Association Between Coronary Artery Spasm and Atherosclerotic Disease.

In at least one-half of the patients with angina or ischemia and nonobstructive coronary arteries undergoing coronary function testing, coronary artery spasm (CAS) is detected. CAS is associated with an adverse prognosis regarding recurrent complaints and ischemic events. Current treatment options are mainly focused on the complaints, not on the underlying pathophysiological process. In this review we discuss available evidence regarding the presence, amount, and morphology of atherosclerosis in CAS patients. The reviewed evidence confirmed that atherosclerosis and vulnerable plaque characteristics are often detected in patients with CAS. The amount of atherosclerosis is higher in patients with focal CAS compared with patients with diffuse CAS. Severity of atherosclerosis is associated with the presence of CAS and the prognosis in CAS patients with atherosclerotic stenosis is worse. Therefore, CAS patients with atherosclerosis might benefit from targeted atherosclerotic treatment. Longitudinal studies are needed to elucidate the exact relation between atherosclerosis and CAS.

Effects of age on microvascular function in patients with normal coronary arteries.

BACKGROUND: It has been suggested that coronary microvascular function decreases with age, irrespective of the presence of epicardial atherosclerosis. AIMS: Our aim is to quantitatively investigate the effects of age on microvascular function in patients with normal coronary arteries. METHODS: In 314 patients with angina with no obstructive coronary artery disease (ANOCA), microcirculatory function was tested using the continuous thermodilution method. In 305 patients, the association between age and both resting and hyperaemic myocardial blood flow (Q), microvascular resistance (Rµ), absolute coronary flow reserve (CFR) and microvascular resistance reserve (MRR) was assessed. In addition, patients were divided into 3 groups to test for differences based on age quartiles (≤52 years [24.9%], 53-64 years [49.2%], ≥65 years [25.9%]). RESULTS: The mean age was 59±9 years with a range from 22 to 79 years. The mean resting Q (Qrest) was not different in the 3 age groups (88±34 mL/min, 82±29 mL/min, and 86±38 mL/min, R2=0.001; p=0.62). A trend towards a decreasing mean hyperaemic Q (Qmax) was observed with increasing age (223±79 mL/min, 209±84 mL/min, 200±80 mL/min, R2=0.010; p=0.083). The mean resting Rµ (Rµ,rest) were 1,204±460 Wood units (WU), 1,260±411 WU, and 1,289±455 WU (p=0.23). The mean hyperaemic Rµ (Rµ,hyp) increased significantly with advancing age (429±149 WU, 464±164 WU, 503±162 WU, R2=0.026; p=0.005). Consequently, MRR decreased with age (3.2±1.2, 3.1±1.0, 2.9±0.9; p=0.038). This trend was present in both the patients with (n=121) and without (n=184) coronary microvascular dysfunction (CMD). CONCLUSIONS: There is an age-dependent physiological increase in minimal microvascular resistance and decrease in microvascular function, which is represented by a decreased MRR and is independent of atherosclerosis. The age-dependent decrease in MRR was present in both patients with and without CMD and was most evident in patients with smooth coronary arteries.

ANOCA patients with and without coronary vasomotor dysfunction present with limited electrocardiographic remodeling.

Background: Coronary vasomotor dysfunction (CVDys) comprises coronary vasospasm (CVS) and/or coronary microvascular dysfunction (CMD) and is highly prevalent in patients with angina and non-obstructive coronary artery disease (ANOCA). Invasive coronary function testing (CFT) to diagnose CVDys is becoming more common, enabling pathophysiologic research of CVDys. This study aims to explore the electrophysiological characteristics of ANOCA patients with CVDys. Methods: We collected pre-procedural 12-lead electrocardiograms of ANOCA patients with CVS (n = 35), CMD (n = 24), CVS/CMD (n = 26) and patients without CVDys (CFT-, n = 23) who participated in the NL-CFT registry and underwent CFT. Heart axis and conduction times were compared between patients with CVS, CMD or CVS/CMD and patients without CVDys. Results: Heart axis, heart rate, PQ interval and QRS duration were comparable between the groups. A small prolongation of the QT-interval corrected with Bazett (QTcB) and Fridericia (QTcF) was observed in patients with CVDys compared to patients without CVDys (CVS vs CFT-: QTcB = 422 ± 18 vs 414 ± 18 ms (p = 0.14), QTcF = 410 ± 14 vs 406 ± 12 ms (p = 0.21); CMD vs CFT-: QTcB = 426 ± 17 vs 414 ± 18 ms (p = 0.03), QTcF = 413 ± 11 vs 406 ± 12 ms (p = 0.04); CVS/CMD vs CFT-: QTcB = 424 ± 17 vs 414 ± 18 ms (p = 0.05), QTcF = 414 ± 14 vs 406 ± 12 ms (p = 0.04)). Conclusions: Pre-procedural 12-lead electrocardiograms were comparable between patients with and without CVDys undergoing CFT except for a slightly longer QTc interval in patients with CVDys compared to patients without CVDys, suggesting limited cardiac remodeling in patients with CVDys.

Continuous Versus Bolus Thermodilution-Derived Coronary Flow Reserve and Microvascular Resistance Reserve and Their Association With Angina and Quality of Life in Patients With Angina and Nonobstructive Coronaries: A Head-to-Head Comparison.

Background Coronary flow reserve (CFR) and microvascular resistance reserve (MRR) are physiological parameters to assess coronary microvascular dysfunction. CFR and MRR can be assessed using bolus or continuous thermodilution, and the correlation between these methods has not been clarified. Furthermore, their association with angina and quality of life is unknown. Methods and Results In total, 246 consecutive patients with angina and nonobstructive coronary arteries from the multicenter Netherlands Registry of Invasive Coronary Vasomotor Function Testing (NL-CFT) were investigated. The 36-item Short Form Health Survey Quality of Life and Seattle Angina questionnaires were completed by 153 patients before the invasive measurements. CFR and MRR were measured consecutively with bolus and continuous thermodilution. Mean continuous thermodilution-derived coronary flow reserve (CFRabs) was significantly lower than mean bolus thermodilution-derived coronary flow reserve (CFRbolus) (2.6±1.0 versus 3.5±1.8; P<0.001), with a modest correlation (ρ=0.305; P<0.001). Mean continuous thermodilution-derived microvascular resistance reserve (MRRabs) was also significantly lower than mean bolus thermodilution-derived MRR (MRRbolus) (3.1±1.1 versus 4.2±2.5; P<0.001), with a weak correlation (ρ=0.280; P<0.001). CFRbolus and MRRbolus showed no correlation with any of the angina and quality of life domains, whereas CFRabs and MRRabs showed a significant correlation with physical limitation (P=0.005, P=0.009, respectively) and health (P=0.026, P=0.012). In a subanalysis in patients in whom spasm was excluded, the correlation further improved (MRRabs versus physical limitation: ρ=0.363; P=0.041, MRRabs versus physical health: ρ=0.482; P=0.004). No association with angina frequency and stability was found. Conclusions Absolute flow measurements using continuous thermodilution to calculate CFRabs and MRRabs weakly correlate with, and are lower than, the surrogates CFRbolus and MRRbolus. Absolute flow parameters showed a relationship with physical complaints. No relationship with angina frequency and stability was found.

Prognostic Value of Cardiac Magnetic Resonance Imaging in Patients With a Working Diagnosis of MINOCA-An Outcome Study With up to 10 Years of Follow-Up.

BACKGROUND: Patients with a working diagnosis of myocardial infarction with unobstructed coronary arteries (MINOCA) represent a heterogeneous cohort. The prognosis could vary substantially depending on the underlying cause. Although cardiac magnetic resonance (CMR) is considered a key diagnostic tool in these patients, there are limited data linking the CMR diagnosis with the outcome. METHODS: This study is a prospective outcomes registry of consecutive patients presenting with a working diagnosis of MINOCA who were clinically referred for CMR at an academic hospital from October 2003 to February 2020. We assessed the relationships between the prespecified CMR diagnoses of acute myocardial infarction (AMI), myocarditis, nonischemic cardiomyopathy (NICM), normal CMR study, and major adverse cardiac events (MACEs). RESULTS: Of 252 patients, the CMR diagnosis was AMI in 63 (25%), myocarditis in 33 (13%), NICM in 111 (44%), normal CMR in 37 (15%), and other diagnoses in 8 (3%). A specific nonischemic cause was diagnosed allowing true MINOCA to be ruled-out in 57% of the cohort. During up to 10 years of follow-up (1595 patient-years), MACE occurred in 84 patients (33%), which included 64 deaths (25%). The unadjusted cumulative 10-year rate of MACE was 47% in AMI, 24% in myocarditis, 50% in NICM, and 3.5% in patients with a normal CMR (Log-rank P<0.001). The CMR diagnosis provided incremental prognostic value over clinical factors including age, gender, coronary artery disease risk factors, presentation with ST-elevation, and peak troponin (incremental χ² 17.9, P<0.001); and patients with diagnoses of AMI, myocarditis, and NICM had worse MACE-free survival than patients with a normal CMR. CONCLUSIONS: In patients with a working diagnosis of MINOCA, CMR allows ruling-out true MINOCA in over half of the patients. CMR diagnoses of AMI, myocarditis, and NICM are associated with worse MACE-free survival, whereas a normal CMR study portends a benign prognosis.

Microvascular Resistance Reserve to Assess Microvascular Dysfunction in ANOCA Patients.

BACKGROUND: Microvascular resistance reserve (MRR) is a new index to assess coronary microvascular (dys)function, which can be easily measured invasively using continuous thermodilution. In contrast to coronary flow reserve (CFR), MRR is independent of epicardial coronary disease and hemodynamic variations. Its measurement is accurate, reproducible, and operator independent. OBJECTIVES: The aim of this study was to establish the range of normal values for MRR and to determine an optimal cutoff point. METHODS: In this exploratory study in 214 patients with angina and no obstructive coronary artery disease, after excluding significant epicardial disease, all physiological parameters, such as fractional flow reserve, index of microvascular resistance, CFR, absolute blood flow, absolute microvascular resistance, and MRR, were measured. On the basis of concordant positive or concordant negative results of index of microvascular resistance and CFR, subgroups of patients were defined with high probability of either normal (n = 122) or abnormal (n = 24) microcirculatory function, and MRR was studied in these groups. RESULTS: Mean MRR in the "normal" group was 3.4 compared with a mean MRR of 1.9 in the "abnormal" group; these values were significantly different between the groups. MRR >2.7 ruled out coronary microvascular dysfunction (CMD) with a certainty of 96%, whereas MRR <2.1 indicated the presence of CMD with a similar high certainty of 96%. CONCLUSIONS: MRR is a suitable index to distinguish the presence or absence of CMD in patients with angina and no obstructive coronary artery disease. The present data indicate that an MRR of 2.7 virtually excludes the presence of CMD, while an MRR value <2.1 confirms its presence.

ShareHeart: A patient journey map of patients with ischemia and non-obstructive coronary artery disease based on qualitative research.

AIMS AND OBJECTIVES: To visualise the health care experiences and needs of patients with ischemia with non-obstructive coronary arteries in a patient journey map. As such, future design challenges can be provided, and it can be used for future healthcare optimization. BACKGROUND: Ischemia with non-obstructive coronary arteries is a chronic cardiac condition caused by vascular dysfunctions. Ischemia with non-obstructive coronary arteries is often unrecognised, significantly impairs daily functioning, and is more prevalent among women. Patients' experiences remain unexplored, and a clear patient-centered care pathway is lacking. DESIGN: A qualitative interpretative research design was performed and the standards for reporting qualitative research (SRQR) has been used. METHODS: In total, 36 women were included and participated in eight semi-structured focus group interviews. Thematic analysis was used, and identified themes were further classified using 'patient journey mapping.' Additionally, Picker's 'eight principles of patient-centered care' were linked to the results and integrated in the patient journey map. RESULTS: Participants experienced a lack of familiarity with the specific cardiac condition by healthcare providers, repeated hospitalisation, testing and referrals, shortage of specialised cardiologists, and feelings of not being heard. In addition, needs for a multidisciplinary treatment program (including physical and psychological support), better information provision, and an easily accessible contact person were expressed. CONCLUSIONS: The resulting patient journey map shows how patients experienced and interacted with the current healthcare system. Overall, the results show a complex and long healthcare pathway and important themes for healthcare experiences and needs were identified. Future research could focus on the development and implementation of a patient-centered evidence-based clinical pathway optimising experiences and quality of life. RELEVANCE TO CLINICAL PRACTICE: The visual tool can help health care professionals, policy makers, and researchers improve healthcare provision which is patient-centered and tailored to the preferences of patients with ischemia with non-obstructive coronary arteries.

Contemporary and future invasive coronary vasomotor function testing and treatment in patients with ischaemia with no obstructive coronary arteries.

In the current review, we emphasize the importance of diagnostics and therapy in patients with ischaemia with no obstructive coronary arteries (INOCA). The importance of the diagnostic coronary function test (CFT) procedure is described, including future components including angiography-derived physiology and invasive continuous thermodilution. Furthermore, the main components of treatment are discussed. Future directions include the national registration ensuring a high quality of INOCA care, besides a potential source to improve our understanding of pathophysiology in the various phenotypes of coronary vascular dysfunction, the diagnostic CFT procedure, and treatment.

Efficacy of Diltiazem to Improve Coronary Vasomotor Dysfunction in ANOCA: The EDIT-CMD Randomized Clinical Trial.

BACKGROUND: Diltiazem is recommended and frequently prescribed in patients with angina and nonobstructive coronary artery disease (ANOCA), suspected of coronary vasomotor dysfunction (CVDys). However, studies substantiating its effect is this patient group are lacking. OBJECTIVES: The randomized, placebo-controlled EDIT-CMD (Efficacy of Diltiazem to Improve Coronary Microvascular Dysfunction: A Randomized Clinical Trial) evaluated the effect of diltiazem on CVDys, as assessed by repeated coronary function testing (CFT), angina, and quality of life. METHODS: A total of 126 patients with ANOCA were included and underwent CFT. CVDys, defined as the presence of vasospasm (after intracoronary acetylcholine provocation) and/or microvascular dysfunction (coronary flow reserve: <2.0, index of microvascular resistance: ≥25), was confirmed in 99 patients, of whom 85 were randomized to receive either oral diltiazem or placebo up to 360 mg/d. After 6 weeks, a second CFT was performed. The primary end point was the proportion of patients having a successful treatment, defined as normalization of 1 abnormal parameter of CVDys and no normal parameter becoming abnormal. Secondary end points were changes from baseline to 6-week follow-up in vasospasm, index of microvascular resistance, coronary flow reserve, symptoms (Seattle Angina Questionnaire), or quality of life (Research and Development Questionnaire 36). RESULTS: In total, 73 patients (38 diltiazem vs 35 placebo) underwent the second CFT. Improvement of the CFT did not differ between the groups (diltiazem vs placebo: 21% vs 29%; P = 0.46). However, more patients on diltiazem treatment progressed from epicardial spasm to microvascular or no spasm (47% vs 6%; P = 0.006). No significant differences were observed between the diltiazem and placebo group in microvascular dysfunction, Seattle Angina Questionnaire, or Research and Development Questionnaire 36. CONCLUSIONS: This first performed randomized, placebo-controlled trial in patients with ANOCA showed that 6 weeks of therapy with diltiazem, when compared with placebo, did not substantially improve CVDys, symptoms, or quality of life, but diltiazem therapy did reduce prevalence of epicardial spasm. (Efficacy of Diltiazem to Improve Coronary Microvascular Dysfunction: A Randomized Clinical Trial [EDIT-CMD]; NCT04777045).

Features of atherosclerosis in patients with angina and no obstructive coronary artery disease.

BACKGROUND: An association between atherosclerosis and coronary vasospasm has previously been suggested. However, to date, no conclusive data on the whole spectrum of these disorders have been published. AIMS: This study aimed to define specific morphological features of atherosclerosis in patients with angina and no obstructive coronary artery disease (ANOCA) due to coronary vasospasm. METHODS: From February 2019 to January 2020, we enrolled 75 patients referred to our laboratory for a coronary function test (CFT) due to ANOCA and suspected coronary vasomotor dysfunction. The CFT consisted of an acetylcholine test and a physiology assessment with hyperaemic indexes using adenosine. Patients were divided into two groups according to the presence or absence of coronary vasospasm triggered by acetylcholine (ACH+ and ACH-, respectively). In addition, optical coherence tomography (OCT) was performed to assess the lipid index (LI), a surrogate for lipid area, and the prevalence of markers of plaque vulnerability. RESULTS: ACH+ patients had a higher LI than ACH- patients (LI: 819.85 [460.95-2489.03] vs 269.95 [243.50-878.05], respectively, p=0.03), and a higher prevalence of vulnerable plaques (66% vs 38%, p=0.04). Moreover, ACH+ patients showed a higher prevalence of neovascularisation compared to ACH- subjects (37% vs 6%, p=0.02) and a trend towards a higher prevalence of all individual markers, in particular thin-cap fibroatheroma (20% vs 0%, p=0.06). No differences were detected between patterns of coronary vasospasm. CONCLUSIONS: The presence of coronary vasospasm, regardless of its phenotype, is associated with higher lipid burden, plaque vulnerability and neovascularisation.

Prevalence of microvascular angina among patients with stable symptoms in the absence of obstructive coronary artery disease: a systematic review.

Our purpose was to perform a systematic review to assess the prevalence of microvascular angina (MVA) among patients with stable symptoms in the absence of obstructive coronary artery disease (CAD). We performed a systematic review of the literature to group the prevalence of MVA, based on diagnostic pathways and modalities. We defined MVA using three definitions: (i) suspected MVA using non-invasive ischaemia tests; proportion of patients with non-obstructive CAD among patients with symptoms and a positive non-invasive ischaemia test result, (ii) suspected MVA using specific modalities for MVA; proportion of patients with evidence of impaired microvascular function among patients with symptoms and non-obstructive CAD, and (iii) definitive MVA; proportion of patients with positive ischaemia test results among patients with an objectified impaired microvascular dysfunction. We further examined the ratio of women-to-men for the different groups. Of the 4547 abstracts, 20 studies reported data on MVA prevalence. The median prevalence was 43% for suspected MVA using non-invasive ischaemia test, 28% for suspected MVA using specific modalities for MVA, and 30% for definitive MVA. Overall, more women were included in the studies reporting sex-specific data. The women-to-men ratio for included participants was 1.29. However, the average women-to-men ratio for the MVA cases was 2.50. In patients with stable symptoms of ischaemia in the absence of CAD, the prevalences of suspected and definitive MVA are substantial. The results of this study should warrant cardiologists to support, promote and facilitate the comprehensive evaluation of the coronary microcirculation for all patients with symptoms and non-obstructive CAD.

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.

Assessing Microvascular Dysfunction in Angina With Unobstructed Coronary Arteries: JACC Review Topic of the Week.

Coronary microvascular dysfunction is a highly prevalent condition of both structural and functional coronary disorders in patients with angina and nonobstructive coronary artery disease (ANOCA). Current diagnostic modalities to assess microvascular function are related to prognosis, but these modalities have several technical shortcomings and lack the opportunity to determine true coronary blood flow and microvascular resistance. Intracoronary continuous thermodilution assessment of absolute coronary flow (Q) and microvascular resistance (R) was recently shown to be safe and feasible in ANOCA. Further exploration and implementation could lead to a better understanding and treatment of patients with ANOCA. This review discuss the coronary pathophysiology of microvascular dysfunction, provides an overview of noninvasive and invasive diagnostics, and focuses on the novel continuous thermodilution method. Finally, how these measurements of absolute Q and R could be integrated and how this would affect future clinical care are discussed.