Microvascular Spasm Research Articles

Complete Blood Count-Derived Indices as Prognostic Factors of 5-Year Outcomes in Patients With Confirmed Coronary Microvascular Spasm.

BackgroundCoronary microcirculatory dysfunction is a meaningful factor in the development of ischemic heart disease. We investigated the relationship between coronary microvascular spasm and complete blood count indices.MethodsBetween 2010 and 2013, we performed acetylcholine test (AChT) in subjects with suspicion of angina evoked by epicardial coronary spasm or coronary microvascular spasm according to COVADIS criteria. We administered acetylcholine in increasing doses of 25, 50, and 75 μg into the right coronary artery and 25, 50, and 100 μg into the left coronary artery. Patients were followed up for 60 months.ResultsIn total, 211 patients (60.5 ± 7.8 years, 67.8% women) were included in the study. The AChT revealed angina due to epicardial coronary spasm in 99 patients (46.9%) and coronary microvascular spasm in 72 (34.1%). White blood cell (WBC), red blood cell distribution width (RDW), platelets (PLT), mean platelet volume (MPV), and platelet distribution width (PDW) values were significantly higher in patients with coronary microvascular spasm than in patients from the other two groups, i.e., epicardial coronary spasm and negative AChT. PDW showed the highest sensitivity (65%) and specificity (72%) at the cutoff value of 15.32% [area under the curve, 0.723; 95% confidence interval (CI) 0.64–0.83; P < 0.001]. Independent risk factors for coronary microvascular spasm diagnosis using AChT were as follows: female sex (OR, 1.199), PDW (OR, 2.891), and RDW (OR, 1.567).ConclusionPDW and RDW are significantly associated with the diagnosis of coronary microvascular spasm in patients undergoing AChT as well as with poor prognosis in such patients at 5 years.

Safety of Provocative Testing With Intracoronary Acetylcholine and Implications for Standard Protocols

BackgroundHeterogeneity in diagnostic criteria and provocation protocols has posed challenges in understanding the safety of coronary provocation testing with intracoronary acetylcholine (ACh) for the contemporary diagnosis of epicardial and microvascular spasm. ObjectivesWe examined the safety of testing and subgroup differences in procedural risks based on ethnicity, diagnostic criteria, and provocation protocols. MethodsPubMed and Embase were searched in November 2021 to identify original articles reporting procedural complications associated with intracoronary ACh administration. The primary outcome was the pooled estimate of the incidence of major complications including death, myocardial infarction, ventricular tachycardia/fibrillation, and shock. ResultsA total of 16 studies with 12,585 patients were included in the meta-analysis. The overall pooled estimate of the incidence of major complications was 0.5% (95% CI: 0.0%-1.3%) without any reports of death. Exploratory subgroup analyses revealed that the pooled incidence of major complications was significantly higher in the studies that followed the contemporary diagnosis criteria for epicardial spasm defined as ≥90% diameter reduction (1.0%; 95% CI: 0.3%-2.0%) but significantly lower in Western populations (0.0%; 95% CI: 0.0%-0.45%). The rate of positive epicardial spasm and the incidence of major complications were similar between provocation protocols using the maximum ACh doses of 100 μg and 200 μg. ConclusionsIntracoronary ACh administration for the contemporary diagnosis of epicardial and microvascular spasm is a safe procedure. Moreover, excellent safety records are observed in Western populations primarily presenting with myocardial ischemia and/or infarction with nonobstructive coronary arteries. This study will help standardize ACh testing to improve clinical diagnosis and ensure procedural safety.

Coronary microvascular dysfunction: mechanisms and clinical outcome

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.

Epicardial and microvascular coronary artery spasm in biopsy-proven viral myocarditis

BackgroundCoronary spasm has been suggested to be the underlying mechanism of chest pain in patients with myocarditis and unobstructed coronary arteries. Here we sought to investigate a potential association between virus type and coronary spasm endotype in patients with biopsy-proven viral myocarditis. MethodsA total of 618 consecutive patients with unobstructed coronary arteries who underwent endomyocardial biopsy between 2008 and 2018 were screened. Viral myocarditis defined as (immuno-)histological evidence of myocardial inflammation and proof of viral genome by PCR was confirmed in 114 patients. Of these, 34 patients had undergone additional intracoronary acetylcholine (ACh) testing and served as the final study cohort. ResultsPatients in this study were 51 ± 27 years old, 41% were female and mean left ventricular ejection fraction was 58 ± 23%. Most frequently, virus DNA was detected by PCR from parvovirus B19 (PVB19, 59%) and human herpesvirus 6 (HHV6, 26%). ACh testing revealed epicardial spasm in 10 patients (29%) and microvascular spasm in 11 patients (32%). The rate of coronary spasm was higher in patients with PVB19-associated myocarditis compared to those with HHV6-associated myocarditis (80% vs. 33%, p = 0.031). In particular, there was a higher prevalence of microvascular spasm in patients with PVB19 compared to HHV6 infection (45% vs. 0%, p = 0.018). ConclusionCoronary spasm is a frequent finding in patients with biopsy-proven viral myocarditis supporting the hypothesis that coronary spasm may contribute to chest pain in these patients. We observed a particular association of microvascular spasm with PVB19 infection.

P045 Octopus Toes?

Abstract Background/Aims Takotsubo cardiomyopathy is a relatively rare condition. Its name derives from the distinctive apical ballooning seen on cardiac angiography, which resembles the shape of takotsubo, a Japanese octopus trap. The clinical presentation is similar to acute coronary syndrome (ACS). Ischaemic ECG changes and elevated serum cardiac biomarkers are seen despite normal coronary artery angiography. Methods: History A 72-year-old female presented with a five-day history of constant bilateral foot pain and toe discolouration, associated with reduced sensation. She had a past history of hypertension and Raynaud’s phenomenon. She had recently been admitted with an alcohol withdrawal seizure and had recent severe stressful life events. She denied chest pain or dyspnoea and was a non-smoker. Her medications were ramipril and thiamine. Examination: Both feet were warm to touch proximal to the toes, with tenderness and diminished sensation in the distal feet. The toes were dusky but pedal pulses were palpable with good biphasic Doppler signal. Blood pressure was 117/105 mmHg on admission, with normal nail folds and heart sound, and no splinter haemorrhages were seen. Results: Investigations Blood parameters were CRP 60 mg/L, eGFR 47 mL/min, troponin &amp;gt;25,000 ng/L, and negative RF, ANA, ANCA, MPO, PR3, C3, C4. ECG showed lateral ST-segment elevation but normal coronary vessels were seen on coronary angiography. Echocardiogram revealed hypokinetic apical region and mid-anterior wall, reduced ejection fraction 35-40 % with apical ballooning, consistent with Takotsubo cardiomyopathy. Urine catecholamines, normetadrenaline, metadrenaline and 3-methoxytyramine levels were normal when measured eight days after the initial presentation. Management Daily Iloprost was given for five days with aspirin, furosemide, spironolactone and ivabradine, but no significant improvement was observed in the ischaemic feet. Her foot pain gradually subsided but the toes remained necrotic. Over the next six months, her toes mummified and auto-amputated. She has had no further ischaemic events. Conclusion Takotsubo cardiomyopathy accounts for 1-2% of troponin positive suspected ACS. It is most common in older females. The cause is not clear, but the predominant hypothesis is that a catecholamine surge leads to microvascular spasm and myocardial stunning. Raised catecholamine levels at presentation have been documented in patients with takotsubo cardiomyopathy, and the syndrome has been described in patients exposed to exogenous catecholamines. Digital ischaemia has been described in phaeochromocytoma. We postulate that our patient’s background of Raynaud’s phenomenon predisposed her to digital ischaemia during a period of catecholamine excess, which led to takotsubo cardiomyopathy. To our knowledge, this phenomenon has not previously been described. Given the profound effect of the presumed catecholamine surge on cardiac function in takotsubo cardiomyopathy and the high prevalence of Raynaud's phenomenon in the general population, it is perhaps surprising that ischaemia in digits and other organs is not more commonly observed. Disclosure K. Yeap: None. C. Badu-Boateng: None. M. Lloyd: None.

Acetylcholine Re-Challenge After Intracoronary Nitroglycerine Administration.

Coronary artery spasm (CAS) can be diagnosed in a large proportion of patients with recurrent angina with non-obstructive coronary artery disease (ANOCA) using acetylcholine (ACh) spasm provocation testing. CAS can further be divided into different subtypes (e.g., focal, diffuse epicardial, or microvascular spasm), each with different pathophysiological mechanisms that may require tailored drug treatment. The evidence behind the role of nitrates in the setting of each CAS subtype is lacking, and the effectivity can vary on a per-patient basis. In order to assess on a per-patient level whether nitroglycerine (NTG) can prevent inducible spasm, the vasospastic ACh dose can be readministered after NTG administration as part of the spasm provocation test. The preventive effect of NTG is assessed by evaluating improvements in the severity of induced symptoms, ischemic ECG changes, and by reassessing the site and mode of spasm on angiography. This technique can therefore be used to assess the nitrate responsiveness on a per-patient level and unmask co-existing microvascular spasm in patients with epicardial spasm that is prevented with NTG. The NTG rechallenge, therefore, allows to further guide targeted therapy for CAS and provide new insights into the pathophysiological mechanism behind vasospastic disorders.

Prevalence of Coronary Microvascular Disease and Coronary Vasospasm in Patients With Nonobstructive Coronary Artery Disease: Systematic Review and Meta-Analysis.

BackgroundA relevant proportion of patients with suspected coronary artery disease undergo invasive coronary angiography showing normal or nonobstructive coronary arteries. However, the prevalence of coronary microvascular disease (CMD) and coronary spasm in patients with nonobstructive coronary artery disease remains to be determined. The objective of this study was to determine the prevalence of coronary CMD and coronary vasospastic angina in patients with no obstructive coronary artery disease.Methods and ResultsA systematic review and meta‐analysis of studies assessing the prevalence of CMD and vasospastic angina in patients with no obstructive coronary artery disease was performed. Random‐effects models were used to determine the prevalence of these 2 disease entities. Fifty‐six studies comprising 14 427 patients were included. The pooled prevalence of CMD was 0.41 (95% CI, 0.36–0.47), epicardial vasospasm 0.40 (95% CI, 0.34–0.46) and microvascular spasm 24% (95% CI, 0.21–0.28). The prevalence of combined CMD and vasospastic angina was 0.23 (95% CI, 0.17–0.31). Female patients had a higher risk of presenting with CMD compared with male patients (risk ratio, 1.45 [95% CI, 1.11–1.90]). CMD prevalence was similar when assessed using noninvasive or invasive diagnostic methods.ConclusionsIn patients with no obstructive coronary artery disease, approximately half of the cases were reported to have CMD and/or coronary spasm. CMD was more prevalent among female patients. Greater awareness among physicians of ischemia with no obstructive coronary arteries is urgently needed for accurate diagnosis and patient‐tailored management.

Trigeminal Nerve Stimulation Improves Cerebral Macrocirculation and Microcirculation After Subarachnoid Hemorrhage: An Exploratory Study.

Delayed cerebral ischemia (DCI) is the most consequential secondary insult after aneurysmal subarachnoid hemorrhage (SAH). It is a multifactorial process caused by a combination of large artery vasospasm and microcirculatory dysregulation. Despite numerous efforts, no effective therapeutic strategies are available to prevent DCI. The trigeminal nerve richly innervates cerebral blood vessels and releases a host of vasoactive agents upon stimulation. As such, electrical trigeminal nerve stimulation (TNS) has the capability of enhancing cerebral circulation. To determine whether TNS can restore impaired cerebral macrocirculation and microcirculation in an experimental rat model of SAH. The animals were randomly assigned to sham-operated, SAH-control, and SAH-TNS groups. SAH was induced by endovascular perforation on Day 0, followed by KCl-induced cortical spreading depolarization on day 1, and sample collection on day 2. TNS was delivered on day 1. Multiple end points were assessed including cerebral vasospasm, microvascular spasm, microthrombosis, calcitonin gene-related peptide and intercellular adhesion molecule-1 concentrations, degree of cerebral ischemia and apoptosis, and neurobehavioral outcomes. SAH resulted in significant vasoconstriction in both major cerebral vessels and cortical pial arterioles. Compared with the SAH-control group, TNS increased lumen diameters of the internal carotid artery, middle cerebral artery, and anterior cerebral artery, and decreased pial arteriolar wall thickness. Additionally, TNS increased cerebrospinal fluid calcitonin gene-related peptide levels, and decreased cortical intercellular adhesion molecule-1 expression, parenchymal microthrombi formation, ischemia-induced hypoxic injury, cellular apoptosis, and neurobehavioral deficits. Our results suggest that TNS can enhance cerebral circulation at multiple levels, lessen the impact of cerebral ischemia, and ameliorate the consequences of DCI after SAH.

Intracoronary ergonovine testing among 505 consecutive Japanese patients with angina-like chest pain and unobstructed coronary artery disease.

Intracoronary ergonovine (ER) testing is useful for the detection of epicardial spasm (ES) and coronary microvascular spasm (CMS). We retrospectively analyzed the incidence of ES and CMS in consecutive Japanese patients with unobstructed coronary artery disease. From January 1991 to February 2019, we performed intracoronary ER testing of 1196 patients. Among these patients, a total of 505 consecutive patients (207 women, mean age 64 ± 11years) who underwent first diagnostic angiography for suspected myocardial ischemia and had unobstructed coronary arteries (< 50%) were enrolled. Resting chest pain was reported by 229 patients, exertional chest pain was reported by 62 patients, exertional and resting chest pain was reported by 61 patients, and another chest symptom (not typical chest pain but suspected to be myocardial ischemia) was reported by 153 patients. ES was defined as ≥ 90% stenosis and usual chest symptoms and ischemic ECG changes, while CMS was defined as < 75% stenosis (no epicardial spasm) and usual chest symptoms and ischemic ECG changes. We performed intracoronary ER testing on both coronary arteries in 86% (432/505) of all subjects. Overall, ES was found in 82 patients (16%), whereas CMS was revealed in 12 patients (2%). In patients with ES, women made up 9%, and 70% of the patients had resting chest pain. In contrast, women composed 67% (8/12) of those with CMS, and 5 patients with CMS had another chest symptom. Ventricular fibrillation was observed in two patients who had sinus rhythm after thump version or cardiac resuscitation. However, we observed no irreversible complications during ER testing. CMS was recognized in only 2% of consecutive Japanese patients with unobstructed coronary artery disease by intracoronary ER testing, whereas ES was revealed in 16% of those patients. CMS was often observed in women.

Relation Between Coronary Tortuosity and Vasomotor Dysfunction in Patients Without Obstructed Coronaries?

Background: A large proportion of patients with angina and no obstructive coronary artery disease (ANOCA) has underlying coronary vasomotor dysfunction (CVDys), which can be diagnosed by a coronary function test (CFT). Coronary tortuosity is a common angiographic finding during the CFT. Yet, no data exist on the association between vasomotor dysfunction and coronary tortuosity.Aim: To investigate the association between CVDys and coronary tortuosity in patients with ANOCAMethods: All consecutive ANOCA patients who underwent clinically indicated CFT between February 2019 and November 2020 were included. CFT included acetylcholine spasm testing to diagnose epicardial or microvascular spasm, and adenosine testing to diagnose microvascular dysfunction (MVD). MVD was defined as an index of microvascular resistance (IMR) ≥ 25 and/or coronary flow reserve (CFR) <2.0. Coronary tortuosity, was scored (no, mild, moderate or severe) based on the angles of the curvatures in the left anterior descending (LAD) artery on angiography.Results: In total, 228 patients were included (86% female, mean age 56 ± 9 years). We found coronary artery spasm in 81% of patients and MVD in 45% of patients (15%: abnormal CFR, 30%: abnormal IMR). There were 73 patients with no tortuosity, 114 with mild tortuosity, 41 with moderate tortuosity, and no patients with severe tortuosity. No differences were found in cardiovascular risk factors or medical history, and the prevalence of CVDys did not differ between the no tortuosity, mild tortuosity and moderate tortuosity group (82, 82, and 85%, respectively).Conclusion: In this study, CVDys was not associated with coronary tortuosity. Future experimental and clinical studies on the complex interplay between coronary tortuosity, wall shear stress, endothelial dysfunction and coronary flow are warranted.

Acetylcholine Rechallenge: A First Step Toward Tailored Treatment in Patients With Coronary Artery Spasm.

The present study aimed to assess the feasibility and clinical value of acetylcholine (ACh) rechallenge for the detection of coexisting epicardial and microvascular spasm and to determine the efficacy of nitroglycerin in these spasm endotypes. The coexistence of epicardial and microvascular spasm is difficult to identify; thus, its frequency is unknown. Nitroglycerin treatment is equally recommended for both epicardial and microvascular coronary spasm despite contradictory data. In this multicenter study, 95 patients with coronary spasm were included to undergo ACh rechallenge, which consisted of repeated ACh provocation 3minutes after intracoronary nitroglycerin administration using the same dose that previously induced spasm. In total, 95 patients (age 61 ± 12 years, 69% female) were included. Fifty-five patients (58%) had microvascular spasm, and 40 patients (42%) had epicardial spasm during initial ACh provocation. In 48% of patients with epicardial spasm, ACh rechallenge revealed coexisting nitroglycerin-persistent microvascular spasm. Nitroglycerin administration before ACh rechallenge prevented reinducibility of epicardial spasm in all patients with focal spasm and in 80% of patients with diffuse spasm. Microvascular spasm was prevented in only 20% by prior nitroglycerin administration but was attenuated in another 49% of patients. This study demonstrates a high frequency of epicardial spasm with coexisting nitroglycerin-persistent microvascular spasm. Intracoronary nitroglycerin was very effective in preventing reinducibility of epicardial spasm, whereas it prevented microvascular spasm in only 20% of patients. ACh rechallenge is a novel method that facilitates the detection of coexisting spasm endotypes and may pave the way towards tailored treatment of vasospastic angina.

Clinico-pathophysiological considerations in coronary microvascular disorders

Around half of the patients undergoing an elective coronary angiogram to investigate typical stable angina symptoms are found to have non-obstructive coronary arteries (defined as &lt; 50% stenosis). These patients are younger with a female predilection. While underlying mechanisms responsible for these presentations are heterogeneous, structural and functional abnormalities of the coronary microvasculature are highly prevalent. Thus, coronary microvascular dysfunction (CMD) is increasingly recognised as an important consideration in patients with non-obstructive coronary arteries. This review will focus on primary coronary microvascular disorders and summarise the four common clinical presentation pictures which can be considered as endotypes - Microvascular Ischaemia (formerly “Syndrome X”), Microvascular Angina, Microvascular Spasm, and Coronary Slow Flow. Furthermore, the pathophysiological mechanisms associated with CMD are also heterogenous. CMD may arise from an increased microvascular resistance, impaired microvascular dilation, and/or inducible microvascular spasm, ultimately causing myocardial ischaemia and angina. Alternatively, chest pain may arise from hypersensitivity of myocardial pain receptors rather than myocardial ischaemia. These two major abnormalities should be considered when assessing an individual clinical picture, and ultimately, the question arises whether to target the heart or the pain perception to treat the anginal symptoms.

Coronary Microvascular Vasodilatory Function: Related Clinical Features and Differences According to the Different Coronary Arteries and Types of Coronary Spasm.

Background: In the clinical setting; the microvascular vasodilatory function test (MVFT) with a pressure wire has been used in ischaemia patients with non-obstructive coronary arteries (INOCA), including vasospastic angina (VSA) and microvascular angina (MVA). The exact factors that affect the microvascular vasodilatory function (MVF) in such patients are still unknown. We aimed to identify the factors, including clinical parameters and lesion characteristics, affecting the MVF in such patients. Methods: A total of 53 patients who underwent coronary angiography, spasm provocation tests (SPTs) and MVFTs were enrolled. In the MVFT, the coronary flow reserve (CFR) and index of microcirculatory resistance (IMR) were measured. Of the 53 patients, MVFT data in the left anterior descending coronary artery (LAD) were obtained from 49 patients, and the clinical parameters were checked in all of them. Based on the results of the SPT, coronary spasms were divided into focal spasm, diffuse spasm, and microvascular spasm (MVS). To assess the lesion characteristics influencing MVF, MVFT data were compared according to the types of coronary spasm and coronary vessels in 73 vessels of the 53 patients. Results: In 49 patients who underwent the MVFT in the LAD, the IMR was higher in active smokers (n = 7) than in former smokers (n = 15) and never smokers (n = 27, p < 0.01). In the 73 coronary arteries in this study, the type of coronary spasm did not correlate with the CFR or IMR, whereas a higher IMR were more frequently observed in cases of focal spasm than in cases of diffuse spasm (p = 0.03). In addition, the IMR was higher in the right coronary artery (RCA) than in the LAD (p = 0.02). Conclusion: These results indicate that the smoking status affected the MVF in patients with INOCA, suggesting the possibility of improvement in the MVF by smoking cessation in such patients. In addition, in the assessment of MVF, it may be important to take into account which coronary artery or types of coronary spasm are being evaluated.

Myocardial Infarction with Non-Obstructive Coronary Artery Disease: The Labyrinth of Investigations. Case Report and Review of the Literature.

Myocardial infarction with non-obstructive coronary artery disease (MINOCA) accounts for approximately 5–15% of acute myocardial infarctions (MI). This infarction type raises a series of questions about the underlying mechanism of myocardial damage, the diagnostic pathway, optimal therapy, and the outcomes of these patients when compared to MI associated with obstructive coronary artery disease. We present the case of a 60-year-old patient with multiple cardiovascular risk factors and comorbidities who is admitted in an emergency setting. The patient is known with a conservatively treated inferior myocardial infarction which occurred 3 months prior, with reduced left ventricular ejection fraction. Emergency coronary angiography revealed normal epicardial coronary arteries, which led to further investigations of the underlying cause. Considering the absence of epicardial and microvascular spasm, CMR (cardiac magnetic resonance) confirmation of two transmural myocardial infarctions in the territories tributary to coronary arteries, and a high index of myocardial resistance in culprit arteries, we concluded the diagnosis of MINOCA due to the microvascular endothelial dysfunction. Although the concept of MINOCA was devised almost a decade ago, and these patients are an important part of MI presentations, it still represents a diagnostic challenge with multiple explorations required to establish the precise etiology.

Outpatient Management of Patients With Angina With No Obstructive Coronary Arteries: How to Come to a Proper Diagnosis and Therapy.

Two-thirds of women and one-third of men who undergo a clinically indicated coronary angiography for stable angina, have no obstructive coronary artery disease (CAD). Coronary vascular dysfunction is a highly prevalent underlying cause of angina in these so called “Angina with No Obstructive Coronary Arteries (ANOCA)” patients, foremost in middle aged women. Coronary vascular dysfunction encompasses various endotypes, namely epicardial and microvascular coronary spasms, impaired vasodilatation, and increased microvascular resistance. ANOCA patients, especially those with underlying coronary vascular dysfunction, have an adverse cardiovascular prognosis, poor physical functioning, and a reduced quality of life. Since standard ischemia detection tests and coronary angiograms are not designed to diagnose coronary vascular dysfunction, this ischemic heart disease is often overlooked and hence undertreated. But adequate diagnosis is vital, so that treatment can be started to reduce symptoms, reduce healthcare costs and improve quality of life and cardiovascular prognosis. The purpose of this review is to give a contemporary overview of ANOCA with focus on coronary vascular dysfunction. We will provide a possible work-up of patients suspected of coronary vascular dysfunction in the outpatient clinical setting, based on the latest scientific insights and international consensus documents. We will discuss the value of ischemia detection testing, and non-invasive and invasive methods to diagnose coronary vascular dysfunction. Furthermore, we will go into pharmacological and non-pharmacological therapeutic options including anti-anginal regimens and lifestyle interventions.

Sex Differences in Coronary Function Test Results in Patient With Angina and Nonobstructive Disease.

Introduction: Invasive coronary function testing (CFT) has become the recommended diagnostic tool to assess the various endotypes of coronary vasomotor dysfunction in patients with angina and no obstructive coronary artery disease (ANOCA), which has implications for therapy and prognosis. Although the expanding performance of CFT is leading to increased knowledge of coronary vasomotor dysfunction, little is known about sex-related differences in the results of comprehensive CFT.Methods: We conducted a prospective study of all consecutive patients with ANOCA that underwent clinically indicated CFT in a tertiary interventional from February 2019 to February 2021. CFT consisted of acetylcholine testing to diagnose epicardial or microvascular spasm, and adenosine testing to diagnose CMD. CMD was defined as an index of microvascular resistance (IMR) ≥ 25 and/or coronary flow reserve (CFR) < 2.0.Results: In total, 228 women and 38 men underwent CFT. No differences in traditional risk factors were seen, but women had a higher prevalence of migraine (45 vs. 14%, p = 0.001). Men more often had a history of percutaneous coronary intervention (12 vs. 49%, p = 0.001). We found no difference in clinical presentation. Coronary vasomotor dysfunction was present in 95% of men and 88% of women (p = 0.25), but males show more often epicardial spasm and less microvascular spasm than women (63 vs. 42% and 29 vs. 40% respectively, p = 0.039). Impaired CFR was more prevalent among females (6 vs 20%, p = 0.033). IMR [median of 23 (15–32) vs. 19 (13–25), p = 0.08] did not differ between the sexes.Conclusion: Men undergoing CFT show a comparable prevalence of coronary vascular dysfunction as women. However, men have a higher prevalence of epicardial spasm and a lower prevalence of microvascular spasm compared with women. An impaired CFR was more often present in women, with an equally impairment of IMR.

Long-term follow-up of patients with MINOCA (myocardial infarction with unobstructed coronary arteries) undergoing intracoronary spasm provocation testing

Abstract Background Up to 30% of patients presenting with acute coronary syndrome undergoing coronary angiography are found to have no culprit lesion. Among them, epicardial or microvascular spasm can be diagnosed in ∼50% of patients undergoing provocative testing. While prognostic data in patients with coronary spasm and stable angina are abundant, the outcome of patients with myocardial infarction and unobstructed coronaries (MINOCA) and coronary spasm is not clear. Purpose The aim of this study was to investigate the prognosis of a cohort of patients presenting with MINOCA undergoing intracoronary acetylcholine (ACH) spasm testing. Methods We evaluated consecutive patients with MINOCA undergoing acetylcholine testing to detect epicardial or microvascular spasm from 2014 to 2017. Other aetiologies for MINOCA such as myocarditis, supraventricular tachycardia, pulmonary embolism etc. were excluded. Data regarding mortality (cardiac/non-cardiac), nonfatal myocardial infarction (MI), repeated coronary angiography and percutaneous coronary intervention (PCI) were recorded. Results Of 112 patients in our study, follow-up data were available for 96 patients (86%, 51% women, mean age 63±13 years). Acetylcholine testing was positive in 51 (53%) patients. Among patients with a positive test, epicardial spasm was detected in 26 (51%) and microvascular spasm in 25 (49%) patients. After a median follow-up of 5±3.5 years, 7 deaths (7%) and 20 nonfatal myocardial infarctions (21%) occurred. Moreover, 19 patients (20%) underwent coronary angiography and 9 patients (9%) received a PCI. Comparisons of the Kaplan–Meier curves by log-rank test showed that patients with positive acetylcholine test had a worse outcome compared to those with a negative test in terms of death from any cause (p=0.01), myocardial infarction (p=0.03) and repeated coronary angiography (p=0.05). Conclusion This follow-up study shows that prognosis of MINOCA patients with coronary spasm on provocative testing is worse compared to patients with an uneventful test. The results underline the potential prognostic value of spasm testing in MINOCA patients. Funding Acknowledgement Type of funding sources: None.

Coronary microvascular function in patients with angina with no obstructive coronary artery disease-What factors affect it clinically or angiographically?

Abstract Background In the clinical setting, we have often experienced patients with angina with no obstructive coronary artery disease (ANOCA), and it has been proposed that the presence of coronary microvascular dysfunction (CMD) play a pivotal role in the pathogenesis of ANOCA. Thus, it is important to assess coronary microvascular function (CMF). However, it has not been clarified what clinical factors or lesion characteristics on coronary angiography (CAG) affect CMF. Thus, we investigated the relationship between CMF and clinical factors or lesion characteristics on CAG in patients with ANOCA. Methods Thirty-four patients with chest pain, who underwent CAG, spasm provocation test (SPT) and CMF test, were enrolled. We excluded patients who had moderate coronary stenosis (% stenosis &amp;gt;30%). In the SPT with acetylcholine for left coronary artery and right coronary artery (RCA), the coronary spasm was defined as &amp;gt;90% narrowing of coronary artery on CAG accompanied with chest symptoms and/or ST-T changes on ECG during SPT, and coronary microvascular spasm (MVS) was defined as ≤90% narrowing of coronary artery on CAG with accompanied with chest pain and ST-T changes during SPT. In each coronary artery, the presences of atherosclerosis (20%≤%stenosis≤30%), focal spasm (spasm occurred within one segment of AHA classification), diffuse spasm (spasm occurred over two segments of AHA classification) and MVS, were checked. In the CMF test with a pressure-wire during adenosine triphosphate infusion, the index of microvascular resistance (IMR) was measured. IMR values were obtained in 34 of the left anterior descending coronary artery (LAD) and 12 in RCA. In each patient, conventional coronary risk factors, blood chemical parameters, peripheral endothelial function such as flow-mediated dilation (FMD) of brachial artery and left ventricular mass index (LVMI) were checked. Results In 34 patients, clinical factors including blood chemical parameters, FMD and LVMI, except for smoking status did not affect IMR values on LAD. Only the smoking status was associated with IMR values as follows: median IMR values were 44, 22 and 25 in current smokers (n=5), past smokers (n=8) and never smokers (n=21, p=0.03), respectively. In 46 coronary arteries, the presence of atherosclerosis, the type of the coronary spasm, such as focal and diffuse spasm and MVS, did not affect the IMR values, however, it was significantly higher in the RCA (median 38) than that in the LAD (median 26, p=0.02). Conclusion These results suggest that smoking status affected CMF in patients with ANOCA, suggesting the possibility of improvement of CMF by stop smoking in such patients. In addition, in the assessment of CMF, it may be important to take into account which coronary artery being evaluated. Funding Acknowledgement Type of funding sources: None.

Myocardial ischaemia of non-obstructive origin as a cause of new onset anginal chest pain in the long COVID syndrome

Abstract Background New-onset chest pain occurs in around 20% of patients with long COVID syndrome (LCS). Being the vascular endothelium one of the targets of the SARS-CoV-2 virus, we hypothesized that new onset anginal symptoms in LCS could be due to endothelium dysfunction and other non-obstructive causes of myocardial ischaemia. Methods We investigated 11 consecutive patients who developed new onset anginal chest pain, suggestive of myocardial ischaemia, after documented SARS-CoV-2 infection. Intracoronary assessment included endothelium-dependent evaluation with acetylcholine testing (Ach), and endothelium-independent assessment with coronary flow reserve (CFR) and microcirculatory resistance (MR). Criteria for positiveness of these tests and medical treatment recommendation were obtained from 2019 ESC guidelines and 2020 EAPCI consensus document on ischaemia with non-obstructive coronary arteries (INOCA). Results Mean patient age was 56 years (SD ± 15); 10 (91%) were female. In the acute COVID-19 phase, 4 patients (36%) had had pulmonary infiltrates and 2 (18%) required hospitalization. Conclusive non-invasive tests were obtained in 7 (64%), showing exercise-related myocardial ischaemia in 6 (86%). Coronary angiography ruled out obstructive epicardial stenoses in all the patients. Ach testing revealed abnormal endothelium-dependent responses in 9 (82%) patients: 5 (56%) had epicardial vessel and 4 (44%) microvascular spasm. Endothelium-independent assessment was abnormal in 6 (54%) cases, with abnormal CFR in 2 (33%), abnormal MR in 2 (33) and both abnormal CFR and MR in 2 (33%) patients. The most frequent endotype was combined endothelium dependent- and independent abnormalities (6/9, 67%). Stratified medical treatment according to endotype led to significant improvement in Seattle Angina Scores for angina frequency (+22 points, p=0.013) and a notable trend towards angina stability (+25 points, p=0.093) at a mean follow-up time of 222 days. Conclusions Myocardial ischaemia of non-obstructive origin is common in patients with chest pain and LCS. Vasomotor abnormalities related to endothelial dysfunction occurred in 82% of patients, frequently associated to impaired microvascular vasodilation or high microvascular resistance. Stratified medical treatment led to significant improvement in angina stability and frequency. Funding Acknowledgement Type of funding sources: None.

Noninvasive functional testing in ANOCA: hyperventilation-exercise study for spasm (SESPASM)

Abstract Introduction In patients with angina and no obstructive coronary artery disease (ANOCA), different mechanisms of ischaemia, epicardial spasm, microvascular spasm, and impaired microvascular dilatation frequently coexist. The aim was to assess CFVR changes during coronary vasoconstrictor and vasodilator stimuli in patients with ANOCA. Methods In a prospective single center study, we enrolled 29 ANOCA patients (age 59.6±11 years, 27 females) with previously normal angiograms. All underwent SE testing with hyperventilation (HYP, respiratory rate of 30 per min for 5') followed by supine bicycle exercise (HYP+EXE); and adenosine CFV evaluation (ADO 140 mcg/kg in 1 min) on the other day. Coronary flow velocity (CFV) was assessed in distal LAD by Transthoracic Doppler echocardiography. The ratio of peak/rest changes of CFV during HYP in LAD was taken as an index of vasoconstriction, and CFV reserve was evaluated after EXE. An abnormal response to HYP was a CFV ratio &amp;lt;1.0 (vasoconstrictor response). An abnormal response to ADO was a CFV reserve &amp;lt;2.0 (blunted vasodilatory response). CFVR at peak HYP+ EXE was an indicator of endothelial dependent vasodilatation. Results The double product increased during HYP, in comparison to rest (13213 vs 10517, p&amp;lt;0.01), and further increased with EXE (23387 vs HYP, p&amp;lt;0.001). Chest pain or dyspnea were present in 4/29 pts during HYP, and in 7/29 patients during HYP+EXE (13.8% vs 24.1%, p=0.001). ST segment depression (≥1mm) was present in 7/29 patients during HYP, and 14/29 during HYP+EXE (24.13% vs 48.3%, p&amp;lt;0.01). Five patients (17%) showed regional wall motion abnormalities with HYP+EXE. CFVR response was abnormal in 19/29 (65%) patients during HYP+EXE, and abnormal for vasoconstriction during HYP in 13 (44%). Vasodilation during ADO was preserved in all patients.There was significant difference between CFVR response during HYP+EXE and ADO (1.9±0.35 vs 2.47±0.42 respectively, p&amp;lt;0.01), and between CFVR HYP and ADO (1.28±0.29 vs 2.47±0.42, p&amp;lt;0.001). Conclusion In patients with ANOCA, HYP+EXE is a more powerful ischemic stress than HYP alone. In over one-half of patients HYP+EXE unmasks abnormalities in CFVR response and/or regional wall motion, likely unmasking the underlying endothelium dependent microcirculatory dysfunction with enhanced vasoconstriction in 44% of the patients and mixed vasoconstriction and reduced relaxation in 65%. Funding Acknowledgement Type of funding sources: Public hospital(s). Main funding source(s): University Clinical Centre of Serbia, Faculty of Medicine