Anginal Symptoms Research Articles

Abstract 4126987: A Case of Recurrent Neurocardiogenic Syncope in a COVID-19 Patient

Background: COVID-19 infection has been associated with a broad range of clinical manifestations. There are very few reported cases of COVID-19 patients presenting with syncope as an initial symptom. We present an extraordinary case of recurrent neurocardiogenic syncope in a COVID-19 patient. Case: A 66-year-old male presented after experiencing two episodes of syncope. He denied any prodromal or anginal symptoms. His medications included propranolol 10 mg twice daily for essential tremors. He had no family history of unexplained syncope or sudden cardiac death. He was hemodynamically stable and had one episode of fever at 102°F. Telemetry recording showed vagal-mediated sinus arrest and pauses without escape. Blood work showed normal cell counts, electrolytes, thyroid-stimulating hormone, and erythrocyte sedimentation rate, with a slightly elevated C-reactive protein of 22.2 mg/L. He tested positive for COVID-19 and had negative Lyme and Ehrlichia serologies. Decision Making: Due to symptomatic long sinus pauses, propranolol was discontinued, and he received a temporary pacemaker set at 50 beats per minute (bpm). He had another syncopal episode while being paced at 50 bpm, suggesting a neurocardiogenic mechanism, so the pacing rate was increased to 70 bpm. An echocardiogram showed a normal ejection fraction without any significant valvular disease. The syncope was determined to be vasovagal due to autonomic dysfunction in the setting of COVID-19. After 72 hours without further syncope, the temporary pacemaker was removed, and he was discharged home with an implantable loop recorder (ILR). A one-month follow-up showed no syncope, and ILR interrogation showed no bradycardia or pauses. Conclusion: Neurocardiogenic syncope with prolonged asystole and sinus pauses is an uncommon presentation of COVID-19 infection. The clinical course of autonomic dysfunction following COVID-19 is not very clear, and monitoring with an ILR is reasonable before considering permanent pacemaker implantation.

Efficacy and Safety of Yangxinshi versus Trimetazidine on Exercise Tolerance in Patients with Coronary Heart Disease after Percutaneous Coronary Intervention: Multicenter, Double-Blind Clinical Trial

BackgroundOptimizing medication to improve exercise tolerance in patients with coronary heart disease (CHD) after percutaneous coronary intervention (PCI) is limited. Yangxinshi tablets, an herbal-based oral medicine, relieve symptoms of angina might be that they can improve energy metabolism of the ischemic myocardium. We conducted a randomized trial to assess the efficacy and safety of Yangxinshi vs. trimetazidine in improving exercise tolerance in patients with CHD after PCI. MethodsThis prospective, randomized, double-blind, double-dummy, multicenter, non-inferiority study enrolled patients aged 18–75 years with CHD who underwent their first PCI within 2 months of diagnosis. Patients were randomized to Yangxinshi plus trimetazidine-placebo or trimetazidine plus Yangxinshi-placebo for 24 weeks. The primary endpoint was the change in metabolic equivalents (METs) assessed by cardiopulmonary exercise test (CPET) between 0 and 24 weeks. Secondary endpoints were comprehensive variables of the CPET, health status and adverse events. This study has been registered at ClinicalTrials. gov (NCT03809273). ResultsBetween August 1, 2019, and March 31, 2022, a total of 681 patients were randomized to Yangxinshi (n=341) or trimetazidine (n=340). After 24 weeks, the exercise tolerance of patients increased by 0.77±1.25 METs in the Yangxinshi group and 0.76±1.00 METs in the trimetazidine group (difference, 0.01; 95% confidence interval [CI], −0.17 to 0.19), meeting the predefined non-inferiority threshold. Better outcomes were observed in the Yangxinshi group compared with the trimetazidine group for patient-reported depression (PHQ-9; −1.88±3.32 vs. −0.93±3.68; P < 0.001) and anxiety (GAD-7; −1.70±3.26 vs. −0.39±3.29; P < 0.001). Adverse events were similar in both groups. ConclusionsIn patients with CHD after PCI, Yangxinshi was non-inferior to trimetazidine in improving exercise tolerance during the 24-week treatment period. Notably, patients in the Yangxinshi group showed a better mental health profile compared with trimetazidine recipients.

Efficacy and safety of Danlou tablets in the treatment of stable angina pectoris with intermingled phlegm and blood stasis syndrome in coronary heart disease: a multicenter randomized controlled study

ObjectivesIn this study, we assessed the clinical efficacy and safety of Danlou tablets in the treatment of stable angina pectoris (SAP) with intermingled phlegm and blood stasis (IPBS), to provide high-quality evidence-based medical evidence for the prevention and treatment of coronary heart disease.MethodsIn this multicenter randomized controlled study, 304 patients diagnosed with stable angina pectoris with IPBS enrolled from 12 national traditional Chinese medicine (TCM) clinical research centers in China were randomly assigned to the treatment group and the control group at a ratio of 1:1. Each group was divided into four subgroups based on the results of TCM syndrome differentiation: IPBS, IPBS combined with qi deficiency, IPBS combined with qi stagnation, and IPBS combined with toxin accumulation. The control group was treated with routine Western medicine. In addition to routine Western medicine treatment, the treatment group (the IPBS group) was treated with Danlou tablets or Danlou tablets supplemented by interventional therapies based on the results of traditional Chinese medicine differentiation. The frequency of angina attacks per week was the main efficacy evaluation indicator and the secondary efficacy evaluation indicators included angina symptom score, Seattle Angina Questionnaire, an electrocardiogram (ECG) efficacy evaluation, a cardiac Doppler two-dimensional ultrasound, an electrocardiogram treadmill exercise test, blood lipids, blood glucose, a coagulation function test, hemorheology indicators, homocysteine, C-reactive protein (CRP) or high sensitivity-CRP, TCM syndromes (syndrome score, tongue, pulse), and long-term prognosis (endpoint outcome, cardiovascular events).ResultsThere were 300 cases in the full analysis set (FAS), 266 in the per-protocol set (PPS), and 300 in the safety set. Regarding the main efficacy indicator, after treatment, the reduction in the frequency of weekly angina attacks in the treatment group was significantly greater than that in the control group (P &amp;lt; 0.05). The results of the FAS and PPS were consistent. Regarding the secondary efficacy evaluation indicators, the angina symptom, TCM syndrome, ECG evaluation, Seattle Angina Pectoris Questionnaire, and 36-item Health Status Survey Summary Form scores of the treatment group were significantly higher than the control group (P &amp;lt; 0.05) and the homocysteine levels of the treatment group were significantly reduced (P &amp;lt; 0.05). The results of the FAS and PPS were consistent. In the PPS, the triglyceride levels in the treatment group were significantly lower than those in the control group after treatment (P &amp;lt; 0.05). The activated partial thromboplastin time in the treatment group decreased significantly (P &amp;lt; 0.05). There was no statistically significant difference in the safety indicators and incidence of adverse reactions between the two groups.ConclusionTreatment with Danlou tablets and the modified combination therapy based on Western medicine treatment could improve angina pectoris symptoms of patients with SAP and IPBS syndrome and its concurrent syndromes, and improve patients’ quality of life. Furthermore, the treatment is safe, has a long-term prognosis, and is worth further promotion and application in clinical practice.Clinical Trial Registrationhttps://www.chictr.org.cn/showprojEN.html?proj=235570, ChiCTR registry, ChiCTR1900023708.

Using anginal symptoms to predict underlying etiology in patients with angina and no obstructive coronary disease (ANOCA)

Abstract Background Patients with angina with no obstructive coronary disease (ANOCA) can present with exertional anginal symptoms or angina at rest. Invasive coronary functional angiography (CFA) is used to diagnose endothelial-dependent and independent coronary microvascular dysfunction (CMD), microvascular spasm, and epicardial spasm. Historically, the type of anginal symptoms has been thought to be suboptimal in predicting the etiology of ANOCA. However, the sensitivity, specificity, predictive value, and correlation of angina type related to CFA abnormalities are unknown. We hypothesize that patients with predominantly exertional angina are more likely to have endothelial-independent and dependent CMD, and patients with angina at rest are more likely to have microvascular or epicardial spasm. Objective To explore sensitivity, specificity, predictive value, and correlation of angina type with underlying etiology of ANOCA as diagnosed by CFA. Methods A prospective registry-based cohort study of consecutive CFA performed in 197 ANOCA patients between 2020 and 2023 using the Doppler-tipped guidewire method. ANOCA was defined as &amp;lt;50% stenosis in any major epicardial artery at time of CFA. Patients were classified based on CFA diagnosis: (1) endothelial-independent CMD (coronary flow reserve [CFR] &amp;lt; 2.5 in response to adenosine), (2) endothelial-dependent CMD (coronary blood flow [CBF] &amp;lt; 50% or no change in vessel diameter in response to 54mcg intracoronary acetylcholine), (3) microvascular (&amp;lt;90% constriction) and epicardial spasm (&amp;gt;90% constriction) to 108 mcg intracoronary acetylcholine. Patients were categorized based on anginal symptoms (exertional angina or at rest angina) documented at cardiologist visit prior to CFA. McNemar’s test and Spearman correlations were performed for both types of angina and the 3 ANOCA underlying diagnoses. Results Among 197 ANOCA patients, the average age was 56.5 ± 11.9 years and 91% were female. Angina at rest had a high specificity (91.3%) but a low sensitivity (25.2%) for the diagnosis of spasm with a PPV of 90.5 (Table 1). There was a significant correlation between angina at rest and spasm (p=0.012). Angina at rest had a similarly intermediate sensitivity and specificity for endothelial independent and dependent CMD. Exertional angina had similar sensitivity, specificity, and a high PPV for endothelial independent and dependent CMD. There was a significant correlation between exertional angina and endothelial dependent CMD (p=0.025). McNemar’s test was statistically significant (p&amp;lt;0.001) for all analyses. Conclusion ANOCA patients with symptoms of angina at rest had a significant correlation with coronary spasms and exertional angina correlates with endothelial-dependent CMD. We demonstrate that angina at rest can be 90% specific for the diagnosis of spasm. Our findings warrant further investigation but suggest that empiric therapy based on angina type is a reasonable first step before invasive testing.

A randomized, double-blind, placebo-controlled, mechanistic trial on the safety, tolerability and pharmacodynamics of ninerafaxstat in patients with angina and chronic coronary syndrome

Abstract Background/Introduction Symptoms of angina resulting from reversible myocardial ischemia in chronic coronary syndromes have a negative impact on quality of life. Metabolic alterations are a key feature of ischemia, including reduced ATP generation by mitochondrial oxidative phosphorylation, NAD+ depletion, anaerobic glycolysis, proton &amp; lactate accumulation leading to contractile dysfunction. Ninerafaxstat is a novel cardiac mitotrope that shifts metabolism from fatty acids towards glucose utilization, optimizing myocardial energy production during ischemia. Purpose We aimed to investigate the safety, tolerability, impact on myocardial glucose utilization and preliminary anti-ischemic efficacy of ninerafaxstat administered for 8 weeks to patients with symptomatic chronic stable angina who were on anti-anginal therapy and had evidence of myocardial stress hypoperfusion using 15O-H2O PET imaging. Methods IMPROVE-Ischemia was an international, randomized, double-blind, placebo-controlled mechanistic trial comparing ninerafaxstat vs. placebo in patients with symptomatic chronic coronary syndrome. The primary endpoint was the safety and tolerability of ninerafaxstat. Key efficacy evaluations were undertaken at baseline and end-of-treatment (Week 8) including imaging core laboratory assessments of 15O-H2O PET perfusion rest and stress imaging to quantify absolute myocardial blood flow (MBF), dobutamine stress echo with contrast for evaluation of LV contractile response during demand stress using the wall motion score index (WMSI) and, in a subgroup of subjects, 18F-FDG-PET imaging of myocardial glucose metabolism. Results The study randomized 58 subjects (mean age 68.6±7.1 years) with symptomatic stable angina and inducible hypoperfusion from 4 sites across 3 countries (Denmark, Finland, Sweden). 22% had type 2 diabetes and 50% had undergone percutaneous and/or surgical coronary revascularization. The majority (68%) were on ≥2 (up to 4) regular anti-anginals. Ninerafaxstat was well tolerated without impact on systemic hemodynamics. At Week 8, ninerafaxstat significantly increased myocardial glucose utilization and, in those with dobutamine-induced deterioration in wall motion at baseline assessment (n=25, pre-specified subgroup), resulted in a ~50% improvement in mean and peak stress WMSI, without altering rest or hyperemic stress MBF (Table 1). Conclusion(s) Treatment with ninerafaxstat was well-tolerated and showed a neutral hemodynamic profile. Ninerafaxstat significantly increased myocardial glucose utilization consistent with its mechanism of action and improved myocardial contractile response to dobutamine stress in subjects with baseline stress inducible deterioration of wall motion. These findings support a direct, metabolically-mediated, anti-ischemic effect of ninerafaxstat on top of existing anti-anginal agents, supporting its further development in cardiac pathologies characterised by ischemia.

Prognostic impact of the presence and absence of angina on mortality and cardiovascular outcomes in the ISCHEMIA trial

Abstract Introduction Patients with chronic coronary syndromes (CCS) manifested by myocardial ischemia may present with typical angina or with no anginal symptoms. It is unclear whether symptom status affects prognosis in these patients. Purpose To assess whether the risk of all-cause mortality and other cardiovascular (CV) outcomes varied according to the presence or absence of angina in patients with CCS and moderate to severe myocardial ischemia in the ISCHEMIA trial. Methods The ISCHEMIA data set was obtained from the National Heart, Lung, and Blood Institute under a data use agreement. Subjects were divided into quartiles by baseline Seattle Angina Questionnaire Angina Frequency (SAQ AF) score. Quartile (Q)1 included patients with SAQ AF scores from 1-70 whereas all patients in Q4 had SAQ AF scores of 100, indicating no angina at baseline. Categorical variables were compared using the chi-squared or Fisher’s exact test. Continuous variables were compared using the student T-test or Wilcoxon rank sum test. The cumulative incidence rate of outcomes up to five years was estimated with the Kaplan-Meier method and the rate curves were compared using the log-rank test. Multivariable Cox regression models were used to estimate hazard ratios (HRs) with potential confounders from baseline characteristics, clinical history, and angiographic characteristics included. All tests were two-sided and P&amp;lt;0.05 was considered statistically significant. Results Of the 5,179 patients with CCS and at least moderate ischemia on stress testing, 1,434 were in Q1 and 1,635 were in Q4. Compared to Q1, patients in Q4 were older (66.4 (9.0) vs. 62.8 (9.6); P&amp;lt;0.001), more often male (82% vs. 73%; P&amp;lt;0.001), more often diabetic (43% vs. 38%; P=0.006) and less often current smokers (12% vs. 15%; P=0.001). The estimated glomerular filtration rate was lower in Q4 (82(22) vs. 86 (38); P=0.002). Fewer patients in Q4 had NYHA class II heart failure (37% vs. 62%) and more had Class I symptoms (63% vs. 38%) (P&amp;lt;0.001). Q4 patients had a lower ejection fraction (59% vs. 60%; P=0.002), a lower Duke jeopardy score (4.9(3.5) vs. 5.5 (3.3); P&amp;lt;0.001), less often had severe ischemia (47% vs. 56%), and more often had moderate ischemia (40% vs. 32 %) (P&amp;lt;0.001). The cumulative 5-year event rates for Q4 vs. Q1 were: all-cause death, 10.6% and 6.4% (P=0.002); CV death/MI, 16.3% vs. 13.7% (P=0.97); CV death, 7% vs. 3.7% (P=0.009); MI, 11.4% vs. 11.4% (P=0.2). On multivariable Cox regression, angina quartile (Q4 vs. Q1) was not independently associated with all-cause death (HR 1.34, 95% CI: 0.76-2.31; P=0.33), CV death/MI (HR 0.77, 95% CI: 0.52-1.14; P=0.19), CV death (HR 1.10, 95% CI: 0.50-2.43; P=0.82), or MI (HR 0.70; 95% CI: 0.45-1.08; P=0.11). Conclusion In the ISCHEMIA trial, patients with CCS and moderate to severe myocardial ischemia are at elevated risk for all-cause mortality and other major CV outcomes. This risk is not modified by the presence or absence of angina.

Effect of empagliflozin on no-reflow in patients with st elevation myocardial infarction undergoing primary percutaneous coronary intervention

Abstract Background Primary percutaneous coronary intervention (PPCI) restores myocardial tissue perfusion successfully in over 90 % of ST-elevation myocardial infarction (STEMI) patients .However there remains a small proportion of patients who exhibit no-reflow.(1) Empagliflozin is a sodium glucose co-transporter 2 (SGLT2) inhibitor that acts as a powerful anti-oxidant and has beneficial effects on endothelial function and reducing burden of ischemia in-vitro.(2) Aim and Objectives: To Assess the effect of Empagliflozin preloading in non-diabetic STEMI patients before PPCI on procedural, in-hospital outcomes and short-term Major Adverse Cardiovascular events (MACE) in a single tertiary center. Patients and Methods: The study was carried out on 200 non-diabetic STEMI patients presenting to our university hospital within the first 8 hours of symptom onset. Patients were randomised into 2 groups , the intervention group received 10mg Empagliflozin before PPCI with the standard medical therapy while the control group received only the standard medical therapy. Patients were assessed for demographic data, risk factors, procedural outcomes, clinical and in-hospital outcomes, and short-term MACE up to 1 month. Results: Our study found a significant difference between the intervention and control groups regarding contrast volume with a mean of 131 ml in the intervention group and 144 ml in control group with a p value of 0.009, incidence of no-reflow with 34.5% in the control group and only 18.2% in the intervention group and a p value of 0.014 and myocardial blush grade (MBG) were 84.1% of the patients in intervention group had MBG III after PCI while only 65.5% of the patients in the control group showed the same results with a p value of 0.019. Also, there was a significant difference in St-segment resolution post PCI as 59.1% of patients in the intervention group had complete ST segment resolution and only 39.1% of the patients in the control group had complete resolution with a p-value of 0.027, and total MACE in the first month which affected 44.8% of the patients in the control group and only 28.4% of those in the intervention group with a p-value of 0.024. Conclusion Our study showed that pre-loading of STEMI patients with Empagliflozin resulted in improvement in procedural outcomes, decreasing the incidence of coronary no-reflow, improvement in patient’s course during hospital stay and short-term MACE. Improvement in MACE was mainly due to reduced HF hospitalisations and anginal symptoms.

Electrocardiogram-based artificial intelligence to identify prevalent coronary artery disease

Abstract Background Coronary artery disease (CAD) often goes undetected for years before it manifests and results in substantial morbidity and mortality. Some patients have neither typical risk factors nor symptomatic angina despite progressive disease. Purpose Develop a deep-learning model to detect prevalent CAD and identify people at risk for adverse events using electrocardiograms (ECG) in a primary care setting. Methods We developed a convolutional neural network using 12-lead ECG waveforms to discriminate the presence of CAD defined using diagnostic codes ("ECG2CAD"). ECG2CAD was trained on 764,670 ECGs from 137,199 individuals at the Massachusetts General Hospital (MGH). Model performance for discrimination of prevalent CAD was measured using AUROC and AUPRC, and compared against a model comprising age and sex, as well as the Pooled Cohort Equations (PCE), in three test sets independent of model training: MGH, Brigham and Women’s Hospital (BWH) and UK Biobank. ECG2CAD was assessed across subgroups of age, sex and self-reported ethnicity and for incident CAD-related events in the BWH primary care subset. Results ECG2CAD was evaluated in MGH (N=18,706 [N=6,051 cases], age 57±16 years), BWH (N=88,270 [N=27,898 cases], age 57±16 years), and UK Biobank (N=42,147 [N=1,509 cases], age 65±8 years). ECG2CAD consistently discriminated prevalent CAD (MGH: AUROC 0.782, AUPRC 0.639; BWH: AUROC 0.747, AUPRC 0.588; UK Biobank: AUROC 0.760, AUPRC 0.155) and incrementally improved upon both a model based on age and sex (p&amp;lt;0.01) and the PCE (p&amp;lt;0.01) in MGH and BWH. In the BWH primary care subset (N=51,808), model performance was consistent in subgroups defined by age, sex and self-reported ethnicity/race. The incorporation of ECG2CAD in addition to age and sex consistently improved discrimination (AUROC delta of 0.011-0.086) in all subgroups. In the BWH primary care subset with over 10 years of follow-up, we observed that either the presence of ECG2CAD-predicted CAD (HR 2.18, 95% CI 2.00-2.38, P&amp;lt;0.001) and ICD-based known CAD (HR 2.13, 95% CI 1.86-2.45, P&amp;lt;0.001) were associated with increased risk for incident myocardial infarction. The presence of both definitions was associated with an almost five-fold increase in risk (HR 4.97, 95% CI 4.51-5.48, P&amp;lt;0.001). The risk of incident adverse events was highest among people in the top quintile of ECG-based predicted risk (high risk) compared with people from quintile 4-2 (intermediate risk) or the lowest quintile (low risk), even when excluding those with known prevalent CAD at baseline. Conclusions Artificial intelligence-enabled analysis of the 12-lead ECG may facilitate efficient identification of individuals with possible undiagnosed CAD and inform downstream testing and preventive measures.

Overview of the risk of myocardial infarction in patients with aortic stenosis: insights from the VALVENOR Registry

Abstract Background Close interaction between aortic stenosis (AS) and coronary artery disease (CAD) has been suggested. However, the risk of myocardial infarction (MI) in patients with AS is poorly described outside the context of aortic valve replacement. Objectives To assess the incidence, correlates and impact on outcomes of MI occurrence in patients with different degrees of AS severity. Methods Between 2016 and 2017, the multicenter prospective VALVENOR registry enrolled 2,830 outpatients with native valvular AS (peak aortic jet velocity (Vmax) ≥ 2.5m/s). AS was defined as mild (Vmax 2.5-2.9), moderate (Vmax 3-3.9) or severe (Vmax ≥4). MI was defined using the 4th universal definition (type 2 MI were not considered). Results The mean age was 76.0 years, 54% of the patients were men and 18.3% had experienced prior coronary event (PCE). Altogether, one third (n=820 [30.3%]) of the patients had diabetes. At 5 years, the cumulative incidence of MI (death as competing event) was only 2.5% (n=72, 1/3 of ST-elevation MI). Sixty MI (83.3%) were categorized as type 1 MI while 12 were peri-procedural MI (surgical aortic valve replacement, n=5; transcatheter aortic valve replacement, n=2; coronary artery bypass surgery, n=1; percutaneous coronary intervention, n=3; coronary angiography, n=1). PCE and angina symptoms were associated with an increased risk, whereas female gender with a decreased risk. By contrast, AS severity was not associated with the risk of MI. Five-year cumulative incidence of MI was 6.5% [95% CI, 4.5 - 8.9] in patients with PCE vs. 1.7% [95% CI, 1.2 - 2.3] in patients with no PCE (P&amp;lt;0.001), 8.3% [95% CI, 4.1 - 14.4] in patients with angina vs. 2.3% [95% CI, 1.8 - 2.9] in patients without angina (P&amp;lt;0.001), and 3.2% [95% CI, 2.4 - 4.2] in men vs. 1.8% [95% CI, 1.1 - 2.6] in women (P=0.014). Subsequent mortality was high and at 52.8% during follow-up (median 648 days after MI occurrence). When analyzed as a time-dependent variable, incident MI was a powerful predictor of mortality (HR=2.00, P&amp;lt;0.001 after adjustment). Conclusions In patients with AS, the risk of MI is relatively low especially in patients without PCE and without angina. No association between the risk of MI and AS severity was observed. Although rare, incident MI is strongly associated with subsequent mortality.

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 &amp;lt;2.5 or &amp;lt;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&amp;lt;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&amp;lt;0.01 and β=-0.15; p=0.05, respectively) and lower resistive reserve ratio (RRR) (β=-0.28; p&amp;lt;0.01 and β=-0.17; p=0.04, respectively). When using a threshold of &amp;lt;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

Prognosis of Zero Coronary Artery Calcium Score in Symptomatic Patients of South Asian Descent - an Experience from a Tertiary Care Center in Pakistan.

The absence of CAC in asymptomatic individuals is associated with a very low incidence of cardiovascular events. Of symptomatic patients, 1-2% with zero CAC score have non-calcified coronary artery atherosclerosis, and at least one third of cardiovascular events occur in individuals with zero CAC. South Asians (SA) have proportionally higher case fatality rates for CVD, relatively younger age of presentation, and accelerated rate of atherosclerosis when compared with other ethnic groups. All consecutive patients who underwent a CTCA to evaluate angina or angina-equivalent symptoms during the study duration were enrolled retrospectively. Patients with prior myocardial infarction, history of revascularization, and congenital heart disease were excluded. MACE was defined as the total of cardiac death, non-fatal myocardial infarction, and/or non-elective revascularization. A total of 534 patients were enrolled after final exclusion. The mean age was 53 years ± 11. Males constituted 68.4% of the study population. Dyslipidemia was the most common co-morbid condition identified (50%), followed by diabetes (18.4%) and hypertension (3.6%). At least 28.8% of patients with zero CAC scores had the presence of coronary artery disease (soft plaque) of any degree. Obstructive CAD (>50%) was present in 5.8% of patients. Follow-up was available for 61.4% of patients. On a mean follow-up of 96.6 months ± 49.8 (range 21-194 months), all-cause MACE was observed in 8.8% of patients. The most common MACE was angina (3.96%) and all-cause mortality (3%). The baseline characteristics and MACE did not differ in patients with and without obstructive CAD. The baseline characteristics did not differ significantly between patients with and without MACE. The incidence of soft plaque in this SA cohort is higher than that reported in international studies. However, in symptomatic SA, a CAC score of zero carries a good long-term prognosis, irrespective of the degree of CAD.

Efficacy and safety of Shexiang Baoxin pill in patients with ischemia with non-obstructive coronary arteries (LESS): a phase 4, multicenter, randomized, double-blind, placebo-controlled clinical trial

Abstract Background Patients with ischemia with non-obstructive coronary arteries (INOCA) present with ischemic signs and symptoms but no obstructive coronary artery disease (CAD) at coronary angiography. Shexiang Baoxin pill (MUSKARDIA) is effective in reducing angina frequency in patients with stable CAD. Purpose This phase 4 trial was conducted to evaluate the efficacy and safety of MUSKARDIA in INOCA patients. Methods This was a multicenter, randomized, double-blind, placebo-controlled clinical trial (NCT04897126). The enrolled patients with INOCA confirmed as eligible by leading PI were randomly assigned in a 1:1 ratio to receive MUSKARDIA or placebo (oral 4 pills 3 times a day) on the basis of conventional treatment until the end of follow-up. The primary endpoint was the angina-related outcomes based on the Seattle Angina Questionnaire (SAQ) score that assessed by same doctor at week 12. Results 236 INOCA patients were randomized (MUSKARDIA group, n = 117; placebo group, n=119). At week 12, patients in MUSKARDIA group showed higher SAQ scores compared with placebo group (all P&amp;lt;0.0001, Figure 1) indicating MUSKARDIA could significantly relieve symptoms of angina. According to the Canadian Cardiovascular Society (CCS) grading of angina pectoris, the severity of angina pectoris was significantly reduced in MUSKARDIA group compared with placebo group at week 12 (grade Ⅰ [91.09% vs 48.15%]; grade Ⅱ [8.91% vs 25.93%]; grade Ⅲ [0% vs 19.44%]; grade Ⅳ [0% vs 6.48%]; P&amp;lt;0.001). After 12 weeks of treatment with MUSKARDIA, numbers of weekly angina attacks were significantly reduced compared with placebo group (-2.60 vs -0.42; LSM difference: -2.18; P&amp;lt;0.0001). The percentage of patients who did not used nitroglycerin was noticeably higher in MUSKARDIA group than that in placebo group (84.16% vs 58.33%, P&amp;lt;0.001). The incidence of adverse events did not differ meaningfully between two groups. Conclusion MUSKARDIA was confirmed to be an effective, safe and well-tolerated treatment for INOCA patients in clinical settings.

Invasive quantitative assessment of coronary microvascular dysfunction in patients with hypertrophic cardiomyopathy

Abstract Background Patients (P) with hypertrophic cardiomyopathy (HCM) commonly suffer from coronary microvascular dysfunction (CMD) - the affection of function/structure of the coronary microvasculature. Invasive assessment of CMD through thermodilution methods allows for the calculation of coronary flow reserve (CFR) and index of microvascular resistance (IMR). These methods, while extensively studied in the context of non-obstructive coronary artery disease and myocardial infarction, have not been thoroughly validated in HCM P. Objectives To invasively assess the presence of CMD in P with HCM and to determine clinical predictors of invasively assessed CMD. Methods In a prospective single-centre study, we opportunistically recruited consecutive adult P with an established diagnosis of HCM with or without LVOTO that had an indication to pursue elective coronarography – such as pre-procedural evaluation for alcoholic septal ablation (ASA) or exclusion of epicardial coronary artery disease. P characteristics and coronary hemodynamic invasive assessment data were extracted. CFR was calculated as the ratio between resting and hyperemia mean transit times (TmnRest;TmnHyper). IMR was calculated as the ratio between distal coronary pressure (Pd) and the inverse of TmnHyper (IMR=Pd/TmnHyper-1). A cutoff of ≤22.0 in IMR, an ≥d 2 in CFR was used. We excluded P with end-stage HCM (LV EF &amp;lt;50% and/or or left ventricular wall thinning), or with epicardial coronary artery disease. Continuous variables were reported as mean ± SD or median and IQR depending on data distribution pattern and categorical data as frequencies and percentages. A linear regression model was used to test predictors of IMR and CFR involvement. Results 25 HCM P with a mean age of 63±10 years were included, 14 (56%) were female. In 20 (80%) of the P the cause for coronary angiography was ASA. All P referred for ASA had LVOTO and were on beta-blocker therapy (Table 1.). Median CFR was 2.5 [1.5-3] and median IMR was 19 [14-22], both within normal range. A total of 13 (44%) P had a reduced CFR and 5 (20%) of P had an increased IMR. 14 P (56%) had an altered CFR or IMR value, with the presence of a functional CMD phenotype in 10 P (40%) (Table 2). Angina was associated with a higher IMR (5.3, 95% CI - 0.05-10, p=0.053) and for each +1 increase in CCS a larger increase in the likelihood of a higher IMR was observed (CCS 1, +7 (95%CI 0.68 – 14); CCS 2, +9 (95%CI 4 – 14); CCS 3, 10 (95%CI 2 – 18)). A similar but non significant trend was observed for higher CCS correlating with lower CFR (Table 3). Conclusion In a prospective cohort of HCM P submited to invasive angiographic evaluation 56% had at least one invasive measure compatible with CMD. Angina, and a higher degree of anginal symptoms correlated positively with the presence of higher IMR and therefore with a higher level of CMD. In the future, we intend to correlate these findings with multimodality imaging/clinical outcomes.Patient characteristics and LR results

Exploring the impact of coronary microvascular dysfunction on cardiac remodeling after st-elevation myocardial infarction

Abstract Background The complex interplay between Coronary Microvascular Dysfunction (CMD) and ST-segment Elevation Myocardial Infarction (STEMI) presents significant clinical hurdles. CMD, commonly seen as a complication following STEMI, is associated with adverse cardiovascular outcomes and persistent anginal symptoms. Despite its clinical relevance, the link between CMD post-STEMI and subsequent left ventricular (LV) diastolic dysfunction, along with functional LV remodelling (FLVR), is yet to be fully explored. Purpose Examine the link between CMD 3 months post-STEMI and its impact on FLVR and diastolic dysfunction. Methods This prospective, observational cohort study focused on STEMI patients. At 3-month post-STEMI, a comprehensive coronary physiology assessment of the culprit artery was conducted using the thermodilution method to measure fractional flow reserve (FFR), coronary flow reserve (CFR), and the index of microcirculatory resistance (IMR). CMD was identified with an IMR ≥ 25 or a CFR &amp;lt; 2.0, assuming an FFR &amp;gt; 0.80. Diastolic dysfunction was classified according to ASE/EACVI 2016 guidelines. FLVR was categorized as per Surenjav Chimed et al.'s criteria: Group I with no significant changes in LV size or function, Group II with a decrease in LV ejection fraction (LVEF) greater than 5% without LV dilatation, Group III with an increase in left ventricular end-diastolic volume (LVEDV) ≥ 20%, and Group IV showing both an increase in LVEDV ≥ 20% and a decrease in LVEF over 5%. The study aimed to elucidate the relationship between CMD and the progression of FLVR and diastolic dysfunction, tracked over a 12-month period. Results The study involved 210 patients, mostly men (59.5%), with a median age of 65 (IQR: 58–76). At the 3-month follow-up, CMD was observed in 57 (27.1%) patients. CMD patients had a higher female prevalence (63.2% vs. 32.0%; p &amp;lt; 0.001) and more diabetes (42.1% vs. 17.7%; p &amp;lt; 0.001) compared to non-CMD patients. Both groups shared similar body mass indices, medications, and other risk factors. Laboratory results were similar between groups, except brain natriuretic peptide levels were higher in CMD patients (70.0 vs. 37.0 ng/L; p &amp;lt; 0.001). After 12 months, CMD patients demonstrated significantly less recovery in LVEF (-10.00% vs. 8.00%; p &amp;lt; 0.001), higher prevalence of grade 2 LV diastolic dysfunction (73.08% vs. 1.32%; p &amp;lt; 0.001), and a higher incidence of advanced FLVR (notably in Groups 3 and 4) compared to non-CMD (11.32% vs. 7.28% and 22.64% vs. 1.99%, respectively; p &amp;lt; 0.001). In the adjusted multivariable logistic regression analysis, IMR values independently predicted more severe FLVR and diastolic dysfunction. Conclusions This study highlights that CMD 3 months after STEMI is linked to worse FLVR, diastolic dysfunction, and less recovery in LVEF, emphasizing the need for early CMD detection for better risk assessment. Further research is essential to explore underlying mechanisms and intervention opportunities.LVEF Changes at 12 Months by CMD StatusDiastolic Dysfunction and LV Remodeling

Dynamics and prognostic role of persistent angina in chronic coronary syndrome with clinical, angiographic and stress CMR evidence of ischemia

Abstract Background In patients with established chronic coronary syndrome (CCS), the significance of myocardial ischemia is a controversial issue. Persistent angina within the first year after treatment intervention has ranged widely in previous studies and its association with subsequent hard clinical events is unclear. We aim to evaluate the long-term dynamics of angina class and the prognostic role of persistent angina in symptomatic chronic coronary syndrome (CCS) patients with abnormal stress cardiovascular magnetic resonance (CMR) and altered angiography. Methods We analyzed 486 CCS patients with Canadian Cardiovascular Society angina class ≥2, perfusion deficit in stress CMR and severe lesions in angiography submitted to treatment intervention (medical therapy plus, if feasible, CMR-guided revascularization). The dynamics and association of persistent angina at 6 months post-intervention with subsequent cardiac death, myocardial infarction, and admission for heart failure were investigated. Results All patients displayed angina class ≥2 (mean: 2.7±0.7), abnormal stress CMR (mean ischemic burden: 6.2±3 segments) and severe angiographic lesions. Most underwent CMR-guided revascularization (n=392, 81%). The angina resolution rate was 78% at 6 months, and 79%, 77%, and 75% at 1, 2, and 5 years respectively. Compared with medical treatment alone, CMR-guided revascularization was associated with less persistent angina (19% vs. 35%; HR 0.42 [0.2–0.7]; p=0.003). During an 8.3-year median follow-up, persistent angina was independently associated with higher subsequent cardiac death rates (18% vs. 4%; HR 10.9 [4.1–29.2]; p&amp;lt;0.001), myocardial infarction (24% vs. 6%; HR 5.8 [3.2–10.4]; p&amp;lt;0.001), and admission for heart failure (31% vs. 14%; HR 2.7 [1.7–4.2]; p&amp;lt;0.001). Conclusions In CCS patients with robust diagnostic evidence by symptoms, stress CMR and angiography, sustained improvement of anginal symptoms can be achieved in most patients after treatment intervention. Angina resolution is more frequent in patients treated with CMR-guided revascularization and is associated with fewer cardiac events.Central Figure.Persistent angina and MACE risk

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&amp;lt; 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) &amp;lt; 2.5 with intra-coronary adenosine, and endothelium dependent, defined as &amp;lt; 50% increase in coronary blood flow with acetylcholine. Epicardial vasoconstriction &amp;gt; 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.

Diagnostic potential of relative changes in high-sensitivity troponin levels during intracoronary acetylcholine provocation testing

Abstract Background Intracoronary acetylcholine (ACh) provocation testing is useful for the diagnosis of vasospastic angina (VSA). However, the positive or negative diagnosis of ACh testing is often challenging when lacking typical anginal symptoms and electrocardiographic changes during provocation tests. We hypothesized that relative changes in cardiac troponin levels during ACh provocation testing may be suggestive of myocardial ischemia and would be helpful for the VSA diagnosis. Purpose To evaluate the diagnostic potential of relative changes in high sensitivity troponin I (hs-TnI) levels during intracoronary ACh provocation test. Methods This preliminary study included a total of 29 patients undergoing invasive coronary angiography with or without ACh provocation tests. Patients were divided into three groups; no ACh provocation tests (i.e. angiography alone), negative ACh tests, and positive ACh tests. Blood samples were obtained twice, before and after angiography, through the arterial sheath to evaluate hs-TnI. The primary measure was relative changes in hs-TnI (i.e. Δhs-TnI). Positive ACh provocation test was defined as total or subtotal coronary occlusion accompanied by chest pain and/or ischemic electrocardiographic changes. Results Of the 29 patients, 10 (34.5%) underwent coronary angiography alone, while ACh provocation testing was performed in 19 (65.5%) patients, of whom 7 (36.8%) and 12 (63.2%) had negative and positive ACh test results. Overall, the mean time interval between the blood sample collections was 76 minutes. Levels of hs-TnI before angiography did not differ significantly in the no, negative, and positive ACh test groups (5.3 [2.8, 8.6] vs. 2.9 [1.3, 8.8] vs. 3.3 [1.6, 8.5] pg/ml, p=0.76), while Δhs-TnI was highest in the positive ACh test group, followed by the negative and no ACh test groups (4.2 [0.5, 8.1] vs. 0.8 [0.4, 4.6] vs. −0.3 [−0.6, 0.3], p=0.002) (Figure). Conclusions In patients undergoing intracoronary ACh testing for the VSA diagnosis, a relative increase in Δhs-TnI during angiography was observed than in those who did not undergo the provocation tests, particularly when the ACh test diagnosis was positive. Our findings suggest that Δhs-TnI has the potential to aid in the positive or negative diagnosis of ACh provocation testing.

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 (&amp;lt;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] &amp;lt;2.5) to adenosine testing, (2) endothelial-dependent CMD (coronary blood flow [CBF]&amp;lt;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&amp;lt;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.

Symptom assessment and angina classification of patients with ischemia and nonobstructive coronary arteries undergoing invasive coronary function testing: from the DISCOVER INOCA multicenter registry

Abstract Background Patients with ischemia and nonobstructive coronary arteries (INOCA) suffer from a broad range of anginal symptoms that may differ depending on the biologic sex of the patient, the underlying coronary vasomotor disorder, or the type of presentation. Purpose We sought to characterize the symptom description and angina classification of patients referred for invasive coronary function testing (CFT) in the DISCOVER INOCA multicenter registry, stratified by type of presentation (stable vs unstable), biologic sex, and underlying diagnosis, including coronary microvascular dysfunction (CMD), vasospastic angina (VSA), or other disorders such as symptomatic myocardial bridging. Methods DISCOVER INOCA is a prospective, multicenter registry in the United States that includes patients who are referred for clinically indicated coronary angiography and found to have INOCA. All patients underwent protocol-guided angiography, acetylcholine provocation, coronary thermodilution, and intravascular imaging. Symptom characteristics were compared between groups. Results From September 2022 until February 2024, 104 patients were enrolled, 78% were female, and mean age was 57 ± 11 years. The post-procedure diagnosis was CMD in 19%, VSA in 41%, a mixed syndrome in 15%, or other diagnosis in 26%. The average coronary flow reserve (CFR) was 2.9 ± 1.1 in the CMD group and 5.3 ± 3.0 in the VSA group, (p &amp;lt; 0.001). 53% of patients presented with stable angina and 47% with unstable or progressive symptoms. Symptoms included chest pain (89%), chest tightness (42%), chest pressure (39%), shortness of breath (53%), and fatigue (16%), and no significant differences were reported when stratified by diagnostic phenotype. Female patients were more likely to report arm/neck/back/jaw pain (25% vs 5% in men, p = 0.038). Symptom triggers included exertion/activity in 73%, emotional stress in 12%, and resting symptoms in 58%. In female patients 4% reported catamenial symptoms. Of patients with stable angina, the Canadian Cardiovascular Society (CCS) Angina Classification was Grade I in 25%, Grade II in 52%, Grade III in 21%, and Grade IV in 2%. In patients with unstable angina, the Braunwald Angina Classification was Class I in 9%, Class II in 73%, and Class III in 18%. Conclusions Patients with INOCA referred for clinically indicated coronary angiography and CFT were predominantly female and most commonly reported chest pain as a presenting symptom. Female patients were more likely to report arm/neck/back/jaw pain than male patients. Over half of patients reported resting symptoms with no differences between the diagnostic phenotypes (CMD, VSA, or other). The CCS and Braunwald angina classification indicated that most patients had moderate intensity symptoms. Patient-reported outcome measures will be used to systematically categorize the symptom burden in these patients.

Fractional Flow Reserve and Instantaneous Wave-Free Ratio as Predictors of the Placebo-Controlled Response to Percutaneous Coronary Intervention in Stable Coronary Artery Disease.

The Placebo-controlled Trial of Percutaneous Coronary Intervention for the Relief of Stable Angina (ORBITA-2) provided evidence for the role of percutaneous coronary intervention (PCI) for angina relief in stable coronary artery disease (CAD). Fractional flow reserve (FFR) and instantaneous wave-free ratio (iFR) are often used to guide PCI, however their ability to predict placebo-controlled angina improvement is unknown. Participants with angina, ischemia, and stable CAD were enrolled and antianginal medications were stopped. Participants reported angina episodes daily for 2 weeks using the ORBITA-app. At the research angiogram, FFR and iFR were measured. After sedation and auditory isolation, participants were randomized to PCI or placebo, before entering a 12-week blinded follow-up phase with daily angina reporting. The ability of FFR and iFR, analyzed as continuous variables, to predict the placebo-controlled effect of PCI, was tested using Bayesian proportional odds modelling. Invasive physiology data were available in 279 patients (140 PCI and 139 placebo). The median (IQR) age was 65 years (59.0 to 70.5) and 223 (79.9%) were male. Median FFR was 0.60 (0.46 to 0.73) and median iFR was 0.76 (0.50 to 0.86). The lower the FFR or iFR, the greater the placebo-controlled improvement with PCI across all endpoints. There was strong evidence that a patient with an FFR at the lower quartile would have a greater placebo-controlled improvement in angina symptom score with PCI than a patient at the upper quartile (FFR 0.46 vs. 0.73: OR 2.01, 95% CrI 1.79 to 2.26, Pr(Interaction)>99.9%). Similarly, there was strong evidence that a patient with an iFR at the lower quartile would have a greater placebo controlled improvement in angina symptom score with PCI than a patient with an iFR at the upper quartile (iFR 0.50 vs. 0.86: OR 2.13, 95% CrI 1.87 to 2.45, Pr(Interaction) >99.9%). The relationship between benefit and physiology was seen in both Rose angina and Rose nonangina. Physiological stenosis severity, as measured by FFR and iFR, predicts placebo-controlled angina relief from PCI. Invasive coronary physiology can be used to target PCI to those patients who are most likely to experience benefit.