The Diagnostic Value of ECG Characteristics for Vasospastic and Microvascular Angina: A Systematic Review.

BACKGROUND: Coronary vascular dysfunction comprises VSA and/or MVA and is more common in women than in men with angina without obstructive coronary artery disease (ANOCA). Invasive coronary function testing is considered the reference test for diagnosis, but its burden on patients is large. We aimed to investigate the potential of electrocardiography (ECG) as noninvasive marker for vasospastic angina (VSA) and microvascular angina (MVA) diagnosis. METHODS: We systematically screened Pubmed and EMBASE databases for studies reporting on ECG characteristics in ANOCA patients with (a suspicion of) coronary vascular dysfunction. We assessed study quality using QUADAS-2. We extracted data on diagnostic values of different ECG characteristics and analyzed whether the studies were sex-stratified. RESULTS: Thirty publications met our criteria, 13 reported on VSA and 17 on MVA. The majority addressed repolarization-related ECG parameters. Only 1 of the 13 VSA papers and 4 of the 17 MVA papers showed diagnostic accuracy measures of the ECG characteristics. The presence of early repolarization, T-wave alternans, and inverted U waves showed of predictive value for VSA diagnosis. The QTc interval was predictive for MVA diagnosis in all six studies reporting on QTc interval. Sex-stratified results were reported in only 5 of the 30 studies and 3 of those observed sex-based differences. CONCLUSIONS: ECG features are not widely evaluated in diagnostic studies for VSA and MVA. Those features predictive for VSA and MVA diagnosis mostly point to repolarization abnormalities and may contribute to noninvasive risk stratification.

Inflammatory biomarkers in cardiac syndrome X: a systematic review and meta-analysis.

INTRODUCTION: In the current systematic review and meta-analysis, we aim to analyze the existing literature to evaluate the role of inflammatory biomarkers, including neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR), C-reactive protein (CRP), tumor necrosis factor-a (TNF-a), and interleukin-6 (IL-6) among individuals with cardiac syndrome X (CSX) compared to healthy controls. METHODS: We used PubMed, Web of Science, Scopus, Science Direct, and Embase to systematically search relevant publications published before April 2, 2023. We performed the meta-analysis using Stata 11.2 software (Stata Corp, College Station, TX). So, we used standardized mean difference (SMD) with a 95% confidence interval (CI) to compare the biomarker level between patients and healthy controls. The I2 and Cochran's Q tests were adopted to determine the heterogeneity of the included studies. RESULTS: Overall, 29 articles with 3480 participants (1855 with CSX and 1625 healthy controls) were included in the analysis. There was a significantly higher level of NLR (SMD = 0.85, 95%CI = 0.55-1.15, I2 = 89.0 %), CRP (SMD = 0.69, 95%CI = 0.38 to 1.02, p < 0.0001), IL-6 (SMD = 5.70, 95%CI = 1.91 to 9.50, p = 0.003), TNF-a (SMD = 3.78, 95%CI = 0.63 to 6.92, p = 0.019), and PLR (SMD = 1.38, 95%CI = 0.50 to 2.28, p = 0.02) in the CSX group in comparison with healthy controls. CONCLUSION: The results of this study showed that CSX leads to a significant increase in inflammatory biomarkers, including NLR, CRP, IL-6, TNF-a, and PLR.

Coronary microvascular dysfunction assessment: A comparative analysis of procedural aspects.

BACKGROUND: Full adoption of coronary microvascular dysfunction (CMD) assessment faces challenges due to its invasive nature and concerns about prolonged procedure time and increased contrast and/or radiation exposure. We compared procedural aspects of CMD invasive assessment to diagnostic left heart catheterization (DLHC) in patients with chest pain who were not found to have obstructive coronary artery disease. METHODS: A total of 227 patients in the Coronary Microvascular Disease Registry were compared to 1592 patients who underwent DLHC from August 2021 to November 2023. The two cohorts were compared using propensity-score matching; primary outcomes were fluoroscopy time and total contrast use. RESULTS: The participants' mean age was 64.1 ± 12.6 years. CMD-assessed patients were more likely to be female (66.5% vs. 45.2%, p < 0.001) and have hypertension (80.2% vs. 44.5%, p < 0.001), history of stroke (11.9% vs. 6.3%, p = 0.002), and history of myocardial infarction (20.3% vs. 7.7%, p < 0.001). CMD assessment was safe, without any reported adverse outcomes. A propensity-matched analysis showed that patients who underwent CMD assessment had slightly higher median contrast exposure (50 vs. 40 mL, p < 0.001), and slightly longer fluoroscopy time (6.9 vs. 4.7 min, p < 0.001). However, there was no difference in radiation dose (209.3 vs. 219 mGy, p = 0.58) and overall procedure time (31 vs. 29 min, p = 0.37). CONCLUSION: Compared to DLHC, CMD assessment is safe and requires only slightly additional contrast use (10 mL) and slightly longer fluoroscopy time (2 min) without clinical implications. These findings emphasize the favorable safety and feasibility of invasive CMD assessment.

Beyond Coronary Artery Disease: Assessing the Microcirculation.

Ischemic heart disease (IHD) affects more than 20 million adults in the United States. Although classically attributed to atherosclerosis of the epicardial coronary arteries, nearly half of patients with stable angina and IHD who undergo invasive coronary angiography do not have obstructive epicardial coronary artery disease. Ischemia with nonobstructive coronary arteries is frequently caused by microvascular angina with underlying coronary microvascular dysfunction (CMD). Greater understanding the pathophysiology, diagnosis, and treatment of CMD holds promise to improve clinical outcomes of patients with ischemic heart disease.

Understanding Patient Characteristics and Coronary Microvasculature: Early Insights from the Coronary Microvascular Disease Registry.

Coronary angiography has limitations in accurately assessing the coronary microcirculation. A new comprehensive invasive hemodynamic assessment method utilizing coronary flow reserve (CFR) and the index of microvascular resistance (IMR) offers improved diagnostic capabilities. This study aimed to present early real-world experience with invasive hemodynamic assessment of the coronary microvasculature in symptomatic patients with nonobstructive coronary artery disease (CAD) from the Coronary Microvascular Disease Registry, which is a prospective, multi-center registry that standardized the evaluation of patients with angina and nonobstructive CAD who underwent invasive hemodynamic assessment of the coronary microvasculature using the Coroventis CoroFlow Cardiovascular System. All patients underwent comprehensive invasive hemodynamic assessment. Analysis was performed on the first 154 patients enrolled in the Coronary Microvascular Disease Registry; their mean age was 62.4 years and 65.6% were female. A notable proportion of patients (31.8%) presented with a Canadian Cardiovascular Society Angina Score of 3 or 4. Coronary microvascular dysfunction was diagnosed in 39 of 154 patients (25.3%), with mean fractional flow reserve of 0.89 ± 0.43, mean resting full cycle ratio of 0.93 ± 0.08, mean CFR of 1.8 ± 0.9, and mean IMR of 36.26 ± 19.23. No in-hospital adverse events were reported in the patients. This study demonstrates the potential of invasive hemodynamic assessment using CFR and IMR to accurately evaluate the coronary microvasculature in patients with nonobstructive CAD. These findings have important implications for improving the diagnosis and management of coronary microvascular dysfunction, leading to more targeted and effective therapies for patients with microvascular angina.

Coronary Microvascular Disease in Contemporary Clinical Practice.

Coronary microvascular disease (CMD) causes myocardial ischemia in a variety of clinical scenarios. Clinical practice guidelines support routine testing for CMD in patients with ischemia with nonobstructive coronary artery disease. Invasive testing to identify CMD requires Doppler or thermodilution measures of flow to determine the coronary flow reserve and measures of microvascular resistance. Acetylcholine coronary reactivity testing identifies concomitant endothelial dysfunction, microvascular spasm, or epicardial coronary spasm. Comprehensive testing may improve symptoms, quality of life, and patient satisfaction by establishing a diagnosis and guiding-targeted medical therapy and lifestyle measures. Beyond ischemia with nonobstructive coronary artery disease, testing for CMD may play a role in patients with acute myocardial infarction, angina following coronary revascularization, heart failure with preserved ejection fraction, Takotsubo syndrome, and after heart transplantation. Additional education and provider awareness of CMD and its role in cardiovascular disease is needed to improve patient-centered outcomes of ischemic heart disease.

Predictive value of the systemic immune inflammatory index in cardiac syndrome x.

INTRODUCTION: Patients with normal coronary arteries in whom increased vasospasm cannot be detected with the stress test should be evaluated in terms of cardiac syndrome x (CSX). Inflammatory systems are effective in endothelial activation and dysfunction in CSX. The systemic immune inflammation index (SII) is thought to be an important factor in determining the course of diseases, especially in infectious diseases or other diseases, as an indicator of the inflammation process. The aim of this study is to determine the role of SII levels in the diagnosis of CSX disease. METHODS: The study group included 80 patients who applied to the cardiology department of Firat University with typical anginal complaints between October 2021 and April 2022, and were diagnosed with ischemia after the myocardial perfusion scan, and then coronary angiography was performed and normal coronary arteries were observed. RESULTS: When the study and control groups were examined according to age, gender and body mass index, hypertension, smoking, diabetes mellitus, dyslipidemia and family history, no statistical significant difference was observed between the groups. It was observed that there was a significant difference between the high sensitive C- reactive protin levels of the individuals in the study and control groups (p = 0.028). SII levels measured in samples taken from patients were significantly higher than control subjects (p = 0.003). SII cutoff at admission was 582 with 82% sensitivity and 84% specificity (area under the curve 0.972; 95% CI:0.95-0.98;p < 0.001). CONCLUSION: It has been demonstrated that systemic SII parameters, which can be simply calculated with the data obtained from the complete blood count and do not require additional costs, can contribute to the prediction of CSX disease.

Initial single-center experience of a standardized protocol for invasive assessment of ischemia and non-obstructive coronary artery disease.

INTRODUCTION: Coronary vasomotion disorders (CVDs), including microvascular angina (MVA) and vasospastic angina (VSA), account for significant morbidity among patients with non-obstructive coronary artery disease (NOCAD). However, protocols for CVD assessment in clinical practice are seldom standardized and may be difficult to implement. PURPOSE: To assess the safety and feasibility of a comprehensive coronary function test (CFT) protocol for assessment of CVD and the prevalence of different phenotypes of CVD in patients with angina and NOCAD (ANOCA). METHODS: Patients with persistent angina referred for invasive coronary angiogram and found to have NOCAD were prospectively recruited and underwent a CFT. Functional parameters (fractional flow reserve, coronary flow reserve and index of myocardial resistance) and coronary vasoreactivity were assessed in all patients. RESULTS: Of the 20 patients included, the mean age was 63±13 years and 50% were females. Most patients had persistent typical angina and evidence of ischemia in noninvasive tests (75%). The CFT was successfully performed in all subjects without serious complications. Isolated MVA was found in 25%, isolated VSA in 40%, both MVA and VSA in 10% and noncardiac chest pain in 25% of patients. Antianginal therapy was modified after the results of CFT in 70% of patients. CONCLUSION: A coronary function test was feasible and safe in a cohort of patients with ANOCA. CVD were prevalent in this selected group of patients, and some presented mixed CVD phenotypes. CFT may provide a definitive diagnosis in patients with persistent angina and prompt the stratification of pharmacological therapy.

[Angina Pectoris and the Importance of Coronary Microcirculation in Practice]. / Angina pectoris und die Bedeutung der koronaren Mikrozirkulation in der Praxis.

Angina Pectoris and the Importance of Coronary Microcirculation in Practice Abstract. Microvascular angina is a common manifestation of coronary microvascular dysfunction, particulary prevalent in post-menopausal women above the age of 50 and associated with impaired quality of life and poor clinical outcomes. However, microvascular angina remains largely undetected given the underuse of diagnostic tools for the assessment of coronary microvascular function. As a consequence, many of these patients suffering from coronary microvascular dysfunction fail to receive the appropriate medical treatment and remain in the long term symptomatic. Invasive coronary catheterization with measurement of coronary flow reserve and intracoronary acetylcholine provocation testing allows for the assessment of coronary microvascular dysfunction, and a therapy targeting specific physiological pathways can be implemented. A targeted therapy includes lifestyle modifications, secondary prevention measures, and anti-anginal medication. Ongoing clinical research in the field is expected to deliver novel diagnostic and therapeutic concepts for an improved management of patients with coronary microvascular disease.

Beyond Coronary Artery Disease: Assessing the Microcirculation.

Ischemic heart disease (IHD) affects more than 20 million adults in the United States. Although classically attributed to atherosclerosis of the epicardial coronary arteries, nearly half of patients with stable angina and IHD who undergo invasive coronary angiography do not have obstructive epicardial coronary artery disease. Ischemia with nonobstructive coronary arteries is frequently caused by microvascular angina with underlying coronary microvascular dysfunction (CMD). Greater understanding the pathophysiology, diagnosis, and treatment of CMD holds promise to improve clinical outcomes of patients with ischemic heart disease.

Updates on Pharmacologic Management of Microvascular Angina.

Microvascular angina (MVA), historically called cardiac syndrome X, refers to angina with nonobstructive coronary artery disease. This female-predominant cardiovascular disorder adds considerable health-related costs due to repeated diagnostic angiography and frequent hospital admissions. Despite the high prevalence of this diagnosis in patients undergoing coronary angiography, it is still a therapeutic challenge for cardiologists. Unlike obstructive coronary artery disease, with multiple evidence-based therapies and management guidelines, little is known regarding the management of MVA. During the last decade, many therapeutic interventions have been suggested for the treatment of MVA. However, there is a lack of summarization tab and update of current knowledge about pharmacologic management of MVA, mostly due to unclear pathophysiology. In this article, we have reviewed the underlying mechanisms of MVA and the outcomes of various medications in patients with this disease. Contrary to vasospastic angina in which normal angiogram is observed as well, nitrates are not effective in the treatment of MVA. Beta-blockers and calcium channel blockers have the strongest evidence of improving the symptoms. Moreover, the use of angiotensin-converting enzyme inhibitors or angiotensin receptor blockers, statins, estrogen, and novel antianginal drugs has had promising outcomes. Investigations are still ongoing for vitamin D, omega-3, incretins, and n-acetyl cysteine, which have resulted in beneficial initial outcomes. We believe that the employment of the available results and results of the future large-scale trials into cardiac care guidelines would help reduce the global cost of cardiac care tremendously.

Predictive value of lymphocyte to monocyte ratio for cardiac syndrome X.

OBJECTIVE: Cardiac syndrome X (CSX) is typically described with ischemia in stress tests in addition to angina-like chest pain and without stenosis in coronary angiography. We aimed at determining the relationship between LMR and CSX. PATIENTS AND METHODS: We retrospectively collected patients with CSX between January 2016 and December 2019. Patients with typical angina-like chest pain, normal 12-lead electrocardiography at rest, a positive response to the exercise test (> 0.1 mV ST-segment depression at 80 ms after the J point in two or more contiguous leads) or ischemia on myocardial perfusion scintigraphy and normal coronary angiography were included in the study as CSX patients. RESULTS: This study consisted of 116 patients with CSX and 153 control groups. The mean age of the patients with CSX was 52.7±9.7 years, and the mean age of the control group was 53.7±10.6 years (p= 0.416). The patients with CSX were more likely to have higher monocyte counts and LMR. According to the Pearson correlation test, the CRP value negatively correlated with the LMR. In multivariate logistic regression analysis, LMR remained a significant predictor of CSX. In ROC analysis, LMR < 4.1 had 64% sensitivity and 50% specificity (ROC area under curve: 0.587, 95% CI: 0.519-0.655, p=0.015) in accurately predicting a CSX diagnosis. CONCLUSIONS: We showed that lower LMR levels were associated with the presence of CSX.

[Non-invasive follow-up of adjusted treatment in patients with microvascular angina]. / Seguimiento no invasivo del tratamiento ajustado en pacientes con angina microvascular.

There are currently multiple invasive and non-invasive methods that can be used to establish the diagnosis of microvascular dysfunction (MVD) in patients with INOCA (Ischemia with Non-Obstructive Coronary Arteries) and microvascular angina. However, we still do not have a specific treatment approach for this group of patients. The current trend is to adjust the treatment to the pathophysiological mechanism involved, adding calcium blockers in those patients where endothelial dysfunction is demonstrated or beta blockers in those patients who present smooth muscle-dependent dysfunction. We present three clinical cases of INOCA with suspected microvascular angina. Two of them underwent a non-invasive diagnosis of MVD by CZT-SPECT, using dipyridamole to evaluate the smooth muscle-dependent mechanism and cold pressor test to evaluate the endothelium-dependent mechanism. According to the results obtained, the treatment was adju sted, clinical follow-up was carried out and angina was assessed using the Seattle scale, with a new microcirculation assessment at 6 months. The third clinical case, on the other hand, was a patient who began empirical treatment for both mechanisms and subsequently abandoned the established treatment. Microvascular function was evaluated under pharmacological treatment and without it.

Actualmente existen múltiples métodos invasivos y no invasivos que pueden emplearse para establecer el diagnóstico de disfunción microvascular (DMV) en pacientes con INOCA (por sus siglas en inglés: Ischemia with Non-Obstructive Coronary Arteries) y angina microvascular (AMV). No obstante, todavía no contamos con un enfoque de tratamiento específico para este grupo de pacientes. La tendencia act ual es ajustar el tratamiento al mecanismo fisiopatológico implicado, añadiendo antagonistas del calcio en aquellos pacientes en los que se demuestre disfunción endotelial, o bien bloqueadores beta en aquellos que presenten disfunción músculo liso dependiente. Presentamos tres casos clínicos de INOCA con sospecha de AMV. A dos de ellos se les realizó diagnóstico no invasivo de DMV mediante CZT-SPECT, utilizando como apremio dipiridamol para evaluar el mecanismo músculo liso dependiente y test de frío para evaluar el mecanismo endotelio dependiente. Según los resultados obtenidos se ajustó el tratamiento, se realizó seguimiento clínico y valoración de la angina por la escala de Seattle, con nueva valoración de la función microvascular a los 6 meses. El tercer caso clínico, en cambio, es una paciente que inició tratamiento empírico para ambos mecanismos y posteriormente abandonó el tratamiento instaurado, evaluándose la función microvascular bajo tratamiento farmacológico y sin el mismo.

[Coronary microvascular dysfunction: mechanisms and clinical outcome]. / La patologia microvascolare coronarica: meccanismi e contesti clinici.

A large percentage of patients, predominantly female, who undergo coronary angiography for typical chest pain do not have significant coronary stenosis. Many of these patients with microvascular myocardial disease have left ventricular hypertrophy, cardiomyopathies, valve disease, or other clinical conditions. The definition of microvascular angina is based on (i) symptoms of myocardial ischemia, (ii) absence of obstructive coronary artery disease (<50% stenosis on coronary angiography or coronary computed tomography scan), (iii) objective evidence of myocardial ischemia (ischemic electrocardiographic abnormalities during episodes of chest pain and/or myocardial perfusion defects or regional contractility abnormalities), and (iv) pathological indices of microcirculation (index of microcirculatory resistance >25, coronary flow reserve <2.0) and/or microvascular spasm (TIMI flow <2) during intracoronary vasoreactivity tests. The basic mechanisms and the diagnostic tests of microvascular dysfunction are reported in detail.From a clinical standpoint, while the crucial role of microcirculation in determining short- and long-term prognosis is evident, efforts to date to improve clinical outcomes in patients with microvascular obstruction have had limited success, most likely because microvascular dysfunction is a multifactorial process with several interdependent underlying pathophysiological mechanisms. Therefore, further studies are needed to develop effective therapeutic strategies for microvascular myocardial disease.

Definition and epidemiology of coronary microvascular disease.

Ischemic heart disease remains one of the leading causes of death and disability worldwide. However, most patients referred for a noninvasive computed tomography coronary angiogram (CTA) or invasive coronary angiogram for the investigation of angina do not have obstructive coronary artery disease (CAD). Approximately two in five referred patients have coronary microvascular disease (CMD) as a primary diagnosis and, in addition, CMD also associates with CAD and myocardial disease (dual pathology). CMD underpins excess morbidity, impaired quality of life, significant health resource utilization, and adverse cardiovascular events. However, CMD often passes undiagnosed and the onward management of these patients is uncertain and heterogeneous. International standardized diagnostic criteria allow for the accurate diagnosis of CMD, ensuring an often overlooked patient population can be diagnosed and stratified for targeted medical therapy. Key to this is assessing coronary microvascular function-including coronary flow reserve, coronary microvascular resistance, and coronary microvascular spasm. This can be done by invasive methods (intracoronary temperature-pressure wire, intracoronary Doppler flow-pressure wire, intracoronary provocation testing) and non-invasive methods [positron emission tomography (PET), cardiac magnetic resonance imaging (CMR), transthoracic Doppler echocardiography (TTDE), cardiac computed tomography (CT)]. Coronary CTA is insensitive for CMD. Functional coronary angiography represents the combination of CAD imaging and invasive diagnostic procedures.

Systemic Immune-Inflammation Index as a Predictor of Microvascular Dysfunction in Patients With Cardiac Syndrome X.

The systemic immune inflammation index (SII; platelet count x neutrophil-lymphocyte ratio), a new marker, predicts adverse clinical outcomes in many conditions, including acute and chronic coronary syndromes, pulmonary embolism, cancers, and contrast nephropathy. The aim of this study was to determine the relationship between SII and microvascular dysfunction in patients with Cardiac Syndrome X (CSX); 105 patients with CSX and 105 patients with normal coronary arteries were included. Microvascular dysfunction was determined angiographically using myocardial blush grade (MBG) and total myocardial blush score (TMBS). We observed that the SII levels were higher in the CSX (+) group (687 [355-2211] vs 418 [198-1614], P<.001). The SII levels were also found to be significant independent predictors for CSX in multiple regression analysis (P=.001). SII levels >440 had 83.8% sensitivity and 55.2% specificity (area under the curve [AUC]: .923, 95% CI: .895-.999, P<.001) for predicting CSX. There is a significant correlation between SII levels and CSX.

Biomarkers of Coronary Microvascular Dysfunction in Patients With Microvascular Angina: A Narrative Review.

The current gold standard for diagnosis of coronary microvascular dysfunction (CMD) in the absence of myocardial diseases, whose clinical manifestation is microvascular angina (MVA), is reactivity testing using adenosine or acetylcholine during coronary angiography. This invasive test can be difficult to perform, expensive, and harmful. The identification of easily obtainable blood biomarkers which reflect the pathophysiology of CMD, characterized by high reliability, precision, accuracy, and accessibility may reduce risks and costs related to invasive procedures and even facilitate the screening and diagnosis of CMD. In this review, we summarized the results of several studies that have investigated the possible relationships between blood biomarkers involved with CMD and MVA. More specifically, we have divided the analyzed biomarkers into 3 different groups, according to the main mechanisms underlying CMD: biomarkers of "endothelial dysfunction," "vascular inflammation," and "oxidative stress." Finally, in the last section of the review, we consider mixed mechanisms and biomarkers which are not included in the 3 major categories mentioned above, but could be involved in the pathogenesis of CMD.