Clinical Significance of Aldosterone Levels and Low Grade Inflammation in Patients with Coronary Vasospasm Department of Cardiology Keiji Inoue Akira Ueoka, Naoki Maruyama, Yoshiaki Shimoda, Eigo Kishita, Yoshinori Tsubakimoto, Tomohiko Sakatani, Akiko Matsuo, Hiroshi Fujita, Makoto Kitamura
Background 1 1. Coronary spasm has been shown to play an important role in the pathogenesis of not only vasospastic angina but also ischemic heart disease including angina pectoris, myocardial infarction and sudden death. 2. Despite a large number of experimental and clinical investigations, the precise pathophysiology and mechanisms of vasospasm remains unknown.
Background 2 1. Patients with coronary spasm may have endothelial cell dysfunction lead by oxidative stress. 2. Impaired reactivity of vascular smooth muscle has been reported as a chief mechanism of vasospasm. 3. Chronic low-grade inflammation seems to be associated with the pathogenesis of coronary spasm. 4. The renin-angiotensin-aldosterone system (RAAS) may cause both endothelial dysfunction and hypercontraction of coronary smooth muscle cell. 5. The aldosterone has the potential to increase vascular inflammatory reaction.
Circulation. 23;18:24-246.
Circulation. 27;116:2435-2443.
Control Aldosterone Kidney International. 25;67:168-1682
Am J Physiol Heart Circ Physiol. 22;283:182-181.
Hypothesis The elevated aldostrone, final mediator of RAAS, is supposed to induce vascular inflammatory injury followed by vasospasm. Aim We elucidated the role of the aldosterone and inflammation in coronary vasospasm patients.
Methods 1 1. Consecutive 48 patients without organic coronary lesion (213 men, 195 women, age 67.4±12.6) were studied. 2. After diagnostic coronary angiography spasm provocation test was performed using ergonovine maleate. 3. Patients with proven coronary vasospasm (> 9% vessel diameter reduction during selective intracoronary ergonovine maleate as compared with the diameter following intracoronary nitroglycerin) but without coronary stenosis were diagnosed as vasospasm angina. 4. Patients without vasospasm and organic coronary lesion were diagnosed as non-spasm disease.
Methods 2 1. According to the results of the provocation test, the subjects were divided into two groups: the Spasm group of 144 patients and the Non-spasm group of 264 patients. 2. The levels of aldosterone and C-reactive protein (CRP) measured immediately before angiography were examined. Clinical data including aldosterone and CRP and other coronary risk factors were compared between 2 groups. 3. Exclusion criteria acute coronary syndrome, end stage renal failure systemic inflammatory disease, malignant disease, aldosterone antagonist user
Results Non-Spasm Spasm P-value Number 264 144 Age y.o. 67.1±13.9 67.8±1.1.1571 Gender M/F 116/148 97/47 <.1 Height cm 159.2±9.5 161.9±9.9.57 Weight kg 58.6±35.3 62.1±13.4.5945 BMI kg/m2 23.±19. 23.5±3.7.448 Hypertension % 53.8 68.8.77 Diabetes % 17.1 19.3.685 Dyslipidemia % 31.8 4..26 Hyperuremia % 14.4 27.1.18 Smoker % 3.3 53.5.9 Brinkman index 233.5±933.9 555.8±736.9 <.1
Results Non-Spasm Spasm P-value SBP mmhg 131.5±21.1 126.9±18.8.217 DBP mmhg 75.9±12.6 72.2±14.8.42 PP mmhg 55.3±15.2 54.4±13.3.546 HR /min 72.4±12.8 73.3±12.1.7657 EF % 75.2±7.46 7.1±11.2 <.1
Results Non-Spasm Spasm P-value BNP pg/ml 34.7±57.4 91.5±147.9. <.1 Aldosterone pg/ml 19.5±59.6 142.8±68.9 <.1 Renin activity ng/ml/hr 3.3±11.7 5.3±8.8.321 WBC /mm 3 57.8±1453.4 6175.5±942.2.2 Neutrophil /mm3 3382.±1117.7 3796.1±861.1.1 Lymphocyte /mm3 1838.7±111.4 18.1±555.8.5465 Fibrinogen mg/dl 292.7±78.3 34.7±59.1.752 CRP mg/l.93±1.2 1.45±.95 <.1
Results Non-Spasm Spasm P-value Total-cholesterol mg/dl 199.7±33.8 187.8±36.6.11 Trigriceride mg/dl 139.3±89.6 15.7±156.1.2838 HDL-cholesterol mg/dl 54.6±15.4 5.1±17.8.4 Uric Acid mg/dl 5.5±5.3 5.8±1.5.1138 Blood sugar mg/dl 111.4±43.2 119.4±95.5.369 HbA1c % 5.5±.9 5.6±.7.514 BUN mg/dl 16.2±4.7 17.2±5.9.883 Creatinine mg/dl.8±.23.93±.62.94 egfr ml/min/1.73m 2 78.5±23.4 7.7±24.1.22 Na meq/l 14.4±2.5 141.1±2.7.7652 K meq/l 4.2±.4 4.2±.3.869 Cl meq/l 12.1±2.3 11.7±3.4.4439
%male 1 8 Gender BMI Smoking P =.12 kg/m 2 5 4 5 (Brinkman index ) n.s. P =.12 4 6 3 3 4 2 2 2 1 1 Non-spasm Spasm Non-spasm Spasm Non-spasm Spasm
BNP Aldosterone Renin pg/ml 16 pg/ml 8 ng/ml/hr 1 P =.17 P <.1 n.s. 8 4 5 Non-spasm Spasm Non-spasm Spasm Non-spasm Spasm
CRP Neutrophil Fibrinogen mg/l 1. /mm 3 16 mg/dl 1 P <.1 14 P <.1 8 n.s. 12 5. 1 8 6 6 4 4 2 2 Non-spasm Spasm Non-spasm Spasm Non-spasm Spasm
Non-spasm Spasm CRP (mg/l) 1. n = 264 CRP (mg/l) 1. n = 144 8. R =.4 P =.8466 8. R =.79 P <.1 6. 6. 4. 4. 2. 2. 1 2 3 4 5 6 1 2 3 4 5 6 Plasma Aldosterone (pg/ml) Plasma Aldosterone (pg/ml) y =.2x + 1.51; R 2 =.1525 y =.97x +.544; R2=.524
Spasm Neutrophil (/mm 3 ) 1 8 Fibrinogen (mg/dl) n = 12 1 n = 12 R =.391 R =.426 P <.1 8 P <.1 6 6 4 4 2 2 1 2 3 4 5 6 Plasma Aldosterone (pg/ml) 1 2 3 4 5 6 Plasma Aldosterone (pg/ml) y = 4.8831x + 3146.2; R 2 =.1528 2 y =.3546x + 255.16; R =.1812
Multivariate Analysis Odds ratio (95% CI) P-value Aldosterone 1.6 (1.2-1.1).19 CRP 1.291 (1.41-1.6).198 Neutrophil 1. (.999-1.).653 Smoker 1.75 (.993-2.928).529
Summary 1. Levels of aldosterone and CRP were significantly higher in the spasm group than in the non-spasm group 2. Patients with coronary vasospasm were likely to have high levels of white blood cell count and neutrophil count. 3. There is a positive correlation between aldosternoe and CRP in the spasm group. 4. Multivariate analysis showed that elevation of aldosterone and CRP level were independently associated with vasospasm.
RAA system Aldosterone Aldosterone Receptors in Vessels Non-RAA system Adipocyte ACTH Potassium Endothelin Deleterious Effects of Aldosterone in Artery Coronary spasm? Endothelial Dysfunction VSMC Hypercontraction Oxidative Stress Inflammatory Reaction Thrombotic Phenomena Vascular Fibrosis
Pathogenesis of vasospasm 1. Shear stress, Acetylcholine, Bradykinin, Serotonin, Histamine, Substance P 2. Endothelial dysfunction Endothlium-dependent vaso-relaxation factors =EDRF (NO), EDHF Endothlium-derived contracting factors (EDCF) =ET-1, Angiotensin II, PGH2, TXA2, Super oxide 3. Oxidative stress Aldosterone NADPH oxidase activation 4. Chronic low-grade vascular inflammation 5. Hyper contractility of vascular smooth muscle cell Rho/ROCK activity 6. Deficiency of magnesium (endgenous Ca antagonist) 7. Loss of estrogen
Limitations 1. Cause of elevated aldosterone 2. Role of cortisol 3. Expression of mineral corticoid receptor 4. Effect of mineral corticoid receptor blocker 5. Racial differences, Ethnic characteristics
Conclusions 1. The levels of aldosternoe and CRP which were strongly associated with vasospasm had positive interactions. 2. Our results suggested elevated aldosterone in conjunction with inflammatory reaction may be involved in the pathogenesis of coronary spasm.