Increase In Coronary Blood Flow Research Articles

Abstract 4123637: Prevalence of Invasively Diagnosed Coronary Endothelial Dysfunction in Patients with Chest Pain and Normal Coronary Flow Reserve: The Systematically Missed Diagnosis on Non-invasive Testing

Background: Invasive coronary reactivity testing (CRT) is the gold standard for comprehensive assessment of coronary endothelial and microvascular dysfunction in patients with angina and non-obstructive CAD (ANOCA). Non-invasive imaging modalities (PET and CMR) have emerged as potential alternatives. However, due to the inability to systemically administer acetylcholine, patients with normal coronary flow reserve (CFR) but abnormal endothelial function on invasive Ach testing are systemically missed on non-invasive testing. We aimed to assess the prevalence of coronary endothelial dysfunction in ANOCA patients with normal CFR. Methods: Consecutive patients undergoing CRT at our institution were included. Those with normal adenosine-based CFR (>2.5), were further stratified as having normal coronary endothelial function (NEF, <20% epicardial coronary diameter constriction and >50% increase in coronary blood flow in response to ACh) vs abnormal endothelial function (AEF, >20% epicardial coronary diameter constriction and/or <50% increase in coronary blood flow in response to Ach). We then assessed the proportion of AEF patients who would have been otherwise diagnosed with normal coronary physiology based on CFR alone on non-invasive testing. Results: 37 patients underwent CRT. Mean age was 55 years ± 25, 68% were females. 25 out of 37 patients (68%) had normal CFR. Of those patients, 17 (68%) patients had AEF. Distribution of coronary epicardial vs microvascular endothelial dysfunction is represented in Fig. 1. Conclusion: 68% of ANOCA patients with normal CFR had coronary epicardial and/or microvascular endothelial dysfunction and would have otherwise been labeled as ‘normal coronary physiology’ by non-invasive microvascular function testing. Our findings re-enforce the need for comprehensive invasive CRT for accurate comprehensive diagnosis of patients with ANOCA.

Coronary Sinus Reducer Improves Angina, Quality of Life, and CoronaryFlow Reserve in MicrovascularDysfunction.

Coronary microvascular dysfunction (CMD) is a common cause of angina with no obstructive coronary artery disease (ANOCA), and effective treatment options are limited. This study aims to assess the safety and efficacy of the coronary sinus (CS) Reducer (Neovasc, Inc/Shockwave Medical) for treatment of angina in patients with CMD. This Phase II trial enrolled 30 patients with ANOCA, invasively diagnosed CMD, and Canadian Cardiovascular Society (CCS) class 3 to 4 angina despite medical therapy. CMD was defined by coronary flow reserve (CFR)≤2.5 and/or≤50% increase in coronary blood flow (CBF) in response to intracoronary infusion of acetylcholine. Invasive coronary microvascular function testing was performed before and at 120days postimplantation. The primary endpoint was change in microvascular function at 120days. Secondary endpoints were changes in CCS angina class and Seattle Angina Questionnaire (SAQ) scores. Mean age was 54.8 ± 11.0 years; 67% (20/30) were women. In patients with low baseline CFR (endothelium-independent CMD), CFR increased significantly from 2.1 (1.95-2.30) to 2.7 (2.45-2.95) (n=19; P=0.0011). Patients with abnormal CBF response to acetylcholine at baseline (endothelium-dependent CMD) had an increase in CBF response to acetylcholine:-11.0% (-20.15% to 5.85%) to 11.5% (-4.82% to 39.29%) (n=11; P=0.042). There was a significant improvement in CCS angina class from 4.0 (3.25-4.0) to 2.0 (2.0-3.0) (P< 0.001) and increase in each domain of the SAQ questionnaire (P< 0.006 for all). This study demonstrates that the CS Reducer is associated with significant improvement in angina, quality of life, and coronary microvascular function in patients with CMD and may emerge as a novel therapy for patients with ANOCA.

Danggui Buxue Decoction and its components dilate coronary artery through activating the inward rectification K+ channels pathway

Ethnopharmacological relevanceDanggui Buxue Decoction (DBD), a classic representative prescription of invigorating Qi and producing blood, is used to treat coronary heart disease angina pectoris and vascular injury diseases. Abnormal coronary artery is an important cause of cardiovascular disease. However, the mechanism of DBD dilates coronary arteries is still unclear. Aim of the studyThis study aimed to elucidate the impacts and distinctions among DBD, Astragalus, Angelica sinensis, and identified active components on pre-constricted coronary arteries, as well as to delve deeper into their respective mechanisms. Materials and methodsAfter the preconstriction of a rat isolated coronary artery ring with either 30 mM KCl or 200 nM U46619, the vascular tension was observed following the addition of DBD, and other components. Subsequently, the impact of these active components on coronary blood flow (CBF) was confirmed through in vivo testing. Further investigation into the underlying mechanism was carried out using a combination of blockers, molecular docking, surface plasmon resonance (SPR), cell heat transfer analysis (CETSA), and patch-clamp techniques. ResultsIn vitro experiments showed that DBD and its components butylidenephthalide, ligustilide, calycosin, and quercetin could dilate coronary artery preconstricted with either 30 mM KCl or 200 nM U46619. In addition, the active ingredient was found to significantly increase CBF. Mechanistically, BaCl2 was found to reduce the relaxation effect of the drug by adding a blocker. Molecular docking, SPR and CETSA results showed that the active ingredients had a strong binding potential with inward rectification K+ channels (KIR) channel protein. Patch clamp studies demonstrate that quercetin can increase KIR current, and BaCl2 can significantly reduce its current. ConclusionsThe active components of DBD, butylidenephthalide, ligustilide, calycosin, and quercetin, activate KIR channels to relax coronary artery and increase CBF.

Prevalence of coronary microvascular disease in myocardial infarction with non-obstructive coronary artery disease

Abstract Background Six percent of patients presenting with acute myocardial infarction (MI) have MI with non-obstructed coronary artery disease (MINOCA). Coronary microvascular disease (CMD) is common in angina with non-obstructive coronary artery disease (ANOCA), but its prevalence and severity in MINOCA is undefined. Purpose Patients with CMD may have elevated risk of myocardial infarction despite no significant stenosis. We tested the hypothesis that patients with MINOCA have more significant burden of CMD than patients with ANOCA. Methods A retrospective case-control study was performed on patients who underwent invasive testing for signs of coronary ischemia and found to have non-obstructive disease (stenoses&amp;lt; 50%). Cases of MI were classified as MINOCA (n=87) and compared to patients with ANOCA (n=552). Patients with spontaneous coronary artery dissection, myocarditis, Takotsubo cardiomyopathy or prior atherothrombotic MI were excluded. Coronary catheterization was performed followed by invasive provocation testing with adenosine and acetylcholine using a Doppler flow wire. CMD was subdivided into endothelium-independent, defined as coronary flow reserve (CFR) &amp;lt; 2.5 with intra-coronary adenosine, and endothelium dependent, defined as &amp;lt; 50% increase in coronary blood flow with acetylcholine. Epicardial vasoconstriction &amp;gt; 90% with typical anginal symptoms was classified as epicardial vasospasm. Results There was no difference in age, sex or traditional coronary risk factors between the MINOCA and ANOCA groups (Table 1). Fifty (57%) of patients with MINOCA had type 2 MI secondary to supply-demand mismatch. Both MINOCA and suspected ANOCA patients had a high prevalence of CMD (71% vs 67%) and endothelium-independent CMD is more prevalent in MINOCA (64.5% vs 50.4%). Although odds of endothelium-dependent CMD were similar, the CFR within this group and CMD overall was worse in MINOCA patients (Figure 1). There was no difference in epicardial spasm. Conclusion Coronary microvascular disease and vasomotor dysfunction are common in patients with MINOCA, with a higher prevalence of endothelium-independent CMD and more severe CMD overall compared to patients with ANOCA. Treatment of CMD in patients with MINOCA may help reduce recurrence and warrants further investigation.

Assessment of coronary endothelial dysfunction using contemporary coronary function testing

BackgroundThe established diagnosis of coronary endothelial dysfunction (CED) is through the response to low-dose acetylcholine during invasive coronary function testing (CFT). Current diagnostic criteria encompass deficient epicardial vasodilation and/or insufficient increase in coronary blood flow (CBF) calculated from additional Doppler flow velocity measurements. The aim is to evaluate the diagnostic yield of using angiographic epicardial vasomotion and CBF as single criteria for diagnosing CED during CFT. MethodsA total of 110 patients with angina and non-obstructive coronary arteries who underwent clinically indicated CFT were included. CED was defined as any reduction in epicardial diameter through quantitative coronary angiography and/or < 50 % increase in CBF compared to baseline after low-dose acetylcholine. ResultsBased on current diagnostic criteria, 78 % of patients (N = 86/110) was diagnosed with CED. When only considering epicardial diameter, 24 % CED (N = 21/86) and 50 % severe CED diagnoses (N = 19/38) were missed. When only considering CBF, 27 % CED (N = 23/86) and 18 % severe CED diagnoses (N = 7/38) were missed. A similar diagnostic yield for CED detection was found for both parameters (OR: 0.913, 95 %CI 0.481–1.726, p = 0.763). The incidence of CFT diagnoses was comparable among all groups. ConclusionsAs single parameters, both epicardial diameter and CBF were ineffective in accurately diagnosing CED compared to the current diagnostic criteria. Combining both parameters is necessary to diagnose the complete spectrum of CED, as missed diagnoses of deficient CBF responses (e.g., microvascular CED) and epicardial vasomotion (e.g., epicardial CED) might occur when relying on these parameters as single diagnostic criteria for CED.

THE INTELLIGENT USE OF ADRENALINE

Abstract Case Report A 52–year–old patient experienced anterior and inferior ST–elevation myocardial infarction, leading to cardiogenic shock necessitating invasive hemodynamic and pharmacological support. During angiography, an intra–aortic balloon pump (IABP) was inserted, and a norepinephrine infusion along with dobutamine was initiated, showing partial clinical and laboratory improvement. Critical disease in all three vessels was detected, prompting angioplasty with stenting of the right coronary artery and left anterior descending artery. Echocardiography revealed severe reduction in left ventricular systolic function (ejection fraction 10%). Despite revascularization and intensive support, the patient‘s hemodynamic status deteriorated (SCAI D), necessitating the addition of adrenaline (0.03 μg/kg/min) to the ongoing dobutamine infusion, suspending noradrenaline. Subsequent days showed gradual improvement, allowing for withdrawal from amine support and discontinuation of the IABP. Follow–up included a cardiac MRI displaying severe systolic dysfunction (EF 21%), extensive ischemic–pattern delayed enhancement across three–vessel distribution. Given the persistent severe left ventricular dysfunction, the patient underwent subcutaneous defibrillator implantation for primary prevention after optimizing anti–remodeling therapy. Despite optimized medical therapy and cycles of levosimendan, the patient experienced heart failure exacerbation, requiring hospitalization (INTERMACS 3). Considering the clinical condition and absence of contraindications, the patient was listed for heart transplantation. Due to refractory hemodynamic instability despite inotropic agents, a left ventricular assist device was implanted as a bridge to transplantation. Roughly 6 months later, the patient successfully underwent heart transplantation without acute complications. Conclusions Very low doses of adrenaline demonstrate increased sensitivity to β2 receptors over α receptors, thereby enhancing mean arterial pressure and peripheral perfusion. At the cardiac level, it induces an increase in both heart rate and coronary blood flow, while peripherally reducing resistances, predominantly due to the prevalence of β2 receptors in skeletal muscle. This improvement contributes to the enhancement of ventricular–arterial coupling. In conditions characterized by a primary pump deficit, such as cardiogenic shock, the use of low–dose adrenaline emerges as a valid therapeutic option.

Patients With Coronary Microvascular Dysfunction Have Less Circulating α-Klotho.

Coronary microvascular dysfunction (CMD) represents an early functional characteristic of coronary vascular aging. Klotho (α-klotho) is a circulating protein inversely linked to physiological aging. We examined low klotho as a potential marker for vascular aging in patients with CMD and no coronary artery disease. Patients undergoing nonurgent angiogram for chest pain who had no coronary artery disease underwent invasive coronary microvascular and endothelial function testing. CMD was defined by ≤50% increase in coronary blood flow (percentage change in coronary blood flow) in response to intracoronary acetylcholine or coronary flow reserve ≤2. Fresh arterial whole blood was used to analyze circulating endothelial progenitor cells with flow cytometry. Stored arterial plasma was used for klotho analysis by ELISA. Participants with CMD (n=62) were compared with those without CMD (n=36). Those with CMD were age 55±10 years (versus 51±11 years; P=0.07) and 73% women (versus 81%; P=0.38). Traditional risk factors for coronary artery disease were similar between groups. Patients with CMD had less klotho (0.88±1.50 versus 1.75±2.38 ng/mL; P=0.03), and the odds of low klotho in CMD were significant in a logistic regression model after adjusting for traditional cardiovascular risk factors (odds ratio [OR], 0.80 [95% CI, 0.636-0.996]; P=0.05). Higher klotho was associated with higher numbers of endothelial progenitor cells with vascular regenerative potential (CD34+ and CD34+CD133+KDR+). Among a subgroup of patients with atherosclerotic cardiovascular disease risk <5% (n=58), CMD remained associated with lower klotho (OR, 0.80 [95% CI, 0.636-0.996]; P=0.047). Klotho may be a biomarker for CMD and may be a therapeutic target for groups of patients without significant traditional cardiovascular risk.

The Arterial Baroreflex Buffers Muscle Metaboreflex-Induced Coronary Vasoconstriction

The ability to increase cardiac output and thereby skeletal muscle blood flow during dynamic exercise is paramount to maintaining exercise workload. Increases in cardiac output are driven via increases in heart rate, ventricular function, and central blood volume mobilization which raises arterial blood pressure, in part, due to activation of the muscle metaboreflex. The increase in cardiac sympathetic tone also activates coronary vascular alpha-adrenergic receptors which restrains increases in coronary blood flow which limits increases in ventricular function. During submaximal dynamic exercise, the muscle metaboreflex acts primarily to raise cardiac output with little net peripheral vasoconstriction. However, after sinoaortic baroreceptor denervation (SAD), the muscle metaboreflex causes increases in both cardiac output and total peripheral resistance indicating that the baroreflex buffers the muscle metaboreflex mainly via restraint of peripheral vasoconstriction. To what degree the arterial baroreflex restrains muscle metaboreflex-induced coronary vasoconstriction is unknown. Therefore, we utilized our chronically instrumented canine model to evaluate if SAD would significantly impact muscle metaboreflex-induced coronary vasoconstriction. Canines were chronically instrumented to measure cardiac output, left circumflex coronary artery blood flow, hindlimb blood flow and arterial blood pressure. During steady-state mild treadmill exercise (3.2 kph, 0% grade) the muscle metaboreflex was activated via partial inflation of vascular occluders placed distal to the hindlimb blood flow probe. Metaboreflex activation caused substantial increases in cardiac output, heart rate, cardiac power, coronary blood flow, and arterial blood pressure. Assessment of coronary vasodilation was performed via linear regression of the relationship between coronary vascular conductance (CVC; coronary blood flow/mean arterial pressure) vs. cardiac power (CP, an index of O2 demand). Experiments were performed at least 2 weeks after chronic bilateral SAD. Muscle metaboreflex activation after SAD caused a significantly greater pressor response driven by increases in both cardiac output and total peripheral resistance. Furthermore, after SAD the slope of the CVC-CP relationship was significantly lower during muscle metaboreflex activation (0.072 ml/min/mmHg/Watt, control vs 0.033 ml/min/mmHg/Watt, SAD; p&lt;0.05) We conclude that the arterial baroreflex buffers the muscle metaboreflex and restrains the reflex coronary vasoconstriction. This baroreflex-induced restraint of metaboreflex mediated coronary vasoconstriction potentially limits metaboreflex-induced reductions myocardial oxygen delivery. Augmented coronary vasoconstriction with metaboreflex activation after SAD likely contributes to the smaller role of cardiac output in mediating the rise in arterial blood pressure after SAD, and provides further evidence that baroreflex buffering of metaboreflex responses improves cardiac function. Thus, reduced baroreflex function in heart failure may contribute to the accentuated metaboreflex coronary vasoconstriction which impairs ventricular performance during exercise in heart failure. This work was supported by the National Heart, Lung and, Blood Institute grants HL-055473, HL-126706. This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Comparison of the Diagnostic Yield of Intracoronary Acetylcholine Infusion and Acetylcholine Bolus Injection Protocols During Invasive Coronary Function Testing

Coronary endothelial dysfunction (CED) and coronary artery spasm (CAS) are causes of angina in patients with no obstructive coronary arteries (ANOCA). Both can be diagnosed by invasive coronary function testing (ICFT) using Acetylcholine (ACh). This study aimed to evaluate the diagnostic yield of a 3-minute ACh infusion as compared to a 1-minute ACh bolus injection protocol in testing CED and CAS. In total 220 consecutive ANOCA patients underwent ICFT using continuous Doppler flow measurements. Per protocol, 110 patients were tested using 3-minute infusion and thereafter 110 patients using 1-minute bolus injections, due to a protocol change. CED was defined as a <50% increase in coronary blood flow or any epicardial vasoconstriction in reaction to low dose ACh and CAS according to the COVADIS criteria, both with and without T-wave abnormalities, in reaction to high dose ACh. The prevalence of CED was equal in both protocols (78% vs 79%; p=0.869). Regarding the endotypes of CAS according to COVADIS, the equivocal endotype was diagnosed less often in the 3-minutes vs 1-minute protocol (24% vs 44%; p=0.004). Including T-wave abnormalities to the COVADIS criteria resulted in a similar diagnostic yield of both protocols. Hemodynamic changes from baseline to the low or high ACh doses were comparable between the protocols for each endotype. In conclusion, ICFT using 3-minute infusion or 1-minute bolus injections of ACh showed a similar diagnostic yield of CED. When using the COVADIS criteria, a difference in the equivocal diagnosis was observed. Including T-wave abnormalities as diagnostic criterion reclassified equivocal test results into CAS and decreased this difference. For clinical practice, we recommend the inclusion of T-wave abnormalities as diagnostic criterion for CAS and the 1-minute bolus protocol for practicality.

Sympathetic transduction of cardiac sympathetic nerve activity in healthy, conscious sheep.

Sympathetic transduction is the study of how impulses of sympathetic nerve activity (SNA) affect end-organ function. Recently, the transduction of resting bursts of muscle SNA (MSNA) has been investigated and shown to have a role in the maintenance of blood pressure through changes in vascular tone in humans. In the present study, we investigate whether directly recorded resting cardiac SNA (CSNA) regulates heart rate (HR), coronary blood flow (CoBF), coronary vascular conductance (CVC), cardiac output (CO) and mean arterial pressure. Instrumentation was undertaken to record CSNA and relevant vascular variables in conscious sheep. Recordings were performed at baseline, as well as after the infusion of a β-adrenoceptor blocker (propranolol) to determine the role of β-adrenergic signalling in sympathetic transduction in the heart. The results show that after every burst of CSNA, there was a significant effect of time on HR (n=10, ∆: +2.1±1.4 beatsmin-1 , P=0.002) and CO (n=8, ∆: +100±150mLmin-1 , P=0.002) was elevated, followed by an increase in CoBF (n=9, ∆: +0.76mLmin-1 , P=0.001) and CVC (n=8, ∆: +0.0038mLmin-1 mmHg-1 , P=0.0028). The changes in HR were graded depending on the size and pattern of CSNA bursts. The HR response was significantly attenuated after the infusion of propranolol. Our study is the first to explore resting sympathetic transduction in the heart, suggesting that CSNA can dynamically change HR mediated by an action on β-adrenoceptors. KEY POINTS: Sympathetic transduction is the study of how impulses of sympathetic nerve activity (SNA) affect end-organ function. Previous studies have examined sympathetic transduction primarily in the skeletal muscle and shown that bursts of muscle SNA alter blood flow to skeletal muscle and mean arterial pressure, although this has not been examined in the heart. We investigated sympathetic transduction in the heart and show that, in the conscious condition, the size of bursts of SNA to the heart can result in incremental increases in heart rate and coronary blood flow mediated by β-adrenoceptors. The pattern of bursts of SNA to the heart also resulted in incremental increases in heart rate mediated by β-adrenoceptors. This is the first study to explore the transduction of bursts of SNA to the heart.

The regulatory effects of mesedin and beditin alpha2-adrenoblockers on the functional activity of the nervous, cardiovascular, and endocrine systems in rats under the hypoxic conditions.

One of the reasons of the development of pathologies causing death is hypoxia. The purposes of this study were (1) to study some physiological and biochemical mechanisms of α2-adrenoblockers, which ensure the tissue resistance increase to hypoxia; (2) to offer new drugs contributing to the increase of tissues' stability towards the hypoxic affection; and (3) to submit new medications to surpass by their anti-hypoxic activity of those already used in modern medicine and have some advantages. The reactivity of postsynaptic vascular α2-adrenoceptors was determined on the damaged spinal cord expressed by the blood pressure increase in response to intravenous administration of azepexole that selectively binds to α2-adrenoceptors. Determination of the systemic hemodynamic values and the vascular resistance to the blood flow was performed by the method with plastic microspheres of marked isotopes. pO2 in the blood and the oxygen-transporting function were determined in a sample of 0.1ml of blood in 30, 90, and 180min after the α2-adrenoblockers' injections. It has been found that one of the major hemodynamic effects of mesedin and beditin was an improvement in cardiac output, as well as a prolonged increase in coronary blood flow and vasodilation of the heart vessels. Some anti-hypoxic mechanisms of the studied α2-adrenoblockers are an improvement of blood oxygen-transporting function followed by tissue oxygenation and the increased level of corticosterone and resistance to hypoxia. Revealing the mechanisms of action of the postsynaptic α2-adrenoceptors suggests that mesedin and beditin are potentially effective therapeutic means for many hypoxic conditions.

Muscle metaboreflex stimulates the cardiac sympathetic afferent reflex causing positive feedback amplification of sympathetic activity: effect of heart failure.

Exercise intolerance is a hallmark symptom of heart failure and to a large extent stems from reductions in cardiac output that occur due to the inherent ventricular dysfunction coupled with enhanced muscle metaboreflex-induced functional coronary vasoconstriction, which limits increases in coronary blood flow. This creates a further mismatch between O2 delivery and O2 demand, which may activate the cardiac sympathetic afferent reflex (CSAR), causing amplification of the already increased sympathetic activity in a positive-feedback fashion. We used our chronically instrumented conscious canine model to evaluate if chronic ablation of afferents responsible for the CSAR would attenuate the gain of muscle metaboreflex before and after induction of heart failure. After afferent ablation, the gain of the muscle metaboreflex control of mean arterial pressure was significantly reduced before (-239.5 ± 16 to -95.2 ± 8 mmHg/L/min) and after the induction of heart failure (-185.6 ± 14 to -95.7 ± 12 mmHg/L/min). Similar results were observed for the strength (gain) of muscle metaboreflex control of heart rate, cardiac output, and ventricular contractility. Thus, we conclude that the CSAR contributes significantly to the strength of the muscle metaboreflex in normal animals with heart failure serving as an effective positive-feedback amplifier thereby further increasing sympathetic activity.NEW & NOTEWORTHY The powerful pressor responses from the CSAR arise via O2 delivery versus O2 demand imbalance. Muscle metaboreflex activation (MMA) simultaneously elicits coronary vasoconstriction (which is augmented in heart failure) and profound increases in cardiac work thereby upsetting oxygen balance. Whether MMA activates the CSAR thereby amplifying MMA responses is unknown. We observed that removal of the CSAR afferents attenuated the strength of the muscle metaboreflex in normal and subjects with heart failure.

Altered autonomic control or coronary artery blood flow by the aortic body chemoreceptors in conscious normotensive and hypertensive sheep

Peripheral arterial chemoreceptors monitor the chemical composition of the blood. While, the carotid bodies located at the bifurcation of the common carotid arteries have been extensively studied. The physiological role of the aortic bodies located in the walls of the aortic arch remains relatively under-studied, and its role in hypertension is unexplored.We hypothesized that activation of the aortic bodies would increase coronary blood flow in the normotensive state and that the parasympathetic nerves to the heart would mediate this.Experiments were conducted in conscious and anesthetized ewes instrumented to record arterial pressure, coronary blood flow, and cardiac output. Two groups of animals were studied, one made hypertensive using a 2 kidney one-clip model (HTN. n=6) and a sham-clipped normotensive group (Con. n=6). Unilateral renal clipping increased resting mean arterial pressure (Con: 84±5 vs HTN 115±6 mmHg). The aortic body chemoreceptors were stimulated by a bolus infusion of potassium cyanide (KCN; 10-30 μg/kg) into the left ventricle.Activation of the aortic bodies in the normotensive and hypertensive animals resulted in a significant increase in coronary blood flow ( P&lt;0.05, 2-way ANOVA, interaction effect), which was not different between groups. In normotensive sheep, the aortic body chemoreflex-mediated coronary vasodilation was attenuated by atropine infusion. Interestingly, the coronary vasodilation in hypertensive animals was not altered by the blockade of muscarinic receptors but was attenuated after propranolol infusion ( P&lt;0.05, interaction effect). Bilateral vagotomy is not possible in conscious animals; under anesthesia, the coronary blood flow response to aortic body stimulation was significantly attenuated in normotensive sheep. Neither atropine nor propranolol affected the aortic body chemoreflex meditated changes in either group's blood pressure, heart rate, or cardiac output. This data suggests that the aortic bodies play an important role in modulating coronary blood flow and that their effector mechanism is altered in hypertension. Many patients with hypertension are on beta-blockers. Our finding indicates that the aortic bodies modulate coronary blood flow via a beta-adrenergic mechanism in hypertension, which may have important implications for regulating coronary blood flow during exertion in hypertensive patients. Work is supported by the Health Research Council (HRC) of New Zealand. This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

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.

Abstract 14553: Clonal Hematopoiesis of Indeterminate Potential is Associated With Atrial Fibrillation in Patients With Early Coronary Artery Disease

Introduction: The mechanistic link between early coronary artery disease (CAD) and atrial fibrillation (AF) continues to be explored. Clonal hematopoiesis of indeterminate potential (CHIP) is increasingly recognized as a risk factor for cardiovascular disease. We hypothesize CHIP further increases the risk for AF in early CAD. Methods: 184 participants underwent invasive coronary angiogram with endothelial function testing. Buffy coat was used for whole exosome sequencing to identify CHIP (variant allele frequency &gt; 2% and minor allele frequency ≤ 0.1%). Early CAD was defined by the presence of coronary endothelial dysfunction (CED) in the absence of obstructive CAD. Invasive coronary angiography with endothelial function testing characterized CED as ≥ 20% increase in coronary artery diameter or ≤ 50% increase in coronary blood flow in response to acetylcholine. AF was identified by ICD-10 code or patient survey and confirmed by an independent investigator by chart review. Cox proportional hazard regression was adjusted for age, sex, and conventional cardiovascular comorbidities (hypertension, diabetes, and total cholesterol). Results: Of the 184 participants, we identified 23 cases with both early CAD and CHIP and 62 normal controls without CHIP or CAD. Case patients were significantly older (mean 60 ±9 vs 52 ±10 years, p = 0.004 years) and predominantly female (74% vs 81%, p = 0.506). AF was more likely among case participants when compared to normal controls (29% vs 10%, p = 0.036). Mean time to AF or last follow-up was 11 ±7 years. Case patients with both early CAD and CHIP were nearly 10 times more likely to develop AF when compared to normal controls in a Cox regression model adjusted for age, sex, and conventional cardiovascular comorbidities (HR 9.52, 95% CI 1.93 - 47.02, p = 0.006). The risk for AF was not significant if we defined cases by only the presence of CHIP (n = 30) or early CAD (n = 122). Conclusions: Patients with both CHIP and early CAD may have greater risk for developing AF beyond the presence of CHIP or CAD alone. Our findings suggest an added mechanistic role of CHIP that further increases the risk for AF in early CAD.

Haemodynamic characterisation of different endotypes in coronary artery vasospasm in reaction to acetylcholine.

Vasoreactivity testing with high-dose acetylcholine is considered vasospasm provocation and low-dose as endothelial function testing. To assess the changes in reaction to low- and high-dose acetylcholine in the endotypes of CAS as defined by the Coronary Vasomotor Disorders International Study Group (COVADIS) working group. Changes in coronary epicardial diameter, coronary blood flow (CBF) and vascular resistance were determined at low-dose acetylcholine. A total of 88 ANOCA patients were included in this analysis. In the negative group (n=14) incremental infusion of acetylcholine produced a progressive increase in CBF (p=0.008). In reaction to low-dose acetylcholine, the epicardial vasospasm group (n=30) is characterised by epicardial vasoconstriction that is significantly more severe compared to the microvascular vasospasm group (p=0.004)(n=23). The equivocal group (n=21) is characterised by an increase in CBF and reduction in vascular resistance that are both significantly different compared to the epicardial vasospasm group (p=0.036 and p=0.007, respectively). High-dose acetylcholine decreased epicardial diameter and CBF significantly in the epicardial vasospasm, microvascular vasospasm and in the equivocal group (all p<0.05. Vascular resistance increased significantly in the epicardial vasospasm group (p<0.001) and equivocal group (p=0.009). In reaction to low-dose acetylcholine the negative and equivocal endotype has haemodynamic changes that suggest intact endothelium. In reaction to high-dose acetylcholine the epicardial vasospasm, microvascular vasospasm and equivocal endotype have hemodynamic changes that suggest VSMC-hyperreactivity. These results suggest that the equivocal endotype is a positive test comparable to microvascular vasospasm in the presence of normal endothelial function.

Presence of Coronary Endothelial Dysfunction, Coronary Vasospasm, and Adenosine-Mediated Vasodilatory Disorders in Patients With Ischemia and Nonobstructive Coronary Arteries.

Coronary function testing in patients with ischemia and nonobstructive coronary arteries (INOCA) commonly includes assessment of adenosine-mediated vasodilation and acetylcholine spasm provocation. The purpose of this study was to evaluate the diagnostic value of additional endothelial function testing for the diagnosis of vasomotor dysfunction in patients with INOCA. In this retrospective cohort study, we included patients with INOCA who underwent clinically indicated comprehensive coronary function testing. Endothelial dysfunction was defined as a <50% increase in coronary blood flow, determined by Doppler flow, and/or epicardial vasoconstriction compared to baseline, in response to low-dose acetylcholine. Coronary artery spasm (CAS) was defined as vasospastic angina or microvascular angina in response to coronary high-dose acetylcholine. An impaired adenosine-mediated vasodilation was defined as a coronary flow reserve <2.5 and/or hyperemic microvascular resistance ≥2.5. Among all 110 patients, 79% had endothelial dysfunction, 62% had CAS, and 29% had an impaired adenosine-mediated vasodilation. Endothelial dysfunction was present in 80% of patients who tested positively for CAS and/or an impaired adenosine-mediated vasodilation. Endothelial function testing increases the diagnostic yield of coronary function testing that only incorporates adenosine testing and spasm provocation by 17% to 92%. Of patients with normal adenosine-mediated vasodilation and no inducible CAS, 68% had endothelial dysfunction. Concomitant endothelial dysfunction was prevalent in the vast majority of patients with INOCA with inducible CAS and/or an impaired adenosine-mediated vasodilation. In patients with INOCA without inducible CAS and normal adenosine-mediated vasodilation, two-thirds had endothelial dysfunction. These results indicate the relevance to perform endothelial function testing in patients with INOCA in view of its therapeutic implication.

Aortic Body Chemoreceptors Regulate Coronary Blood Flow in Conscious Control and Hypertensive Sheep.

Peripheral arterial chemoreceptors monitor the chemical composition of arterial blood and include both the carotid and aortic bodies (ABs). While the role of the carotid bodies has been extensively studied, the physiological role of the ABs remains relatively under-studied, and its role in hypertension is unexplored. We hypothesized that activation of the ABs would increase coronary blood flow in the normotensive state and that this would be mediated by the parasympathetic nerves to the heart. In addition, we determined whether the coronary blood flow response to stimulation of the ABs was altered in an ovine model of renovascular hypertension. Experiments were conducted in conscious and anesthetized ewes instrumented to record arterial pressure, coronary blood flow, and cardiac output. Two groups of animals were studied, one made hypertensive using a 2 kidney one clip model (n=6) and a sham-clipped normotensive group (n=6). Activation of the ABs in the normotensive animals resulted in a significant increase in coronary blood flow, mediated, in part by a cholinergic mechanism since it was attenuated by atropine infusion. Activation of the ABs in the hypertensive animals also increased coronary blood flow (P<0.05), which was not different from the normotensive group. Interestingly, the coronary vasodilation in the hypertensive animals was not altered by blockade of muscarinic receptors but was attenuated after propranolol infusion. Taken together, these data suggest that the ABs play an important role in modulating coronary blood flow and that their effector mechanism is altered in hypertension.

Hypoxemia Augments the Local Metabolic Error Signal and Improves Coronary Pressure‐Flow Autoregulation

The local metabolic hypothesis proposes that myocardial oxygen tension, indexed by coronary venous PO2 (CvPO2), determines the degree of coronary pressure‐flow autoregulation by increasing the production of vasodilator metabolites as coronary perfusion pressure (CPP) is reduced. We tested this hypothesis by examining the extent to which exaggeration of the metabolic error signal influences coronary autoregulatory capability. Experiments were performed in anesthetized, open chest swine (n = 8) in which the left anterior descending coronary artery was cannulated and connected to a servo‐controlled roller pump system. This allowed CPP to be reduced from 140 to 40 mmHg in increments of 10 mmHg before and during hypoxemia (PaO2 from 138 ± 5 to 34 ± 1 mmHg). Under control‐normoxic conditions, CvPO2 decreased from 33 ± 1 to 20 ± 1 mmHg and coronary blood flow fell from 0.81 ± 0.09 to 0.35 ± 0.04 ml/min/g as CPP was reduced from 140 to 40 mmHg. Hypoxemia augmented myocardial oxygen consumption (P &lt; 0.01), increased coronary blood flow (P &lt; 0.0001), and reduced CvPO2 (22 ± 1 to 14 ± 1 mmHg; P &lt; 0.0001) over the same range of CPPs. Increases in coronary blood flow during hypoxemia were sufficient to maintain myocardial oxygen delivery at values equivalent to normoxic conditions (P = 0.20). Calculation of closed‐loop autoregulatory gain (Gc) over a CPP range of 120 to 60 mmHg (value of 1 represents perfect autoregulation) demonstrated that Gc was improved from 0.18 ± 0.05 to 0.45 ± 0.14 under normoxic vs. hypoxemic conditions respectively (P = 0.02). Gc was also inversely related to CvPO2 and the slope increased ~4‐fold by hypoxemia. These findings support that coronary pressure‐flow autoregulatory capability is augmented by hypoxemia‐induced increases in the local metabolic error signal.

Modeling the oxygen transport to the myocardium at maximal exercise at high altitude.

Exposure to high altitude induces a decrease in oxygen pressure and saturation in the arterial blood, which is aggravated by exercise. Heart rate (HR) at maximal exercise decreases when altitude increases in prolonged exposure to hypoxia. We developed a simple model of myocardial oxygenation in order to demonstrate that the observed blunting of maximal HR at high altitude is necessary for the maintenance of a normal myocardial oxygenation. Using data from the available scientific literature, we estimated the myocardial venous oxygen pressure and saturation at maximal exercise in two conditions: (1) with actual values of maximal HR (decreasing with altitude); (2) with sea‐level values of maximal heart rate, whatever the altitude (no change in HR). We demonstrated that, in the absence of autoregulation of maximal HR, myocardial tissue oxygenation would be incompatible with life above 6200 m–7600 m, depending on the hypothesis concerning a possible increase in coronary reserve (increase in coronary blood flow at exercise). The decrease in maximal HR at high altitude could be explained by several biological mechanisms involving the autonomic nervous system and its receptors on myocytes. These experimental and clinical observations support the hypothesis that there exists an integrated system at the cellular level, which protects the myocardium from a hazardous disequilibrium between O2 supply and O2 consumption at high altitude.