perfusion to local tissue demands.

70Autonomic dysfunction in atrial fibrillation (AF) patients: absent vasomotor reflex to decreased cardiac venous return during af in comparison to sinus rhythm; implications for earlier rhythm control

Funding Acknowledgements Dr Malik is supported by an Australian Postgraduate Award Scholarship from the University of Adelaide. OnBehalf Centre for Heart Rhythm Disorders, University of Adelaide & Royal Adelaide Hospital Background A bi-directional relationship exists between AF and the autonomic nervous system (ANS). Patients with AF studied in sinus rhythm (SR) have impaired vasomotor responses to decreased cardiac volume. Whether autonomic dysfunction worsens during AF itself, is unknown. Purpose We examined haemodynamic responses to lower body negative pressure (LBNP) in patients with persistent AF compared to AF studied in SR. LBNP decreases cardiac volume, deactivates atrial stretch receptors and induces a reflex to maintain blood pressure by increasing systemic vascular resistance (SVR). Methods 21 consecutive patients with paroxysmal or persistent AF were studied; during AF (n = 8) or SR (n = 13). Anti-arrhythmic and anti-hypertensives were withheld for 5 half-lives. Patients underwent LBNP using a custom-made chamber sealing both lower limbs. Negative pressure at sham (-0 mmHg), low (-20 mmHg) and high level (-40 mmHg) was applied for 5 minutes each. Finger photo plethysmography was used for beat-beat-blood pressure. Computation of SVR during AF is not feasible with this method. Therefore, the right forearm was used to perform venous occlusion plethysmography (VOP); non-invasive, well validated with LBNP and impervious to AF: to estimate forearm blood flow (FBF) and SVR (inversely proportional). Results Baseline characteristics and responses to LBNP are presented in Table 1. MAP was maintained, and HR rose slightly, in the SR group. MAP and HR decreased in the AF group. VOP demonstrates a reduction in FBF in the SR group (vasoconstriction); whereas the vasomotor response to LBNP was absent during AF. Figure 1 (Panels A-C). Conclusion The presence of AF is associated with autonomic dysfunction from impaired cardiac volume regulation. This novel finding may contribute to the known risk of falls and syncope due to AF. Further studies are needed to evaluate whether abnormal cardiac reflexes are involved in atrial remodelling and AF progression. Table 1 Baseline Characteristics During AF During SR P Value Age 65 ± 5 59 ± 3 0.4 AAD & Anti-HTN medications withheld (%) 75 85 0.6 Resting mean arterial pressure (MAP) 109 ± 9 93 ± 6 0.1 Resting heart rate (HR) 94 ± 6 60 ± 4 0.0001* Haemodynamic response to LBNP % Δ MAP due to LBNP -9 ± 5 +0.5 ± 3 0.2 % Δ HR due to LBNP -6 ± 3 +5 ± 3 0.03* % Δ FBF due to LBNP +75 ± 59 -27 ± 8 0.02* AAD Anti-arrhthmic. HTN: Hypertension. Mean +/- SEM. Abstract Figure. Vasomotor response to LBNP: in AF vs SR

Contactless Monitoring of Microcirculation Reaction on Local Temperature Changes

Assessment of skin blood flow is an important clinical task which is required to study mechanisms of microcirculation regulation including thermoregulation. Contactless assessment of vasomotor reactivity in response to thermal exposure is currently not available. The aim of this study is to show the applicability of the imaging photoplethysmography (IPPG) method to measure quantitatively the vasomotor response to local thermal exposure. Seventeen healthy subjects aged 23 ± 7 years participated in the study. A warm transparent compress applied to subject’s forehead served as a thermal impact. A custom-made IPPG system operating at green polarized light was used to monitor the subject’s face continuously and simultaneously with skin temperature and electrocardiogram (ECG) recordings. We found that the thermal impact leads to an increase in the amplitude of blood pulsations (BPA) simultaneously with the skin temperature increase. However, a multiple increase in BPA remained after the compress was removed, whereas the skin temperature returned to the baseline. Moreover, the BPA increase and duration of the vasomotor response was associated with the degree of external heating. Therefore, the IPPG method allows us to quantify the parameters of capillary blood flow during local thermal exposure to the skin. This proposed technique of assessing the thermal reactivity of microcirculation can be applied for both clinical use and for biomedical research.

Dynamic connectivity maps of pericytes and endothelial cells mediate neurovascular coupling in health and disease

SummaryFunctional hyperemia, or matching blood flow to activity, is spatially accurate to direct the oxygen and nutrients to regionally firing neurons. The underlying signaling mechanisms of neurovascular coupling remain unclear, but are critical for brain function and establish the diagnostic power of BOLD-fMRI. Here, we described a mosaic of pericytes, the vasomotor capillary cells in the living retina. We then tested if this symmetric net of pericytes and surrounding neuroglia predicted a connectivity map in response to sensory stimuli. Surprisingly, we found that these connections were not only discriminatory across cell types, but also highly asymmetric spatially. First, pericytes connected predominantly to other neighboring pericytes and endothelial cells, and less to arteriolar smooth muscle cells, and not to surrounding neurons or glia. Second, focal, but not global stimulation evoked a directional vasomotor response by strengthening connections along the feeding vascular branch. This activity required local NO signaling and occurred by means of direct coupling via gap-junctions. By contrast, bath application of NO or diabetes, a common microvascular pathology, not only weakened the vascular signaling but also abolished its directionality. We conclude that the discriminatory nature of neurovascular interactions may thus establish spatial accuracy of blood delivery with the precision of the neuronal receptive field size, and is disrupted early in microvascular disease.HighlightsWithin a structurally symmetric mosaic, pericytes form discriminatory connectionsPericyte connectome tunes with a precision matching a neuronal receptive fieldFocal but not global input evokes a vasomotor response by strengthening the gap-junction mediated signaling towards a feeding vascular branchDisrupted functional connectivity map triggers loss of the functional hyperemia in diabetic neuropathy