Effect of Chinese medicine for promoting blood circulation on microvascular angina: A systematic review and meta-analysis.

BACKGROUND: Blood-activating drugs (BADs) are widely used to treat microvascular angina in China. This study aims to summarize relevant evidence from randomized controlled trials (RCTs) to assess the efficacy and safety of BADs in the treatment of microvascular angina. METHODS: We searched for relevant studies before June 2019 from seven databases. Twenty-four studies were included of 1903 patients with microvascular angina. All studies compared the use of traditional Chinese medicine for activating blood circulation (BADs) and Western medicine (WM) with the use of Western medicine alone. RESULTS: In all, 15 trials reported a significant effect of BADs on improving clinical symptoms compared with the control treatment (P < .00001), and 8 trials reported significant effects of BADs on reducing the frequency of angina pectoris attacks compared with Western medicine treatment (P < .00001). The pooled results also demonstrated that BADs provided a significant benefit in reducing the dosage of nitroglycerin required (P = .02), the maximum range of ST-segment depression (P = .003) and the descending degree of the ST-T segment of ECG (P = .0002); prolonging the total time of treadmill exercise (P < .00001) and the time of ST-segment depression of 1 mm (P = .002); enhancing the total effective rate of Traditional Chinese Medicine (TCM) syndromes (P < .00001); improving endothelial function (P < .00001); and reducing the levels of high-sensitivity C-reactive protein (hs-CRP) (P < .00001). BAD treatment showed no statistically significant effect on the levels of TNF-a (P = .8) or IL-6 (P = .13). No severe adverse events were reported. CONCLUSION: This meta-analysis shows that BADs are effective for the treatment of microvascular angina. Although concerns regarding selective bias and low methodological quality were raised, our findings suggest that BADs are beneficial for patients with microvascular angina and should be given priority for future clinical studies.

Optimal Use of Vasodilators for Diagnosis of Microvascular Angina in the Cardiac Catheterization Laboratory.

BACKGROUND: Among patients with angina and nonobstructive coronary artery disease, those with coronary microvascular dysfunction have a poor outcome. Coronary microvascular dysfunction is usually diagnosed by assessing flow reserve with an endothelium-independent vasodilator like adenosine, but the optimal diagnostic threshold is unclear. Furthermore, the incremental value of testing endothelial function has never been assessed before. We sought to determine what pharmacological thresholds correspond to exercise pathophysiology and myocardial ischemia in patients with coronary microvascular dysfunction. METHODS: Patients with angina and nonobstructive coronary artery disease underwent simultaneous acquisition of coronary pressure and flow during rest, supine bicycle exercise, and pharmacological vasodilatation with adenosine and acetylcholine. Adenosine and acetylcholine coronary flow reserve were calculated as vasodilator/resting coronary blood flow (CFR and AchFR, respectively). Coronary wave intensity analysis was used to quantify the proportion of accelerating wave energy; a normal exercise response was defined as an increase in accelerating wave energy from rest to peak exercise. Ischemia was assessed by quantitative 3-Tesla stress perfusion cardiac magnetic resonance imaging and dichotomously defined by a hyperemic endo-epicardial gradient <1.0. RESULTS: Ninety patients were enrolled (58±10 years, 77% female). Area under the curve using receiver-operating characteristic analysis demonstrated optimal CFR and AchFR thresholds for identifying exercise pathophysiology and ischemia as 2.6 and 1.5, with positive and negative predictive values of 91% and 86%, respectively. Fifty-eight percent had an abnormal CFR (of which 96% also had an abnormal AchFR). Of those with a normal CFR, 53% had an abnormal AchFR, and 47% had a normal AchFR; ischemia rates were 83%, 63%, and 14%, respectively. CONCLUSIONS: The optimal CFR and AchFR diagnostic thresholds are 2.6 and 1.5, with high-positive and negative predictive values, respectively. A normal CFR value should prompt the measurement of AchFR. A stepwise algorithm incorporating both vasodilators can accurately identify an ischemic cause in patients with nonobstructive coronary artery disease.

Ischemia and No Obstructive Coronary Artery Disease: Prevalence and Correlates of Coronary Vasomotion Disorders.

BACKGROUND: Determine the prevalence and correlates of microvascular and vasospastic angina in patients with symptoms and signs of ischemia but no obstructive coronary artery disease (INOCA). METHODS: Three hundred ninety-one patients with angina were enrolled at 2 regional centers over 12 months from November 2016 (NCT03193294). INOCA subjects (n=185; 47%) had more limiting dyspnea (New York Heart Association classification III/IV 54% versus 37%; odds ratio [OR], 2.0 [1.3-3.0]; P=0.001) and were more likely to be female (68% INOCA versus 38% in coronary artery disease; OR, 1.9 [1.5 to 2.5]; P<0.001) but with lower cardiovascular risk scores (ASSIGN score median 20% versus 24%; P=0.003). INOCA subjects had similar burden of angina (Seattle Angina Questionnaire) but reduced quality of life compared with coronary artery disease; subjects (EQ5D-5 L index 0.60 versus 0.65 units; P=0.041). RESULTS: An interventional diagnostic procedure with reference invasive tests including coronary flow reserve, microvascular resistance, and vasomotor responses to intracoronary acetylcholine (vasospasm provocation) was performed in 151 INOCA subjects. Overall, 78 (52%) had isolated microvascular angina, 25 (17%) had isolated vasospastic angina, 31 (20%) had both, and 17 (11%) had noncardiac chest pain. Regression analysis showed inducible ischemia on treadmill testing (OR, 7.5 [95% CI, 1.7-33.0]; P=0.008) and typical angina (OR, 2.7 [1.1-6.6]; P=0.032) were independently associated with microvascular angina. Female sex tended to associate with a diagnosis of microvascular angina although this was not significant (OR, 2.7 [0.9-7.9]; P=0.063). Vasospastic angina was associated with smoking (OR, 9.5 [2.8-32.7]; P<0.001) and age (OR, 1.1 per year, [1.0-1.2]; P=0.032]. CONCLUSIONS: Over three quarters of patients with INOCA have identifiable disorders of coronary vasomotion including microvascular and vasospastic angina. These patients have comparable angina burden but reduced quality of life compared to patients with obstructive coronary artery disease. Microvascular angina and vasospastic angina are distinct disorders that may coexist but differ in associated clinical characteristics, symptoms, and angina severity. CLINICAL TRIAL REGISTRATION: URL: https://www.clinicaltrials.gov. Unique identifier: NCT03193294.

Retinal microvascular changes in microvascular angina: Findings from the Australian Heart Eye Study.

OBJECTIVE: Microvascular changes in microvascular angina are poorly understood due to difficulties in imaging the coronary microcirculation in vivo. The retinal microvasculature may reflect changes in coronary microcirculation. We assessed microvascular changes in the retina in patients with microvascular angina and compared them with patients with angiographically proven coronary artery disease. METHODS: We performed retinal photography and coronary angiography on 915 patients. Retinal vessel calibers were measured using a validated computer-assisted method; coronary artery disease was graded from coronary angiograms. Microvascular angina was defined as angina with <25% stenosis in all coronary epicardial arteries. RESULTS: A total of 139 patients (15.2%) had microvascular angina, while 776 (84.8%) had coronary artery disease. Participants with microvascular angina and coronary artery disease had similar retinal arteriolar and venular calibers. After adjustment for age, ethnicity, mean arterial pressure, diabetes, current smoking, body mass index, and fellow vessel caliber, women with smaller venules were threefold more likely to have microvascular angina than women with larger venules (multivariable-adjusted odds ratio 3.54, 95% confidence interval 1.35 to 9.24, P < 0.01). This difference was not observed in men. CONCLUSIONS: Microvascular angina in women was associated with microvascular changes distinct from those in coronary artery disease.

Systemic microvascular dysfunction in microvascular and vasospastic angina.

Aims: Coronary microvascular dysfunction and/or vasospasm are potential causes of ischaemia in patients with no obstructive coronary artery disease (INOCA). We tested the hypothesis that these patients also have functional abnormalities in peripheral small arteries. Methods and results: Patients were prospectively enrolled and categorised as having microvascular angina (MVA), vasospastic angina (VSA) or normal control based on invasive coronary artery function tests incorporating probes of endothelial and endothelial-independent function (acetylcholine and adenosine). Gluteal biopsies of subcutaneous fat were performed in 81 subjects (62 years, 69% female, 59 MVA, 11 VSA, and 11 controls). Resistance arteries were dissected enabling study using wire myography. Maximum relaxation to ACh (endothelial function) was reduced in MVA vs. controls [median 77.6 vs. 98.7%; 95% confidence interval (CI) of difference 2.3-38%; P = 0.0047]. Endothelium-independent relaxation [sodium nitroprusside (SNP)] was similar between all groups. The maximum contractile response to endothelin-1 (ET-1) was greater in MVA (median 121%) vs. controls (100%; 95% CI of median difference 4.7-45%, P = 0.015). Response to the thromboxane agonist, U46619, was also greater in MVA (143%) vs. controls (109%; 95% CI of difference 13-57%, P = 0.003). Patients with VSA had similar abnormal patterns of peripheral vascular reactivity including reduced maximum relaxation to ACh (median 79.0% vs. 98.7%; P = 0.03) and increased response to constrictor agonists including ET-1 (median 125% vs. 100%; P = 0.02). In all groups, resistance arteries were ≈50-fold more sensitive to the constrictor effects of ET-1 compared with U46619. Conclusions: Systemic microvascular abnormalities are common in patients with MVA and VSA. These mechanisms may involve ET-1 and were characterized by endothelial dysfunction and enhanced vasoconstriction. Clinical trial registration: ClinicalTrials.gov registration is NCT03193294.

Effect of ACE-inhibition on coronary microvascular function and symptoms in normotensive women with microvascular angina: A randomized placebo-controlled trial.

OBJECTIVE: Studies have suggested a beneficial effect of angiotensin-converting enzyme (ACE) inhibition. To explore whether the ACE inhibitor ramipril has a direct effect on the microvasculature beyond the blood pressure (BP) lowering effect, we investigated whether ramipril improved coronary microvascular function in normotensive women with coronary microvascular dysfunction (CMD). METHODS: We included 63 normotensive women with angina, no epicardial stenosis>50% and CMD defined as a coronary flow velocity reserve (CFVR)<2.2 assessed by adenosine stress-echocardiography in a randomized double-blinded, superiority trial with 1:1 allocation to placebo or ramipril (maximum dose 10 mg depending on blood pressure) for 24±6 weeks. Primary outcome was CFVR. Secondary outcomes were left ventricular systolic and diastolic function and symptoms evaluated by Seattle Angina Questionnaire (clinicaltrials.gov, NCT02525081). RESULTS: Follow-up was available on 55 patients. BP remained unchanged during treatment in both groups. CFVR improved in both the ramipril (p = 0.004) and placebo group (p = 0.026) with no difference between groups (p = 0.63). Symptoms improved in both groups with no significant between-group differences. No changes were detected in parameters of systolic and diastolic function. No serious adverse reactions were reported. CONCLUSIONS: In normotensive women with angina and CMD, treatment with ramipril had no significant effect on CFVR or symptoms compared with placebo. The effect of ACE inhibition previously reported may be mediated by blood pressure reduction.

Novel Scoring System for Prediction of Cardiac Syndrome X in Women with Typical Angina and a Positive Exercise Tolerance Test.

A major diagnostic challenge for cardiologists is to distinguish cardiac syndrome X (CSX) from obstructive coronary artery disease in women with typical angina and a positive exercise tolerance test (ETT). We performed this study to develop a scoring system that more accurately predicts CSX in this patient population. Data on 976 women with typical angina and a positive ETT who underwent coronary angiography at our center were randomly divided into derivation and validation datasets. We developed a backward stepwise logistic regression model that predicted the presence of CSX, and a scoring system was derived from it. The derivation dataset (809 patients) was calibrated by uing a Hosmer-Lemeshow goodness-of-fit test (8 degrees of freedom; χ2=12.9; P=0.115), and the area under the curve was 0.758. The validation dataset (167 patients) was calibrated in the same way (8 degrees of freedom; χ2=9.0; P=0.339), and the area under the curve was 0.782. Independent predictors of CSX were age <55 years; negative histories of smoking, diabetes mellitus, hyperlipidemia, hypertension, or familial premature coronary artery disease; and highly positive ETTs. A total score >9.5 was the optimal cutoff point for differentiating CSX from obstructive coronary artery disease. Our proposed scoring system is a simple, objective, and accurate system for distinguishing CSX from obstructive coronary artery disease in women with typical angina and positive ETTs. It may help determine which of these patients need invasive coronary angiograms or noninvasive tests like computed tomographic coronary angiography.

Diagnosis of Microvascular Angina Using Cardiac Magnetic Resonance.

BACKGROUND: In patients with angina and nonobstructive coronary artery disease (NOCAD), confirming symptoms due to coronary microvascular dysfunction (CMD) remains challenging. Cardiac magnetic resonance (CMR) assesses myocardial perfusion with high spatial resolution and is widely used for diagnosing obstructive coronary artery disease (CAD). OBJECTIVES: The goal of this study was to validate CMR for diagnosing microvascular angina in patients with NOCAD, compared with patients with obstructive CAD and correlated to the index of microcirculatory resistance (IMR) during invasive coronary angiography. METHODS: Fifty patients with angina (65 ± 9 years of age) and 20 age-matched healthy control subjects underwent adenosine stress CMR (1.5- and 3-T) to assess left ventricular function, inducible ischemia (myocardial perfusion reserve index [MPRI]; myocardial blood flow [MBF]), and infarction (late gadolinium enhancement). During subsequent angiography within 7 days, 28 patients had obstructive CAD (fractional flow reserve [FFR] ≤0.8) and 22 patients had NOCAD (FFR >0.8) who underwent 3-vessel IMR measurements. RESULTS: In patients with NOCAD, myocardium with IMR <25 U had normal MPRI (1.9 ± 0.4 vs. controls 2.0 ± 0.3; p = 0.49); myocardium with IMR ≥25 U had significantly impaired MPRI, similar to ischemic myocardium downstream of obstructive CAD (1.2 ± 0.3 vs. 1.2 ± 0.4; p = 0.61). An MPRI of 1.4 accurately detected impaired perfusion related to CMD (IMR ≥25 U; FFR >0.8) (area under the curve: 0.90; specificity: 95%; sensitivity: 89%; p < 0.001). Impaired MPRI in patients with NOCAD was driven by impaired augmentation of MBF during stress, with normal resting MBF. Myocardium with FFR >0.8 and normal IMR (<25 U) still had blunted stress MBF, suggesting mild CMD, which was distinguishable from control subjects by using a stress MBF threshold of 2.3 ml/min/g with 100% positive predictive value. CONCLUSIONS: In angina patients with NOCAD, CMR can objectively and noninvasively assess microvascular angina. A CMR-based combined diagnostic pathway for both epicardial and microvascular CAD deserves further clinical validation.

Biopsy-confirmed endothelial cell activation in patients with coronary microvascular dysfunction.

BACKGROUND: Patients with angina yet having unobstructed coronaries are found in ∼50% of cases undergoing invasive angiography. Coronary spasm and microvascular dysfunction can be responsible for the clinical presentation in ∼60% of cases. However, little is known about structural changes in the myocardium. The aim of this study was to describe findings in endomyocardial biopsies of symptomatic patients with unobstructed coronaries. PATIENTS AND METHODS: We retrospectively analyzed a cohort of 1416 consecutive patients who underwent endomyocardial biopsy sampling and coronary angiography between 2002 and 2016 for various clinical indications. Of them, 309 patients had also undergone intracoronary acetylcholine testing (ACH-test). To be eligible for the study, patients had to have normal left ventricular ejection fraction, unobstructed coronaries and absence of viral genomes in the myocardium. RESULTS: Among the final cohort of 33 (70% female, mean age 53) patients, the ACH-test revealed coronary microvascular spasm in 11 (33.3%) patients. Twelve (36.4%) patients had epicardial spasm and 10 (30.3%) had an uneventful ACH-test. Immunohistology revealed activated macrophages in 10 (30%) cases and activated endothelial cells as well as perivascular or interstitial fibrosis in 17 (52%). Myocardial hypertrophy was seen in nine (27%) patients, and smooth muscle cell proliferation was present in 11 (33%) cases. Compared with the rest of the cohort, patients with microvascular spasm significantly more often had activated endothelial cells (P=0.003). CONCLUSION: This study gives unique insights into structural myocardial alterations in patients with angina, unobstructed coronaries and abnormal coronary vasomotion, suggesting that a combination of both structural and functional alterations is frequent.

Microvascular Angina　- Long-Term Exercise Stress Test Follow-up.

BACKGROUND: A sizeable proportion of patients with primary stable microvascular angina (MVA; exercise-induced angina, positive exercise stress test [EST], normal coronary arteries) have recurrent symptoms during follow-up. There have been no previous studies, however, on the long-term results of EST and their correlation with symptom outcome.Methods and Results:Follow-up EST was performed in 71 MVA patients at an average of 16.2 years (range, 5-25 years) from the first EST. Angina status was assessed on weekly frequency of angina episodes and nitroglycerin consumption and by whether symptoms had worsened, improved, or remained unchanged over time. At follow-up EST, 41 patients (group 1) had exercise-induced ischemia, whereas 30 patients (group 2) had negative EST. Compared to group 2, group 1 patients more frequently had exercise-induced dyspnea, and had a greater maximum ST-segment depression and a lower coronary blood flow response to adenosine and cold pressor test, but group 2 patients had a more frequent history of rest angina. No differences between the 2 groups were found at follow-up in angina status or change in symptom status during follow-up. CONCLUSIONS: Electrocardiogram results improve significantly in a sizeable proportion of patients with MVA. Changes in EST results, however, were not associated with clinical outcome.

The APEX trial: Effects of allopurinol on exercise capacity, coronary and peripheral endothelial function, and natriuretic peptides in patients with cardiac syndrome X.

The role of endothelial dysfunction and oxidative stress in the pathogenesis of cardiac syndrome X has recently been recognized. Allopurinol has previously been shown to improve endothelial dysfunction, reduce oxidative stress burden, and improve myocardial efficiency. In this "proof of concept" study, we investigated the effect of allopurinol on exercise capacity, coronary and peripheral endothelial function, and serum B-type natriuretic peptide (BNP: a marker of cardiac function and myocardial ischemia) in patients with cardiac syndrome X. METHODS AND RESULTS: This study was a randomized, double-blind, placebo-control crossover trial. Nineteen patients (mean age 59 ± 10 years, 11 women and 8 men) with cardiac syndrome X were randomized to a 6-week treatment with either allopurinol (600 mg/day) or placebo. After 4 weeks of washout period, they were crossed over to the other arm. Outcomes measured at baseline and after treatment were maximum exercise time (ET) derived from Bruce protocol exercise treadmill test, serum BNP measurement, coronary flow reserve (CFR) as assessed by measuring the response of flow velocity in the left anterior descending artery to adenosine, and flow-mediated vasodilatation of the brachial artery (FMD). Allopurinol significantly reduced serum uric acid levels when compared with placebo (-48 ± 24% vs 1.9 ± 11%, P < .001). There was no significant difference in maximum ET, CFR, and FMD between allopurinol and placebo. However, there was a trend that allopurinol reduced serum BNP when compared to placebo (-8% [interquartile range -22% to 65%] vs 44% [interquartile range -18% to 140%]; P = .07). CONCLUSION: In patients with cardiac syndrome X, high-dose allopurinol did not improve exercise capacity, and coronary or peripheral endothelial function.

Association of Inflammation and Endothelial Dysfunction with Coronary Microvascular Resistance in Patients with Cardiac Syndrome X / Associação de Inflamação e Disfunção Endotelial com Resistência Microvascular Coronariana em Pacientes com Síndrome Cardíaca X

Abstract Background: Although a proportion of CSX patients have impaired brachial artery flow-mediated dilatation (FMD) in response to hyperemia, suggesting that endothelial dysfunction in these patients may be systemic and not just confined to the coronary circulation; the underlying mechanisms triggering endothelial dysfunction in these patients are still incompletely understood. Objectives: To assess the association of the index of Microcirculatory Resistance (IMR) with endothelial dysfunction and inflammation in patients with CSX. Methods: We studied 20 CSX patients and 20 age and gender-matched control subjects. Thermodilution-derived coronary flow reserve (CFR) and IMR were measured using a pressure-temperature sensor-tipped guidewire. Brachial artery FMD was measured using high-resolution, two-dimensional ultrasound images obtained with a Doppler ultrasound device (HDI-ATL 5000, USA) with a 5 MHz to 12 MHz linear-array transducer. Results: Compared with in control subjects, CFR was significantly lower (2.42 ± 0.78 vs. 3.59 ± 0.79, p < 0.001); IMR was higher (32.2 ± 8.0 vs. 19.5 ± 5.5, p < 0.001); the concentration of hs-CRP and FMD was higher (4.75 ± 1.62 vs. 2.75 ± 1.50; 5.24 ± 2.41 vs. 8.57 ± 2.46, p < 0.001) in CSX patients. The Duke treadmill score (DTS) was correlated positively to CFR and FMD (0.489 and 0.661, p < 0.001), it was negative to IMR and hsCRP (-0.761 and -0.087, p < 0.001) in CSX patients. Conclusions: The main finding in this study is that the DTS measured in patients with CSX was associated to hsCRP and FMD. Moreover, the independent effects of exercise tolerance can significantly impair FMD and hsCRP in CSX patients; especially it is particularly important to whom where FMD was associated negatively with IMR.

Resumo Fundamentos: Embora uma proporção de pacientes com SCX tenha dilatação mediada por fluxo da artéria braquial (DMF) prejudicada em resposta à hiperemia, sugerindo que a disfunção endotelial nestes pacientes pode ser sistémica e não limitar-se à circulação coronariana, os mecanismos subjacentes que desencadeiam a disfunção endotelial nestes pacientes ainda não são completamente compreendidos. Objetivos: Avaliar a associação do índice de resistência microcirculatória (IMR) com a disfunção endotelial e a inflamação em pacientes com SCX. Métodos: Estudaram-se 20 pacientes com SCX e 20 sujeitos de controle emparelhados em idade e género. A reserva de fluxo coronariano derivada da termodiluição (RFC) e a IMR forma medidas usando um fio guia com ponta de sensor de temperatura e pressão. A DMF da artéria braquial foi medida utilizando imagens ultrassónicas bidimensionais de alta resolução obtidas com um aparelho de ultrassom Doppler (HDI-ATL 5000, EE.UU.) com transdutor linear de 5 MHz a 12 MHz. Resultados: Em comparação com os sujeitos de controle, a RFC foi significativamente menor (2,42 ± 0,78 vs 3,59 ± 0,79, p < 0,001); o IMR foi maior (32,2 ± 8,0 frente a 19,5 ± 5,5, p < 0,001); a concentração de PCR-as e DMF foi maior (4,75 ± 1,62 frente a 2,75 ± 1,50, 5,24 ± 2,41 diante de 8,57 ± 2,46, p < 0,001) em pacientes com SCX. A escore de Duke (ED) se correlacionou positivamente com RFC e DMF (0,489 e 0,661, p < 0,001), foi negativa para IMR e PCR-as (-0,761 e -0,087, p < 0,001) em pacientes com SCX. Conclusões: O principal achado neste estudo é que o ED medido em pacientes com SCX esteve associado a PCR-as e DMF. Por outra parte, os efeitos independentes da tolerância ao exercício podem piorar significativamente a DMF e a PCR-as em pacientes com SCX especialmente, é particularmente importante que a DMF se associou negativamente com a RIM.

[Optimal Diagnostics and Therapy for Microvascular Angina Pectoris]. / Optimale Diagnostik und Therapie der mikrovaskulären Angina pectoris.

Patients with microvascular angina are characterized by angina pectoris with proof of myocardial ischemia in the absence of any relevant epicardial stenosis and without myocardial disease (type 1 coronary microvascular dysfunction according to Crea and Camici). Structural and functional alterations of the coronary microvessels (diameter < 500 µm) are the reason for this phenomenon. Frequently such alterations are associated with cardiovascular risk factors. Patients with angina pectoris without epicardial stenoses represent for 10 - 50 % of all patients undergoing coronary angiography depending on the clinical presentation. Diagnostic approaches include non-invasive (e. g. combination of coronary CT-angiography and positron emission tomography/echo Doppler-based coronary flow reserve measurements) as well as invasive procedures (coronary flow reserve measurements in response to adenosine, intracoronary acetylcholine testing). Pharmacological treatment of these patients is often challenging and should be based on the characterization of the underlying mechanisms. Moreover, strict risk factor control and individually titrated combinations of antianginal substances (e. g. beta blockers, calcium channel blockers, nitrates, ranolazine, ivabradine etc.) are recommended.

Non-invasive assessment of microvascular dysfunction in patients with microvascular angina.

BACKGROUND: We aimed to evaluate the microvascular function in patients with microvascular angina (MVA) by assessing 1) the endothelial glycocalyx barrier properties using sublingual microscopy, and 2) the myocardial perfusion reserve using cardiovascular magnetic resonance (CMR) imaging. METHODS: Sublingual microscopy was performed in 13 MVA patients (angina pectoris, ST-depression on treadmill testing, normal coronary angiogram) and compared with 2 control groups of 13 volunteers and 14 patients with known obstructive coronary artery disease (CAD). To test the glycocalyx-mediated microvascular responsiveness, the erythrocyte perfused boundary region (PBR) was assessed at baseline and after nitroglycerin challenge. RESULTS: The baseline PBR of MVA patients was similar to controls with CAD (p=0.72), and larger than in volunteers (p=0.02). Only the volunteers demonstrated a significant increase in PBR after nitroglycerin (p=0.03). In the 13 MVA patients, adenosine stress CMR perfusion imaging was performed. Although a significant increase in myocardial perfusion was observed in both the subendocardium and subepicardium during stress, the subendocardial perfusion reserve was significantly lower (p=0.02). The PBR responsiveness of the sublingual microvasculature showed a strong correlation with the transmural myocardial perfusion reserve (r=0.86, p<0.001). CONCLUSIONS: Patients with MVA can be characterized by microvascular glycocalyx dysfunction using sublingual microscopy. The strong correlation between sublingual PBR responsiveness and myocardial perfusion reserve suggests that the glycocalyx may play an important role in the regulation of microvascular volume for myocardial perfusion and supports the concept of impaired glycocalyx barrier properties in MVA.

Left atrial volume and function in patients with cardiac syndrome X assessed by real time three-dimensional echocardiography.

OBJECTIVE: The aim of this study was to evaluate left atrial (LA) volume and function using real time three-dimensional echocardiography (RT3DE) in patients with cardiac syndrome X (CSX). METHODS: Fifty patients with CSX (28 females; mean age 50.9±10.9 years) and 50 age- and gender-matched healthy controls (30 females; mean age 52.3±9.8 years) who had negative treadmill exercise test and normal coronary arteries on invasive coronary angiography were included in the study. Comprehensive two-dimensional (2D), pulsed and tissue Doppler, speckle tracking echocardiography, and RT3DE for the assessment of LA dynamics were performed in all study participants. RESULTS: Cardiac syndrome X and control groups have similar clinical characteristics regarding age, sex, body mass index, hypertension, diabetes, and smoking habit. 2D echocardiographic parameters were also similar between groups. Pulsed- and tissue Doppler parameters, IVRT, A, and Am values, were higher in CSX group, while Em , E/A, and Em /Am ratios were higher in the control group reflecting mild diastolic dysfunction. Regarding RT3DE parameters, LA maximum volume, minimum volume, volume before atrial contraction, LA maximum volume index, total and active stroke volumes were found to be increased in CSX patients. However, LA total stroke fraction, passive stroke volume, passive stroke fraction, peak systolic, and diastolic longitudinal strains were found to be lower in CSX patients. CONCLUSION: The main finding of this study was that CSX patients had altered LA booster pump, reservoir, and conduit functions. This finding may have clinical implications for early detection of abnormal LA dynamics in CSX patients.

Transthoracic Doppler echocardiography compared with positron emission tomography for assessment of coronary microvascular dysfunction: The iPOWER study.

BACKGROUND: Coronary microvascular function can be assessed by transthoracic Doppler echocardiography as a coronary flow velocity reserve (TTDE CFVR) and by positron emission tomography as a myocardial blood flow reserve (PET MBFR). PET MBFR is regarded the noninvasive reference standard for measuring coronary microvascular function but has limited availability. We compared TTDE CFVR with PET MBFR in women with angina pectoris and no obstructive coronary artery disease and assessed repeatability of TTDE CFVR. METHODS: From a cohort of women with angina and no obstructive coronary artery stenosis at invasive coronary angiography, TTDE CFVR by dipyridamole induced stress and MBFR by rubidium-82 PET with adenosine was successfully measured in 107 subjects. Repeatability of TTDE CFVR was assessed in 10 symptomatic women and in 10 healthy individuals. RESULTS: MBFR was systematically higher than CFVR. Median MBFR (interquartile range, IQR) was 2.68 (2.29-3.10) and CFVR (IQR) was 2.31 (1.89-2.72). Pearson's correlation coefficient was 0.36 (p<0.01). Limits of agreement (2·standard deviation) assessed by the Bland-Altman (confidence interval, CI) method was 1.49 (1.29;1.69) and unaffected by time-interval between examinations. Results were similar when adjusting for rate pressure product or focusing on perfusion of the left anterior descending artery region. Limits of agreement (CI) for repeated CFVR in 10 healthy individuals and in 10 women with angina was 0.44 (0.21;0.68) and 0.48 (0.22; 0.74), respectively. CONCLUSION: CFVR had a good repeatability, but the agreement between CFVR and MBFR was modest. Divergence could be due to methodology differences; TTDE estimates flow velocities whereas PET estimates myocardial blood flow.

Coronary Microvascular Function and Cardiovascular Risk Factors in Women With Angina Pectoris and No Obstructive Coronary Artery Disease: The iPOWER Study.

BACKGROUND: The majority of women with angina-like chest pain have no obstructive coronary artery disease when evaluated with coronary angiography. Coronary microvascular dysfunction is a possible explanation and associated with a poor prognosis. This study evaluated the prevalence of coronary microvascular dysfunction and the association with symptoms, cardiovascular risk factors, psychosocial factors, and results from diagnostic stress testing. METHODS AND RESULTS: After screening 3568 women, 963 women with angina-like chest pain and a diagnostic coronary angiogram without significant coronary artery stenosis (<50%) were consecutively included. Mean age (SD) was 62.1 (9.7). Assessment included demographic and clinical data, blood samples, questionnaires, and transthoracic echocardiography during rest and high-dose dipyridamole (0.84 mg/kg) with measurement of coronary flow velocity reserve (CFVR) by Doppler examination of the left anterior descending coronary artery. CFVR was successfully measured in 919 (95%) women. Median (IQR) CFVR was 2.33 (1.98-2.76), and 241 (26%) had markedly impaired CFVR (<2). In multivariable regression analysis, predictors of impaired CFVR were age (P<0.01), hypertension (P=0.02), current smoking (P<0.01), elevated heart rate (P<0.01), and low high-density lipoprotein cholesterol (P=0.02), but these variables explained only a little of the CFVR variation (r(2)=0.09). CFVR was not associated with chest pain characteristics or results from diagnostic stress testing. CONCLUSION: Impaired CFVR was detected in a substantial proportion, which suggests that coronary microvascular dysfunction plays a role in the development of angina pectoris. CFVR was associated with few cardiovascular risk factors, suggesting that CFVR is an independent parameter in the risk evaluation of these women. Symptom characteristics and results from stress testing did not identify individuals with impaired CFVR.

Coronary Microvascular Dysfunction as a Mechanism of Angina in Severe AS: Prospective Adenosine-Stress CMR Study.

BACKGROUND: Although a common symptom in patients with severe aortic stenosis (AS) without obstructive coronary artery disease (CAD), little is known about the pathogenesis of exertional angina. OBJECTIVES: This study sought to prove that microvascular dysfunction is responsible for chest pain in patients with severe AS and normal epicardial coronary arteries using adenosine-stress cardiac magnetic resonance (CMR) imaging. METHODS: Between June 2012 and April 2015, 117 patients with severe AS without obstructive CAD and 20 normal controls were enrolled prospectively. After exclusions, study patients were divided into 2 groups according to presence of exertional chest pain: an angina group (n = 43) and an asymptomatic group (n = 41), and the semiquantitative myocardial perfusion reserve index (MPRI) was calculated. RESULTS: MPRI values were significantly lower in severe AS patients than in normal controls (0.90 ± 0.31 vs. 1.25 ± 0.21; p < 0.001), and were much lower in the angina group than the asymptomatic group (0.74 ± 0.25 vs. 1.08 ± 0.28; p < 0.001). In logistic regression analysis, the only independent predictor for angina was MPRI (odds ratio: 0.003; p < 0.001). Univariate associations with MPRI were identified for diastolic blood pressure, E/e' ratio, left ventricular volume and ejection fraction, cardiac index, presence of late gadolinium enhancement, and left ventricular mass index (LVMI). In multivariate analysis, LVMI was the strongest contributing factor to MPRI (standardization coefficient: -0.428; p < 0.001). CONCLUSIONS: Our results suggest that, in patients with severe AS without obstructive CAD, angina is related to impaired coronary microvascular function along with LV hypertrophy detectable by semiquantitative MPRI using adenosine-stress CMR. CLINICAL TRIAL REGISTRATION: NCT02575768.

Prevalence of Coronary Microvascular Dysfunction Among Patients With Chest Pain and Nonobstructive Coronary Artery Disease.

OBJECTIVES: This study assessed the prevalence of coronary microvascular abnormalities in patients presenting with chest pain and nonobstructive coronary artery disease (CAD). BACKGROUND: Coronary microvascular abnormalities mediate ischemia and can lead to an increased risk of cardiovascular events. METHODS: Using an intracoronary Doppler guidewire, endothelial-dependent microvascular function was examined by evaluating changes in coronary blood flow in response to acetylcholine, whereas endothelial-independent microvascular function was examined by evaluating changes in coronary flow velocity reserve in response to intracoronary adenosine. Patients were divided into 4 groups depending on whether they had a normal (+) or abnormal (-) coronary blood flow (CBF) in response to acetylcholine (Ach) and a normal (+) or abnormal (-) coronary flow velocity reserve (CFR) in response to adenosine (Adn): CBFAch+, CFRAdn+ (n = 520); CBFAch-, CFRAdn+ (n = 478); CBFAch+, CFRAdn- (n = 173); and CBFAch-, CFRAdn- (n = 268). RESULTS: Two-thirds of all patients had some sort of microvascular dysfunction. Women were more prevalent in each group (56% to 82%). Diabetes was uncommon in all groups (7% to 12%), whereas hypertension and hyperlipidemia were relatively more prevalent in each group, although rates for most conventional cardiovascular risk factors did not differ significantly between groups. There were no significant differences in the findings of noninvasive functional testing between groups. In a multivariable analysis, age was the only variable that independently predicted abnormal microvascular function. CONCLUSIONS: Patients with chest pain and nonobstructive CAD have a high prevalence of coronary microvascular abnormalities. These abnormalities correlate poorly with conventional cardiovascular risk factors and are dissociated from the findings of noninvasive functional testing.

Disfunção coronariana microvascular / Coronary Microvascular Dysfunction

Nas duas últimas décadas, uma série de estudos relatou que as anormalidades na função e estrutura da microcirculação coronariana podem ocorrer em pacientes sem aterosclerose obstrutiva, em pacientes com fatores de risco, com doenças do miocárdio, bem como na aterosclerose obstrutiva. A disfunção microvascular coronariana pode ser iatrogênica e é importante marcador de risco, contribuindo para a patogênese de doenças cardiovasculares e do miocárdio. Devido a sua importância torna-se alvo terapêutico. Este artigo apresenta uma atualização sobre a relevância clínica da disfunção microvascular coronariana em diferentes situações clínicas.

In the last two decades, a number of studies reported that abnormalities in the coronary microcirculation function and structure may occur in patients without obstructive atherosclerosis, in patients with risk factors, with myocardial diseases, as well as inobstructive atherosclerosis. Coronary microvascular coronary dysfunction may be iatrogenic and is an important risk marker, contributing to the pathogenesis of cardiovascular and myocardial diseases. Due to its importance, it becomes a therapeutic target.This article presents an update on the clinical relevance of coronary microvascular dysfunction in different clinical situations.