Annemiek de Vos

Background and Aims: Comprehensive evaluation by invasive coronary function test (CFT) of patients with angina and non-obstructive coronary artery disease is recommended in the current guidelines. The prognosis of patients with CFT-proven coronary vasomotor dysfunction (CVDys) is less well-known. Methods: Patients that provided consent for the previously published NL-CFT registry who underwent clinically indicated invasive CFT between 1 February 2019 and 1 June 2024 were included. Patients with CVDys, defined as an abnormal spasm provocation test and/or microvascular functional assessment, were compared to patients with normal CFT. The primary outcome of major adverse cardiovascular events and emergency room visits for angina (MACE-EA) was defined as a composite of all-cause death, acute coronary syndrome, stroke/transient ischaemic attack, revascularization, repeat angiography without intervention, heart failure hospitalizations, and unplanned hospitalizations or emergency room visits due to angina. Results: In total, 1355 patients were included. In 79.8%, CFT was abnormal, and vasospasm was the most prevalent endotype. In 1252 patients, follow-up of clinical events was complete. During a mean follow-up of 33 ± 13 months, CVDys patients had almost double the number of primary outcome events compared with patients with a normal CFT (31.2% vs 16.8%, P < .001), driven by emergency care visits for angina. Secondary clinical endpoints including death, myocardial infarction, stroke, or revascularization were low and comparable between the groups. Conclusions: The long-term risk of MACE-EA is doubled in ANOCA patients with CFT-confirmed CVDys compared with normal CFT results. Events are dominated by emergency room visits due to angina, illustrating the high disease burden of CVDys. Their (angina-related) health status is significantly worse at follow-up.

BACKGROUND: Coronary vasomotor dysfunction is diagnosed by a coronary function testing (CFT). However, protocols vary, and the influence of access site and concomitant vasodilator medication on the diagnostic yield and safety of CFT is unclear. This study assessed the diagnostic yield and safety of CFT by radial access with intraarterial calcium channel blockers compared with CFT by femoral access. METHODS: Data were obtained from the Netherlands Registry of Invasive Coronary Vasomotor Function Testing, a Dutch multicenter collaboration on CFT. Patients who underwent CFT between December 2020 and July 2025 were included. RESULTS: A total of 1885 patients were included, 1436 (76.2%) with primary radial access and 380 (20.2%) with primary femoral access. In 69 (3.7%) patients conversion from radial to femoral access was necessary. The conversion group was analyzed separately. The total diagnostic yield of coronary vasomotor dysfunction was 78.5%. There was no significant difference in the prevalence of coronary vasomotor dysfunction between patients with primary radial versus femoral access (79.2% versus 75.3%; P =0.1). There was also no difference in total diagnostic yield between the group without conversion and the conversion group (78.4% versus 82.6%; P =0.4); however, spasm was more prevalent in the conversion group (67.7% versus 79.4%; P =0.04). There were no differences in CFT complication rates between groups. CONCLUSIONS: Primary radial access with routine administration of calcium channel blockers was not associated with a lower diagnostic yield in CFT than primary femoral access. Procedural safety was comparable.

In recent years, there have been numerous developments in the field of coronary physiology with the addition of new indices for the evaluation of the coronary microcirculation, such as invasive measurement of absolute coronary blood flow and microvascular resistance. This has resulted in more accurate diagnostic tools for patients with angina and no obstructive coronary artery disease (ANOCA), with the possibility to distinguish different endotypes of coronary microvascular dysfunction (CMD). Because of the growing recognition of ANOCA and, along with that, the increasing application of coronary function testing due to the latest guideline recommendations, it is timely and important to further explain the concept of absolute coronary flow, microvascular resistance, and the latest addition to the field: Microvascular Resistance Reserve (MRR). Differentiation between specific endotypes of CMD will help to develop tailored therapy for ANOCA patients.

Background and Objectives: Up to 40% of patients undergoing a coronary angiogram due to angina pectoris have no obstructive coronary artery disease, also known as angina with non-obstructive coronary arteries (ANOCA). ANOCA is associated with significant impairment in patients’ quality of life, increased risk of myocardial infarction and all-cause mortality. Approximately 25% of patients with ANOCA have persisting symptoms despite optimal medical therapy. There is a lack of in-depth knowledge regarding tailored treatment for patients with ANOCA due to a scarcity of trials designed to assess the effect of treatment modalities. The aim of this systematic review and meta-analysis is to give clinicians an overview of the efficacy of current treatment modalities for patients with ANOCA. Methods: PudMed/MEDLINE, Embase, the Cochrane Library and clinical trial registries were searched for randomised controlled and cohort studies regarding treatment modalities for ANOCA. The main outcome was change in angina pectoris frequency for each treatment modality. Secondary outcomes included changes in exercise capacity, quality of life, Canadian Cardiovascular Society (CCS) class, coronary flow reserve (CFR) and survival. Results: In total, 80 studies were included and used in the meta-analysis, of which ten studies met the current definition of ANOCA. Angina pectoris frequency improved significantly in the majority of the treatment modalities, with neuromodulation resulting in −3.35 standardised mean difference (SMD) (95% CI: −5.13; −1.56), trimetazidine in −1.74 SMD (−2.63; −0.85), traditional Chinese medicine in −1.55 SMD (−2.36; −0.75), beta-blockers in −1.32 SMD (−1.88; −0.77), enhanced external counterpulsation in −1.27 SMD (−2.04; −0.49), stem cell therapy in −1.04 SMD (−1.51; −0.57), lifestyle interventions in −0.86 SMD (−1.15; −0.57), RAAS-inhibitors in −0.83 SMD (−1.31; −0.35) and calcium channel blockers in −0.64 SMD (−0.92; −0.35). Conclusions: This meta-analysis into treatment modalities for patients with ANOCA shows a significant improvement in angina pectoris frequency in the majority of included treatment modalities. However, these results should be interpreted cautiously, as only ten of the studies included in the meta-analysis meet the current definition of ANOCA. This review underlines the importance of undertaking new studies with existing treatment modalities to determine the efficacy in patients with ANOCA.

Background: Mental stress is a well-known trigger of cardiac symptoms in patients with coronary artery spasms. Hence, stress management is recommended along with medical therapy. However, specific programs for patients with coronary spasms are lacking. We collaborated with patients to develop a smartphone-based app as a tailored solution. The app provides biofeedback based on heart rate variability–driven stress level estimations. Objective: This study aimed to evaluate the effect of a biofeedback-driven smartphone stress management app on cardiac symptoms in women with coronary vasospasms. Methods: We enrolled 117 women aged 18 to 70 years diagnosed with coronary vasospasms, as confirmed by a gold standard coronary function test. A multicenter, single-sequence, 2-period crossover study was conducted, comprising a 4-week control period followed by a 4-week period using the Wavy intervention app. The intervention comprised breathing-based exercises that were prompted when measured stress levels were too high. The primary outcome was the Seattle Angina Questionnaire Summary Score, and the secondary outcomes included the 36-Item Short Form Health Survey and the Perceived Stress Scale-10 items. Additionally, the user experience and the impact of the breathing exercise on heart rate variability were evaluated. Results: A total of 102 patients completed the study, yet no significant improvements were observed in the Seattle Angina Questionnaire following the intervention period, with the control group scores at 50.4 (SD 15.4) and the intervention group scores at 50.9 (SD 15.0; P=.92). Similarly, no differences were found in the 36-Item Short Form Health Survey and the Perceived Stress Score. However, the 1236 breathing relaxation exercises performed during the study led to a significant improvement in heart rate variability, as indicated by a median root mean square of successive differences increase from 18.59 (IQR 8.38-36.58) milliseconds before the exercises to 34.93 (IQR 24.19-50.64) milliseconds after the exercises (z=−13.72; P<.001). Furthermore, two-thirds of participants (68/102, 66.7%) indicated that they would use a more refined version of the app in the future. Conclusions: A 4-week intervention using the Wavy app did not significantly alleviate anginal symptoms in female patients with coronary vasospasms. However, the breathing exercises demonstrated a notable improvement in heart rate variability, suggesting a reduction in stress levels. Patient feedback indicated broad support for the app and its wearable-based functionality, emphasizing the need for substantial refinements. Future development should incorporate patient perspectives to optimize the app as a comprehensive lifestyle management tool. Trial Registration: ClinicalTrials.gov NCT06171893; https://classic.clinicaltrials.gov/ct2/show/NCT06171893

BACKGROUND Mental stress is a well-known trigger of cardiac symptoms in patients with coronary artery spasms. Hence, stress management is recommended beyond medical therapy. However, specific programs for patients with coronary spasms are lacking. We collaborated with patients to develop a smartphone-based application as a tailored solution. The application provides biofeedback based on HRV-driven stress level estimations. OBJECTIVE Our study aimed to evaluate the effect of a biofeedback-driven smartphone stress management application on cardiac symptoms in women with coronary vasospasms. METHODS We enrolled 117 women aged 18-70 diagnosed with coronary vasospasms, as confirmed by a gold standard coronary function test. A multicenter single sequence 2-period cross-over study was performed, consisting of a four-week control period followed by four weeks using the Wavy intervention app. The intervention comprised suggested breathing-based exercises if measured stress levels were too high. The primary outcome was the Seattle Angina Questionnaire summary score; secondary outcomes included quality of life using the SF-36, stress by means of the PSS-10. Additionally, the user experience and the impact of the breathing exercise on HRV were evaluated. RESULTS Within the 102 patients that finished the study, no significant improvements were observed in the SAQ-SS scores following the intervention period, with control group values at 50.4 ± 15.4 SD and intervention group values at 50.9 ± 15.0 SD. Similarly, no differences were found in the quality-of-life and perceived stress m hebben tezamen met patiënten en een ergotherapeut nieuwe functionaliteiten etrics. However, the 1,236 breathing relaxation exercises performed during the study led to a significant improvement in heart rate variability (HRV), as indicated by a median (IQR) RMSSD increase from 18.59 ms (8.38–36.58) before the exercises to 34.93 ms (24.19–50.64) after the exercises (Z = -13.72, p < 0.001). Furthermore, two-thirds of participants indicated they would use a more refined version in the future. CONCLUSIONS A four-week intervention using the Wavy application did not significantly alleviate anginal symptoms in female patients with coronary vasospasms. However, the breathing exercises demonstrated a notable improvement in HRV values, suggesting a reduction in stress levels. Patient feedback indicated broad support for the application and its wearable-based functionality, emphasizing the need for substantial refinements. Future development should incorporate patient perspectives to optimize the application as a comprehensive lifestyle management tool. CLINICALTRIAL ClinicalTrials.gov Identifier: NCT06171893. Assessing the Effect of the 'Wavy' Application, on Stress and Burden of Disease in Women With INOCA, available at https://classic.clinicaltrials.gov/ct2/show/NCT06171893.

Background: A coronary function test (CFT) is the recommended diagnostic test to identify coronary vasomotor dysfunction as a cause of symptoms in patients with angina and nonobstructive coronary arteries (ANOCA). Acetylcholine is the commonly used pharmacological agent for spasm provocation. We aimed to investigate an association between severity of symptoms and provocative acetylcholine dose. Methods and Results: We included ANOCA patients undergoing clinically indicated CFT from the Netherlands Registry of Invasive Coronary Vasomotor Function Testing: NL‐CFT. Patients with epicardial spasm (n=251) were divided according to acetylcholine spasm triggering dose: low (2–20 mcg, EpiLOW), middle (100 mcg, EpiMIDDLE) or high (200 mcg, EpiHIGH). Patients with microvascular spasm (n=157) were analyzed irrespective of triggering dose. The patient groups were compared to each other and to a control group with negative CFT results (n=101). We assessed mean Seattle Angina Questionnaire angina frequency and summary scores at baseline and follow‐up and the proportion of patients improving or deteriorating. An inverse relationship between provocation dosage and angina frequency at baseline was found in epicardial spasm: the lower the triggering dose, the more frequently patients experienced angina (EpiLOW 48±20, EpiMIDDLE 53±21, EpiHIGH 57±19, microvascular spasm 61±21, controls 64±21, overall P =0.003). A trend was seen toward most patients improving in the high triggering dose group, and most patients deteriorating in the low triggering dose group. Conclusions: A significant dose‐dependent relationship between spasm provocation and anginal complaints exists. Acetylcholine provocation dose could be incorporated as a risk stratification factor or surrogate outcome in future clinical trials. Registration: URL: https://www.clinicaltrials.gov ; Unique identifier: NCT06083155.

Continuous infusion thermodilution is an established technique for the assessment of absolute coronary blood flow and microvascular resistance due to its proven accuracy and reproducibility. However, for this technique to yield reliable measurements, direct and homogenous mixing of injected saline and blood is mandatory. This study aimed to assess and compare the mixing properties of two different microcatheters, namely the Rayflow® (with sideholes for infusion) and the Finecross® catheter (single end-hole for infusion), which are commonly used in the catheterization laboratory. The study employed three different methods to evaluate the mixing properties of the catheters. Firstly, a qualitative assessment of mixing was performed using ink injections in an in vitro bench model of a coronary artery. Secondly, in analogy to the human catheterization laboratory, mixing properties over the length of the coronary artery were assessed semi-quantitatively by temperature measurements in the bench model. Lastly, a quantitative assessment was performed by 3D computational fluid dynamics, where the standard deviation and entropy ratio of the temperature over the cross-section in the coronary artery model were calculated for both catheters. All three evaluation methods demonstrated that the Rayflow catheter’s specific design leads to a more optimal, homogeneous mixture of blood and saline over both the cross-section and length of a coronary vessel, as compared with the standard end-hole catheter. Methods and main results are shown for in vitro measurements and 3D computational fluid dynamics.