Coronary Artery Constriction Research Articles

The Beneficial Effect of the SGLT2 Inhibitor Dapagliflozin in Alleviating Acute Myocardial Infarction-Induced Cardiomyocyte Injury by Increasing the Sirtuin Family SIRT1/SIRT3 and Cascade Signaling.

Sodium-glucose cotransporter-2 inhibitors (SGLT2i) have a variety of cardiovascular and renoprotective effects and have been developed as novel agents for the treatment of heart failure. However, the beneficial mechanisms of SGLT2i on cardiac tissue need to be investigated further. In this study, we established a mouse model of acute myocardial infarction (AMI) using coronary artery constriction surgery and investigated the role of dapagliflozin (DAPA) in protecting cardiomyocytes from hypoxic injury induced by AMI. In vitro experiments were done using hypoxic cultured H9c2 ventricular cells to verify this potential mechanism. Expression of the SIRT family and related genes and proteins was verified by qPCR, Western blotting and immunofluorescence staining, and the intrinsic potential mechanism of cardiomyocyte death due to AMI and hypoxia was comprehensively investigated by RNA sequencing. The RNA sequencing results of cardiomyocytes from AMI mice showed that the SIRT family may be mainly involved in the mechanisms of hypoxia-induced cardiomyocyte death. In vitro hypoxia-induced ventricular cells showed the role of dapagliflozin in conferring resistance to hypoxic injury in cardiomyocytes. It showed that SIRT1/3/6 were downregulated in H9c2 cells in a hypoxic environment, and the addition of dapagliflozin significantly increased the gene and protein expression of SIRT1, 3 and 6. We then verified the underlying mechanisms induced by dapagliflozin in hypoxic cardiomyocytes using RNA-seq, and found that dapagliflozin upregulated the hypoxia-induced gene downregulation, which includes ESRRA, EPAS1, AGTRAP, etc., that associated with SIRTs-related and apoptosis-related signaling to prevent H9c2 cell death. This study provides laboratory data for SGLT2i dapagliflozin treatment of AMI and confirms that dapagliflozin can be used to treat hypoxia-induced cellular necrosis in cardiomyocytes, in which SIRT1 and SIRT3 may play an important role. This opens up further opportunities for SGLT2i in the treatment of heart disease.

Factors Contributing to Coronary Microvascular Dysfunction in Patients with Angina and Non-Obstructive Coronary Artery Disease.

Coronary microvascular dysfunction (CMD), characterised by a reduced coronary flow reserve (CFR) or an increased index of microcirculatory resistance (IMR), has received considerable attention as a cause of chest pain in recent years. However, the risks and causes of CMD remain unclear; therefore, effective treatment strategies have not yet been established. Heart failure or coronary artery disease (CAD) is a risk factor for CMD, with a higher prevalence among women. However, the other contributing factors remain unclear. In this study, we assessed the risk in patients with angina and non-obstructive coronary artery disease (ANOCA), excluding those with heart failure or organic stenosis of the coronary arteries. Furthermore, we analysed whether the risk of CMD differed according to component factors and sex. This study included 84 patients with ANOCA (36 men and 48 women; mean age, 63 years) who underwent coronary angiography and functional testing (CFT). The CFT included a spasm provocation test (SPT), followed by a coronary microvascular function test (CMVF). In the SPT, patients were mainly provoked by acetylcholine (ACh), and coronary spasm was defined as >90% transient coronary artery constriction on coronary angiography, accompanied by chest pain or ischaemic changes on electrocardiography. In 15 patients (18%) with negative ACh provocation, ergonovine maleate (EM) was administered as an additional provocative drug. In the CMVF, a pressure wire was inserted into the left anterior descending coronary artery using intravenous adenosine triphosphate, and the CFR and IMR were measured using previously described methods. A CFR < 2.0 or IMR ≥ 25 was indicative of CMD. The correlations between various laboratory indices and CMD and its components were investigated, and logistic regression analysis was performed, focusing on factors where p < 0.05. Of the 84 patients, a CFR < 2.0 was found in 22 (26%) and an IMR ≥ 25 in 40 (48%) patients, with CMD identified in 46 (55%) patients. CMD was correlated with smoking (p = 0.020) and the use of EM (p = 0.020). The factors that correlated with a CFR < 2.0 included the echocardiograph index E/e' (p = 0.013), which showed a weak but positive correlation with the CFR (r = 0.268, p = 0.013). Conversely, the factors correlated with an IMR ≥ 25 included RAS inhibitor usage (p = 0.018) and smoking (p = 0.042). Assessment of the risk of CMD according to sex revealed that smoking (p = 0.036) was the only factor associated with CMD in men, whereas the left ventricular mass index (p = 0.010) and low glycated haemoglobin levels (p = 0.012) were associated with CMD in women. Our results indicated that smoking status and EM use were associated with CMD. The risk of CMD differed between the two CMD components and sex. Although these factors should be considered when treating CMD, smoking cessation remains important. In addition, CMD assessment should be performed carefully when EM is used after ACh provocation. Further validation of our findings using prospective studies and large registries is warranted.

Intramyocardial injection of hypoxia-conditioned extracellular vesicles increases myocardial perfusion in a swine model of chronic coronary disease

ObjectiveCoronary artery disease remains a leading cause of morbidity and mortality worldwide. Patients with advanced coronary artery disease who are not eligible for endovascular or surgical revascularization have limited options. Extracellular vesicles have shown potential to improve myocardial function in preclinical models. Extracellular vesicles can be conditioned to modify their components. Hypoxia-conditioned extracellular vesicles have demonstrated the ability to reduce infarct size and apoptosis in small animals. Our objective is to assess the potential benefits of hypoxia-conditioned extracellular vesicles in a large animal model of coronary artery disease. MethodsCoronary artery disease was induced in 14 Yorkshire swine by ameroid constriction of the left circumflex coronary artery. Two weeks postsurgery, swine underwent a repeat left thoracotomy for injections of hypoxia-conditioned extracellular vesicles (n = 7) or saline (control, n = 7). Five weeks later, all animals underwent terminal harvest for perfusion measurements and myocardial sectioning. ResultsMyocardial perfusion analysis demonstrated a trend toward increase at rest and a significant increase during rapid pacing (P = .09, P < .001). There were significant increases in activated phosphorylated endothelial nitric oxide synthase, endothelial nitric oxide synthase, phosphatidylinositol 3-kinase, phosphorylated protein kinase B, and the phosphorylated protein kinase B/protein kinase B ratio in the hypoxia-conditioned extracellular vesicles group compared with the control group (all P < .05). Additionally, there was a significant decrease in the antiangiogenic proteins collagen 18 and angiostatin (P = .01, P = .01) in the hypoxia-conditioned extracellular vesicles group. ConclusionsIntramyocardial injection of hypoxia-conditioned extracellular vesicles results in increased myocardial perfusion without a corresponding change in vessel density. Therefore, this improvement in perfusion is possibly due to changes in nitric oxide signaling. Hypoxia-conditioned extracellular vesicles represent a potential therapeutic strategy to increase myocardial perfusion in patients with advanced coronary artery disease.

Abstract 14662: What Factors Contribute to the Presence of Coronary Microvascular Dysfunction in Patients With Non-Obstructive Coronary Artery Disease?

Introduction: In recent years, there has been growing interest in coronary microvascular dysfunction (CMD). Several risk factors have been discussed as causes of CMD, but there are still many unknowns. Hypothesis: In this study, we evaluated clinical risk factors for CMD in patients with chest pain with non-obstructive coronary artery disease (INOCA). Methods: Sixty-two patients who were able to undergo comprehensive coronary angiography at the time of chest pain screening were included in the study. Patients with a history of heart failure were excluded. Comprehensive angiography excluded patients with organic coronary artery stenosis (%stenosis&gt;50%) and was performed with the spasm provocation test using acetylcholine (ACh) to induce coronary spasm and with a pressure wire to evaluate CMD. Positive coronary spasm was defined as the presence of usual chest pain or electrocardiographic changes and &gt;90% coronary artery constriction on angiograms in response to ACh provocation. In addition, a coronary spasm within one section of the American Heart Association’s classification was defined as a focal spasm. CMD was defined as the presence of coronary flow reserve (CFR) &lt; 2.0 or an index of microcirculatory resistance (IMR) ≥ 25 obtained from a pressure wire. The clinical background leading to CMD was investigated and evaluated by logistic analysis. Results: Of 62 patients with INOCA, 26 (42%) had CMD. The results are shown in the table. Conclusions: These results suggested that factors contributing to CMD in INOCA patients were diverse: women, smoking, focal spasm, and elevated NTproBNP level. It is necessary to identify the cause of CMD before treatment in such patients.

Role of Dopamine in the Heart in Health and Disease.

Dopamine has effects on the mammalian heart. These effects can include an increase in the force of contraction, and an elevation of the beating rate and the constriction of coronary arteries. Depending on the species studied, positive inotropic effects were strong, very modest, or absent, or even negative inotropic effects occurred. We can discern five dopamine receptors. In addition, the signal transduction by dopamine receptors and the regulation of the expression of cardiac dopamine receptors will be of interest to us, because this might be a tempting area of drug development. Dopamine acts in a species-dependent fashion on these cardiac dopamine receptors, but also on cardiac adrenergic receptors. We will discuss the utility of drugs that are currently available as tools to understand cardiac dopamine receptors. The molecule dopamine itself is present in the mammalian heart. Therefore, cardiac dopamine might act as an autocrine or paracrine compound in the mammalian heart. Dopamine itself might cause cardiac diseases. Moreover, the cardiac function of dopamine and the expression of dopamine receptors in the heart can be altered in diseases such as sepsis. Various drugs for cardiac and non-cardiac diseases are currently in the clinic that are, at least in part, agonists or antagonists at dopamine receptors. We define the research needs in order to understand dopamine receptors in the heart better. All in all, an update on the role of dopamine receptors in the human heart appears to be clinically relevant, and is thus presented here.

Clinical Characteristics and Prognosis of Patients with Vasospastic Angina Subjected to the Spasm Provocation Test and the Unavoidable Use of Nitroglycerin.

Multi-vessel spasm (MVS) has a prognostic impact in patients with vasospastic angina (VSA). Thus, the presence of coronary spasm in both the left coronary artery (LCA) and right coronary artery (RCA) should be assessed through the spasm provocation test (SPT). Nitroglycerin (NTG) is used to avoid SPT-related complications; however, this unavoidable use of NTG may decrease the detection of MVS. Therefore, we investigated the frequency of the unavoidable use of NTG during SPT and clarified the clinical characteristics in patients with VSA who underwent the unavoidable use of NTG during STP. A total of 141 patients with positive SPT were evaluated. A positive SPT was defined as &gt; 90% constriction in epicardial coronary arteries in response to acetylcholine, accompanied by the usual chest symptoms and/or ischaemic ST-T changes on electrocardiography. When a coronary spasm occurred, we usually wait for the spontaneous relief of the coronary spasm. However, if a prolonged coronary spasm or unstable haemodynamics occurred, 0.3 mg NTG was administered intracoronarily to promptly relieve the coronary spasm and this was defined as the unavoidable use of NTG. Even when the unavoidable use of NTG was administered in one coronary artery, an additional SPT was performed on another coronary artery. If a coronary spasm occurred in another coronary artery, a positive SPT was diagnosed. In contrast, if a coronary spasm was not induced after the unavoidable use of NTG, the judgement was classified as undiagnosed. The patients were divided into two groups according to the unavoidable use of NTG: U-NTG (n = 42) and the final use of NTG: F-NTG (n = 99). The clinical characteristics and frequencies of MVS (≥2 major coronary arteries in which a coronary spasm was provoked) and complications (malignant arrhythmia and unstable haemodynamics requiring catecholamines) during the SPT were compared between the groups. Except for smoking status, all other clinical characteristics did not differ significantly between the groups. More current smokers were observed in the U-NTG group (29%) than in the F-NTG group (12%, p = 0.02). The frequency of MVS did not vary significantly between the groups (p = 0.28), with 64% for U-NTG and 55% for F-NTG. No significant difference was found between the groups in the frequency of severe complications during SPT (p = 0.83), with 2% for U-NTG and 3% for F-NTG. In the U-NTG group, the positive induction rate of coronary spasm in another coronary artery was 40% (17/42). Conclusions: The unavoidable use of NTG occurred in ~30% of patients with VSA, most of whom were current smokers. It did not decrease the detection of MVS and potentially prevented severe complications during SPT. Therefore, the unavoidable use of NTG is acceptable during SPT. However, an additional test may need to be performed to assess the presence of MVS.

Refractory Coronary Vasospasm After Spine Surgery; A Rare Case Report

Refractory vasospastic angina (RVSA) is a rare condition leading to several episodes of constriction of coronary arteries which eventually leads to myocardial ischemia. Calcium-channel blockers (CCBs) and nitrates are usually used, however, sometimes the vasospasm is refractory and recurrent leading to high morbidity and mortality. A 35-year-old man known case of hypertension underwent two times operation due to T9-T10 discopathy and decompressive laminectomy of three segments T8/T9/ T10 following a previous car accident 4 months before this admission. Three days postoperatively he developed chest pain, dyspnea and diaphoresis. Electrocardiography showed inverted T wave in leads I, II and ST elevation in pericardial leads of V1-V4. Left anterior descending (LAD) artery stenosis was present (99%) at mid part that resolved after Trinitroglycerin (TNG) injection during angiography. Totally, he underwent 3 times coronary angiography due to recurrent chest pain refractory to conventional management of Prinzmetal’s angina. Coronary stent could not be placed due to severe spasm. Finally, he developed refractory chest pain and dyspnea and cardiac arrest in the CCU despite receiving intravenous high dose TNG, Diltiazem, Nicorandil and Hydrocortisone. He expired after several times of cardiopulmonary resuscitation. Refractory VSA after spine surgery has not been reported in the literature yet. This patient was resistant to available medications. There is no consensus regarding the treatment unfortunately. Randomized clinical trials have to be done to find ways regarding unconventional treatment options such as alpha-2-agonists, Corticosteroids, rho-kinase-inhibitors, statins and magnesium. Despite the fact, some surgical interventions with sympathetic denervation like left-stellate-ganglion denervation must be assessed.

DELAYED-ONSET CORONARY VASOSPASM FOLLOWING RADIOFREQUENCY CATHETER ABLATION OF ATRIAL FIBRILLATION

DELAYED-ONSET CORONARY VASOSPASM FOLLOWING RADIOFREQUENCY CATHETER ABLATION OF ATRIAL FIBRILLATION

Abstract 12505: Clinical Characteristics of Patients With Vasospastic Angina Subjected to the Spasm Provocation Test Involving the Unavoidable Use of Nitroglycerin

Introduction: Multivessel spasm (MVS) has a prognostic impact in patients with vasospastic angina (VSA). Thus, assessing for the presence of MVS in both left coronary artery and right coronary artery is preferable in the spasm provocation test (SPT). The use of nitroglycerin is necessary to avoid the complications related to SPT; however, this unavoidable use of NTG (U-NTG) may decrease the detection of MVS. Hypothesis: We investigated the frequency of U-NTG during SPT and clarified the clinical characteristics in VSA patients, with U-NTG during STP. Methods: Total 142 patients with positive SPT were evaluated. A positive SPT was defined as &gt;90% constriction in coronary arteries, accompanied by the chest symptoms and/or ischemic ST-T changes. When a coronary spasm occurred, we usually waited for the spontaneous relief of the coronary spasm. However, if a prolonged coronary spasm or unstable hemodynamics occurred, NTG was administered to relieve the coronary spasm promptly (U-NTG). Even when U-NTG was administered in one coronary artery, an additional SPT was performed on another coronary artery. The patients were divided into two groups according to U-NTG: U-NTG(+) (n = 42) and U-NTG(-), (n = 100). The clinical characteristics and frequencies of MVS and complications (unstable hemodynamics) during the SPT were compared between the groups. Results: Except for smoking status, all other clinical characteristics status did not differ significantly between the groups. More current smokers were observed in the U-NTG(+) group (29%) compared with that in the U-NTG(-) group (12%, p = 0.03). The frequency of MVD did not vary significantly between the groups, with 64% in the U-NTG(+) and 52% in the U-NTG(-). No significant difference was found between the groups in the frequency of severe complications during SPT, with 5% in U-NTG(+) and 3% in U-NTG(-). In U-NTG(+), the positive induction of coronary spasm in another coronary artery was 40% (17/42). Conclusions: Our results show that U-NTG occurred in ~30% of VSA patients, especially in current smokers, and that it did not decrease the detection of MVS and prevented severe complications during SPT. Therefore, U-NTG is acceptable during SPT, after which, another test may be performed to assess the presence of MVS.

Subendothelial Accumulation of Exosomes and Coronary Microvascular Dysfunction in Mice Lacking Acid Ceramidase

Coronary microvascular dysfunction (CMD) has been demonstrated to be one of the major factors contributing to ischemic heart disease. However, the mechanisms initiating CMD remain poorly understood. The present study tested the hypothesis that lysosomal acid ceramidase finely controls subendothelial accumulation of exosomes leading CMD and subsequent myocardial ischemia. Using an endothelial-specific acid ceramidase (AC) gene (mouse gene code: Asah1) knockout (Asah1fl/fl/ECcre) mouse model fed with the Western diet (WD), we found that Asah1fl/fl/ECcre mice on the WD have more thickening of mid-layer in their small coronary arteries as shown significantly increased media/lumen ratio compared to the WD-fed wild type littermates (WT/WT). By nanoparticle tracking analysis (NTA) using NanoSight NS300 nanoparticle analyzer, we also observed that exosomes (~80-130 nm) in the blood stream were markedly increased in WD-fed Asah1fl/fl/ECcre mice compared to WT/WT mice. There were also more exosomes detected in the subendothelial space of coronary arterial wall, as shown by remarkable increase in colocalization of exosome marker CD63 or Annexin II with proteoglycans, bioglycan or decorin (subendothelial matrix markers) in Asah1fl/fl/ECcre mice. By electron microscopy (EM), we further confirmed that Asah1fl/fl/ECcre mice on the WD also significantly augmented the accumulation of exosomes under the endothelium small coronary arteries. Functionally, electrocardiogram (ECG) recording showed that in response to ergonovine, a coronary artery constrictor, the elevation of S-T segment was more remarkable in WD-fed Asah1fl/fl/ECcre than WT/WT mice. Using HypoxyProbe-1, the myocardial ischemic response to ergonovine was also detected more in the heart of WD-fed Asah1fl/fl/ECcre than WT/WT mice. Together, these results indicate that subendothelial exosome accumulation due to defect of lysosomal AC gene expression and activity may be a crucial pathogenic factor for CMD.

Artificial intelligence-derived physiological aging is associated with coronary endothelial dysfunction

Abstract Background An Artificial intelligence (AI)-enabled algorithm can provide an age estimate from a single standard resting ECG. The gap between AI-estimated age (ECG age) and chronological age (Age-Gap) has been associated with total and cardiovascular mortality. We hypothesized that coronary endothelial dysfunction (CED), an early feature of coronary atherosclerosis, is associated with physiological aging, as measured by ECG age. Purpose The aim of this study is to investigate the association of CED, a potential index of cardiac aging, and AI-estimated physiological aging. Methods 1902 patients with signs and/or symptoms of ischemia and with non-obstructive coronary artery disease (&amp;lt;40% angiographic stenosis) who underwent functional coronary angiography with intracoronary (IC) acetylcholine (Ach) infusions and a resting ECG within one year were included in this analysis. CED was defined as coronary artery constriction [%ΔCoronary artery diameter (CAD) &amp;lt;0] in response to IC Ach. Patients were categorized as CED+ or CED−. The ECG age were calculated by a previously-trained AI algorithm that was built using the Keras framework with Tensorflow backend and Python. The association between ECG-age and Age-Gap, with CED was investigated. Results Average chronological age was 50.9±12.5, ECG age was 54.1±11.6, 1261 (66%) were females. Compared to CED−, the CED+ group had more males and hyperlipidaemia (p&amp;lt;0.05 for both). Age-gap was significantly higher in patients with CED+ (Fig. A). Multiple regression analysis showed that CED+ was associated with Age-gap (standardized β [sβ] coefficient = 0.08, P=0.001) even after adjustment for chronological age (sβ coefficient = 0.07, P=0.001), and even after adjusting for other cardiovascular risk factors like gender and obesity (sβ coefficient = 0.07, P&amp;lt;0.0001). Furthermore, there is a significant gradual increase in vasoconstriction, in response to IC Ach, with increasing Age-gap (Fig. B). Conclusion Abnormal coronary endothelial function is associated with an increased AI-estimated age which could indicate a higher physiological age. Funding Acknowledgement Type of funding source: None

Evaluation of myocardial blood flow and coronary flow reserve — the physiological foundation and clinical significance of myocardial perfusion scintigraphy in the examination of patients with chronic coronary syndrome

Non-invasive cardiovascular imaging plays an important role in examination of patients with chronic coronary syndrome. Positron emission tomography (PET) has the highest diagnostic accuracy and prognostic significance due to the ability to assess myocardial blood flow (MBF) and coronary flow reserve (CFR). These physiological processes provide myocardial oxygen demand, both at rest and stress, as well as maintaining sufficient myocardial circulation during coronary artery constriction. At the same time, the high cost and low availability of assessing MBF and CFR by PET do not allow widespread use of this approach in clinical practice. The use of modern gamma cameras with cadmium zinc telluride detectors can be an alternative to PET. The aim of the review is to present fundamental information about MBF and CFR, as well as about the possibilities of using scintigraphy for determination of these parameters and their clinical significance.

BKCa compensates impaired coronary vasoreactivity through RhoA/ROCK pathway in hind-limb unweighted rats.

Previous studies have demonstrated cardiac and vascular remodeling induced by microgravity exposure. Yet, as the most important branch of vasculatures circulating the heart, the coronary artery has been seldomly studied about its adaptations under microgravity conditions. Large-conductance Ca2+-activated potassium channel (BKCa) and the Ras homolog family member A (RhoA)/Rho kinase (ROCK) pathway play key roles in control of vascular tone and mediation of microgravity-induced vascular adjustments. Therefore, we investigated the adaptation of coronary vasoreactivity to simulated microgravity and the role of BKCa and the RhoA/ROCK pathway in it. Four-week-old hind-limb unweighted (HU) rats were adopted to simulate effects of microgravity. Right coronary artery (RCA) constriction was measured by isometric force recording. The activity and expression of BKCa and the RhoA/ROCK pathway were examined by Western blot, patch-clamp recordings, and immunoprecipitation. We found HU significantly decreased RCA vasoconstriction to KCl, serotonin, and U-46619, but increased protein expression and current densities of BKCa, inhibition of which by iberiotoxin (IBTX) further decreased RCA vasoconstriction (P < 0.05). Expression of RhoA and ROCK as well as active RhoA and phosphorylation of myosin light chain (MLC) at Ser19 and MLC phosphatase target-1 at Thr696 were significantly increased by HU, and ROCK inhibitor Y-27632 exerted greater suppressing effect on HU RCA vasoconstriction than that of control (P < 0.05). BKCa opener NS1619 increased HU RCA vasoconstriction, which was blocked by both RhoA and ROCK inhibitor, similar to the effect of IBTX. These results indicate that HU impairs coronary vasoconstriction but enhances BKCa activity acting as a protective mechanism avoiding excessive decrease of coronary vasoreactivity through activation of the RhoA/ROCK pathway.-Wu, Y., Yue, Z., Wang, Q., Lv, Q., Liu, H., Bai, Y., Li, S., Xie, M., Bao, J., Ma, J., Zhu, X., Wang, Z. BKCa compensates impaired coronary vasoreactivity through RhoA/ROCK pathway in hind-limb unweighted rats.

Prevalence of Coronary Endothelial and Microvascular Dysfunction in Women with Symptoms of Ischemia and No Obstructive Coronary Artery Disease Is Confirmed by a New Cohort: The NHLBI-Sponsored Women's Ischemia Syndrome Evaluation-Coronary Vascular Dysfunction (WISE-CVD).

Objective In a separate, contemporary cohort, we sought to confirm findings of the original Women's Ischemia Syndrome Evaluation (WISE). Background The original WISE observed a high prevalence of both invasively determined coronary endothelial and coronary microvascular dysfunction (CMD) that predicted adverse events in follow-up. Methods We comparatively studied the WISE-Coronary Vascular Dysfunction (CVD) cohort (2009-2011), with signs and symptoms of ischemia but without significant CAD, to the original WISE (1997-2001) cohort. CMD was defined as coronary flow reserve (CFR) ≤2.5, or endothelial dysfunction as epicardial coronary artery constriction to acetylcholine (ACH), or <20% epicardial coronary dilation to nitroglycerin (NTG). Results In WISE (n=181) and WISE-CVD (n=235) women, mean age in both was 54 years, and 83% were white (WISE) vs 74% (WISE-CVD, p=0.04). Use of hormone replacement therapy was less frequent in WISE-CVD vs WISE (46% vs 57%, p=0.026) as was presence of hypertension (40% vs 52%, p=0.013), hyperlipidemia (20% vs 46%, p<0.0001), and smoking (46% vs 56%, p=0.036). Similar rates were observed in WISE-CVD and WISE cohorts for CMD (mean CFR 2.7±0.6 vs 2.6±0.8, p=0.35), mean change in diameter with intracoronary ACH (0.2±10.0 vs 1.6±12.8 mm, p=0.34), and mean change in diameter with intracoronary NTG (9.7±13.0 vs 9.8±13.5 mm, p=0.94), respectively. Conclusions This study confirms prevalence of CMD in the contemporary WISE-CVD cohort similar to that of the original WISE cohort, despite a lower risk factor burden in WISE-CVD. Because these coronary functional abnormalities predict major adverse cardiac events, clinical trials of therapies targeting these abnormalities are indicated.

TRPA1 and TRPV1 contribute to propofol-mediated antagonism of U46619-induced constriction in murine coronary arteries.

BackgroundTransient receptor potential (TRP) ion channels have emerged as key components contributing to vasoreactivity. Propofol, an anesthetic is associated with adverse side effects including hypotension and acute pain upon infusion. Our objective was to determine the extent to which TRPA1 and/or TRPV1 ion channels are involved in mediating propofol-induced vasorelaxation of mouse coronary arterioles in vitro and elucidate the potential cellular signal transduction pathway by which this occurs.MethodsHearts were excised from anesthetized mice and coronary arterioles were dissected from control C57Bl/6J, TRPA1-/-, TRPV1-/- and double-knockout mice (TRPAV-/-). Isolated microvessels were cannulated and secured in a temperature-controlled chamber and allowed to equilibrate for 1 hr. Vasoreactivity studies were performed in microvessels pre-constricted with U46619 to assess the dose-dependent relaxation effects of propofol on coronary microvascular tone.ResultsPropofol-induced relaxation was unaffected in vessels obtained from TRPV1-/- mice, markedly attenuated in pre-constricted vessels obtained from TRPA1-/- mice and abolished in vessels obtained from TRPAV-/- mice. Furthermore, NOS inhibition with L-NAME or endothelium denuding abolished the proporfol-induced depressor response in pre-constricted vessels obtained from all mice. In the absence of L-NAME, BKCa inhibition with penitrem A markedly attenuated propofol-mediated relaxation in vessels obtained from wild-type mice and to a lesser extent in vessels obtained from TRPV1-/-, mice with no effect in vessels obtained from TRPA1-/- or TRPAV-/- mice.ConclusionsTRPA1 and TRPV1 appear to contribute to the propofol-mediated antagonism of U46619-induced constriction in murine coronary microvessels that involves activation of NOS and BKCa.

Effects of neuropeptide Y on coronary artery vasomotion in patients with microvascular angina

BackgroundPatients with microvascular angina (exertional angina, positive exercise tests and normal coronary arteriograms) usually have a reduced coronary blood flow reserve. Neuropeptide Y (NPY) is a potent endogenous vasoconstrictor involved in modulation of coronary vasomotor tone and may play a role in microvascular angina. MethodsWe compared the effects of NPY (0.2–1.0pmol/kg, intracoronary) on the vasomotor response of proximal and distal segments of the coronary arteries in 7 patients with microvascular angina, 9 with chronic stable angina, and 9 control individuals. The coronary response to the administration of ergonovine was also assessed in 9 other patients with microvascular angina. Computerized coronary artery diameter measurements were carried out before (baseline) and after the administration of the vasoactive agents. ResultsMean baseline coronary lumen diameters were similar in control, microvascular angina, and coronary artery disease patients. NPY constricted proximal coronary segments by 8±2%, 5±2% and 6±3% and distal segments by 14±2%, 11±2% and 10±2% in control, microvascular angina, and coronary artery disease patients, respectively (p=NS between groups). In patients with microvascular angina, ergonovine constricted proximal coronary segments by 7±1.5% and distal segments by 12.5±3% (p=NS vs. NPY). During NPY administration four microvascular angina patients developed chest pain, ST segment depression, and a marked lengthening of the contrast medium run off, in the absence of epicardial coronary artery spasm. Control individuals and coronary artery disease patients did not experience chest pain, ST segment shifts, or lengthening of the run off during NPY administration. Ergonovine administration caused chest pain and lengthening of the contrast run-off, in the absence of epicardial coronary artery spasm, in one microvascular angina patient. ConclusionsExogenous NPY causes mild epicardial coronary artery constriction which is similar in patients with non-cardiac chest pain, microvascular angina and coronary artery disease. Myocardial ischemia and marked lengthening of the contrast run off in response to NPY occurred in microvascular angina patients but not in control or coronary artery disease patients. An abnormal constrictor response to NPY at the microcirculation level could be the mechanism underlying the ischemic manifestations observed in patients with microvascular angina. Condensed abstract (table of contents)The vasomotor response of proximal and distal coronary artery segments was studied in twenty five patients: 7 microvascular angina, 9 chronic stable angina, and 9 control subjects. Computerized measurements of coronary diameters were carried out before and after the intracoronary administration of neuropeptide Y (NPY) and ergonovine. Constriction of epicardial arteries in response to NPY was mild and not significantly different in control, microvascular angina and coronary artery disease patients. Ergonovine-induced epicardial coronary artery constriction was similar to that of NPY. However, NPY caused transient myocardial ischemia in patients with microvascular angina (probably through constriction of the small intramyocardial vessels), but not in control subjects or coronary artery disease patients.

Feasibility of omitting provocation test with 50μg of acetylcholine in left coronary artery.

According to the Japanese Circulation Society guideline of vasospastic angina, incremental doses of acetylcholine (ACh) are prescribed for coronary spasm provocation: 20 and 50μg for the right coronary artery (RCA), and 20, 50 and 100μg for the left coronary artery (LCA). However, provocation by low doses of ACh in patients with low vasoreactivity may be less needed, and the requirement of 50μg of ACh for the LCA in these patients has not been evaluated. In the present study, patients who underwent ACh provocation test for both the RCA and LCA were included. The positive diagnosis of intracoronary ACh provocation test was defined as total or subtotal coronary artery narrowing (i.e., angiographic coronary artery spasm) accompanied by chest pain and/or ischemic electrocardiographic changes. Coronary artery constriction was visually evaluated and defined as coronary artery diameter reduction <25 or 25-90% in patients without angiographic coronary artery spasm by 20µg of ACh in the LCA. There were 33 out of 249 patients (13%) with LCA spasm by 20µg of ACh. In subjects without LCA spasm by 20µg of ACh, patients with coronary constriction <25% (n=101) by 20µg of ACh in the LCA rarely showed coronary artery spasm induced by 50μg of ACh in the LCA, in comparison to those with coronary constriction 25-90% (n=115) (2.6 vs. 32.7%, p<0.001). None of the patients with coronary constriction <25% by 20µg of ACh in the LCA had cardiac complications associated with administration of ACh. In conclusion, omission of 50µg of ACh in the LCA may be possible when there is little coronary artery constriction by 20µg of ACh in the LCA during provocation test, leading to less contrast and shortens overall procedure time.

Selective subepicardial localization of monocyte subsets in response to progressive coronary artery constriction.

Following myocardial infarction and atherosclerotic lesion development, monocytes contribute to myocardial protection and repair, while also partaking in myocardial ischemic injury. The balance of proinflammatory and reparative monocyte subsets is crucial in governing these therapeutic and pathological outcomes. Myocardial ischemic damage displays heterogeneity across the myocardium, whereby the subendocardium shows greatest vulnerability to ischemic damage. In this study we examined the transmural distribution of monocyte subsets in response to gradual coronary artery occlusion. CD14(+) monocytes were isolated from peripheral blood of New Zealand White rabbits and divided into two subgroups based on the expression of CD62L. We employed a rabbit model of progressive coronary artery obstruction to induce chronic myocardial ischemia and reinfused fluorescently labeled autologous monocytes. The distribution of fluorescently labeled autologous monocytes was examined with a high-resolution three-dimensional imaging cryomicrotome. The subepicardial layer contained the largest infiltration of both monocyte subgroups, with a significantly greater proportion of CD14(+)CD62L(+) monocytes at the time when the ischemic area was at a maximum. By targeting CD13(+) angiogenic vessels, we confirmed the presence of angiogenesis in epicardial and midmyocardial regions. These myocardial regions demonstrated the highest level of infiltration of both monocyte subsets. Furthermore, CD14(+)CD62L(+) monocytes showed significantly greater migration towards monocyte chemoattractant protein-1, greater adhesive capacity, and higher expression of C-C chemokine receptor type-2 relative to CD14(+)CD62L(-) monocytes. In conclusion, we note selective subepicardial distribution of monocyte subpopulations, with changes in proportion depending on the time after onset of coronary narrowing. Selective homing is supported by divergent migratory properties of each respective monocyte subgroup.

Perivascular tissue inhibits rho-kinase-dependent smooth muscle Ca(2+) sensitivity and endothelium-dependent H2 S signalling in rat coronary arteries.

Interactions between perivascular tissue (PVT) and the vascular wall modify artery tone and contribute to local blood flow regulation. Using isometric myography, fluorescence microscopy, membrane potential recordings and phosphospecific immunoblotting, we investigated the cellular mechanisms by which PVT affects constriction and relaxation of rat coronary septal arteries. PVT inhibited vasoconstriction to thromboxane, serotonin and α1 -adrenergic stimulation but not to depolarization with elevated extracellular [K(+) ]. When PVT was wrapped around isolated arteries or placed at the bottom of the myograph chamber, a smaller yet significant inhibition of vasoconstriction was observed. Resting membrane potential, depolarization to serotonin or thromboxane stimulation, and resting and serotonin-stimulated vascular smooth muscle [Ca(2+) ]-levels were unaffected by PVT. Serotonin-induced vasoconstriction was almost abolished by rho-kinase inhibitor Y-27632 and modestly reduced by protein kinase C inhibitor bisindolylmaleimide X. PVT reduced phosphorylation of myosin phosphatase targeting subunit (MYPT) at Thr850 by ∼40% in serotonin-stimulated arteries but had no effect on MYPT-phosphorylation in arteries depolarized with elevated extracellular [K(+) ]. The net anti-contractile effect of PVT was accentuated after endothelial denudation. PVT also impaired vasorelaxation and endothelial Ca(2+) responses to cholinergic stimulation. Methacholine-induced vasorelaxation was mediated by NO and H2 S, and particularly the H2 S-dependent (dl-propargylglycine- and XE991-sensitive) component was attenuated by PVT. Vasorelaxation to NO- and H2 S-donors was maintained in arteries with PVT. In conclusion, cardiomyocyte-rich PVT surrounding coronary arteries releases diffusible factors that reduce rho-kinase-dependent smooth muscle Ca(2+) sensitivity and endothelial Ca(2+) responses. These mechanisms inhibit agonist-induced vasoconstriction and endothelium-dependent vasorelaxation and suggest new signalling pathways for metabolic regulation of blood flow.

Water-soluble jack-knife prawn extract inhibits 5-hydroxytryptamine-induced vasoconstriction and platelet aggregation in humans.

Coronary artery spasm plays an important role in the pathogenesis of various ischemic heart diseases or serious arrhythmia. The aim of this study is to look for functional foods which have physiologically active substances preventing 5-hydroxytryptamine (5-HT)-related vasospastic diseases including peri- and postoperative ischemic complications of coronary artery bypass grafting (CABG) from ocean resources in Japanese coastal waters. First, we evaluated the effect of water-soluble ocean resource extracts on the response to 5-HT in HEK293 cells which have forcibly expressed cyan fluorescent protein-fused 5-HT2A receptors (5-HT2A-CFP). Among 5 different water-soluble extracts of ocean resources, the crude water-soluble jack-knife prawn extract (WJPE) significantly reduced maximal Ca(2+) influx induced by 0.1 μM 5-HT in a concentration-dependent manner. The Crude WJPE significantly inhibited, in a concentration-dependent manner, 5-HT-induced constriction of human saphenous vein. 5-HT released from activated platelets plays a crucial roles in the constriction of coronary artery. Next the WJPE was purified for applying the experiment of 5-HT-induced human platelet aggregation. The purified WJPE significantly inhibited 5-HT-induced human platelet aggregation also in a concentration-dependent manner. Based on our findings, jack-knife prawn could be one of a functional food with health-promoting benefits for most people with vasospastic diseases including patients who have gone CABG.