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Microvascular angina is caused by cardiac small vessel disease, and dysregulation of the endothelin system is implicated. The minor G allele of the non-coding single nucleotide polymorphism (SNP) rs9349379 enhances expression of the endothelin 1 gene in human vascular cells, increasing circulating concentrations of ET-1. The prevalence of this allele is higher in patients with ischemic heart disease. Zibotentan is a potent, selective inhibitor of the ETA receptor. We have identified zibotentan as a potential disease-modifying therapy for patients with microvascular angina. We will assess the efficacy and safety of adjunctive treatment with oral zibotentan (10 mg daily) in patients with microvascular angina and assess whether rs9349379 (minor G allele; population prevalence ~36%) acts as a theragnostic biomarker of the response to treatment with zibotentan. The PRIZE trial is a prospective, randomized, double-blind, placebo-controlled, sequential cross-over trial. The study population will be enriched to ensure a G-allele frequency of 50% for the rs9349379 SNP. The participants will receive a single-blind placebo run-in followed by treatment with either 10 mg of zibotentan daily for 12 weeks then placebo for 12 weeks, or vice versa, in random order. The primary outcome is treadmill exercise duration using the Bruce protocol. The primary analysis will assess the within-subject difference in exercise duration following treatment with zibotentan versus placebo. PRIZE invokes precision medicine in microvascular angina. Should our hypotheses be confirmed, this developmental trial will inform the rationale and design for undertaking a larger multicenter trial.

PurposeCoronary vasomotor dysfunction embraces two specific clinical entities: coronary (micro)vascular spasm and microvascular dysfunction. The clinical manifestations of these entities are respectively called vasospastic angina (VSA) and microvascular angina (MVA). Over the years, these diseases have become more and more prominent and several studies aimed to investigate the best diagnostic and therapeutic strategies. Patients with coronary vasomotor disorders are often undertreated due to the absence of evidence-based guidelines. The purpose of this overview is to illustrate the various therapeutic options available for the optimized management of these patients.MethodsA Medline search of full-text articles published in English from 1980 to April 2022 was performed. The main analyzed aspects of vasomotor disorders were treatment options. We also performed research on “Clinicaltrial.gov” for ongoing trials.ConclusionCoronary (micro)vascular spasm and microvascular dysfunction are clinical entities characterized by high prevalence and clinical representation. Several therapeutic strategies, both innovative and established, are available to optimize treatment and improve the quality of life of these patients.

Coronary microvascular dysfunction (CMD) carries a poor cardiovascular prognosis and may explain angina in women without obstructive coronary artery disease (CAD). Currently, no evidence-based treatment for CMD exists. We investigated whether reducing cardiovascular risk factors improves symptoms and microvascular function in women with non-endothelial dependent CMD and no obstructive CAD. We randomized 62 women aged 40-75, with body mass index (BMI) >25 kg/m2, angina ≥monthly, and coronary flow velocity reserve (CFVR) ≤2.5 to a 24-week intervention comprising low energy diet, exercise training, and optimized treatment of hypertension, dyslipidemia and diabetes or to control. Patients were assessed before randomization and after 24 weeks. Primary outcomes were CFVR assessed by transthoracic Doppler stress-echocardiography and angina burden by Seattle Angina Questionnaire (SAQ). Secondary outcomes were exercise capacity, body composition, glycemic control, myocardial function, and anxiety and depression symptoms. Fifty-six participants (90%) completed the study. Median (IQR) age was 65.2 (57.1;70.7) years, BMI was 30.1 (28.4;32.7) kg/m2. The intervention resulted in relevant improvement in angina symptoms (9-21-point increase on SAQ-scales (all p<0.01)) but had no effect on CFVR (p = 0.468). Mean (CI) weight loss was 9.6 (7.80;11.48) kg, (p<0.0001). There was a significant mean (CI) decrease in depression symptoms = 1.16 (0.22;2.12), triglycerides = 0.52 (0.25;0.78) mmol/L, total cholesterol = 0.55 (0.12;0.98) mmol/L, and HbA1c in diabetics = 27.1 (1.60;52.6) mmol/mol but no effect on other secondary outcomes. A major weight loss and intensified risk factor control resulted in significantly improved angina burden but no improvement of coronary microvascular function among women with microvascular angina.

Background The ratio of coronary artery volume to left ventricular myocardial mass (V/M) reflects the hemodynamic association between epicardial coronary arteries and myocardium. Evidence suggests a significant decrease in V/M among patients with primary microvascular angina (PMVA). However, V/M values may be influenced by anatomic and physiological varieties, necessitating independent evaluation in different ethnic groups. We aimed to explore the potential of V/M in predicting PMVA in Chinese population. Methods We conducted a retrospective case-control analysis on 23 PMVA patients and 25 controls matched by age, sex, body mass index, smoking history, hypertension, diabetes, and dyslipidemia. For each patient, the computed tomography (CT) images were three-dimensionally reconstructed to calculate patient-specific V/M and vessel-specific V/M, as well as CT-derived fractional flow reserve (CT-FFR). The results in both groups were compared using t-test or Mann-Whitney U test. Results Compared to the control group, the PMVA group had significantly higher total myocardial mass and lower average V/M ( P  < 0.05 for both). Regarding vessel-specific V/M, PMVA group had significantly lower values of left anterior descending artery and left circumflex artery ( P  < 0.05 for both), with no significant inter-group difference in right coronary artery ( P  > 0.05). There was no significant difference between two groups in vessel-specific CT-FFR ( P  > 0.05 for all). Conclusion The abnormally decreased V/M value may serve as a potential biomarker of PMVA in Chinese population.

Blood-activating drugs (BADs) are widely used to treat microvascular angina in China. This study aims to summarize relevant evidence from randomized controlled trials (RCTs) to assess the efficacy and safety of BADs in the treatment of microvascular angina. We searched for relevant studies before June 2019 from seven databases. Twenty-four studies were included of 1903 patients with microvascular angina. All studies compared the use of traditional Chinese medicine for activating blood circulation (BADs) and Western medicine (WM) with the use of Western medicine alone. In all, 15 trials reported a significant effect of BADs on improving clinical symptoms compared with the control treatment (P < .00001), and 8 trials reported significant effects of BADs on reducing the frequency of angina pectoris attacks compared with Western medicine treatment (P < .00001). The pooled results also demonstrated that BADs provided a significant benefit in reducing the dosage of nitroglycerin required (P = .02), the maximum range of ST-segment depression (P = .003) and the descending degree of the ST-T segment of ECG (P = .0002); prolonging the total time of treadmill exercise (P < .00001) and the time of ST-segment depression of 1 mm (P = .002); enhancing the total effective rate of Traditional Chinese Medicine (TCM) syndromes (P < .00001); improving endothelial function (P < .00001); and reducing the levels of high-sensitivity C-reactive protein (hs-CRP) (P < .00001). BAD treatment showed no statistically significant effect on the levels of TNF-a (P = .8) or IL-6 (P = .13). No severe adverse events were reported. This meta-analysis shows that BADs are effective for the treatment of microvascular angina. Although concerns regarding selective bias and low methodological quality were raised, our findings suggest that BADs are beneficial for patients with microvascular angina and should be given priority for future clinical studies.

BackgroundThe prognosis of myocardial ischaemia with no obstructive coronary artery disease (INOCA) and its underlying vasomotor disorders, vasospastic angina (VSA) and microvascular angina (MVA), is not well defined. The aim of this study was to perform a systematic review and meta-analysis of studies evaluating the long-term prognosis of patients with INOCA.MethodsWe included studies evaluating the prognosis of patients with INOCA published between January 1984 and August 2023 in Medline, Embase, Web of Science and Cochrane databases. Studies were selected if they included patients who fulfilled the Coronary Vasomotor Disorders International Study Group (COVADIS) criteria for either possible or definitive VSA or MVA. The primary outcomes were composite of all-cause death and myocardial infarction (MI), and major adverse cardiovascular event (MACE) at annual intervals up to 5-year follow-up. The incidence of primary outcomes for INOCA, each INOCA endotype and by method used to determine the diagnosis was calculated using the random effects model.ResultsFifty-four studies (17 302 patients) meeting the eligibility criteria were selected. The rate of all-cause death and MI with VSA was 0.7 (95% CI 0.4 to 1.0)/100 patient-years and with MVA was 1.1 (95% CI 0.7 to 1.5)/100 patient-years (p>0.05). The rate of MACE with VSA was 1.1 (95% CI 0.5 to 1.9)/100 patient-years and with MVA was 2.5 (95% CI 1.6 to 3.6)/100 patient-years (p=0.025). Patients with reduced coronary flow reserve (CFR) had higher all-cause death and MI rates than patients whose diagnosis of MVA was established based on an abnormal exercise or imaging stress test (4.7 (95% CI 2.0 to 8.4) vs 0.5 (95% CI 0.1 to 1.1) vs 1.1 (95% CI 0.5 to 2.0)/100 patient-years, p=0.001).ConclusionsOverall, patients with INOCA have a low rate of MACEs, but patients with MVA, especially those with reduced CFR, have a significantly higher rate of MACE than other subgroups, although there is high heterogeneity among the included studies.PROSPERO registration numberCRD42021275070.

Ischemic heart disease (IHD) is a leading global cause of ill-health and premature death. Clinical research into IHD is providing new insights into the pathophysiology, epidemiology and treatment of this condition. The major endotypes of IHD include coronary heart disease (CHD) and vasomotor disorders, including microvascular angina and vasospastic angina. Considering unselected patients presenting with stable chest pain, the pre-test probability of CHD is higher in men whereas the pre-test probability of a vasomotor disorder is higher in women. The diagnostic accuracy of diagnostic tests designed to assess coronary anatomy and disease and/or coronary vascular function (functional tests) differ for coronary endotypes. Clinical management should therefore be personalized and take account of sex-related factors. In this review, we consider the definitions of angina and myocardial ischemia. We then appraise the mechanistic links between myocardial ischemia and anginal symptoms and the relative merits of non-invasive and invasive diagnostic tests and related clinical management. Finally, we describe the rationale and importance of stratified medicine of IHD.

Intracoronary ACh Intracoronary injection of ACh in young and healthy humans causes coronary vasodilation by releasing nitric oxide (NO) from the endothelium, while vasodilatation is impaired in patients with coronary endothelial dysfunction.3 Moreover, the coronary arteries of patients suffering from coronary spasm disorders are very sensitive to the vasoconstrictor effect of intracoronary ACh, resulting in epicardial and/or microvascular coronary spasm.4 ACh-provoked coronary spasm is of short duration, since ACh is rapidly degraded by acetylcholinesterase in vivo.5 Fittingly, there are low incidence rates of serious complications with i.c. ACh of about 0.5% Intracoronary ergonovine Ergonovine is an ergot derivative which stimulates smooth muscle cells. The pharmacological effect of ergonovine is longer in comparison to the effect of ACh. [...]the necessity of i.c. nitrates to relieve prolonged coronary spasm is higher in CFTs using ergonovine compared with ACh.6 Since most coronary spasm provocation test protocols use ACh, the following descriptions are based on using ACh. There is an almost linear relationship between myocardial oxygen demand and coronary blood flow. [...]healthy humans have a CFR up to 5.08 and values below 2.0 or 2.5 are considered pathological. [...]the CFR can only be seen as a parameter of microvascular dysfunction in subjects without obstructed coronary arteries because it does not distinguish between epicardial and microvascular diseases.

Purpose To assess the effects of short-acting nitrates on exercise stress test (EST) results and the relation between EST results and coronary blood flow (CBF) response to nitrates in patients with microvascular angina (MVA). Methods We completed 2 symptom/sign limited ESTs on 2 separate days, in a random sequence and in pharmacological washout, in 29 MVA patients and in 24 patients with obstructive coronary artery disease (CAD): one EST was performed without any intervention (control EST, C-EST), and the other after sublingual isosorbide dinitrate, 5 mg (nitrate EST, N-EST). CBF response to nitroglycerin (25 μg) was assessed in the left anterior descending coronary artery by transthoracic Doppler-echocardiography. Results At C-EST. ST-segment depression ≥1 mm (STD) was induced in 26 (90 %) and 23 (96 %) MVA and CAD patients, respectively ( p  = 0.42), whereas at N-EST, STD was induced in 25 (86 %) and 14 (56 %) MVA and CAD patients, respectively ( p  = 0.01). Time and rate pressure product at 1 mm STD increased during N-EST, compared to C-EST, in CAD patients (475 ± 115 vs. 365 ± 146 s, p  < 0.001; and 23511 ± 4352 vs. 20583 ± 6234 bpm⋅mmHg, respectively, p  = 0.01), but not in MVA patients (308 ± 160 vs. 284 ± 136 s; p  = 0.19; and 21290 ± 5438 vs. 20818 ± 4286 bpm⋅mmHg, respectively, p  = 0.35). In MVA patients, a significant correlation was found between heart rate at STD during N-EST and CBF response to nitroglycerin ( r  = 0.40, p  = 0.04). Conclusions Short-acting nitrates improve EST results in CAD, but not in MVA patients. In MVA patients a lower nitrate-dependent coronary microvascular dilation may contribute to the lack of effects of nitrates on EST results.

Microvascular and/or vasospastic anginas are relevant causes of ischemia with no obstructive coronary artery disease (INOCA) in patients after computed tomography coronary angiography (CTCA). Our research has 2 objectives. The first is to undertake a diagnostic study, and the second is to undertake a nested, clinical trial of stratified medicine. A prospective, multicenter, randomized, blinded, sham-controlled trial of stratified medicine (NCT03477890) will be performed. All-comers referred for clinically indicated CTCA for investigation of suspected coronary artery disease (CAD) will be screened in 3 regional centers. Following informed consent, eligible patients with angina symptoms are enrolled before CTCA and remain eligible if CTCA excludes obstructive CAD. Diagnostic study: Invasive coronary angiography involving an interventional diagnostic procedure (IDP) to assess for disease endotypes: (1) angina due to obstructive CAD (fractional flow reserve ≤0.80); (2) microvascular angina (coronary flow reserve <2.0 and/or index of microvascular resistance >25); (3) microvascular angina due to small vessel spasm (acetylcholine); (4) vasospastic angina due to epicardial coronary spasm (acetylcholine); and (5) noncoronary etiology (normal coronary function). The IDP involves direct invasive measurements using a diagnostic coronary guidewire followed by provocation testing with intracoronary acetylcholine. The primary outcome of the diagnostic study is the reclassification of the initial CTCA diagnosis based on the IDP. Stratified medicine trial: Participants are immediately randomized 1:1 in the catheter laboratory to therapy stratified by endotype (intervention group) or not (control group). The primary outcome of the trial is the mean within-subject change in Seattle Angina Questionnaire score at 6 months. Secondary outcomes include safety, feasibility, diagnostic utility (impact on diagnosis and certainty), and clinical utility (impact on treatment and investigations). Health status assessments include quality of life, illness perception, anxiety-depression score, treatment satisfaction, and physical activity. Participants who are not randomized will enter a follow-up registry. Health and economic outcomes in the longer term will be assessed using electronic patient record linkage. CorCTCA will prospectively characterize the prevalence of disease endotypes in INOCA and determine the clinical value of stratified medicine in this population. [Display omitted]