Coronary Microvascular Disorder Research Articles

The Anti-Anginal Efficacy of Bosentan in the Coronary Slow Flow Phenomenon

Background: The Coronary Slow Flow Phenomenon (CSFP) is a coronary microvascular disorder that presents with recurrent angina for which there is no available effective therapy. The vasoconstrictor Endothelin-1 (ET-1) has been implicated in the pathophysiology of the CSFP. This study aimed to determine whether the ET-1 antagonist (Bosentan) is effective in ameliorating angina symptoms in CSFP patients. Methods: Using a randomised, double-blind, placebo-controlled, cross-over trial methodology, the anti-anginal efficacy of Bosentan 125mg bd was assessed in 23 patients with symptomatic CSFP. Study endpoints were measured following 4 weeks of therapy with the primary endpoint being angina frequency. Secondary endpoints included (1) clinical measures of angina and health status, (2) endothelial function parameters, and (3) inflammatory and oxidative stress markers. Results: There was no statistically significant reduction in angina frequency with Bosentan therapy compared to placebo (median angina episodes/4weeks [25-75% IQ]: Bosentan 14[5,36] vs Placebo 25[9,55]) although a trend for improvement in symptoms during the Bosentan phase was observed. Furthermore, Bosentan did not impact on any of the secondary endpoints compared with placebo. Conclusion: Bosentan did not have a major impact on angina frequency in patients with the CSFP. A small anti-anginal effect cannot be excluded and requires a larger trial.

The Anti-Anginal Efficacy of Bosentan in the Coronary Slow Flow Phenomenon

Background: The Coronary Slow Flow Phenomenon (CSFP) is a coronary microvascular disorder that presents with recurrent angina for which there is no available effective therapy. The vasoconstrictor Endothelin-1 (ET-1) has been implicated in the pathophysiology of the CSFP. This study aimed to determine whether the ET-1 antagonist (Bosentan) is effective in ameliorating angina symptoms in CSFP patients. Methods: Using a randomised, double-blind, placebo-controlled, cross-over trial methodology, the anti-anginal efficacy of Bosentan 125mg bd was assessed in 23 patients with symptomatic CSFP. Study endpoints were measured following 4 weeks of therapy with the primary endpoint being angina frequency. Secondary endpoints included (1) clinical measures of angina and health status, (2) endothelial function parameters, and (3) inflammatory and oxidative stress markers. Results: There was no statistically significant reduction in angina frequency with Bosentan therapy compared to placebo (median angina episodes/4weeks [25-75% IQ]: Bosentan 14[5,36] vs Placebo 25[9,55]) although a trend for improvement in symptoms during the Bosentan phase was observed. Furthermore, Bosentan did not impact on any of the secondary endpoints compared with placebo. Conclusion: Bosentan did not have a major impact on angina frequency in patients with the CSFP. A small anti-anginal effect cannot be excluded and requires a larger trial.

Role of Intracoronary Imaging in Myocardial Infarction with Non-Obstructive Coronary Disease (MINOCA): A Review

Myocardial infarction with non-obstructive coronary artery disease occurs in 6% to 15% of all presentation of myocardial infarctions. The pathophysiologic mechanisms of MINOCA include epicardial vasospasm, coronary microvascular disorder, spontaneous coronary artery dissection, and coronary thrombus/embolism. The diagnosis is challenging, supported by intracoronary imaging with intravascular ultrasound (IVUS) and optical coherent tomography (OCT), coronary physiology testing, and cardiac magnetic resonance imaging (CMR). OCT is able to identify atherosclerotic causes of MINOCA (plaque erosion, plaque rupture, and calcified nodule) and nonatherosclerotic causes (spontaneous artery dissection, and spasm). In this review, we summarize the performance of the two intracoronary imaging modalities (IVUS and OCT) in MINOCA and discuss the importance of supplementing these modalities with CMR in order to drive target therapy.

Myocardial infarction with nonobstructive coronary artery disease (MINOCA): a review of pathophysiology and management.

Myocardial infarction with nonobstructive coronary artery disease (MINOCA) (≥ 50% stenosis) accounts for 5-8% of acute coronary syndrome (ACS) presentations. The demographic characteristics, risk factors, and management of patients with MINOCA differ from those with atherosclerotic ACS. The objective of this review is to provide a contemporary understanding of the epidemiology, pathophysiology, clinical presentation, and management of MINOCA. MINOCA is increasingly being recognized as an important and distinct cause of myocardial infarction among patients presenting with ACS. The predominant pathophysiologic mechanisms of MINOCA include both coronary (epicardial vasospasm, coronary microvascular disorder, spontaneous coronary artery dissection, coronary thrombus/embolism) and noncoronary (Takotsubo cardiomyopathy, myocarditis) pathologies. Coronary imaging with intravascular ultrasound and optical coherent tomography, coronary physiology testing, and cardiac magnetic resonance imaging offers important investigative modalities to facilitate diagnosis for appropriate management of MINOCA patients. MINOCA is an important cause of ACS observed in certain patients with unique challenges for diagnosis and management. A high index of suspicion and a comprehensive diagnostic evaluation are critical for early recognition and successful management.

400.01 Slow Coronary Flow is Associated with Left Ventricular Diastolic Dysfunction and Left Atrial Dilation

Slow coronary flow (SCF) phenomenon is a coronary microvascular disorder characterized by the delayed passage of angiographic contrast in the absence of obstructive epicardial coronary artery disease (CAD). Many patients with SCF suffer from angina-like chest pain and present for angiography

What is the Prognosis for Patients with the Coronary Slow Flow Phenomenon?

Background: The Coronary Slow Flow Phenomenon (CSFP) is an under-recognised coronary microvascular disorder characterised by delayed angiographic distal vessel opacification of contrast, in the absence of significant epicardial coronary stenosis. Although CSFP patients suffer from recurrent chest pain, their prognosis is often considered benign despite a lack of data assessing long term outcomes. Methods: A retrospective medical record review of CSFP patients diagnosed at two tertiary facilities in South Australia between 1987–2014 was conducted to define their long-term clinical outcomes via interrogation of hospital administrative databases and medical record abstraction. Patients were followed up for a minimum of one year from the date of index angiography where CSFP was diagnosed. Results: There were 218 CSFP patients assessed (68% male, 52 ± 12 years). The average follow-up was 12 ± 6 years which was available in 96% of patients (n = 209)Tabled 1OutcomePrevalence in CSFPRepeat Angiography51 (24%)Acute Myocardial Infarction11 (5.2%)Re-hospitalisation for Chest Pain103 (49%)All-Cause Mortality 5 years8 (3.8%)Cardiovascular Mortality 5 years3 (1.4%)All-Cause Mortality 10 years19 (9.7%)Cardiovascular Mortality 10 years4 (2.1%) Open table in a new tab Conclusion: Despite their young age, CSFP patients are at considerable risk for myocardial infarction and suffer significant morbidity with re-hospitalisation for chest pain and repeat angiography common. Since standard treatment strategies have not been established, management approaches are warranted in this population to improve adverse events.

Telmisartan ameliorates vascular endothelial dysfunction in coronary slow flow phenomenon (CSFP).

Coronary slow flow phenomenon (CSFP) is a coronary microvascular disorder with an increasing morbidity, and currently, available therapies are of limited clinical value for its cure. Hence, it is urgent to find a novel approach to CSFP treatment. Several studies show that endothelial dysfunction plays a critical role in the aetiology of CSFP. Telmisartan (TMST) is a clinically available anti-hypertensive medicine and has shown its potential properties for improving vascular endothelial function. Thus, we aimed to investigate the effect of TMST on endothelial dysfunction in CSFP, Endothelial-dependent flow-mediated vasodilation, serum levels of nitric oxide, adiponectin, and endothelin-1 were surveyed before and after 3months of TMST treatment. And the percentages of vasodilator response to acetylcholine (Ach) were detected after 12weeks of TMST treatment. Compare with pretreatment, flow-mediated vasodilation, nitric oxide, and adiponectin were substantially improved after TMST treatment; meanwhile, endothelin-1 was decreased in the TMST group (all P<.01). Compared with the model group, the vasodilator response to Ach was enormously increased after TMST intervention. Additionally, administration of SU11274 or GW9662 would partially reverse the protective effects of TMST on accumulative concentration-vasodilator responses to Ach (P<.01). We demonstrated that administration of TMST could remarkably increase the mRNA and/or protein levels of hepatocyte growth factor, mesenchymal-epithelial transition factor, peroxisome proliferation-activated receptor γ, whereas dramatically diminish mRNA and/or protein levels of p-JNK1/2, mitogen-activated protein kinase, and nuclear factor kappa B (P<.05). Our results thus implicate that TMST ameliorates endothelial dysfunction in CSFP. It is suggested that TSMF may play an important role in the medication of CSFP.

Serum Salusin-β Levels Are Correlated with Slow Coronary Flow.

Slow coronary flow (SCF) is a special coronary microvascular disorder associated with recurrent chest pain. The pathogenesis of SCF remain unclear. We sought to assess whether serum salusin-β levels are correlated with SCF. We enrolled 76 patients with angiographically confirmed SCF and 108 age- and gender-matched controls. We measured serum salusin-β levels by enzyme-linked immunosorbent assay and coronary flow rate was assessed using thrombolysis in myocardial infarction frame count (TFC). Serum salusin-β levels were elevated in SCF patients compared with controls (4.33 [range 3.52-5.87] nmol/L vs. 3.76 [range 2.98-4.67] nmol/L). Multivariate logistic regression analysis revealed that salusin-β in serum was the independent predictor of SCF (odds ratio = 1.814). Serum salusin-β levels were independently correlated with mean-TFC (r = 0.355, p = 0.002). Serum salusin-β levels were independently associated with SCF. Therefore, our findings implicate a potential role of salusin-β in the pathophysiology of SCF and provide insights on both risk stratification and modification in this patient population.

Sex differences in the impact of CYP2C19 polymorphisms and low-grade inflammation on coronary microvascular disorder.

Categorization as a cytochrome P-450 (CYP) 2C19 poor metabolizer (PM) is reported to be an independent risk factor for cardiovascular disease. It is correlated with an increase in the circulating levels of high-sense C-reactive protein (hs-CRP) in women only, although its role in coronary microcirculation is unclear. We examined sex differences in the impact of the CYP2C19 genotype and low-grade inflammation on coronary microvascular disorder (CMVD). We examined CYP2C19 genotypes in patients with CMVD (n = 81) and in healthy subjects as control (n = 81). CMVD was defined as the absence of coronary artery stenosis and epicardial spasms, the presence of inverted lactic acid levels between the intracoronary and coronary sinuses, or an adenosine triphosphate-induced coronary flow reserve ratio < 2.5. CYP2C19 PMs have two loss-of-function (LOF) alleles (*2, *3). Extensive metabolizers have no LOF alleles, and intermediate metabolizers have one LOF allele. The ratio of CYP2C19 PM and hs-CRP levels in CMVD was significantly higher than that of controls, especially in women (40.9 vs. 13.8%, P = 0.013; 0.11 ± 0.06 vs. 0.07 ± 0.04 mg/dl, P = 0.001). Moreover, in each CYP2C19 genotype, hs-CRP levels in CMVD in CYP2C19 PMs were significantly higher than those of the controls, especially in women (0.15 ± 0.06 vs. 0.07 ± 0.03, P = 0.004). Multivariate analysis for CMVD indicated that the female sex, current smoking, and hypertension were predictive factors, and that high levels of hs-CRP and CYP2C19 PM were predictive factors in women only (odds ratio 3.5, 95% confidence interval 1.26-9.93, P = 0.033; odds ratio 4.1, 95% confidence interval 1.15-14.1, P = 0.038). CYP2C19 PM genotype may be a new candidate risk factor for CMVD via inflammation exclusively in the female population.

Abstract 17996: Is There Gender Differences in Effect of CYP2C19 Polymorphisms or Low-grade Inflammation on Coronary Microvascular Disorder (CMVD)?

Background: Specific CYPs localized in vascular smooth muscle and endothelium contribute to the regulation of vascular tone and homeostasis. CYP2C19 poor metabolizer(PM) is reported to be an independent risk factor for coronary artery disease. And, CYP2C19 PM is correlated with an increase in the circulating levels of hs-CRP in female. However, it is unknown whether CYP2C19 genotype is associated with the coronary microvascular disorder (CMVD).So, we examined gender differences in effect of CYP2C19 genotype and low grade inflammation on CMVD. Methods: We examined CYP2C19 genotypes in patients with CMVD (n=54) diagnosed by an intracoronary acetylcholine infusion test, with healthy subjects (n=76) serving as the control. CMVD was defined as the presentation of no coronary artery stenosis in angiography, no epicardial spasms, inversion of lactic acid levels between intracoronary and coronary sinuses in the intracoronary acetylcholine-provocation test, and an adenosine triphosphate-induced CFR&lt;2.5. CYP2C19 genotypes were divided into 3 groups: (1) CYP2C19*1/*1 , extensive metabolizer (EM), (2) one loss-of-function allele (*1/*2, *1/*3; intermediate metabolizer [IM]), and (3) two loss-of-function alleles (*2/*2, *2/*3, *3/*3;[PM]). Results: The ratios of CYP2C19 genotype (EM,IM,and PM) were 31,39,and 30% in CMVD , and 32,49,and 19% in control. There is no significant difference in frequency of CYP2C19 genotype in overall (P=0.146). But, PM frequency was significantly higher in CMVD in only female (34% vs 16%, P=0.042). In level of hs-CRP, there is no significant difference between CMVD and control (0.111±0.080 vs 0.083±0.128,P=0.122), but significantly higher in CMVD in only female (0.112±0.106 vs 0.066±0.106,P=0.002). Moreover, in CMVD, mean of hs-CRP in CYP2C19 PM is significantly higher than that of EM in female (0.115±0.074 vs 0.046±0.039,P=0.034). Multivariate analysis for CMVD indicated that hypertension and chronic kidney disease are predictive factors among all subjects (OR 3.931,P=0.003, OR 3.146,P=0.026). High level of hs-CRP and CYP2C19 PM are predictive factors for CMVD in only female (OR3.864,P=0.047, OR6.079,P=0.042). Conclusion: CYP2C19 PM and low grade inflammation may be associated with CMVD, especially in female.

The role of coronary microvascular disorder in congestive heart failure.

common causes of heart failure are coronary heart disease (coronary artery atherosclerosis), hypertension, cardiomyopathy, and heart valve disease ([4][1]). Accordingly, the most common models of heart failure are coronary arterial occlusion, temporally (partially) or permanently (completely);

Nicorandil improves myocardial function by regulating plasma nitric oxide and endothelin-1 in coronary slow flow.

BackgroundCoronary slow flow (CSF) is a special coronary microvascular disorder. The pathogenesis and effective therapeutics of CSF remain unclear. This study aimed to evaluate the global and regional functions of the left ventricle (LV) and investigate the efficacy of nicorandil in patients with CSF.Patients and methodsThirty-six patients with CSF in the left anterior descending (LAD) branch and 20 patients with normal coronary arteries were included. Global and regional functions of the LV supplied by LAD were measured using conventional Doppler echocardiography and two-dimensional speckle tracking echocardiography, respectively, within 24 h after coronary angiography. Concentrations of plasma nitric oxide (NO) and endothelin-1 (ET-1) were detected using colorimetry and radioimmunoassay, respectively. The function of the LV and the levels of NO and ET-1 were also investigated before and 90 days after treatment with 15 mg/day of nicorandil.ResultsCompared with the control group, the early diastolic peak velocity (E), E/A ratio, and plasma NO levels were lower, whereas the late diastolic peak flow velocity (A) and plasma ET-1 levels were significantly higher in the CSF group (P<0.05). The longitudinal strain rate peak of the LV was reduced significantly in CSF patients (P<0.001). After treatment, 75% (27/36) of CSF patients were free of chest pain. The values of E peak, E/A ratio, longitudinal strain rate peak, and plasma NO level were increased (P<0.001), whereas the ET-1 level was decreased in CSF patients (P<0.001).ConclusionNicorandil may improve chest pain symptoms and the impaired function of the LV, possibly by increasing plasma NO and reducing ET-1 in CSF.

Evaluation of plasma oxidative status in patients with slow coronary flow

Slow coronary flow (SCF) is a coronary microvascular disorder characterised by delayed opacification of coronary vessels in a normal coronary angiogram. Coronary endothelial dysfunction plays an important pathogenetic role in patients with SCF. Oxidative stress is associated with cardiovascular diseases. To assess the total antioxidant capacity (TAC) and total oxidative status (TOS) in patients with SCF. The study included 36 patients with SCF. An age- and gender-matched control group was composed of 30 patients with normal coronary arteries and normal coronary flow. We measured plasma TAC and TOS levels and oxidative stress index(OSI) value in patients and control subjects. Linear regression analysis was performed to identify factors associated with the mean TIMI frame count (TFC). Plasma TOS level and OSI value were significantly higher in the SCF group compared to the control group (p = 0.005 and p = 0.004, respectively). However, there was no significant difference in plasma TAC levels between the groups (p = 0.104). Factors associated with mean TFC were plasma TOS levels (β = 0.425, p = 0.002) and fasting glucose levels (β = 0.099, p = 0.01) in linear regression analysis. We found that plasma TOS and OSI were significantly higher in SCF compared to the control group and plasma TOS levels were independently associated with mean TFC.

Prevalence of Depression in Patients With Chest Pain and Non-Obstructive Coronary Artery Disease

Many studies have demonstrated the prevalence of depression in patients with coronary artery disease (CAD), but few have examined this relation in those with chest pain who do not have obstructive CAD on angiography. The aim of this study was to compare the prevalence of depression amongst patients with chest pain in the presence or absence of obstructive CAD and a healthy control group without chest pain. This prospectively designed, observational cohort study used 2 independent data sets: (1) The Queen Elizabeth Hospital Coronary Angiogram Database (n = 1,144), consisting of 819 patients with obstructive CAD and 325 patients with nonobstructive CAD (NoCAD), all of whom had chest pain and (2) the North West Adelaide Health Study (NWAHS; n = 3,168), a population-based biomedical cohort, from which patients with chest pain were excluded. The presence of depression was determined by a previously validated method using the Short Form 36. The prevalence of depression differed among the 3 groups, with 63% in those with NoCAD, 53% in those with CAD, and only 24% in the healthy NWAHS cohort. Analysis of the angiography cohort revealed age, gender, antidepressant medication, previous myocardial infarction, previous airway disease, Short Form 36 physical summary score, Seattle Angina Questionnaire physical limitation score, and NoCAD on angiography to be independent predictors of depression. In conclusion, these findings highlight the importance of screening for depression in patients with NoCAD.

Acute Effects of Intracoronary Nitroglycerin and Diltiazem in Coronary Slow Flow Phenomenon

BackgroundThe coronary slow flow phenomenon (CSFP) is a coronary microvascular disorder angiographically defined by delayed opacification of the distal vasculature in the absence of obstructive coronary artery disease. We aimed...

Potential mechanisms of the acute coronary syndrome presentation in patients with the coronary slow flow phenomenon — Insight from a plasma proteomic approach

AimsThe coronary slow flow phenomenon [CSFP] is a coronary microvascular disorder, characterized by delayed distal vessel opacification despite the absence of obstructive coronary artery disease. Patients frequently present with an acute coronary syndrome [ACS] although the pathophysiological mechanisms responsible are unknown. The aim of this study was to identify potential mechanisms for the ACS presentation associated with the CSFP using a plasma proteomic profiling approach. Methods and resultsPlasma samples from nine CSFP subjects [56±11years] were assayed for high sensitivity C-reactive protein [hsCRP], troponin T [TnT], creatine kinase [CK], and proteomic analyses (n=6), during an ACS presentation and one month later [chronic phase]. Proteomic analysis involved chromatographic depletion of abundant plasma proteins followed by two-dimensional differential gel electrophoresis [2-D DIGE]. Protein spots demonstrating ±1.5-fold change relative to the control were identified by mass spectrometry and two differentially expressed proteins were selected for validation via Western blotting. During the ACS presentation, hsCRP was elevated [ACS=14.9±3.9mg/L vs chronic=4.23±1.37mg/L, p=0.05] but TnT and CK levels were unchanged. Proteomic analysis identified six proteins that were significantly different in abundance between the acute and chronic samples. During the ACS presentation there was a 1.6±0.13 fold increase in the anti-oxidant enzyme paraoxonase-1 and an increase in inflammatory proteins alpha-1-antichymotrypsin [1.65±0.13 fold] and alpha-1-antitrypsin [2.5±0.34 fold]. The latter was confirmed by Western blotting [1.33±0.17 OD acute/chronic ratio, p=0.05]. ConclusionThe findings from this novel detailed approach, implicate an inflammatory/oxidative stress process in the pathogenesis of the ACS presentation associated with the CSFP. Future studies should further elucidate these mechanisms.

Clinical analysis of the risk factors of slow coronary flow

Slow coronary flow (SCF) phenomenon is a coronary microvascular disorder characterized by the delayed passage of contrast in the absence of obstructive epicardial coronary disease, and is an important clinical entity because it may be the cause of precordial pain when the body is at rest and/or during exercise. Although clinical and pathological features of SCF have been previously described, its etiopathogenesis remains unclear. The present study aims to investigate the risk factors of slow coronary flow, in order to provide the foundation for further exploration of potential mechanisms of SCF. A total of 47 consecutive patients with documented slow coronary flow, and 33 patients with normal coronary flow--as defined by TIMI frame count (TFC)--were recruited for this study. Clinical information was collected, and biochemical indicators including high-sensitivity C-reactive protein (hs-CRP), and a marker of systemic inflammation were detected. Logistic regression analysis was performed for statistical analysis. SCF patients had a higher level of serum uric acid (323.2 ± 79.3 vs. 282.8 ± 82.4 μmol/l, p = 0.03), 2-h postprandial blood glucose (8.6 ± 2.7 vs. 7.5 ± 1.8 mmol/l, p = 0.04), platelet count (165.9 ± 51.6 × 10(3) vs. 127.0 ± 32.0 × 10(3) cells/μl, p = 0.0003) and hs-CRP (3.4 ± 0.8 vs. 2.0 ± 0.9 mg/l, p < 0.0001) than those of patients in the control group. No marked differences in other variables were observed between the two groups. Logistic regression showed serum uric acid level (χ(2) = 3.84, β = 0.007, p = 0.049), 2-h postprandial blood glucose (χ(2) = 5.02, β = 0.277, p = 0.025) and blood platelet count (χ(2) = 12.16, β = 0.026, p = 0.001) were independent predictors of SCF. When hs-CRP was included in the multivariate model, hs-CRP (χ(2) = 21.19, β = 1.90, p < 0.0001) was the only independent predictor of SCF. These findings suggested that an elevation of serum uric acid level, 2-h postprandial blood glucose, and blood platelet count might be the causes of SCF, and inflammation was likely to be implicated in the causal pathway leading to SCF.

Proteomic Studies into the Human Coronary Microvasculature: Plasma Protein Profiles During Acute Coronary Syndrome Presentation

Cardiovascular disease is one of the leading causes of morbidity and mortality. The Coronary Slow Flow Phenomenon (CSFP) is a coronary microvascular disorder that presents as an acute coronary syndrome (ACS) despite normal large vessels. Resulting in frequent and disabling anginal symptoms, the etiology behind the CSFP is unknown. The objective of this study was to explore potential mechanisms for the ACS presentation in CSFP patients, using a proteomic approach.

Simvastatin May Improve Myocardial Perfusion Abnormality in Slow Coronary Flow

Background: The slow coronary flow (SCF) phenomenon is a coronary microvascular disorder characterized by the delayed passage of contrast in the absence of obstructive epicardial coronary disease. Recent studies showed the possible role of endothelial dysfunction, diffuse atherosclerosis and inflammation in the pathogenesis of this phenomenon. We aimed to investigate the effect of statin on myocardial perfusion in patients with SCF. Methods and Results: The study population consisted of 97 patients with SCF. Coronary flow patterns of the cases are determined by thrombolysis in myocardial infarction (TIMI) frame count method. Single-photon emission computed tomographic myocardial perfusion imaging studies and lipid parameters of the patients were obtained before and after 6 months of simvastatin treatment period. During the study, daily single dose of 40 mg simvastatin has been given to each subject. We found a significant positive correlation between mean TIMI frame count and basal reversibility score (r = 0.84, p = 0.0001). In addition, analysis of the reversibility scores demonstrates that simvastatin treatment has significantly improved the myocardial perfusion abnormality at the end of the follow-up period. Conclusion: Present findings allow us to conclude that simvastatin improved myocardial perfusion in patients with SCF.