Pathogenesis Of Vasospastic Angina Research Articles

Allergic Eosinophilic Vasospastic Angina – A New Endotype

Histamine has been implicated in the pathogenesis of vasospastic angina, with coronary artery adventitial mast cells being a potential histamine source. Since histamine is a key mediator of allergic responses, the concept of allergic vasospastic angina (Kounis syndrome) has been introduced; however, histamine release may occur via both allergic and non-allergic pathways. Eosinophil-mediated allergic responses may induce vasospastic angina via histamine release.

Decreased resting coronary flow and impaired endothelial function in patients with vasospastic angina.

Coronary endothelial and circulatory dysfunction plays important roles in the pathogenesis of vasospastic angina (VSA). However, a complete understanding of the entire coronary circulation including microvasculature in patients with VSA is lacking. A total of 32 patients without obstructive coronary artery disease in the left descending coronary artery, who underwent an intracoronary acetylcholine (ACh) provocation test for diagnosis of VSA, were enrolled prospectively. A positive diagnosis of the ACh test was defined as total/subtotal coronary artery narrowing accompanied by chest pain and/or ischemic ECG changes. Angina frequency and severity at baseline, and 1 and 3 months were recorded. Coronary circulation was evaluated invasively using a thermodilution method by obtaining the mean transit time (Tmn) at rest and hyperemia, coronary flow reserve, and index of microcirculatory resistance. Systemic endothelial function was assessed by the reactive hyperemia index. There were 14 (44%) and 18 (56%) patients with and without a positive ACh provocation test. The baseline characteristics did not differ significantly between the two groups. Patients with VSA had a significantly lower reactive hyperemia index compared with those without VSA (1.70±0.33 vs. 2.12±0.53, P=0.02). Coronary flow reserve, index of microcirculatory resistance, and hyperemic Tmn were not different between the two groups, whereas resting Tmn was significantly longer in patients with VSA (1.20±0.44 vs. 0.71±0.37, P=0.002). Although the frequency and severity of angina improved from baseline to 1 and 3 months in patients with both positive and negative ACh tests, there was no difference between the two groups. Patients with VSA had decreased resting coronary flow and impaired endothelial function.

Abstract 11830: Increased Coronary Perivascular Adipose Tissue Volume on Cardiac Computed Tomography in Patients With Vasospastic Angina -Possible Correlation With Adventitial Vasa Vasorum Formation

Background: The adventitial components, such as perivascular adipose tissue (PVAT) and vasa vasorum (VV), play important roles in the pathogenesis of cardiovascular disease. However, the roles of epicardial adipose tissue (EAT) and VV in the pathogenesis of vasospastic angina (VSA) remain to be examined. In this study, we thus examined whether coronary PVAT volume is increased at the spastic coronary segment, and if so, whether the volume is correlated with the extent of VV formation in VSA patients. Methods and Results: We measured the volume of EAT and coronary PVAT of the left anterior descending coronary arteries (LAD) on cardiac computed tomography (CT) in 48 consecutive patients with documented spasm in LAD and 18 control subjects without the spasm. We further examined the extent of VV formation of LAD in 26 VSA patients by using optical frequency domain imaging (OFDI). Patient characteristics were comparable between the 2 groups in terms of sex, age, body weight, body mass index and cardiovascular risks. Although the EAT volume was comparable between the 2 groups, the PVAT volume of LAD was significantly increased in VSA group as compared with control group (VSA, 29.8±15.2 vs. control, 18.8±9.2 cm3, P<0.01) (Figure). Furthermore, there was a significant positive correlation between the PVAT volume of LAD and the VV area (R=0.43, P<0.05) (Figure). Conclusions: These results indicate that the coronary PVAT volume, but not the EAT volume, is increased at the spastic coronary segments associated with enhanced adventitial VV formation in VSA patients, suggesting the pathophysiological correlation between the 2 changes.

Single-wire pressure and flow velocity measurement for quantifying microvascular dysfunction in patients with coronary vasospastic angina.

Endothelial and vascular smooth muscle dysfunction of epicardial coronary arteries play a pivotal role in the pathogenesis of vasospastic angina (VSA). However, coronary microvascular (MV) function in patients with VSA is not fully understood. In the present study, subjects without coronary obstruction were divided into two groups according to the acetylcholine provocation test: VSA group (n = 29) and non-VSA group (n = 21). Hyperemic MV resistance (hMR) was measured using a dual-sensor (Doppler velocity and pressure)-equipped guidewire, and guidewire-derived hemodynamic parameters were compared. There were no between-group differences in clinical demographics, including potential factors affecting MV function (e.g., diabetes). Although coronary flow velocity reserve was similar between the two groups [2.4 ± 1.0 (VSA group) vs. 2.4 ± 0.9 (non-VSA group); P = 0.8], coronary vessel resistance and hMR were significantly elevated in the VSA group compared with the non-VSA group (2.6 ± 3.1 vs. 1.2 ± 0.8, P = 0.04; 1.9 ± 0.6 vs. 1.6 ± 0.5, P = 0.03, respectively). Coronary vasospasm, older age, E/e', and estimated glomerular filtration rate were significantly associated with MV dysfunction [defined as ≥ median value of hMR (1.6)] in univariate analysis. Coronary vasospasm most strongly predicted higher hMR in multivariate logistic regression analysis (odds ratio, 4.61; 95% confidence interval, 0.98-21.60; P = 0.053). In conclusion, coronary MV resistance is impaired in patients with VSA compared with non-VSA patients, whereas coronary flow velocity reserve is maintained at normal levels in both groups. In vivo assessment of hMR might be a promising index of coronary MV dysfunction in patients with VSA.

Abstract 18566: How is the Presence of Obstructive Sleep Apnea Associated with Vasospastic Angina?

Background: Vasospastic angina (VSA) is characterized by transient vasoconstriction of the epicardial coronary arteries leading to myocardial ischemia. It characteristically occurs from midnight to early morning. Obstructive sleep apnea (OSA) is caused by obstruction of the upper air passage during sleep, which leads to hypopnea. Although OSA may have an influence on VSA, the association between these two conditions remains unclear. To clarify this relationship, the frequency of OSA (Study 1) and the association between OSA and anginal attacks (Study 2) were investigated. Methods: (Study 1) Eighty-seven patients (41 men, mean age 67 years) were included in whom spasm-provocation testing for evaluation of chest symptoms was performed. VSA was defined as >90% narrowing of the epicardial coronary arteries on the angiogram during a spasm-provocation test, accompanied by chest pain and/or ST-segment deviation on ECG. Polysomnography (PSG) was performed in all patients. The presence of OSA was verified using the apnea hypopnea index (AHI) >15/h. The frequency of OSA in VSA patients (VSA group, n = 58) was compared with that in patients in whom negative spasm-provocation testing (non-VSA group, n = 29) was performed. (Study 2) Seventy-seven VSA outpatients were examined in whom PSG was performed (45 OSA, 32 non-OSA), and these patients followed up for at least a year. The number of anginal attacks per month was evaluated. The presence of intractable VSA was defined as uncontrollable angina even after administration of two types of coronary vasodilators. Results: (Study 1) No difference was observed in AHI (VSA group: 15.2 ± 1.3/h, non-VSA group: 12.8 ± 1.8/h) and the frequency of OSA (VSA group: 25/58, 43%, non-VSA group: 9/29, 31%) between the two groups. (Study 2) The number of anginal attacks tended to be higher in the OSA group (2.9 ± 0.6/months) than in the non-OSA group (1.3 ± 0.8/months, p = 0.09). The frequency of intractable VSA was higher in the OSA group (47%) than in the non-OSA group (19%, p < 0.05). Logistic regression analysis demonstrated that the presence of OSA was the significant factor responsible for intractable VSA. Conclusions: These results suggest that although OSA may not be involved in the pathogenesis of VSA, it may be a deteriorating factor of VSA.

Rho-Associated Kinase 2 Polymorphism in Patients With Vasospastic Angina

Background and ObjectivesRecent studies indicate that in response to vasoconstrictor stimuli, the small GTPase RhoA and its down-stream effector, Rho-associated kinase 2 (ROCK)/Rho-kinase, are associated with hypercontraction of the vascular smooth muscle of coronary arteries through augmentation of myosin light chain phosphorylation and Ca2+ sensitization. Expression of ROCK/Rho-kinase mRNA was significantly increased and up-regulated in the spastic coronary artery in a porcine model, and a specific inhibitor of ROCK/Rho-kinase inhibited coronary artery spasm in humans. We therefore explored the role of ROCK2 polymorphisms in the pathogenesis of vasospastic angina (VA).Subjects and MethodsWe studied 106 patients with VA who exhibited spontaneous or provoked coronary spasm during coronary angiography and compared the prevalence of ROCK2 polymorphisms between this group of patients with VA and controls whose angiograms were normal, and in whom the ergonovine test did not cause spasm (n=107). Five single nucleotide polymorphisms (SNPs) of the ROCK2 gene were selected. SNPs were genotyped by high-resolution melting. Linkage disequilibrium and haplotype analyses were performed using the SHEsis program.ResultsThe prevalence of genotypes of the 5 interesting SNPs in patients with VA was not different from that in the control group. In haplotype analysis, the haplotype G-T-C-T-G (in order of rs978906, rs2271621, rs2230774, rs1515210, and rs3771106) was significantly associated with a decreased risk of VA (p=0.007).ConclusionThe haplotype G-T-C-T-G in the ROCK2 gene had a protective effect against VA, suggesting the involvement of ROCK2 in VA pathogenesis.

ST-T wave changes in a patient complicated with vasospastic angina and Brugada syndrome: differential responses to acetylcholine in right and left coronary artery

A 49-year-old man with chest pain and syncope presented saddleback or occasionally coved type ST elevation in V1-V3. Coronary spasm in the left anterior descending artery was induced by acetylcholine injection and ST elevation changed from saddleback to coved type in V2-V3 together with ST depression in V4-V5, whereas acetylcholine injection into the right coronary artery did not provoke spasm, but induced augmented and coved type ST elevation in V2 without ST-T changes in V4-V5. These electrocardiographic changes in response to acetylcholine administration into each coronary artery are compatible with pathogenesis of vasospastic angina and Brugada syndrome, respectively.

Coronary Artery Spasm and the Polymorphisms of the Endothelial Nitric Oxide Synthase Gene

Coronary artery spasm plays an important role in the pathogenesis of vasospastic angina, and contributes to the development of several acute coronary syndromes. Endothelial nitric oxide synthase (ecNOS) catalyzes the synthesis of nitric oxide, which regulates vascular tone, and may be related to coronary vasospasm. The present study investigated whether coronary spasm is related to particular polymorphisms of the ecNOS gene. Spasm provocation by serial infusions of acetylcholine was performed on 165 patients who were clinically suspected of having angina. In both study patients and healthy controls (n=400), genomic polymorphisms of the ecNOS gene were determined by using polymerase chain reaction. Quantitative luminal diameter measurements of the 3 major coronary arteries were initially obtained before and after acetylcholine injection, and then after isosorbide dinitrate injection, by using a computer-assisted analysis system. Logistic multiple regression analysis identified the a/a or a/b genotype in intron 4 of ecNOS (NOS4a: p=0.0431, odds ratio (OR) 2.43) and diabetes mellitus (p=0.0060, OR 4.88) as significant predictors of coronary spasm. In the patients with NOS4a, both the induced and spontaneous contractions were augmented. The present study results indicated that NOS4a could be a good marker for coronary artery spasm.

Age-Related Changes of Clinical Features and Prevalences of Coronary Risk Factors in Japanese Patients with Vasospastic Angina

From among 899 consecutive patients who underwent their first coronary arteriography, we selected 147 pts with vasospastic angina (VA) and 356 pts with classic angina (CA) and divided them into three different age groups: -49 years old, 50 to 59, and 60-. In these 899 pts, incidences of VA showed no increase with aging. Prevalence of coronary risk factors in CA, such as diabetes, hypercholesterolemia, hypertension, and obesity, was higher than in VA, although prevalence of smoking in CA was lower than in VA. In VA, we found an age-related increase in the incidence of smoking only, in contrast to the other four risk factors. The VA showed no age-related increase in the incidence of complication of fixed coronary stenosis. These findings suggest that aging and atherosclerosis might not play a major role in pathogenesis of VA, although the mere presence of atherosclerosis irrespective of its severity could interact with local susceptibility to spasm, leading to coronary vasospasm.