Regulation Of Coronary Flow Research Articles

Cycling coupled to intra-coronary thermodilution to evaluate angina with non-obstructive coronary artery disease

Abstract BACKGOUND Patients with Angina and Non-Obstructive Coronary Artery disease (ANOCA) face misdiagnosis and inadequate treatment. A new continuous thermodilution method enables assessment of absolute coronary blood flow (Q) and microvascular resistance (Rµ). The effectiveness of saline-induced hyperemia in capturing exercise-induced coronary flow regulation remains unknown. OBJECTIVE To describe Q and Rµ adaptation during exercise and to explore the correlation between Coronary Flow Reserve (CFR) derived from saline and exercise-induced hyperemia, as well as Microvascular Resistance Reserve (MRR). Methods Q, Rµ, CFR and MRR were first assessed using continuous thermodilution with saline infusion at 10 mL/min (rest) and 20 mL/min (hyperemia) in the left anterior descending artery, followed by subsequent stress testing using a dedicated supine cycling ergometer. The microvascular parameters were assessed during incremental workload of 30 watts every two minutes. CFRsaline<2.5 was considered the cutoff for coronary microvascular dysfunction. A minimal sample size of 29 participants was required to detect a hypothesized Spearman coefficient correlation r=0.5 between CFRsaline and CFRexercise using a 80% power and 5% significance level test. Results Coronary microvascular dysfunction was observed in 53.3% of the participants with suspected ANOCA (16 out of 30). During cycling, participants with coronary microvascular dysfunction had a lower reduction in Rµ (-109 [32; 286] versus -202 [102; 379] WU per 30 watts, p<0.01) and a lower ability to increase coronary flow (7 [30.5; 103.0] versus 21 [5.8; 45.0] mL/min per 30 watts, p=0.01) compared with those without coronary microvascular dysfunction. In the overall population, average CFRsaline and CFRexercise were 2.70±0.90 and 2.85±1.54, respectively (p=0.46) with an agreement classification of 83.3%. A good correlation between the two techniques was observed for both CFR (Spearman coefficient r=0.73, p<0.0001) and MRR (r=0.76, p<0.0001). Monitoring of CFR and Rµ during exercise unmasked functional coronary microvascular dysfunction priorly labeled as normal by saline induced hyperemia in 13.3% of the study population. These individuals had a moderate and late decrease of Rµ during the early stages of exercise, with a plateau up to 75% of their theoretical workload. Conclusion Participants with coronary microvascular dysfunction demonstrated compromised CFR due to impaired reduction of Rµ during physical workload. Saline-induced hyperemia provided a valid surrogate for exercise physiology independently of the absolute level of CFR and MRR, although exercise provided more granularity to evaluate hemodynamic adaptation among participants with functional dysfunction.

Changes in absolute coronary flow and microvascular resistance during exercise in patients with ANOCA.

Whether saline-induced hyperaemia captures exercise-induced coronary flow regulation remains unknown. Through this study, we aimed to describe absolute coronary flow (Q) and microvascular resistance (Rμ) adaptation during exercise in participants with angina with non-obstructive coronary artery disease (ANOCA) and to explore the correlations between saline- and exercise-derived coronary flow reserve (CFR) and microvascular resistance reserve (MRR). Rμ, Q, CFR and MRR were assessed in the left anterior descending artery using continuous thermodilution with saline infusion at 10 mL/min (rest), 20 mL/min (hyperaemia) and finally at a 10 mL/min infusion rate during stress testing with a dedicated supine cycling ergometer. An incremental workload of 30 watts every two minutes was applied. A saline-derived CFR (CFRsaline) cutoff <2.5 was used to identify coronary microvascular dysfunction (CMD). CFRsaline-defined CMD was observed in 53.3% of the participants (16/30). While cycling, these patients less of an ability to increase Q (7 [interquartile range [IQR] 30.5-103.0] vs 21 [IQR 5.8-45.0] mL/min/30 watts; p=0.01) due to a smaller decrease of Rμ (109 {IQR 32-286} vs 202 [IQR 102-379] Wood units [WU]/30 watts; p<0.01) as compared with the group with normal CFRsaline. In the overall population, CFRsaline and exercise-derived CFR (CFRexercise) were 2.70±0.90 and 2.85±1.54, respectively, with an agreement classification of 83.3%. A good correlation between saline and exercise techniques for both CFR (r=0.73; p<0.0001) and MRR (r=0.76; p<0.0001) was observed. Among participants with normal CFRsaline, 28.7% (4/14) had an impaired CFRexercise <2.5 at the peak of exercise due to a moderate and late decrease of Rμ. Saline-induced hyperaemia provided a valid surrogate for exercise physiology independently of the absolute level of CFR and MRR, although exercise provided more granularity to evaluate adaptation among participants with exercise-related CMD.

Reduction of left ventricular diastolic pressure as a key regulator of infarct coronary flow under mechanical left ventricular support.

Restoring ischaemic myocardial tissue perfusion is crucial for minimizing infarct size. Acute mechanical left ventricular (LV) support has been suggested to improve infarct tissue perfusion. However, its regulatory mechanism remains unclear. We investigated the physiological mechanisms in six Yorkshire pigs, which were subjected to 90-min balloon occlusion of the left anterior descending artery. During the acute reperfusion phase, LV support using an Impella heart pump was initiated. LV pressure, coronary flow and pressure of the infarct artery were simultaneously recorded to evaluate the impact of LV support on coronary physiology. Coronary wave intensity was calculated to understand the forces regulating coronary flow. Significant increases in coronary flow velocity and its area under the curve were found after mechanical LV support. Among the coronary flow-regulating factors, coronary pressure was increased mainly during the late diastolic phase with less pulsatility. Meanwhile, LV pressure was reduced throughout diastole resulting in significant and consistent elevation of coronary driving pressure. Interestingly, the duration of diastole was prolonged with LV support. In the wave intensity analysis, the duration between backward suction and pushing waves was extended, indicating that earlier myocardial relaxation and delayed contraction contributed to the extension of diastole. In conclusion, mechanical LV support increases infarct coronary flow by extending diastole and augmenting coronary driving pressure. These changes were mainly driven by reduced LV diastolic pressure, indicatingthat the key regulator of coronary flow under mechanical LV support is downstream of the coronary artery, rather than upstream. Our study highlights the importance of LV diastolic pressure in infarct coronary flow regulation. KEY POINTS: Restoring ischaemic myocardial tissue perfusion is crucial for minimizing infarct size. Although mechanical left ventricular (LV) support has been suggested to improve infarct coronary flow, its specific mechanism remains to be clarified. LV support reduced LV pressure, and elevated coronary pressure during the late diastolic phase, resulting in high coronary driving pressure. This study demonstrated for the first time that mechanical LV support extends diastolic phase, leading to increased infarct coronary flow. Future studies should evaluate the correlation between improved infarct coronary flow and resulting infarct size.

Protection against Ischemic Heart Disease: A Joint Role for eNOS and the KATP Channel.

Genetic susceptibility may influence ischemic heart disease (IHD) predisposition and affect coronary blood flow (CBF) regulation mechanisms. The aim of this study was to investigate the association among single nucleotide polymorphisms (SNPs) of genes encoding for proteins involved in CBF regulation and IHD. A total of 468 consecutive patients were enrolled and divided into three groups according to coronary angiography and intracoronary functional tests results: G1, patients with coronary artery disease (CAD); G2, patients with coronary microvascular dysfunction (CMD); and G3, patients with angiographic and functionally normal coronary arteries. A genetic analysis of the SNPs rs5215 of the potassium inwardly rectifying channel subfamily J member 11 (KCNJ11) gene and rs1799983 of the nitric oxide synthase 3 (NOS3) gene, respectively encoding for the Kir6.2 subunit of ATP sensitive potassium (KATP) channels and nitric oxide synthase (eNOS), was performed on peripheral whole blood samples. A significant association of rs5215_G/G of KCNJ11 and rs1799983_T/T of NOS3 genes was detected in healthy controls compared with CAD and CMD patients. Based on univariable and multivariable analyses, the co-presence of rs5215_G/G of KCNJ11 and rs1799983_T/T of NOS3 may represent an independent protective factor against IHD, regardless of cardiovascular risk factors. This study supports the hypothesis that SNP association may influence the crosstalk between eNOS and the KATP channel that provides a potential protective effect against IHD.

Neural control of coronary artery blood flow by non-adrenergic and non-cholinergic mechanisms.

What is the topic of this review? How non-adrenergic, non-cholinergic neural mechanisms regulate coronary artery blood flow. What advances does it highlight? The main coronary arteries dynamically adapt to maintain adequate blood flow to the working myocardium. There is growing evidence for an important role of non-classic neurotransmitters in regulating coronary blood flow. This review highlights current evidence for non-adrenergic, non-cholinergic control of coronary artery blood flow and our understanding of the dynamics of this system. Blood flow through the coronary vasculature is essential to maintain myocardial function. As the metabolic demand of the heart increases, so does blood flow through the coronary arteries in a dynamic and adaptive manner. Several mechanisms, including local metabolic factors, mechanical forces and autonomic neural control, regulate coronary artery blood flow. To date, neural control has predominantly focused on the classical neurotransmitters of noradrenaline and acetylcholine. However, autonomic nerves, sympathetic, parasympathetic and sensory, release a variety of neurotransmitters that can directly affect the coronary vasculature. Reduced or altered coronary blood flow and autonomic imbalance are hallmarks of most cardiovascular diseases. Understanding the role of autonomic non-adrenergic, non-cholinergic cotransmitters in coronary blood flow regulation is fundamental to furthering our understanding of this vital system and developing novel targeted therapies.

Global trend and future landscape of coronary microcirculation: A bibliometric and visualized analysis from 1990 to 2021

BackgroundCoronary microcirculation has a fundamental role in the regulation of coronary blood flow in response to cardiac requirements, which has aroused wide concerns in basic science and clinical cardiovascular research. We aimed to analyze coronary microcirculation-associated literatures over 30 years and provide insightful information on the evolutionary path, frontier research hotspots, and future developmental trends. MethodsPublications were retrieved from the Web of Science Core Collection (WoSCC). VOSviewer was used to perform co-occurrence analyses for countries, institutions, authors, and keywords and to generate visualized collaboration maps. CiteSpace was used to visualize the knowledge map derived from reference co-citation analysis, burst references, and keywords detection. ResultsThis analysis was performed based on 11,702 publications including 9981 articles and 1721 reviews. The United States and Harvard University ranked at the top among all the countries and institutions. The majority of articles were published in Circulation, and it also was the most co-cited journal. Thematic hotspots and frontiers were focused on coronary microvascular dysfunction, magnetic resonance imaging, fractional flow reserve, STEMI, and heart failure. Additionally, keywords burst and co-occurrence cluster analysis showed that management, microvascular dysfunction, microvascular obstruction, prognostic value, outcomes, and guidelines were current knowledge gaps and future directions. ConclusionsCoronary microcirculation presented a research hotspot relevant wide spectrum of cardiovascular diseases. Definite diagnostics and prognostics are particularly valued. The protection of cardiovascular events that influence clinical outcomes should be an insightful concern in the future. Multidisciplinary collaborations will provide significant advances for the development of coronary microcirculation.

Integrated control of coronary blood flow in exercising swine by adenosine, nitric oxide, and KATP channels.

The interplay of mechanisms regulating coronary blood flow (CBF) remains incompletely understood. Previous studies in dogs indicated that CBF regulation by KATP channels, adenosine, and nitric oxide (NO) follows a nonlinear redundancy design and fully accounted for exercise-induced coronary vasodilation. Conversely, in swine, these mechanisms appear to regulate CBF in a linear additive fashion with considerable exercise-induced vasodilation remaining when all three mechanisms are inhibited. A direct comparison between these studies is hampered by the different doses and administration routes (intravenous vs. intracoronary) of drugs inhibiting these mechanisms. Here, we investigated the role of KATP channels, adenosine, and NO in CBF regulation in swine using identical drug regimen as previously employed in dogs. Instrumented swine were exercised on a motor-driven treadmill, before and after blockade of KATP channels (glibenclamide, 50 µg/kg/min ic) and combination of inhibition of NO synthase (Nω-nitro-l-arginine, NLA, 1.5 mg/kg ic) and adenosine receptors (8-phenyltheophylline, 8PT, 5 mg/kg iv) or their combination NLA + 8PT + glibenclamide. Glibenclamide and NLA + 8PT each produced coronary vasoconstriction both at rest and during exercise, whereas the combination of NLA + 8PT + glibenclamide resulted in a small further coronary vasoconstriction compared with NLA + 8PT that was, however, less than the sum of the vasoconstriction produced by NLA + 8PT and glibenclamide, each. Thus, in contrast to previous observations in the dog, 1) the coronary vasoconstrictor effect of glibenclamide was not enhanced in the presence of NLA + 8PT and 2) the exercise-induced increase in CBF was largely maintained. These findings show profound species differences in the mechanisms controlling CBF at rest and during exercise.NEW & NOTEWORTHY The present study demonstrates important species differences in the regulation of coronary blood flow by adenosine, NO, and KATP channels at rest and during exercise. In swine, these mechanisms follow a linear additive design, as opposed to dogs which follow a nonlinear redundant design. Simultaneous blockade of all three mechanisms virtually abolished exercise-induced coronary vasodilation in dogs, whereas a substantial vasodilator reserve could still be recruited during exercise in swine.

Assessment of absolute coronary flow and microvascular resistance reserve in patients with severe aortic stenosis

Abstract Introduction The development of left ventricular hypertrophy in patients with severe aortic stenosis (AS) is accompanied by adaptive coronary flow regulation, both in epicardial and microvascular compartment, which ultimately lead to a chronic ischemic insult even in the absence of obstructive coronary artery disease. Intracoronary continuous thermodilution of saline through a dedicated infusion catheter is a novel tool that allows to measure absolute coronary flow and microvascular resistance at rest and during hyperemia and to calculate both coronary flow reserve (CFR) and Microvascular Resistance Reserve (MRR) Purpose We aimed to assess absolute coronary flow, microvascular resistance, CFR and MRR in patients with AS, by continuous intracoronary thermodilution, comparing these hemodynamic findings with a propensity-score matched contemporary cohort of patients without AS. Methods Absolute coronary blood flow and microvascular resistance were measured by continuous thermodilution in 29 patients with AS and compared to 15 controls matched for age, gender, diabetes mellitus and functional severity of epicardial coronary lesions. Myocardial work, total myocardial mass and LAD-specific mass were quantified by echocardiography and cardiac-CT. Results Patients with AS presented a significantly positive LV remodeling with lower global longitudinal strain and higher global work index compared to controls (p&amp;lt;0.02). Total LV myocardial mass and LAD-specific myocardial mass were significantly higher in patients with AS. Compared to matched controls, absolute resting flow in the LAD was significantly higher in the AS cohort (86 [66–107] ml/min vs 68 [52–75] ml/min, p=0.036), resulting, in lower CFR (2.30±0.69 vs 2.89±0.77, p=0.005) and MRR (2.73±0.74 vs 3.53±0.95, p=0.005) in the AS cohort compared to controls (Figure 1). No differences were found in hyperemic flow and resting and hyperemic resistances. Interestingly, hyperemic myocardial perfusion (calculated as the ratio between the absolute coronary flow in the LAD and the mass subtended by the vessel, expressed in mL/min/g), but not resting, was significantly lower in the AS group (1.9 [1.5–2.5] ml/min/g vs 2.3 [2–3.1] ml/min/g p=0.036). Conclusions In patients with severe aortic stenosis and non-obstructive coronary artery disease, with the progression of LVH, the compensatory mechanism of increased resting flow maintains an adequate perfusion at rest, but not during hyperemia (Figure 2). As consequence, both CFR and MRR are significantly impaired. Funding Acknowledgement Type of funding sources: None.

Quantitative aspects of nitric oxide production in the heart.

Nitric oxide (NO) has essential roles in heart physiology, including the regulation of myocardial contractility and coronary blood flow, and in heart pathophysiology, particularly in the ischemic heart. NO is produced by both NO synthase (NOS)-dependent and NOS-independent pathways in the heart. This review summarizes quantitative aspects of NO production in the heart; the contribution of cardiomyocytes, endothelial cells (ECs), red blood cells (RBCs), and neurons are also discussed. Based on the available data, under normal conditions, the human heart produces about 50-70 µmol NO per day, primarily attributed to eNOS activity; ECs produce the highest amount of NO compared to other cell types in the heart. On the other hand, during ischemic conditions, NOS-independent NO production participates a significant role in the heart NO production that can exceed NOS-dependent NO generation. These data are relevant as most cardiovascular disorders are associated with NO dysfunction, and increasing NO bioavailability and signaling is a potential therapeutic approach for cardiovascular diseases.

Absolute coronary flow and microvascular resistance reserve in patients with severe aortic stenosis

BackgroundDevelopment of left ventricle (LV) hypertrophy in aortic stenosis (AS) is accompanied by adaptive coronary flow regulation. We aimed to assess absolute coronary flow, microvascular resistance, coronary flow reverse (CFR)...

Red blood cell eNOS is cardioprotective in acute myocardial infarction

Red blood cells (RBCs) were shown to transport and release nitric oxide (NO) bioactivity and carry an endothelial NO synthase (eNOS). However, the pathophysiological significance of RBC eNOS for cardioprotection in vivo is unknown. Here we aimed to analyze the role of RBC eNOS in the regulation of coronary blood flow, cardiac performance, and acute myocardial infarction (AMI) in vivo. To specifically distinguish the role of RBC eNOS from the endothelial cell (EC) eNOS, we generated RBC- and EC-specific knock-out (KO) and knock-in (KI) mice by Cre-induced inactivation or reactivation of eNOS. We found that RBC eNOS KO mice had fully preserved coronary dilatory responses and LV function. Instead, EC eNOS KO mice had a decreased coronary flow response in isolated perfused hearts and an increased LV developed pressure in response to elevated arterial pressure, while stroke volume was preserved. Interestingly, RBC eNOS KO showed a significantly increased infarct size and aggravated LV dysfunction with decreased stroke volume and cardiac output. This is consistent with reduced NO bioavailability and oxygen delivery capacity in RBC eNOS KOs. Crucially, RBC eNOS KI mice had decreased infarct size and preserved LV function after AMI. In contrast, EC eNOS KO and EC eNOS KI had no differences in infarct size or LV dysfunction after AMI, as compared to the controls. These data demonstrate that EC eNOS controls coronary vasodilator function, but does not directly affect infarct size, while RBC eNOS limits infarct size in AMI. Therefore, RBC eNOS signaling may represent a novel target for interventions in ischemia/reperfusion after myocardial infarction.

Cold pressor testing and sympathetic nervous system contribution to ischemia with no obstructive coronary artery disease: Results from the Women's Ischemia Syndrome Evaluation-Coronary Vascular Dysfunction Project

Study objectiveCold pressor testing (CPT) is a known stimulus of the sympathetic nervous system (SNS). To better understand sympathetic contribution to coronary blood flow regulation in women with suspected ischemia and no obstructive coronary arteries (INOCA), we compared myocardial perfusion reserve during CPT stress cardiac magnetic resonance (CMR) imaging between women with suspected INOCA and reference subjects. DesignProspective cohort. SettingAcademic hospital. Participants107 women with suspected INOCA and 21-age-matched reference women. InterventionsCPT stress CMR was performed with measurement of myocardial perfusion reserve index (MPRI), adjusted for rate pressure product (MPRIRPP). Invasive coronary function testing in a subset of INOCA women (n = 42) evaluated for endothelial dysfunction in response to acetylcholine, including impaired coronary diameter response ≤0% and coronary blood flow response (ΔCBF) <50%. Main outcome measureMPRIRPP. ResultsCompared to reference women, the INOCA group demonstrated higher resting RPP (p = 0.005) and CPT MPRIRPP (1.09 ± 0.36 vs 0.83 ± 0.18, p = 0.002). Furthermore, INOCA women with impaired ΔCBF (n = 23) had higher CPT MPRIRPP (p = 0.044) compared to reference women despite lower left ventricular ejection fraction (64 ± 7% vs 69 ± 2%, p = 0.005) and higher mass-to-volume ratio (0.79 ± 0.15 vs 0.62 ± 0.09, p < 0.0001). These differences in CPT MPRIRPP did not persist after adjusting for age, body mass index, and history of hypertension. CPT MPRIRPP among INOCA women did not differ based on defined acetylcholine responses. ConclusionsMyocardial perfusion reserve to CPT stress is greater among women with INOCA compared to reference subjects. This CPT response was also noted in women with coronary endothelial dysfunction, suggesting a greater contribution of the SNS to coronary flow than endothelial dysfunction. Therapies to modulate sympathetic activity should be studied in this population.

Mechanobiology of Microvascular Function and Structure in Health and Disease: Focus on the Coronary Circulation.

The coronary microvasculature plays a key role in regulating the tight coupling between myocardial perfusion and myocardial oxygen demand across a wide range of cardiac activity. Short-term regulation of coronary blood flow in response to metabolic stimuli is achieved via adjustment of vascular diameter in different segments of the microvasculature in conjunction with mechanical forces eliciting myogenic and flow-mediated vasodilation. In contrast, chronic adjustments in flow regulation also involve microvascular structural modifications, termed remodeling. Vascular remodeling encompasses changes in microvascular diameter and/or density being largely modulated by mechanical forces acting on the endothelium and vascular smooth muscle cells. Whereas in recent years, substantial knowledge has been gathered regarding the molecular mechanisms controlling microvascular tone and how these are altered in various diseases, the structural adaptations in response to pathologic situations are less well understood. In this article, we review the factors involved in coronary microvascular functional and structural alterations in obstructive and non-obstructive coronary artery disease and the molecular mechanisms involved therein with a focus on mechanobiology. Cardiovascular risk factors including metabolic dysregulation, hypercholesterolemia, hypertension and aging have been shown to induce microvascular (endothelial) dysfunction and vascular remodeling. Additionally, alterations in biomechanical forces produced by a coronary artery stenosis are associated with microvascular functional and structural alterations. Future studies should be directed at further unraveling the mechanisms underlying the coronary microvascular functional and structural alterations in disease; a deeper understanding of these mechanisms is critical for the identification of potential new targets for the treatment of ischemic heart disease.

Chemical phenotypes of intrinsic cardiac neurons in the newborn pig (Sus scrofa domesticus Erxleben, 1777).

Intrinsic cardiac neurons (ICNs) are crucial cells in the neural regulation of heart rhythm, myocardial contractility, and coronary blood flow. ICNs exhibit diversity in their morphology and neurotransmitters that probably are age-dependent. Therefore, neuroanatomical heart studies have been currently focused on the identification of chemical phenotypes of ICNs to disclose their possible functions in heart neural regulation. Employing whole-mount immunohistochemistry, we examined ICNs from atria of the newborn pigs (Sus scrofa domesticus) as ICNs at this stage of development have never been neurochemically characterized so far. We found that the majority of the examined ICNs (>60%) were of cholinergic phenotype. Biphenotypic neuronal somata (NS), that is, simultaneously positive for two neuronal markers, were also rather common and distributed evenly within the sampled ganglia. Simultaneous positivity for cholinergic and adrenergic neuromarkers was specific in 16.4%, for cholinergic and nitrergic-in 3.5% of the examined NS. Purely either adrenergic or nitrergic ICNs were observed at 13% and 3.1%, correspondingly. Purely adrenergic and nitrergic NS were the most frequent in the ventral left atrial subplexus. Similarly to neuronal phenotype, sizes of NS also varied depending on the atrial region providing insights into their functional implications. Axons, but not NS, positive for classic sensory neuronal markers (vesicular glutamate transporter 2 and calcitonin gene-related peptide) were identified within epicardiac nerves and ganglia. Moreover, a substantial number of ICNs could not be attributed to any phenotype as they were not immunoreactive for antisera used in this study. Numerous dendrites with putative peptidergic and adrenergic contacts on cholinergic NS contributed to neuropil of ganglia. Our observations demonstrate that intrinsic cardiac ganglionated plexus is not fully developed in the newborn pig despite of dense network of neuronal processes and numerous signs of neural contacts within ganglia.

Regulation of Coronary Blood Flow by the Carotid Body Chemoreceptors in Ovine Heart Failure.

Carotid bodies (CBs) are peripheral chemoreceptors, which are primary sensors of systemic hypoxia and their activation produces respiratory, autonomic, and cardiovascular adjustments critical for body homeostasis. We have previously shown that carotid chemoreceptor stimulation increases directly recorded cardiac sympathetic nerve activity (cardiac SNA) which increases coronary blood flow (CoBF) in conscious normal sheep. Previous studies have shown that chemoreflex sensitivity is augmented in heart failure (HF). We hypothesized that carotid chemoreceptor stimulation would increase CoBF to a greater extent in HF than control sheep. Experiments were conducted in conscious HF sheep and control sheep (n = 6/group) implanted with electrodes to record diaphragmatic electromyography (dEMG), flow probes to record CoBF as well as arterial pressure. There was a significant increase in mean arterial pressure (MAP), CoBF and coronary vascular conductance (CVC) in response to potassium cyanide (KCN) in both groups of sheep. To eliminate the effects of metabolic vasodilation, the KCN was repeated while the heart was paced at a constant level. In this paradigm, the increase in CoBF and CVC was augmented in the HF group compared to the control group. Pre-treatment with propranolol did not alter the CoBF or the CVC increase in the HF group indicating this was not mediated by an increase in cardiac sympathetic drive. The pressor response to CB activation was abolished by pre-treatment with intravenous atropine in both groups, but there was no change in the CoBF and vascular conductance responses. Our data suggest that in an ovine model of HF, carotid body (CB) mediated increases in CoBF and CVC are augmented compared to control animals. This increase in CoBF is mediated by an increase in cardiac SNA in the control group but not the HF group.

Mineralocorticoid receptor blockade normalizes coronary resistance in obese swine independent of functional alterations in Kv channels.

Impaired coronary microvascular function (e.g., reduced dilation and coronary flow reserve) predicts cardiac mortality in obesity, yet underlying mechanisms and potential therapeutic strategies remain poorly understood. Mineralocorticoid receptor (MR) antagonism improves coronary microvascular function in obese humans and animals. Whether MR blockade improves in vivo regulation of coronary flow, a process involving voltage-dependent K+ (Kv) channel activation, or reduces coronary structural remodeling in obesity is unclear. Thus, the goals of this investigation were to determine the effects of obesity on coronary responsiveness to reductions in arterial PO2 and potential involvement of Kv channels and whether the benefit of MR blockade involves improved coronary Kv function or altered passive structural properties of the coronary microcirculation. Hypoxemia increased coronary blood flow similarly in lean and obese swine; however, baseline coronary vascular resistance was significantly higher in obese swine. Inhibition of Kv channels reduced coronary blood flow and augmented coronary resistance under baseline conditions in lean but not obese swine and had no impact on hypoxemic coronary vasodilation. Chronic MR inhibition in obese swine normalized baseline coronary resistance, did not influence hypoxemic coronary vasodilation, and did not restore coronary Kv function (assessed in vivo, ex vivo, and via patch clamping). Lastly, MR blockade prevented obesity-associated coronary arteriolar stiffening independent of cardiac capillary density and changes in cardiac function. These data indicate that chronic MR inhibition prevents increased coronary resistance in obesity independent of Kv channel function and is associated with mitigation of obesity-mediated coronary arteriolar stiffening.

СТЕНОКАРДИЯ БЕЗ ОБСТРУКТИВНОГО ПОРАЖЕНИЯ КОРОНАРНЫХ АРТЕРИЙ (Часть 1). ПАТОФИЗИОЛОГИЧЕСКИЕ АСПЕКТЫ РАЗВИТИЯ

Angina pectoris is one of the most common symptoms of ischemic heart disease (IHD). Coronary angiography in a significant part of patients with angina pectoris and signs of myocardial ischemia does not reveal obstructive atherosclerotic changes in the coronary arteries. Independent or additional mechanisms of ischemia can be microvascular dysfunction and epicardial coronary vasospasm. The clinical form of ischemic heart disease, which is based on ischemia caused by dysfunction of the coronary vessels in the absence of obstructive changes, has recently received the definition of INOCA (Ischaemia with No Obstructive Coronary Artery Disease). The concept of INOCA comprises two types of angina pectoris – mi- crovascular and vasospastic. The underlying INOCA coronary vasomotor disorders have both different pathophysiological mechanisms and localization in the vascular system of the coronary circulation itself. Clinically the most important vasomotor disorders are epicardial and microvascular vasospasm, impaired microvascular vasodilation. The article provides a brief overview of the mechanisms of regulation of coronary blood flow under physiological conditions and vascular dysfunction in non-obstructive atherosclerotic lesions.

Role of coronary flow regulation and cardiac-coronary coupling in mechanical dyssynchrony associated with right ventricular pacing.

Mechanical dyssynchrony (MD) affects left ventricular (LV) mechanics and coronary perfusion. To understand the multifactorial effects of MD, we developed a computational model that bidirectionally couples the systemic circulation with the LV and coronary perfusion with flow regulation. In the model, coronary flow in the left anterior descending (LAD) and left circumflex (LCX) arteries affects the corresponding regional contractility based on a prescribed linear LV contractility-coronary flow relationship. The model is calibrated with experimental measurements of LV pressure and volume, as well as LAD and LCX flow rate waveforms acquired under regulated and fully dilated conditions from a swine under right atrial (RA) pacing. The calibrated model is applied to simulate MD. The model can simultaneously reproduce the reduction in mean LV pressure (39.3%), regulated flow (LAD: 7.9%; LCX: 1.9%), LAD passive flow (21.6%), and increase in LCX passive flow (15.9%). These changes are associated with right ventricular pacing compared with RA pacing measured in the same swine only when LV contractility is affected by flow alterations with a slope of 1.4 mmHg/mL2 in a contractility-flow relationship. In sensitivity analyses, the model predicts that coronary flow reserve (CFR) decreases and increases in the LAD and LCX with increasing delay in LV free wall contraction. These findings suggest that asynchronous activation associated with MD impacts 1) the loading conditions that further affect the coronary flow, which may explain some of the changes in CFR, and 2) the coronary flow that reduces global contractility, which contributes to the reduction in LV pressure.NEW & NOTEWORTHY A computational model that couples the systemic circulation of the left ventricular (LV) and coronary perfusion with flow regulation is developed to study the effects of mechanical dyssynchrony. The delayed contraction in the LV free wall with respect to the septum has a significant effect on LV function and coronary flow reserve.

Coronary Flow Reserve and Glycemic Variability in Patients with Coronary Artery Disease.

Objective Glycemic variability is being increasingly recognized as an early indicator of glucose metabolic disorder and may contribute to the development of diabetic vascular complications, such as coronary microvascular dysfunction. The present study sought to investigate the relationship between coronary microvascular function assessed by intracoronary thermodilution method and glycemic variability on a continuous glucose monitoring system (CGMS). Methods We prospectively enrolled 40 patients with or without known diabetes mellitus who had epicardial coronary artery disease referred for coronary angiography and were not treated with diabetic medications. Of these, two had a significant stenosis in the left main coronary artery and were therefore excluded from the analyses. In the end, 38 patients were equipped with a CGMS and underwent intracoronary physiological assessments in the unobstructed left anterior descending artery. The mean amplitude of glycemic excursion (MAGE) and standard deviation were calculated from the obtained CGMS data as indicators of glucose variability. Results Coronary flow reserve (CFR) was negatively correlated with MAGE (r=-0.328, p=0.044) and standard deviation (r=-0.339, p=0.037) on CGMS, while the index of microcirculatory resistance showed no such correlation. Multivariable linear regression analyses showed that MAGE on CGMS was significantly associated with CFR after adjusting for age, sex, fractional flow reserve and hemoglobin A1c. Conclusion Higher MAGE on CGMS was associated with reduced CFR in stable patients with coronary artery disease, suggesting a potential effect of glycemic variability on coronary microvascular flow regulation. A further study with a larger sample size needs to be conducted to confirm our findings.

Coronary Microvascular Dysfunction.

Many patients with chest pain undergoing coronary angiography do not show significant obstructive coronary lesions. A substantial proportion of these patients have abnormalities in the function and structure of coronary microcirculation due to endothelial and smooth muscle cell dysfunction. The coronary microcirculation has a fundamental role in the regulation of coronary blood flow in response to cardiac oxygen requirements. Impairment of this mechanism, defined as coronary microvascular dysfunction (CMD), carries an increased risk of adverse cardiovascular clinical outcomes. Coronary endothelial dysfunction accounts for approximately two-thirds of clinical conditions presenting with symptoms and signs of myocardial ischemia without obstructive coronary disease, termed “ischemia with non-obstructive coronary artery disease” (INOCA) and for a small proportion of “myocardial infarction with non-obstructive coronary artery disease” (MINOCA). More frequently, the clinical presentation of INOCA is microvascular angina due to CMD, while some patients present vasospastic angina due to epicardial spasm, and mixed epicardial and microvascular forms. CMD may be associated with focal and diffuse epicardial coronary atherosclerosis, which may reinforce each other. Both INOCA and MINOCA are more common in females. Clinical classification of CMD includes the association with conditions in which atherosclerosis has limited relevance, with non-obstructive atherosclerosis, and with obstructive atherosclerosis. Several studies already exist which support the evidence that CMD is part of systemic microvascular disease involving multiple organs, such as brain and kidney. Moreover, CMD is strongly associated with the development of heart failure with preserved ejection fraction (HFpEF), diabetes, hypertensive heart disease, and also chronic inflammatory and autoimmune diseases. Since coronary microcirculation is not visible on invasive angiography or computed tomographic coronary angiography (CTCA), the diagnosis of CMD is usually based on functional assessment of microcirculation, which can be performed by both invasive and non-invasive methods, including the assessment of delayed flow of contrast during angiography, measurement of coronary flow reserve (CFR) and index of microvascular resistance (IMR), evaluation of angina induced by intracoronary acetylcholine infusion, and assessment of myocardial perfusion by positron emission tomography (PET) and magnetic resonance (CMR).