Nonobstructive Coronary Artery Disease Research Articles

Index of microvascular resistance (IMR) and fractional flow reserve (FFR) relationship in patients with angina and non-obstructive coronary artery (ANOCA) disease

Abstract Background Despite the plausible physiological connection between the index of microvascular resistance (IMR) and fractional flow reserve (FFR), a comprehensive understanding of their correlation is lacking. Purpose This study aims to elucidate the association between IMR and FFR in patients presenting with angina and non-obstructive coronary artery disease, employing various IMR threshold values. Methods Consecutively enrolled patients with angina and non-obstructive coronary artery disease underwent a thorough functional assessment encompassing both epicardial (Pd/Pa, FFR) and microvascular (coronary flow reserve, CFR; IMR) domains by the thermodilution technique. The hyperemic response to adenosine (Δ) was quantified as the disparity between Pd/Pa and FFR. Correlations between FFR and IMR, as well as between Δ and IMR, were examined globally and categorized based on the presence of coronary microvascular dysfunction (CMD, CFR<2). Subsequently, patients were stratified into three groups based on IMR values: Group 1 (IMR<25), Group 2 (25≤IMR<40), and Group 3 (IMR ≥ 40). Further analyses of adenosine hyperemic response, IMR, and FFR correlations were conducted within each group. Results A total of 116 patients and lesions were evaluated, with 71 in Group 1, 32 in Group 2, and 13 in Group 3. Globally, FFR showed no correlation with IMR (r = 0.025, p = 0.788), regardless of CMD presence (CMD, r = 0.210, p = 0.325; no CMD r = -0.051, p = 0.631). Same results were observed for the relationship of hyperemic response to adenosine and IMR (r = -0.0398, p = 0.673). However, upon stratification by IMR values, only patients in Group 3 exhibited a positive correlation between FFR and IMR (r = 0.580, p = 0.037), with a notable reduction in the hyperemic response to adenosine as IMR values increased (r = -0.5485, p = 0.052). After adjusting for potential confounding factors, a significant increase of 0.01 in FFR values was observed for every 10-unit rise in IMR (p = 0.045) in this Group. Conclusions FFR appears to be particularly influenced by elevated IMR values (≥40). Prudent interpretation of FFR values in such instances is imperative, especially in cases of functionally borderline epicardial stenosis.

A comprehensive approach combining FFR, CFR, and IMR in order to predict adverse cardiovascular events in patients with non-obstructive coronary artery disease

Abstract Background Abnormal coronary circulation is linked to poor patient outcomes. The predictive values of comprehensive physiological assessments in patients with non-obstructive coronary artery disease (NOCAD) have not been fully investigated. Objectives The study aimed to evaluate the predictive value of a comprehensive approach that combines fractional flow reserve (FFR), coronary flow reserve (CFR), and index of microcirculatory resistance (IMR) in patients with NOCAD. Methods FFR, CFR, and IMR were measured in the left anterior descending artery of 226 patients with NOCAD. The primary endpoint was defined as adverse cardiovascular events including cardiovascular death, heart failure, coronary revascularization, cerebral infarction, and peripheral vascular events. Results Optimal cutoffs predicting the endpoint were 0.89 for FFR, 2.3 for CFR and 18.0U for IMR. Among the patients, 53 were negative for all indices, 80 positive for one, and 93 positive for two or three. During a median follow-up period of two years, 29 adverse events occurred, with the distribution as follows: 1 (1.9%) in patients with all negative indices, 5 (6.2%) in those with one positive index, and 23 (24.7%) in those with two or three positive indices. Kaplan-Meier curve analysis demonstrated significantly worse event-free survival in patients with an increasing number of positive indices (χ2=18.5, P<0.001). The presence of two or three positive indices was an independent predictor of the endpoint (hazard ratio 7.280, p<0.001). Conclusions Combining FFR, CFR, and IMR is an effective method for predicting cardiovascular events in patients with NOCAD.

Prevalence of coronary microvascular disease in myocardial infarction with non-obstructive coronary artery disease

Abstract Background Six percent of patients presenting with acute myocardial infarction (MI) have MI with non-obstructed coronary artery disease (MINOCA). Coronary microvascular disease (CMD) is common in angina with non-obstructive coronary artery disease (ANOCA), but its prevalence and severity in MINOCA is undefined. Purpose Patients with CMD may have elevated risk of myocardial infarction despite no significant stenosis. We tested the hypothesis that patients with MINOCA have more significant burden of CMD than patients with ANOCA. Methods A retrospective case-control study was performed on patients who underwent invasive testing for signs of coronary ischemia and found to have non-obstructive disease (stenoses< 50%). Cases of MI were classified as MINOCA (n=87) and compared to patients with ANOCA (n=552). Patients with spontaneous coronary artery dissection, myocarditis, Takotsubo cardiomyopathy or prior atherothrombotic MI were excluded. Coronary catheterization was performed followed by invasive provocation testing with adenosine and acetylcholine using a Doppler flow wire. CMD was subdivided into endothelium-independent, defined as coronary flow reserve (CFR) < 2.5 with intra-coronary adenosine, and endothelium dependent, defined as < 50% increase in coronary blood flow with acetylcholine. Epicardial vasoconstriction > 90% with typical anginal symptoms was classified as epicardial vasospasm. Results There was no difference in age, sex or traditional coronary risk factors between the MINOCA and ANOCA groups (Table 1). Fifty (57%) of patients with MINOCA had type 2 MI secondary to supply-demand mismatch. Both MINOCA and suspected ANOCA patients had a high prevalence of CMD (71% vs 67%) and endothelium-independent CMD is more prevalent in MINOCA (64.5% vs 50.4%). Although odds of endothelium-dependent CMD were similar, the CFR within this group and CMD overall was worse in MINOCA patients (Figure 1). There was no difference in epicardial spasm. Conclusion Coronary microvascular disease and vasomotor dysfunction are common in patients with MINOCA, with a higher prevalence of endothelium-independent CMD and more severe CMD overall compared to patients with ANOCA. Treatment of CMD in patients with MINOCA may help reduce recurrence and warrants further investigation.

Prognostic implication of computational angiography-derived fractional flow reserve in patients with non-obstructive coronary artery disease

Abstract Background Non-obstructive coronary artery disease (NOCAD) is proved to have high association with rate of major adverse cardiovascular events (MACE) in recent studies, yet risk stratification of symptomatic Non-Obstructive Coronary Artery Disease (NOCAD) patients remains uncertain. Objectives Our study assessed clinical value of single-vessel, multi-vessel, and three-vessel computational angiography-derived fractional flow reserve (caFFR) measurement in NOCAD patients. Methods We enrolled patients with ≤ 50% stenosis with a caFFR value ≥ 0.8 in all three coronary arteries on coronary angiography. The sum of caFFR values in the three vessels was computed for each patient. Patient stratification was based on median value of the following criteria: single vessel analysis, multi-vessel analysis, 3-vessel (3V) analysis. The primary endpoint of this study was major adverse cardiac events (MACE) at 5 years, defined as a composite of cardiac death, myocardial infarction, and ischemia-driven revascularization. Results A total of 490 patients were included (mean age 64.39 ± 11.16, 55.5% male). The 5-year MACE rates in single-vessel analysis were statistically insignificant between low and high caFFR groups (Left anterior descending artery (P=0.163); Left circumflex artery (P=0.797); Right coronary artery (P=0.127)). In multi-vessel analysis, patients in multiple-vessel low-caFFR group (with 2-3 vessels lower than median value of all coronary arteries) show an increased risk of 5-year MACE than patients in single-vessel low-caFFR group (0-1 vessel) (hazard ratio [HR] 2.648, 95% confidence interval [CI] 1.141 - 6.145, P = 0.023). In 3-vessel analysis, patients in the low 3V-caFFR group demonstrated a greater 5-year MACE risk than the high 3V-caFFR group ([HR] 2.43, 95% 95%[CI] 1.087 - 5.433, P = 0.031). Conclusion In patients with NOCAD, the higher count of vessels exhibiting with low caFFR values and the low 3V-caFFR values have been found to be associated with increased rate of MACE over a 5-year period. We demonstrated that both multiple-vessel and 3V-caFFR measurements serve as valuable prognostic indicators for risk assessment in NOCAD patients.

Association of metabolic phenotypes with cardiovascular events in primary and secondary prevention

Abstract Background Metabolic disorders are established risk factors for the development of coronary artery disease (CAD) and major adverse cardiovascular events (MACE). Although obesity is strongly related with the metabolic health status, its role as a cardiovascular risk modifier in the absence of metabolic disorders remains controversial. Recent implementation of nutrient-stimulated hormone-based therapies (NUSH) including glucagon-like peptide-1 (GLP-1) receptor agonists in the treatment of obesity even in metabolically healthy individuals requires further understanding to ensure optimal patient management. Purpose The aim of this study is to investigate the association of metabolic phenotypes with cardiovascular events in primary and secondary prevention of CAD. Methods We included patients over 18 years electively evaluated for CAD by invasive coronary angiography (ICA) between 2010 and 2021 in our tertiary referral centre in one of Europe’s largest university hospitals. Metabolic disorder was considered as the presence of diabetes, irrespective of additional risk factors, or hypertension and hyperlipidaemia, and obesity as a BMI of ≥30 kg/m², distinguishing four metabolic phenotypes: metabolically healthy/unhealthy nonobese/obese (MHN, MHO, MUN, MUO). The primary study endpoint MACE was defined as a composite of cardiovascular death, non-fatal myocardial infarction, ischemic stroke, and hospitalization for heart failure. Results The total study population included 12 760 patients (68 [58-76] years; 57.3% male), of whom 56.5% presented metabolically healthy (43.3% MHN; 13.1% MHO) and 43.5% unhealthy (28.3% MUN; 15.2% MUO). During a median follow up time of 3.91 (1.75-7.09) years, 2 592 (20.3%) MACE and 3 351 (26.3%) all-cause deaths occurred. Cox regression analysis adjusted for age, sex, and chronic kidney disease (CKD) showed different risk patterns for distinct metabolic phenotypes (Table 1). While we observed higher event rates in metabolically unhealthy compared to healthy individuals, obesity alone was not associated with increased events (Figure 1). However, metabolically healthy individuals experienced lower event rates with increasing BMI. Among patients without or with nonobstructive CAD, metabolic disease was strongly associated with increased subsequent coronary revascularization regardless of BMI. These patterns were similar across all endpoints irrespective of presence of obstructive or nonobstructive CAD. Conclusions Whereas metabolic disorders are strongly associated with adverse clinical events, obesity alone does not reflect the cardiovascular risk profile in patients with or without obstructive CAD. Thus, focusing on obesity alone for primary or secondary prevention appears unjustified. Particularly after the recent implementation of GLP-1 receptor agonists for the treatment of obesity, precise and individual risk stratification is essential to allow for an optimal personalized patient management.Figure 1Table 1

Cycling coupled to intra-coronary thermodilution to evaluate angina with non-obstructive coronary artery disease

Abstract BACKGOUND Patients with Angina and Non-Obstructive Coronary Artery disease (ANOCA) face misdiagnosis and inadequate treatment. A new continuous thermodilution method enables assessment of absolute coronary blood flow (Q) and microvascular resistance (Rµ). The effectiveness of saline-induced hyperemia in capturing exercise-induced coronary flow regulation remains unknown. OBJECTIVE To describe Q and Rµ adaptation during exercise and to explore the correlation between Coronary Flow Reserve (CFR) derived from saline and exercise-induced hyperemia, as well as Microvascular Resistance Reserve (MRR). Methods Q, Rµ, CFR and MRR were first assessed using continuous thermodilution with saline infusion at 10 mL/min (rest) and 20 mL/min (hyperemia) in the left anterior descending artery, followed by subsequent stress testing using a dedicated supine cycling ergometer. The microvascular parameters were assessed during incremental workload of 30 watts every two minutes. CFRsaline<2.5 was considered the cutoff for coronary microvascular dysfunction. A minimal sample size of 29 participants was required to detect a hypothesized Spearman coefficient correlation r=0.5 between CFRsaline and CFRexercise using a 80% power and 5% significance level test. Results Coronary microvascular dysfunction was observed in 53.3% of the participants with suspected ANOCA (16 out of 30). During cycling, participants with coronary microvascular dysfunction had a lower reduction in Rµ (-109 [32; 286] versus -202 [102; 379] WU per 30 watts, p<0.01) and a lower ability to increase coronary flow (7 [30.5; 103.0] versus 21 [5.8; 45.0] mL/min per 30 watts, p=0.01) compared with those without coronary microvascular dysfunction. In the overall population, average CFRsaline and CFRexercise were 2.70±0.90 and 2.85±1.54, respectively (p=0.46) with an agreement classification of 83.3%. A good correlation between the two techniques was observed for both CFR (Spearman coefficient r=0.73, p<0.0001) and MRR (r=0.76, p<0.0001). Monitoring of CFR and Rµ during exercise unmasked functional coronary microvascular dysfunction priorly labeled as normal by saline induced hyperemia in 13.3% of the study population. These individuals had a moderate and late decrease of Rµ during the early stages of exercise, with a plateau up to 75% of their theoretical workload. Conclusion Participants with coronary microvascular dysfunction demonstrated compromised CFR due to impaired reduction of Rµ during physical workload. Saline-induced hyperemia provided a valid surrogate for exercise physiology independently of the absolute level of CFR and MRR, although exercise provided more granularity to evaluate hemodynamic adaptation among participants with functional dysfunction.

Predictive factors and gender insights into abnormal myocardial flow reserve in non-obstructive coronary artery disease: a CZT-SPECT analysis

Abstract Background Dynamic myocardial perfusion imaging (D-MPI) using cadmium-zinc-telluride (CZT) cardiac-dedicated SPECT has emerged as a valuable method for assessing coronary microcirculation, particularly compared to conventional SPECT. Additionally, gender-specific disparities in microvascular dysfunction require further investigation. Objective This study aims to identify predictive factors for abnormal myocardial flow reserve (MFR) in non-obstructive coronary artery disease (CAD) using CZT-SPECT, with a focus on gender differences in MFR dysfunction. Methods A retrospective analysis was conducted on clinical data from 393 patients presenting with symptoms of "chest pain and/or tightness," all of whom were confirmed to lack obstructive CAD by coronary angiography or CT angiography. MFR was measured using CZT-SPECT, with values ≥2.5 considered normal and values <2.5 considered abnormal. Results Of the patients, 49.1% (193/393) demonstrated abnormal MFR, with females representing 56.7% (223/393). Females with abnormal MFR exhibited higher averages in age, total cholesterol, LDL-C, creatinine, left atrial diameter, left ventricular posterior wall (LVPW) thickness in diastole, and E/e’ ratio (P < 0.05). Additionally, MDRD-eGFR and mitral annular septal velocity e’ were lower in the abnormal MFR cohort (P < 0.05). Multivariate logistic regression analysis identified elevated LDL-C levels (OR = 1.513, 95%CI: 1.122–2.041, P = 0.007) and increased LVPW thickness (OR = 1.717, 95%CI: 1.140–2.585, P = 0.010) as independent predictors of abnormal MFR in females. ROC analysis suggested optimal cutoff for LDL-C at 3.68 mmol/L (sensitivity 31%, specificity 84%, AUC = 0.586; 95%CI: 0.511–0.661) and LVPW thickness at 9.5 mm (sensitivity 62%, specificity 52%, AUC = 0.576; 95%CI: 0.501–0.652). A combined ROC analysis of LDL-C and LVPW thickness showed a sensitivity of 50% and specificity of 73% (AUC = 0.632, 95%CI: 0.559–0.705). In males, greater left ventricular end-diastolic diameter (LVEDD) was significantly associated with abnormal MFR (P = 0.014), with LVEDD identified as a predictor (OR = 1.130, 95%CI: 1.016–1.258, P = 0.025) and an optimal cutoff at 44.5 mm (sensitivity 88%, specificity 37%, AUC = 0.609; 95%CI: 0.524–0.694). No significant gender differences were observed in overall left ventricular resting myocardial blood flow (MBF) among patients with abnormal MFR (P = 0.072); however, female patients exhibited higher resting MBF in specific territories supplied by the left circumflex and right coronary arteries, and higher E/e’ ratios (P < 0.05). Furthermore, a negative correlation was found between resting MBF in the territory supplied by the right coronary artery and E/e’ in females (r = -0.210, P = 0.030). Conclusion Predictors of abnormal MFR in non-obstructive CAD show gender disparities, implicating an association with left ventricular diastolic function.

Age stratified differences in coronary artery plaque phenotype in women and men with non-obstructive coronary artery disease

Abstract Background Development of coronary artery disease (CAD) and risk of acute cardiac events differ between women and men during the life span. The aim of this study was therefore to characterize sex differences in coronary artery plaque phenotype among patients with symptomatic non-obstructive CAD in different age groups. Methods Advanced coronary artery plaque phenotyping by coronary computed tomography angiography was performed in 606 patients (31% women) with symptomatic non-obstructive CAD from the Norwegian Registry of Invasive Cardiology. A 1:1 sex-matched study design ensured equal distribution of the sexes in the different age groups. We assessed total plaque burden adjusted for vessel volume and plaque composition consisting of dense calcium, fibrous, fibro-fatty, and necrotic core. Patients were further stratified into age groups of ≤50, 51-64, and ≥65 years to explore the relationship between age and sex on coronary artery plaque phenotype. Results In the study population, patients ≥65 years had a higher prevalence of hypertension, higher calcium score, coronary artery segment involvement score and total plaque burden, whereas the prevalence of obesity was lower compared to patients aged 51-64 and ≤50 years (all p<0.05). The prevalence of smoking, diabetes and statin treatment was similar between groups. A two-way analysis of variance demonstrated an interaction between sex and age group on total plaque burden (F [2, 600] =3.431, p=0.33), where women aged 51-64 and ≥65 years had a higher total plaque burden compared to men (p=0.002 and p<0.001, respectively, Figure 1). Plaque composition in women ≥65 years was characterized by an increased proportion of stable dense calcified plaques compared to men and younger women (all p<0.05), whereas men ≥65 years had a higher proportion of vulnerable necrotic core plaque phenotype (p<0.001). Women showed consistently lower proportions of more vulnerable fibro-fatty plaques compared to men across all age groups (all p<0.05, Figure 2). Conclusions In non-obstructive CAD, higher total plaque burden was associated with older age and female sex. Women had a lower proportion of vulnerable fibro-fatty plaques across all age groups and a higher proportion of stable dense calcified plaques at an older age compared to men. Future longitudinal studies on coronary artery plaque phenotype during the life span will increase the understanding of sex differences in CAD development and may contribute to customise risk stratification in women and men.Figure 1.Total plaque burdenFigure 2.Compositional plaque burden

How to predict myocardial injury in patients with large ischaemic burden identified during stress echocardiography?

Abstract Background/Introduction Stress echocardiography (SE) is well established diagnostic tool in coronary artery disease (CAD) with broadly agreed consensus for the indications and protocols. There is, however, no clear non-invasive SE parameter in identifying high risk features in patients with large burden of inducible regional wall motion abnormalities (RWMA) that would require prompt treatment or urgent admission. Purpose To identify high risk features during SE associated with myocardial injury following a positive SE with large amount of RWMA. Methods All consecutive patients referred for SE from June 2019 to November 2022 to diagnose coronary artery disease were assessed for inducible RWMAs using a hybrid protocol (low dose Dobutamine and exercise on supine bike with 3 min increments of workload of 25W). Those with ≥4/17 segments of inducible RWMAs underwent measurement of Troponin level 1 hour after the test termination. Somatometric characteristics, risks factors, symptoms, haemodynamic pre- and during SE and results of subsequent coronary angiography were recorded. Results 631 patients were referred for assessment of CAD. 87 patients had ≥4/17 inducible RWMAs out of 152 patients with positive SE. 61/87 who had Troponin measurements were included in the analysis. Mean age was 65 ± 13 yo, 61% were male. There was high prevalence of known CAD (77%) and cardiovascular risks factors as hypertension (59%) and hyperlipidaemia (61%). The median exercise time was 9 minutes, 46% developed chest pain (CP), 49% - ECG changes, 39% - left ventricular (LV) dilatation and 74% - reduction in LVEF. Troponin was positive in 25/61 patients. Invasive coronary angiography confirmed clinical CAD in 51/61 patients. 5 patients had either normal angiogram or non-obstructive CAD, 5 patients were awaiting diagnostic test. The severity of CAD appears to be associated with magnitude of Troponin release (1 vessel disease - 16.5 ng/L, 2 vessels disease - 39.9 ng/L, 3 vessels disease – 58.2 ng/L). All patients (6/61) with higher troponin values (>90ng/L) had multivessel disease involving the left anterior descending (LAD) artery. Interestingly, 2/5 patients without CAD had elevated Troponin suggesting possible ongoing myopathic process. The only non-invasive SE parameters that were significantly related to troponin increase were recovery time (P=0.001) and exercise time (P<0.05) whereas symptoms, BP response and LVEF reduction showed a trend which did not achieve significance. Conclusions In patient with positive SE with large burden of inducible RWMAs prolonged recovery time and low threshold for ischaemia appear to be the most reliable characteristic to identify patients with potential myocardial injury and should be used as a triaging tool for admission or early invasive assessment.

Traditional cardiovascular risk factors and coronary microvascular disease in women and men- a single center study

Abstract Introduction Coronary microvascular dysfunction (CMD) is a common, often missed, cause for effort intolerance and angina symptoms, and is associated with adverse clinical outcomes. Risk factors for the development of CMD have not been fully elucidated, and studies examining sex associated differences in traditional cardiovascular risk factors (TCRs) for obstructive coronary artery disease (CAD) in patients with CMD have yielded conflicting results. Although several non-invasive methods for the evaluation of CMD exist, currently, catheter-based invasive assessment is the gold standard for the diagnosis of coronary microvascular dysfunction. Purpose To examine the association between TCR and CMD and sex associated differences in TCR, in a prospective cohort of patients undergoing invasive microvascular function evaluation in a large tertiary medical center. Methods In this single center, prospective registry, we enrolled patients with non-obstructive CAD undergoing clinically indicated invasive assessment of coronary microvascular function between November 2019 and March 2023. Measurements of microvascular function included CFR, IMR, RRR as well as FFR. Pathologic CFR was defined as <2.5 or <2. Associations between coronary microvascular dysfunction, traditional cardiovascular risk factors, and sex were assessed using univariate and multivariate regression models. Results Overall, 245 patients with non-obstructive CAD were included in the analysis (62.9% female; median age 68 (interquartile range [IQR]: 59,75). Microvascular dysfunction was diagnosed in 141 patients (57.5%). The prevalence of microvascular dysfunction was similar in women and men in the entire cohort (59.0% vs. 57.0%; p=0.77). In 41 patients diagnosed with functional microvascular dysfunction there were more women than men (70.7% vs. 29%). When using a threshold of CFR<2.5 no association was found between traditional risk factors for coronary atherosclerosis and CMD regardless of whether CMD was structural or functional. In women, but not in men, older age and the presence of previous ischemic heart disease were associated with lower coronary flow reserve (CFR) (β=-0.29; p<0.01 and β=-0.15; p=0.05, respectively) and lower resistive reserve ratio (RRR) (β=-0.28; p<0.01 and β=-0.17; p=0.04, respectively). When using a threshold of <2.0 for CFR similar results were found. Conclusion The prevalence of TCRs was similar in patients with and without CMD. In women, older age and previous IHD were associated with lower CFR and RRR values while no association between TCRs and indices of CMD was found in men. It is likely that there are other, currently unknown risk factors for CMD as well as unique risk factors for each of its endotypes, beyond TCRs. It is unclear which parameter of microvascular dysfunction is the most accurate, and whether different parameters should be used in women and men. Large-scale multi-center studies to further evaluate these issues are needed.Variables associated with CMDStudy inclusion process

Coronary slow flow as measured by corrected TIMI frame counts is associated with impaired microvascular resistance

Abstract Background The Coronary Slow Flow Phenomenon (CSFP) reflects an increased resting microvascular resistance and has been defined as a corrected thrombolysis in myocardial infarction frame count (cTFC) >27 in the in the absence of obstructive coronary artery disease (CAD). However, there is limited and conflicting data on the diagnostic utility of CTFC with respect to gold standard coronary haemodynamic parameters; namely coronary flow reserve (CFR) and hyperaemic microvascular resistance (hMR). Purpose To evaluate the relationship between angiography-derived cTFC and the coronary haemodynamic parameters (CFR and hMR). Methods Patients with angina and non-obstructive CAD (< 50% epicardial stenosis; ANOCA) underwent comprehensive functional coronary angiography utilising a dual sensor-tipped pressure-doppler flow wire during adenosine infusion for investigation of coronary microvascular impairment, and acetylcholine provocative testing for the diagnosis of coronary artery spasm. Results In 103 patients who underwent functional coronary angiography, 60 patients had CSFP and this was associated with low flow velocity and higher microvascular resistance at rest as compared with patients without CSFP (19.2 ± 7.3 versus 22.6 ± 6.7, p=0.024; and 5.9 ± 2.0 versus 4.6 ± 1.7, p=0.009, respectively). Whilst cTFC was poorly associated with CFR (r= 0.058, p= 0.564), there was a relatively strong, positive correlation with hMR (r=0.258, p=0.008). Furthermore, receiver operating characteristic analyses demonstrated that CTFC poorly predicts an impaired CFR <2.5 (AUC, 0.479 [0.36-0.59]) but does predict an impaired hMR >2.5 (AUC, 0.623 [0.51-0.74] p=0.037). Conclusion In patients with ANOCA, cTFC is associated with coronary microvascular dysfunction as measured by microvascular resistance during hyperaemia. This data suggests the cTFC may be a surrogate marker for impaired microvascular resistance.cTFC versus hMR

NICE guidance in the rapid access chest pain clinic: does it work?

Abstract Background Rapid Access Chest Pain Clinics (RACPC) were developed following the publication of the National Service Framework for Coronary Heart Disease in 2000(1). The National Institute for Health and Care Excellence (NICE) produces guidelines for the management of patients with recent onset chest pain of suspected cardiac origin(2). In 2016 the guidance was updated and recommended the use of CT coronary angiography (CTCA) as the initial investigation for patients with chest pain which was typical or atypical of angina. Adherence to the guideline may be dependent upon factors such as local availability of CT scanners and clinician preference. The RACPC in this tertiary centre is nurse-run with no medical involvement. There is good engagement with the CT department and in July 2017 the NICE guidance was adopted in the clinic. Purpose To evaluate the use of CTCA as the first line investigation for patients with typical or atypical chest pain. Methods Data from all patients reviewed in the clinic between 01/07/2017 and 31/12/2023 were prospectively collected, entered into a database, and then retrospectively analysed. The data were organised into 3 groups: patients with typical chest pain; atypical pain and those with non-cardiac sounding chest pain. The number of patients in each group who underwent a CTCA, and the outcome of the scan were evaluated. The CT scans were categorised as showing significant coronary artery disease (CAD), non-obstructive CAD, no CAD, or as inconclusive. The outcome of patients who had a positive CTCA was also recorded. Results 2986 patients were reviewed in the RACPC in the above period. 14.2% of patients presented with typical pain, 47.4% with atypical pain, and 30.6% had non-cardiac pain. The remaining patients presented with other symptoms such as breathlessness. CTCA was used as the first investigation in the majority of patients with typical or atypical pain, unless alternative investigations or management were deemed to be more clinically appropriate. In 59.5% of typical and 78.5% of atypical presentations, the CT scan showed no CAD, or non-significant CAD. There was a low incidence of positive scans in both groups, however patients with typical pain were more likely to have significant CAD (Table). All patients who had a CTCA indicating significant CAD, were referred for invasive angiography. 88.0% of typical presentations, and 64.0% of those with atypical pain, underwent revascularisation. No patient who underwent invasive angiography was found to have normal coronary arteries. Conclusion Atypical pain is the most frequent presentation in the RACPC, however the majority of these patients, and most of those with typical pain, do not have significant CAD. Careful assessment and the use of CTCA as the initial investigation, enable the identification of those patients who need invasive angiography. This is a cost-effective strategy which also reduces risk and radiation exposure for patients.

Evaluation of coronary microvascular dysfunction and vasospasm in patients with angina and non-obstructive coronary artery disease

Abstract Background Angina in the absence of obstructive coronary artery disease (CAD) is a growing cause of morbidity and mortality, exceeding the economic burden of CAD. Roughly 50-70% of patients undergoing invasive angiography for anginal symptoms have non-obstructive CAD. Within this category, there are distinct sub-populations including patients with angina without evidence of ischemia on prior stress testing (ANOCA), evidence of ischemia on stress testing (INOCA), or history of obstructive CAD with prior revascularization (ANOCA-HxCAD). Coronary microvascular dysfunction (CMD) and/or epicardial vasospasm are common causes of angina in the absence of epicardial CAD despite optimal medical therapy. Differences between these groups, in terms of risk factors and diagnoses remain relatively unknown. Purpose To compare clinical characteristics, symptoms, and diagnoses between patients with ANOCA, INOCA, and ANOCA-HxCAD. Methods In a prospective registry-based cohort study of 306 patients without obstructive CAD (<50% stenosis in epicardial artery) undergoing coronary functional angiography (CFA), we assessed differences in clinical characteristics, symptoms, and CFA diagnoses: (1) endothelial-independent CMD (coronary flow reserve [CFR] <2.5) to adenosine testing, (2) endothelial-dependent CMD (coronary blood flow [CBF]<50% or no change in vessel diameter to 54 mcg intracoronary acetylcholine [ACH]), (3) epicardial vasospasm to 108 mcg intracoronary ACH in 3 groups of patients (ANOCA, INOCA, and ANOCA-HxCAD). Results Among the 306 patients undergoing CFA, 89% were female with a median age of 58 years (49, 67). Patients with ANOCA-HxCAD had a significantly higher prevalence of hypertension, diabetes, heart failure with preserved ejection fraction, and experienced worse dyspnea on exertion as measured by University of San Diego Shortness of Breath (UCSD SOB) in comparison to ANOCA or INOCA patients. However, there were no differences between the groups in terms of anginal severity, functional capacity, or quality of life. In terms of CFA diagnoses, vasospasm was more prevalent in ANOCA-HxCAD (p<0.001) and CMD was more prevalent in ANOCA and INOCA patients (p=0.034) (Table 1). Conclusions Despite differences in clinical characteristics, patients without obstructive CAD have similar anginal severity, functional capacity, and quality of life regardless of evidence of ischemia on prior stress imaging or history of revascularization. There are differences in CFA diagnoses with higher prevalence of CMD in ANOCA and INOCA patients and higher prevalence of vasospasm in ANOCA-HxCAD patients. Determining the underlying diagnoses changes clinical management; therefore, CFA should be considered in all patients without obstructive CAD.

Noninvasive identification of ANOCA endotypes by stepwise, multi-stress, multi-marker stress echocardiography

Abstract Background Angina with non-obstructive coronary artery disease (ANOCA) is increasingly recognized in clinical practice, but effective therapy is difficult due to the heterogenity of pathophysiological substrates: organic coronary microvascular dysfunction (CMD), functional (vasospastic) CMD, epicardial artery vasospasm, non-cardiac chest pain. Current guidelines recommend invasive coronary function testing with the inherent cost of catheterization time, radiation exposure, iodinated contrast effects and risks of invasive procedures. Objective To evaluate the feasibility of a step-wise, multi-marker, multi-stress assessment of ANOCA patients by stress echocardiography (SE). Methods In a prospective study design, we enrolled 54 ANOCA patients (age =54±14 years, 14 men, 25 %), without significant coronary artery disease (CAD) on invasive or noninvasive angiography. In all patients hyperventilation (HYPER) test (30 deep breaths/min for 5 min) was performed, followed by semi-supine exercise (EX) if negative. All patients underwent adenosine (ADO) test with coronary flow velocity reserve (CFVR) measurement in the mid-distal left anterior descending artery (LAD). Positivity criteria were a coronary flow velocity (CFV) decrease during HYPER despite the increase in the double product (DP) indicating functional CMD i.e. vasoconstriction); the presence of inducible regional wall motion abnormality (RWMA) with HYPER-EX (microvascular/epicardial spasm), and CFVR ≤2.0 with ADO hyperemia (organic CMD). Results Fifty one pts (94%) had normal increase in CFV at ADO: CFV rest 0.264±0.078 vs ADO 0.608±0.133, p<0.001, while 3pts (5%) showed decrease in CFV at ADO suggesting organic CMD. Double product (DP) increased during HYPER (rest 10061 ±2406 vs. HYPER 13580 ±3356, p<0.001). Twenty-nine pts (53%) showed a paradoxical vasoconstrictor response during HYPER despite the increase in DP (CFV decreased during HYPER: CFV rest 0.261±0.059 vs HYP 0.216±0.057, p<0.001). With HYPER-EX, RWMA was induced in 15 patients (27%), while 7 patients had also RWMA during HYPER. Conclusion In patients with ANOCA, a stepwise multi-marker (CFVR and RWMA) and multi-stress (ADO, HYPER and EX) SE identifies CMD phenotypes and actionable therapeutic targets. According to our results functional vasospastic CMD (paradoxical decrease of CFV with HYPER), is more frequent than organic CMD (reduced CFVR with ADO) in patients with ANOCA. Inducible RWMA with HYPER-EX indicate severe vasoconstrictor response.

Coronary Computed Tomographic Angiography (CCTA) in non-ST elevation acute coronary syndromes

Abstract Background In patients presenting with an acute coronary syndrome (ACS), a diverse range of coronary artery disease is observed from structurally normal vessels to non-obstructive atherosclerosis and severe/obstructive coronary artery disease (CAD). In current clinical practice guidelines, the main diagnostic route for optimal management of patients with non-ST segment elevation acute coronary syndrome is invasive coronary angiography. However, in 30-40% of cases, no significant coronary lesions are evident. The purpose of this study is to describe the role of coronary computed tomographic angiography (CCTA) in non-ST elevation acute coronary syndromes in low and intermediate risk patients. Methods We describe the results of 504 patients evaluated with a protocol that includes the use of CCTA in patients with ACS. Patients over 18 years of age with a diagnosis of ACS without ST elevation who did not meet high-risk criteria (hemodynamic instability, dynamic changes in the ST segment or T wave, ventricular arrhythmia, GRACE score >140, refractory angina, heart failure or cardiorespiratory arrest) were included. They underwent CCTA as the initial coronary evaluation. Data collection was carried out between May 11, 2022 and February 20, 2024. Results 504 patients were included, with a mean age of 58 years, of which 44% were women and 56% men. Among the admission diagnoses, 26% were NSTEMI and 74% were unstable angina according to the 4th universal definition of acute myocardial infarction (AMI). The median high-sensitivity cardiac troponin T value was 7 nanograms per liter (interquartile range, 7 to 15) for the first troponin measurement. CCTA was performed in 93% of the patients. It was observed that 28% did not have any coronary lesions or plaques. 36% had non-obstructive coronary artery disease (plaques <50%). The rest had significant lesions in at least one vessel (27%), predominantly in the left anterior descending artery, or were nondiagnostic (9%). 31% had myocardial bridges, while in 13% of the patients a high-risk plaque was found. 38% of the patients included underwent invasive coronary angiography and 23% required revascularisation. Conclusion This study shows that the prevalence of ACS with coronary arteries without significant lesions by CCTA was 28%, which suggests CCTA could have a predominant role in the diagnostic algorithm of acute coronary syndromes without high-risk criteria, implying a decrease in the need of invasive studies in these patients. Only 38% required invasive coronary angiography, while revascularisation was performed in 23% of the patients. Furthermore, CCTA allowed a better detection of non-obstructive coronary artery disease (NOCAD) in 36% of the patients, and a more complete characterization of the atherosclerotic plaque, which could prompt to an initiation of preventive therapies or the optimization of medical treatment in these patients.Table 1CCTA findings

Assessment of cardiopulmonary exercise capacity in suspected heart failure with preserved ejection fraction: impact of coronary flow velocity reserve and body fat

Abstract Background and objectives Heart failure with preserved ejection fraction (HFpEF) has various pathophysiology including coronary microvascular dysfunction (CMD), obesity, and frailty. In the present study, we aimed to assess the cardiopulmonary exercise capacity according to coronary microvascular function and body composition in patients with suspected HFpEF. Methods Patients with chest symptoms with non-obstructive coronary artery disease (<50% stenosis) and preserved left ventricle (LV) ejection fraction (≥50%) were enrolled. LV end-diastolic pressure was measured during coronary angiography. All patients underwent body composition analysis, adenosine stress echocardiography with the evaluation of coronary blood flow, and cardiopulmonary exercise test assessing maximal oxygen consumption (VO2max). Coronary flow velocity reserve (CFvR) was defined as the ratio of peak to baseline mean diastolic velocity of coronary blood flow. Association between VO2max and CFvR as well as body composition was assessed. Results Of the 106 patients (mean age 63.5), 54 (50.9%) were women, 52.4% had hypertension, and 28.6% had diabetes. Baseline LV end-diastolic pressure was 15.3 ± 5.5 mmHg. Median Heart Failure Association-PEFF score was 3, while medial e’ velocity was 6.7 ± 2.0 cm/s and E/e’ was 9.6 (7.6 – 12.0). Mean diastolic velocity of coronary blood flow was 0.17 [interquartile range (IQR) 0.13 – 0.23] m/sec at baseline, while it increased to 0.46 [IQR 0.38 – 0.57] m/sec at peak, resulting in CFvR of 2.75 [IQR 2.10 – 3.67]. Eighteen (17.1%) patients had CMD (CFvR <2.0). VO2max was 23.1 ± 5.4 mL/kg/min with lower value in women (21.7 ± 4.8 vs. 24.5 ± 5.6 mL/kg/min, p = 0.007). CFvR was directly related to VO2max (r = 0.350, p <0.001). In body composition, skeletal muscle mass index, percent body fat, and visceral fat area were associated with VO2max. In multivariable analysis, age, visceral fat area or percent body fat, and CFvR were linearly correlated with VO2max, and estimated VO2max was well correlated with measured VO2max. Conclusions Cardiopulmonary exercise capacity represented by VO2max was correlated with CFvR and body composition including skeletal muscle mass index, percent body fat, and visceral fat area in patients with suspected HFpEF. VO2max could be estimated by CFvR and fat component in the body.

The clinical impact of cardiac magnetic resonance imaging upon suspected myocardial infarction with non-obstructive coronary artery disease

Abstract Background Cardiac magnetic resonance (CMR) may identify the underlying pathology in myocardial infarction with non-obstructed coronary arteries (MINOCA), however there are scant prospective data evaluating the more important measure of actual change in diagnosis and management consequent to CMR. Purpose To evaluate impact of CMR in MINOCA upon diagnosis, diagnostic certainty and management, adjudicated by treating physicians to minimise investigator bias. Methods Prospective, multi-center international pre- and post-CMR study of suspected MINOCA. Physician diagnosis, diagnostic certainty and intended management were established by questionnaire before and after CMR. The primary outcome was change in diagnosis or management. Secondary outcomes were change in diagnosis, change in management, change in diagnostic certainty, and number-needed-to-test for de-prescription of dual antiplatelet therapy (DAPT). Potential predictors of impactful CMR were evaluated by multivariable logistic regression analysis. Results 320 patients referred by 74 clinicians underwent CMR; mean age 55.6 (12.3) years, 48.1% female. CMR was conducted at median 11 days (IQR 6-19) post presentation. CMR led to change in diagnosis or management in 62.8% (95% CI 57.4% - 68.2%, p<0.0001) and significantly increased diagnostic certainty [8/10 post-CMR (5-9) vs 6/10 pre-CMR (4-7), p<0.0001]. Predictors of impactful CMR on multivariable analysis were early CMR (≤14 days), absence of atheroma on coronary angiography, significant pre-CMR diagnostic uncertainty (≤5/10), and a history of vascular disease. DAPT was deprescribed or modified to single antiplatelet in 61.7% patients. The number-needed-to-test to deprescribe DAPT was 2.6 (and 1.6 if a myocardial infarction mimic was co-suspected pre-CMR), which has important cost-benefit implications for CMR in MINOCA. Conclusions In this first prospective multi-centre study of CMR in MINOCA where diagnostic utility was adjudicated by the treating physicians, CMR was associated with frequent and significant changes in diagnosis, clinician certainty and clinical care, including frequent de-prescription of DAPT. Early CMR is to be encouraged, particularly in patients where there is significant diagnostic uncertainty and no atheroma on coronary angiography.

Assessment of structural and functional microvascular dysfunction using microvascular resistance reserve versus invasive exercise stress testing

Abstract Background Coronary microvascular dysfunction is an heterogenous entity with structural dysfunction present in about 60% of cases. Although Coronary Flow Reserve (CFR) is commonly used for diagnosis, this index is nonspecific to the microvasculature. The effectiveness of the recently introduced Microvascular Resistance Reserve (MRR) and absolute microvascular resistance (Rµ) in identifying microvascular dysfunction endotypes remains uncertain. Objective To evaluate whether MRR and hyperemic Rµ assessment are effective in dichotomizing functional and structural microvascular dysfunction as compared with Rµ and coronary blood flow (Q) monitoring during exercise. Methods Rµ and MRR were first assessed using continuous thermodilution with saline infusion at 10 mL/min (rest) and 20 mL/min (hyperemia) in the left anterior descending artery of consecutive patients with Angina and Non-Obstructive Coronary Arteries. An MRR<2.3 was considered the cutoff for coronary microvascular dysfunction. Q and Rµ were assessed during subsequent stress testing with an incremental workload of 30 watts every two minutes, using a dedicated supine cycling ergometer. Results Coronary microvascular dysfunction was observed in 36.6% of the participants with suspected Angina with Non-Obstructive Coronary Artery disease (11 out of 30). Median hyperemic Rµ was 561 [381; 684] Wood Unit (WU) among patients with microvascular dysfunction. Participants with structural dysfunction (MRR<2.3 and hyperemic Rµ>561WU), had a resting Rµ similar to participants without CMD (1286±410 versus 1231±291 WU) but exhibited both impaired reduction of Rµ (139 [64; 288] versus 191 [74; 317] WU per 30 watts) and increase of Q during exercise (20 [1; 37.5] versus 52 [15.5; 92.0] mL/min per 30 watts). Patients with functional dysfunction (MRR<2.3 and hyperemic Rµ<561WU) had lower resting Rµ (672±219 WU) and higher resting Q (152±39 versus 84±24 mL/min) with a similar increase of Q during exercise (55 [30.5; 103.0] than participants without CMD. Mean N-terminal pro B-type natriuretic peptide level was higher in the structural group (425±563 ng/L) as compared to the functional and normal groups (86±10 ng/L and 50±80 ng/L respectively). Conclusion The use of MRR combined to hyperemic Rµ, derived from continuous intracoronary thermodilution, enables the assessment of coronary microvascular dysfunction with an accurate distinction between functional and structural endotypes.Microvascular hemodynamic adaptationNTpBNP level

A practical risk model based on Lasso-Cox regression for angina with nonobstructive coronary arteries (ANOCA) patients

Abstract Background Coronary flow reserve (CFR) reduction is currently one of the main criteria for risk-stratifying patients with angina and nonobstructive coronary artery disease (ANOCA). However, CFR depends on resting and vasodilated coronary hemodynamics, and a theoretical concern remains that physiological changes may inadvertently affect the result. Purpose We aim to fit different risk models for patients with ANOCA, which further provides applicable guidance to clinical doctors for their patients. Methods Between May 2018 and October 2023, 251 consecutive patients who were diagnosed as ANOCA were enrolled from Qilu Hospital of Shandong University, and the median follow-up was 800 (493, 1221) days. Demographic characteristics, cardiovascular risk factors, cardiac structure and function index, echocardiography-derived coronary flow velocity, coronary flow velocity-time integral, and CFR were collected. Least absolute shrinkage and selection operator (LASSO) and multivariable Cox regression analyses were used to screen for significant parameters that were included to develop a novel predictive nomogram model. Receiver operating characteristic curve and calibration curve were used to evaluate the performance and clinical utility of the nomogram. Results In LASSO regression selection, five variables, diabetes, global work efficiency (GWE), global wasted work (GWW), decreased hyperemic coronary flow velocity (<0.63m/s), and peak flow velocity-derived CFR<2.5 (Figure 1) showed their correlation to the occurrence of major adverse cardiovascular events (MACE). Univariate Cox regression analysis shows that diabetes (hazard ratio [HR] = 4.108; 95% confidence interval [CI], 2.296–7.350; p = 0.001), GWE (HR = 0.890; 95% CI, 0.856–0.926; p = 0.001), GWW (HR = 1.005; 95% CI, 1.004–1.007; p = 0.012), decreased hyperemic coronary flow velocity (HR =3.405; 95% CI, 1.730–6.702; p = 0.001) and peak flow velocity-derived CFR<2.5 (HR =3.456; 95% CI, 1.898–6.292; p = 0.001) were predictors of recurrent chest pain. Multivariate analysis showed that the association of diabetes (HR = 2.735; 95% CI, 1.452–5.152; p = 0.002), GWW (HR = 1.004; 95% CI, 1.001–1.007; p = 0.010), and peak flow velocity-derived CFR<2.5 (HR = 2.650; 95% CI, 1.306–5.380; p = 0.007) with MACE remained statistically significant after adjusting for other variables. A nomogram incorporated the predictors mentioned above; it is presented in Fig.2. Internal validation showed that the model has good predictive performance. The areas under the curve (AUCs) for prediction of the risk of MACE was 0.849 (Fig.3). The calibration curve for predicting chest pain recurrence shows a good agreement between prediction and observation (Fig.4). Conclusions Diabetes, GWE, GWW, decreased hyperemic coronary flow velocity (<0.63m/s), and peak flow velocity-derived CFR<2.5 are significant in identifying the occurrence risk of MACE for ANOCA patients.

The association between exercise-induced ventricular premature contractions and long-term mortality in patients without coronary artery disease

Abstract Background/Introduction The treadmill exercise test is widely used clinical test to determine cardiovascular risk and mortality, regardless of clinical risk factors (1). ST-segment changes detected in the exercise test are shown to predict myocardial ischemia (2) and premature ventricular complexes (PVCs) are frequently observed during exercise stress testing (3). Exercise-related PVC is observed in 14% to 23% of healthy individuals without significant heart disease (4,5). The literature on the role of PVCs observed during treadmill exercise testing in predicting prognosis is controversial. Purpose Therefore, we aimed to evaluate the clinical results of PVCs seen during exercise testing in patients who had been diagnosed with non-obstructive coronary artery disease after coronary angiography. Methods The study population consisted of 1624 consecutive patients who were considered high risk according to the Duke treadmill risk score and had no significant stenosis on coronary angiogram from January 2016 to April 2021. Patients with previous history of coronary revascularization, previous myocardial infraction, heart failure, moderate or severe heart valve disease, congenital heart disease, cardiomyopathy, bundle branch block, and left ventricular hypertrophy were excluded from the study. The primary endpoints of the study were long-term all-cause mortality of patients who had PVCs during the exercise test or during the resting phase. Results The long-term mortality was observed in 53 patients out of 1624 patients in the mean follow-up of 47 months. PVCs was observed in 293 (18.7%) patients without long-term mortality, while PVCs was observed in 24 (45.3%) patients with long-term mortality (p<0.001). The model adjusted for all covariates showed that the presence of PVCs in the recovery phase (p<0.007, HR (95% CI) 2.244 (1.244 – 4.047)) and advanced age (p<0.001, HR (95% CI) 1.194 (1.143 – 1.247)) were associated with long-term all-cause mortality (Figure 1). Considering Kaplan-Meier curve, individuals with PVCs in recovery had significantly higher risk of long-term mortality compared with those with without PVCs (log-rank statistic: 22.47, p<0.001) (Figure 2). Conclusion(s) The study highlights that PVCs monitored in the recovery phase of the treadmill exercise test were associated with long -term mortality in patients without structural heart disease and coronary artery disease.Figure 2Figure 1