Exertional angina pectoris caused by coronary arterial spasm: Effects of various drugs

Yasue, Hirofumi; Omote, Shingo; Takizawa, Akinori; Nagao, Michinobu; Miwa, Kunihisa; Tanaka, Satoru

doi:10.1016/0002-9149(79)90026-2

Cited by 241 publications

(47 citation statements)

References 19 publications

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“…[29][30][31] Antianginal mechanisms of combination pharmacologic therapy. In our study, high-dose diltiazem in combination with isosorbide and propranolol produced a significant reduction in heart rate and rate-pressure product at rest as well as during submaximal and peak exercise.…”

Section: Resultsmentioning

confidence: 99%

Beneficial effects of high-dose diltiazem in patients with persistent effort angina on beta-blockers and nitrates: a randomized, double-blind, placebo-controlled cross-over study.

Boden¹,

Bough²,

Reichman³

et al. 1985

Circulation

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The effects of orally administered diltiazem combined with maximally tolerated doses of /3-blockers and nitrates were assessed in 12 patients, who during stress testing exhibited persistent effort angina and continued objective evidence for inducible myocardial ischemia. Patients performed multistage semisupine exercise on a bicycle ergometer during equilibrium-gated radionuclide angiography after consecutive 2 week treatment periods of placebo or diltiazem 90 mg qid (mean dose 340 mg/day) combined with maximally tolerated propranolol (mean dose 178 mg/day) and isosorbide dinitrate (mean dose 137 mg/day). All medications (including diltiazem or placebo) were administered four times daily for the duration of the study. Diltiazem or placebo was administered according to a double-blind design, with randomized cross-over at the end of each 2 week treatment period. The average number of angina attacks decreased during the double-blind cross-over phase of the trial (7 + 7 episodes/week at baseline vs 4 ± 3 on placebo vs 2 ± 2 on diltiazem; p = .08). Angina pectoris was abolished during peak exercise in eight of 12 patients on diltiazem (p < .05 vs placebo). Diltiazem increased total exercise duration from 276 ± 92 to 310 ± 78 sec (p < .005 vs baseline). Diltiazem likewise increased the time to onset of angina from 231 ± 84 sec at baseline to 305 ± 77 sec (p < .005), as well as the time to the onset of 1 mm ischemic ST segment depression (p = .0 1). Diltiazem decreased heart rate at rest, during submaximal workload, and at peak exercise (p < .05), and decreased systolic blood pressure at peak exercise only (p < .05). A significant decline in rate-pressure product at submaximal and peak exercise was noted (p < .05). At any given workload there was significantly less ST segment depression during submaximal (p = .05) and peak exercise (p < .025). No difference was noted in mean left ventricular ejection fraction during placebo or diltiazem therapy at rest and during peak exercise. The effect of adding high-dose diltiazem to maximally tolerated doses of isosorbide and propranolol in improving exercise tolerance and reducing maximal ST segment depression suggests an attenuation of myocardial ischemia. A reduction in rate-pressure product at submaximal and peak workload indicates that patients can perform a higher degree of external work before the onset of ischemia. Thus the principal mechanism for the observed improvement in myocardial ischemia with diltiazem in patients with persistent effort angina in spite of maximally tolerated doses of ,Bblockers and nitrates appears to be a further incremental decrease in myocardial oxygen demand, although the decrease in heart rate may have facilitated an improvement in myocardial oxygen supply. Circulation 71, No. 6, 1197-1205, 1985

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Section: Resultsmentioning

confidence: 99%

Beneficial effects of high-dose diltiazem in patients with persistent effort angina on beta-blockers and nitrates: a randomized, double-blind, placebo-controlled cross-over study.

Boden¹,

Bough²,

Reichman³

et al. 1985

Circulation

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“…There are 3 possible reasons for this. First, the etiology of coronary spasm is multifactorial and factors other than endothelial dysfunction, including a change in autonomic tone, 19,20 enhanced -adrenergic receptor activity, 21 magnesium deficiency 22 and hyperactivity of coronary smooth muscle, 23,24 have been implicated. Second, acute improvement in endothelial function might not prevent coronary spasm in patients with VA, as shown by 4 months of treatment with eicosapentaenoic acid, which improved coronary endothelial function, but did not prevent AChinduced coronary spasm.…”

Section: Failure Of Bh4 To Prevent Coronary Artery Spasmmentioning

confidence: 99%

Tetrahydrobiopterin Improves Coronary Endothelial Function, But Does Not Prevent Coronary Spasm in Patients With Vasospastic Angina

Fukuda

Teragawa

Matsuda

et al. 2002

Circ J

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oronary spasm is believed to play an important role in the pathogenesis of vasospastic angina (VA) and can cause acute myocardial infarction or ischemic sudden death. 1 However, the precise pathophysiology of coronary spasm has yet to be elucidated, although coronary endothelial dysfunction is thought to be one of the mechanisms. 2,3 Tetrahydrobiopterin (BH4) is an essential cofactor for nitric oxide (NO) synthase in both endothelial and vascular smooth muscle cells [4][5][6] and also serves as a scavenger of oxygen-derived free radicals, thereby decreasing NO breakdown. 7 Therefore, BH4 is considered essential for the regulation of NO bioavailability in endothelial cells and for the maintenance of cardiovascular homeostasis. In support of this concept, recent studies have shown that supplementation of BH4 improves impaired endothelial function in humans with various pathologic states, including hypercholesterolemia, smoking and coronary artery disease. [8][9][10][11] Because coronary endothelial dysfunction is commonly observed in patients with VA, 3,12,13 the depletion of BH4 and resultant reduction in NO bioavailability in the coronary circulation may be involved in the pathogenesis of coronary spasm. However, the effects of BH4 supplementation on coronary spasm have not been evaluated and so we investigated the effects of BH4 on the coronary vasoconstrictor response to acetylcholine (ACh) in patients with VA using quantitative coronary angiography. Methods Study PopulationWe enrolled 28 Japanese patients with VA (21 men, 7 women; mean age, 55 years; range, 38-70) who fulfilled the following inclusion criteria: (1) spontaneous chest pain associated with ST-segment elevation or depression at rest on 12-lead ECG or ambulatory ECG; (2) coronary spasm (≥50% reduction in arterial diameter during coronary angiography) in the left coronary artery associated with ST-segment changes and/or typical chest pain after intracoronary injection of ACh (Daiichi Pharmaceutical Co, Tokyo, Japan); and (3) no angiographic organic stenosis in the coronary arteries. Patients with severe left ventricular dysfunction and those with valvular heart disease were excluded. Written consent was obtained from each patient, and the protocol was approved by the Hiroshima University School of Medicine Ethics Committee. Study DesignThe study design has been described previously in detail. 14,15 Briefly, anti-anginal therapy was withheld for at least 48 h before cardiac catheterization, except for unrestricted use of sublingual nitroglycerin (NTG). Diagnostic right and left heart catheterization and coronary angiography were performed using the standard percutaneous femoral approach. A 6Fr guide catheter was introduced into the left main coronary artery, and a 5Fr temporary pacing electrode catheter (Bard, Tewksbury, MA, USA) was placed in the right ventricular apex via the right jugular vein and connected to a temporary pacemaker set at a rate of 50 beats/min. Study ProtocolAfter baseline conditions were established, incremental

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“…In the era of enrollment, calcium channel antagonists were widely used to treat hypertension and angina pectoris, particularly in Japan36 where coronary artery spasm is more prevalent than in the West 37. Beta‐blockers are thought to aggravate coronary spasm 38. After enrollment, patients received tailored medical therapy by the in‐charge cardiologists.…”

Section: Discussionmentioning

confidence: 99%

Association between matrix metalloproteinase‐9 and worsening heart failure events in patients with chronic heart failure

et al. 2017

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AimsMatrix metalloproteinase (MMP) is up‐regulated during heart failure (HF) and influences ventricular remodeling. We hypothesized that disparity between MMP‐9 and tissue inhibitors of MMP‐1 (TIMP‐1) results in clinical manifestations and is related to prognostic risk in patients with chronic HF.Methods and resultsPlasma levels of MMP‐9, TIMP‐1, and brain natriuretic peptide (BNP) were measured in 173 patients with chronic HF. Combined endpoints of worsening HF events were assessed during follow‐up (median 109 months). MMP‐9 and TIMP‐1 levels and the MMP‐9/TIMP‐1 ratio increased with increasing severity of the New York Heart Association class (P for trend = 0.003, 0.011, and 0.005, respectively). Patients with HF events (n = 35) had significantly higher MMP‐9 than those without HF events (P = 0.004). Kaplan–Meier analysis demonstrated a higher probability of HF events with high MMP‐9 values (>23.2 ng/mL; P = 0.005). A multivariate Cox proportional hazard model showed that high MMP‐9 values were an independent predictor of HF events (hazard ratio, 3.73; 95% confidence interval (CI), 1.03–13.46; P = 0.043). In patients with lower BNP levels (≤210 pg/mL), the adjusted hazard ratio for HF events was 3.63 (95% CI, 1.20–11.02; P = 0.023) among patients with high MMP‐9 values compared with patients with low BNP and low MMP‐9 values.ConclusionsMMP‐9 and TIMP‐1 levels correlate with the severity of chronic HF. MMP‐9 is a strong predictor of HF events, suggesting that a disparity between MMP‐9 and TIMP‐1 levels and increased MMP‐9 levels may help predict HF events.

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Exertional angina pectoris caused by coronary arterial spasm: Effects of various drugs

Cited by 241 publications

References 19 publications

Beneficial effects of high-dose diltiazem in patients with persistent effort angina on beta-blockers and nitrates: a randomized, double-blind, placebo-controlled cross-over study.

Beneficial effects of high-dose diltiazem in patients with persistent effort angina on beta-blockers and nitrates: a randomized, double-blind, placebo-controlled cross-over study.

Tetrahydrobiopterin Improves Coronary Endothelial Function, But Does Not Prevent Coronary Spasm in Patients With Vasospastic Angina

Association between matrix metalloproteinase‐9 and worsening heart failure events in patients with chronic heart failure

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