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.

Gender in cardiovascular medicine: chest pain and coronary artery disease.

Ischaemic heart disease (IHD) remains the leading cause of morbidity and mortality among women and men yet women are more often underdiagnosed, have a delay in diagnosis, and/or receive suboptimal treatment. An implicit gender-bias with regard to lack of recognition of sex-related differences in presentation of IHD may, in part, explain these differences in women compared with men. Indeed, existing knowledge demonstrates that angina does not commonly relate to obstructive coronary artery disease (CAD). Emerging knowledge supports an inclusive approach to chest pain symptoms in women, as well as a more thoughtful consideration of percutaneous coronary intervention for angina in stable obstructive CAD, to avoid chasing our tails. Emerging knowledge regarding the cardiac autonomic nervous system and visceral pain pathways in patients with and without obstructive CAD offers explanatory mechanisms for angina. Interdisciplinary investigation approaches that involve cardiologists, biobehavioural specialists, and anaesthesia/pain specialists to improve angina treatment should be pursued.

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.

Evaluation of newer risk markers for coronary heart disease risk classification: a cohort study.

BACKGROUND: Whether newer risk markers for coronary heart disease (CHD) improve CHD risk prediction remains unclear. OBJECTIVE: To assess whether newer risk markers for CHD risk prediction and stratification improve Framingham risk score (FRS) predictions. DESIGN: Prospective population-based study. SETTING: The Rotterdam Study, Rotterdam, the Netherlands. PARTICIPANTS: 5933 asymptomatic, community-dwelling participants (mean age, 69.1 years [SD, 8.5]). MEASUREMENTS: Traditional CHD risk factors used in the FRS (age, sex, systolic blood pressure, treatment of hypertension, total and high-density lipoprotein cholesterol levels, smoking, and diabetes) and newer CHD risk factors (N-terminal fragment of prohormone B-type natriuretic peptide levels, von Willebrand factor antigen levels, fibrinogen levels, chronic kidney disease, leukocyte count, C-reactive protein levels, homocysteine levels, uric acid levels, coronary artery calcium [CAC] scores, carotid intima-media thickness, peripheral arterial disease, and pulse wave velocity). RESULTS: Adding CAC scores to the FRS improved the accuracy of risk predictions (c-statistic increase, 0.05 [95% CI, 0.02 to 0.06]; net reclassification index, 19.3% overall [39.3% in those at intermediate risk, by FRS]). Levels of N-terminal fragment of prohormone B-type natriuretic peptide also improved risk predictions but to a lesser extent (c-statistic increase, 0.02 [CI, 0.01 to 0.04]; net reclassification index, 7.6% overall [33.0% in those at intermediate risk, by FRS]). Improvements in predictions with other newer markers were marginal. LIMITATION: The findings may not be generalizable to younger or nonwhite populations. CONCLUSION: Among 12 CHD risk markers, improvements in FRS predictions were most statistically and clinically significant with the addition of CAC scores. Further investigation is needed to assess whether risk refinements using CAC scores lead to a meaningful change in clinical outcome. Whether to use CAC score screening as a more routine test for risk prediction requires full consideration of the financial and clinical costs of performing versus not performing the test for both persons and health systems. PRIMARY FUNDING SOURCE: Netherlands Organization for Health Research and Development (ZonMw).

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.

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.

Genome-wide association study for coronary artery calcification with follow-up in myocardial infarction.

BACKGROUND: Coronary artery calcification (CAC) detected by computed tomography is a noninvasive measure of coronary atherosclerosis, which underlies most cases of myocardial infarction (MI). We sought to identify common genetic variants associated with CAC and further investigate their associations with MI. METHODS AND RESULTS: Computed tomography was used to assess quantity of CAC. A meta-analysis of genome-wide association studies for CAC was performed in 9961 men and women from 5 independent community-based cohorts, with replication in 3 additional independent cohorts (n=6032). We examined the top single-nucleotide polymorphisms (SNPs) associated with CAC quantity for association with MI in multiple large genome-wide association studies of MI. Genome-wide significant associations with CAC for SNPs on chromosome 9p21 near CDKN2A and CDKN2B (top SNP: rs1333049; P=7.58×10(-19)) and 6p24 (top SNP: rs9349379, within the PHACTR1 gene; P=2.65×10(-11)) replicated for CAC and for MI. Additionally, there is evidence for concordance of SNP associations with both CAC and MI at a number of other loci, including 3q22 (MRAS gene), 13q34 (COL4A1/COL4A2 genes), and 1p13 (SORT1 gene). CONCLUSIONS: SNPs in the 9p21 and PHACTR1 gene loci were strongly associated with CAC and MI, and there are suggestive associations with both CAC and MI of SNPs in additional loci. Multiple genetic loci are associated with development of both underlying coronary atherosclerosis and clinical events.

Calcification in major vessel beds relates to vascular brain disease.

OBJECTIVE: Calcification in atherosclerotic plaques is a novel marker of atherosclerosis and is related to cardiovascular disease. However, its relationship with cerebrovascular disease has not been investigated extensively. We investigated the relationship between calcification in various vessel beds outside the brain and imaging markers of vascular brain disease. METHODS AND RESULTS: A total of 885 community-dwelling people (mean age, 66.7 years) underwent computed tomography of the coronary arteries, aortic arch, and extracranial and intracranial carotid arteries to assess arterial calcification. Brain magnetic resonance imaging scans were performed to assess cerebral infarcts, microbleeds, and white matter lesions (WMLs). Calcification in each vessel bed was associated with presence of cerebral infarcts and with larger WML volume. The most prominent associations were found between intracranial carotid calcification and WML volume and between extracranial carotid calcification and infarcts. Adjustment for cardiovascular risk factors or ultrasound carotid plaque scores did not change these results. No associations were found between calcification and cerebral microbleeds. CONCLUSIONS: Arterial calcification in major vessel beds is associated with vascular brain disease on magnetic resonance imaging. Most notably, larger intracranial carotid calcification load relates to larger WML volumes, and larger extracranial carotid calcification load relates to the presence of cerebral infarcts, independently of ultrasound carotid plaque score. This suggests that calcification of atherosclerotic plaque yields other information in addition to merely the presence of plaques, providing novel insights into the etiology of vascular brain disease.

Burden of atherosclerosis improves the prediction of coronary heart disease but not cerebrovascular events: the Rotterdam Study.

AIMS: Since atherosclerosis is a systemic process, risk prediction would benefit from targeting multiple components of cardiovascular disease simultaneously. To this end, it is useful to examine the predictive value of non-invasive measures of atherosclerosis in various vascular beds for both coronary heart disease (CHD) and cerebrovascular disease. METHODS AND RESULTS: Between September 2003 and February 2006, 2153 asymptomatic participants (69.6±6.6 years) from the Rotterdam Study underwent a multi-detector computed tomography scan. During a median follow-up of 3.5 years, 58 CHD events (myocardial infarction and CHD death) and 52 cerebrovascular events (TIA and stroke) occurred. Participants were classified into low (<5%), intermediate (5-10%), and high (>10%) 5-year risk categories based on a refitted Framingham risk model. The model was extended by coronary, aortic arch, or carotid calcium and reclassification percentages were calculated. For the outcome CHD, the C-statistic improved from 0.693 for the Framingham refitted model to 0.743, 0.740, and 0.749 by addition of coronary, aortic arch, and carotid calcium, respectively. Reclassification was most substantial in the intermediate risk group where addition of coronary calcium reclassified 56% of persons [net reclassification improvement (NRI): 15%; P<0.01)]. Adding aortic arch calcium led to a reclassification of 32% of persons (NRI: 8%; P=0.01) and adding carotid calcium reclassified 51% (NRI: 9%; P=0.02). In contrast, calcification in any of the three vascular beds did not improve cerebrovascular risk prediction. CONCLUSION: Coronary, aortic arch, and carotid artery calcification significantly improved risk prediction of CHD but not of cerebrovascular events.

Atherosclerotic calcification relates to cognitive function and to brain changes on magnetic resonance imaging.

BACKGROUND: Increasing evidence suggests a role of atherosclerosis in the pathogenesis of cognitive impairment and dementia. Calcification volume measured with computed tomography (CT) is a valid marker of atherosclerosis. This study investigates associations of atherosclerosis (measured using CT) at four locations with cognition and brain changes on magnetic resonance imaging (MRI). METHODS: To quantify calcification volume, 2414 nondemented people from the Rotterdam Study underwent CT of the coronary arteries, aortic arch, extracranial carotid arteries, and intracranial carotid arteries. To assess global cognition and performance on memory, executive function, information processing speed, and motor speed, they also underwent neuropsychological tests. In a random subgroup of 844 participants, brain MRI was performed. Automated segmentation and quantification of brain MRI scans yielded brain tissue volumes in milliliters. Diffusion tensor imaging was used to measure the microstructural integrity of the white matter. Relationships of atherosclerotic calcification with cognition, brain tissue volumes, and diffusion tensor imaging measures were assessed with linear regression models and adjusted for relevant confounders. RESULTS: With larger calcification volumes, lower cognitive scores were observed. When calcification volumes were larger, total brain volumes were also smaller. Specifically, larger coronary artery calcification volumes related to smaller gray matter volumes, and extracranial and intracranial carotid calcification volumes related to smaller white matter volumes. Larger calcification volume in all vessel beds was accompanied by worse microstructural integrity of the white matter. CONCLUSIONS: Larger calcification volume is associated with worse cognitive performance. It also relates to smaller brain tissue volumes and worse white matter microstructural integrity, revealing possible mechanisms through which atherosclerosis may lead to poorer cognition.

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.

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.

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).

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.

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 ANOCA Methods: 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.

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.

Absolute Coronary Blood Flow Measured by Continuous Thermodilution in Patients With Ischemia and Nonobstructive Disease.

BACKGROUND: Intracoronary continuous thermodilution is a novel technique to quantify absolute coronary flow (Q) and resistance (R) and has potential advantages over current methods such as coronary flow reserve (CFR) and index of microvascular resistance (IMR). However, no data are available in patients with ischemia and nonobstructive coronary artery disease (INOCA). OBJECTIVES: This study aimed to assess the relationship of Q and R with the established CFR/IMR in INOCA patients, to explore the potential of absolute Q, and to predict self-reported angina. METHODS: Consecutive INOCA patients (n = 84; 87% women; mean age 56 ± 8 years) underwent coronary function testing, including acetylcholine (ACH) provocation testing, adenosine (ADE) testing (CFR/IMR), and continuous thermodilution (absolute Q and R) with saline-induced hyperemia. RESULTS: ACH testing was abnormal (ACH+) in 87%, and ADE testing (ADE+) in 38%. The median absolute Q was 198 ml/min, and the median absolute R was 416 WU. The absolute R was higher in patients with ADE+ versus ADE- (495 WU vs. 375 WU; p = 0.04) but did not differ between patients with ACH+ versus ACH- (421 WU vs. 409 WU; p = 0.74). Low Q and high R were associated with severe angina (odds ratio: 3.09; 95% confidence interval: 1.16 to 8.28; p = 0.03; and odds ratio: 2.60; 95% confidence interval: 0.99 to 6.81; p = 0.05), respectively. CONCLUSIONS: In this study, absolute R was higher in patients with abnormal CFR/IMR, whereas both Q and R were unrelated to coronary vasospasm. Q and R were associated with angina, although their exact predictive value should be determined in larger studies.