Endothelial Nitric Oxide Synthase T-786C Mutation, A Reversible Etiology of Prinzmetal's Angina Pectoris

doi:10.1016/j.amjcard.2009.10.062

The American Journal of Cardiology

Volume 105, Issue 6, 15 March 2010, Pages 792-796

https://doi.org/10.1016/j.amjcard.2009.10.062 Get rights and content

Because the endothelial nitric oxide synthase (eNOS) T-786C polymorphism is associated with reduced nitric oxide production and coronary artery spasm in Japanese patients, we speculated that it might be reversibly associated with Prinzmetal's variant angina in white Americans. Polymerase chain reaction analyses of eNOS T-786C and stromelysin 5A6A polymorphisms were done in 31 women and 12 men (42 white and 1 black American, median age 50 years), with well-documented Prinzmetal's variant angina. We matched each case with 1 healthy control by race and gender. Of the 43 cases, 21 (49%) were homozygous for wild-type normal eNOS, 19 (44%) were T-786C heterozygotes, and 3 (7%) were T-786C homozygotes. Of the 43 controls, 31 (72%) were homozygous for wild-type normal eNOS, 12 (28%) were T-786C heterozygotes, and 0 (0%) were T-786C homozygotes (p = .013). The mutant eNOS T-786C allele frequency in patients was 25 (29%) of 86 vs 12 (14%) of 86 in the controls (p = 0.016). Patients did not differ from controls for the distribution of the stromelysin 6A mutation (p = 0.66) or for the mutant 6A allele frequency (53% in cases, 50% in controls; p = 0.65). Nineteen patients took nitric oxide-elevating l-arginine (9.2 g/day, orally). Of these 19 patients, 10 (53%) became free of angina, 3 (16%) were improved but not angina free, and 6 (32%) had no change in their angina. Using l-arginine, the physical ability score (Seattle Angina Questionnaire) increased from a median of 42 to 72 of a total possible score of 100 (p = 0.011), satisfaction with symptom reduction increased from 53 to 61 (p = 0.004), and the perception of quality of life as acceptable increased from 29 to 50 (p = 0.001). In conclusion, the eNOS T-786C mutation appears to be a reversible etiology of Prinzmetal's variant angina in white Americans whose angina might be ameliorated by l-arginine.

Section snippets

Methods

The present study was conducted according to the principles of the Declaration of Helsinki, and all patients provided written informed consent, following a protocol approved by the Jewish Hospital of Cincinnati institutional review board.

The polymerase chain reaction analyses were done at the Molecular Diagnostic Laboratory (Cincinnati, Ohio).

The patients were studied in the consecutive order of their referral by their cardiologists and physicians. The diagnosis of PVA was confirmed by

Results

The 43 patients with PVA included 31 women and 12 men (42 white and 1 black American, median age 50 years, age range 35 to 74). Of these patients, 3 were current smokers, 6 were previous smokers, 27 had never smoked, and 7 had failed to provide a detailed smoking history. Of the 31 women, 18 were premenopausal and 13 were postmenopausal; 3 were taking exogenous estrogen at diagnosis. All 43 patients were taking calcium channel blockers at study entry and throughout the follow-up period.

Discussion

Despite conventional calcium channel binding drug therapy,¹¹ the median perception of overall quality of life was only 33 of 100 for our 41 patients with PVA who completed the Seattle questionnaire at study entry, consistent with reports by Bory et al,¹¹ Keller and Lemberg,¹² and Ogawa et al.²⁰ A better understanding of the pathophysiology of PVA might facilitate the development of more effective drug therapy.²¹ Our finding of a significant enrichment of the eNOS T-786C mutation in 43

References (33)

M. Yoshimura et al.
A T-786→C mutation in the 5′-flanking region of the endothelial nitric oxide synthase gene and coronary arterial vasomotility
Am J Cardiol
(2000)
C. Jia et al.
Joint effects of eNOS gene T-786C and ADH2 Arg47His polymorphisms on the risk of premature coronary artery disease
Thromb Res
(2007)
H. Yasue et al.
Coronary artery spasm—clinical features, diagnosis, pathogenesis, and treatment
J Cardiol
(2008)
D.L. Rios et al.
Smoking-dependent and haplotype-specific effects of endothelial nitric oxide synthase gene polymorphisms on angiographically assessed coronary artery disease in Caucasian- and African-Brazilians
Atherosclerosis
(2007)
J.A. Spertus et al.
Development and evaluation of the Seattle Angina Questionnaire: a new functional status measure for coronary artery disease
J Am Coll Cardiol
(1995)
D.Z. Cherney et al.
Endothelial nitric oxide synthase gene polymorphisms and the renal hemodynamic response to L-arginine
Kidney Int
(2009)
T.H. Liu et al.
No effect of short-term arginine supplementation on nitric oxide production, metabolism and performance in intermittent exercise in athletes
J Nutr Biochem
(2009)
M. Nakayama et al.
A −786T>C polymorphism in the endothelial nitric oxide synthase gene reduces serum nitrite/nitrate levels from the heart due to an intracoronary injection of acetylcholine
Pharmacogenet Genomics
(2006)
M. Yoshimura et al.
Genetic risk factors for coronary artery spasm: significance of endothelial nitric oxide synthase gene T-786→C and missense Glu298Asp variants
J Investig Med
(2000)
H. Kaneda et al.
Coronary artery spasm and the polymorphisms of the endothelial nitric oxide synthase gene
Circ J
(2006)

T. Nishijima et al.

The endothelial nitric oxide synthase gene −786T/C polymorphism is a predictive factor for reattacks of coronary spasm

Pharmacogenet Genomics

(2007)

M. Nakayama et al.

T-786→C mutation in the 5′-flanking region of the endothelial nitric oxide synthase gene is associated with coronary spasm

Circulation

(1999)

M. Nakayama et al.

Synergistic interaction of T-786→C polymorphism in the endothelial nitric oxide synthase gene and smoking for an enhanced risk for coronary spasm

Pharmacogenetics

(2003)

M. Bory et al.

Coronary artery spasm in patients with normal or near normal coronary arteries: long-term follow-up of 277 patients

Eur Heart J

(1996)

K.B. Keller et al.

Prinzmetal's angina

Am J Crit Care

(2004)

V.V. Balasa et al.

The relationship of mutations in the MTHFR, prothrombin, and PAI-1 genes to plasma levels of homocysteine, prothrombin, and PAI-1 in children and adults

Thromb Haemost

(1999)

Cited by (17)

Impact of statin therapy on long-term clinical outcomes of vasospastic angina without significant stenosis: A propensity-score matched analysis
2016, International Journal of Cardiology
Limited data are available on the efficacy of statin therapy for secondary prevention in patients with vasospastic angina (VSA). We investigated the association of statin therapy with long-term clinical outcomes in VSA patients without significant coronary artery disease.
From January 2003 to June 2014, we enrolled a total of 804 patients with VSA proven by an ergonovine provocation test without significant (≥ 70% diameter stenosis) coronary artery disease. We classified patients into a statin group (n = 330) and a no-statin group (n = 474) according to the use of statin. Primary outcome were major adverse cardiovascular events (MACE) defined as a composite of cardiovascular death, myocardial infarction, and any revascularization.
Median follow-up duration was 4.5 years (interquartile range: 2.0 to 7.3 years). MACE occurred in 14 patients (4.2%) in the statin group, and 21 patients (4.4%) in the no-statin group. There were no differences between the two groups (p = 0.97). After 1:1 propensity-score matching (281 pairs), MACE (statin versus [vs.] no-statin; 3.2% vs. 4.3%, hazard ratio [HR]; 0.80, 95% confidence interval [CI]; 0.34–1.89, p = 0.60) and readmission due to chest pain (17.1% vs. 17.4%, HR; 1.08, 95% CI; 0.72–1.06, p = 0.72) were not statistically different between the two groups.
Our results suggest that statin therapy could not improve long-term clinical outcomes in VSA patients without significant coronary artery disease.
The eNOS T786C mutation, Prinzmetal's Variant Angina, and amelioration of angina by l-arginine in 59 patients with intractable angina despite calcium channel blocker-nitrate therapy
2015, IJC Metabolic and Endocrine
Citation Excerpt :
Our previous studies [10,11], current report, and Blum et al. [30] suggest that l-arginine, an amino-acid precursor for NO [20], effectively reduces intractable angina in PVA patients. Dose ranging studies were not performed in the current report, nor in the two previous studies [10,11] and should be done in the future. In the current study, in 28 patients, after 1 and 5 months of therapy with 9 g l-arginine/day, all 5 components of the Seattle Anginal Questionnaire improved, p ≤ .03 for all.
Despite calcium channel blockers — long acting nitrates (CaCH-LAN), ~ 20% of patients with Prinzmetal's Variant Angina (PVA) retain intractable angina. The endothelial nitric oxide synthase (eNOS) T-786C polymorphism, more common in PVA than normal subjects, decreases the conversion of l-arginine to nitric oxide (NO), promoting coronary artery spasm (CAS)-angina.
PCR measures for the eNOS T-786C polymorphism were done in 59 PVA patients with intractable angina despite CaCH-LAN. Using the Seattle Angina Questionnaire (SAQ), effects of 9 g l-arginine/day were prospectively assessed in 28 patients with ≥ 3 visits, pre-treatment entry and ≥ 2 follow-ups at 1 and 5 months, and in 31 additional patients with 2 visits, entry and 7.7 months on l-arginine. This allowed an assessment of response to l-arginine in 59 patients at entry and 12 months later (last follow-up).
In the cohort of 59 patients, 47% of eNOS alleles were mutant vs. 20% in 72 normal controls, p < .0001. Compared to pre-treatment baseline, all 5 SAQ components improved in 28 patients at 1 (p ≤ .02 for all) and 5 months (p ≤ .03 for all) on l-arginine treatment, and improved in the 59 patients after 12 months on l-arginine, p ≤ .002 for all. The eNOS mutation was a significant positive independent determinant of reduction in anginal symptoms, p = .0002. Patients hetero- and homozygous for the eNOS mutation had greater improvement in anginal symptoms.
In patients with intractable angina despite CaCH-LAN, the eNOS T-786C mutation appears to facilitate CAS via reduced NO production, a condition susceptible to treatment with l-arginine.
Some observations on and controversies about coronary arterial spasm
2015, International Journal of Cardiology
Citation Excerpt :
A clue to possible genetic predisposition is given by some recent studies showing increased incidences of certain variants of genes controlling expression of angiotensin converting enzyme, endothelial nitric oxide synthase (e-NOS) and endothelin-1, and greater Rho-kinase activity in CAS cases [6,49–52]. Some gene variants seem to be actually protective against coronary spasm [49,51,52]. However, if genetic predisposition plays a major role in CAS, why are reports of familial occurrence of coronary spasm so rare [53]?
The pathogenesis, clinical features, diagnosis, and treatment of spasm of epicardial coronary arteries are reviewed briefly, especially with regard to some issues that remain controversial. For diagnosis, emphasis is placed on the need for objective observations during an attack, even if that requires an attempt at pharmacologic provocation during coronary arteriography, or during echocardiography when prior arteriography has demonstrated the absence of severe coronary stenosis.
The endothelial nitric oxide synthase T-786c mutation, a treatable etiology of Prinzmetal's angina
2013, Translational Research
We assessed to what degree the endothelial nitric oxide synthase (eNOS) T-786C polymorphism, leading to reduced nitric oxide (NO) production-coronary artery spasm, was reversibly associated with Prinzmetal’s variant angina (PVA). ENOS T-786C PCR analyses were done in 19 women, 8 men, 26 Caucasian, 1 African-American, median age 53, with well-documented PVA and in 72 healthy controls who did not differ by race or gender. Of the 27 cases, 7 (26%) were homozygous for wild-type normal eNOS (CC), 13 (48%) were T-786C heterozygotes (CT), and 7 (26%) were T-786C homozygotes (TT) vs controls, 44 (61%) CC, 27 (38%) TC, and 1 (1%) TT, P < 0.0001. The mutant eNOS T-786C allele frequency in PVA patients was 27/54 (50%) vs 29/144 (20%) in controls, P < 0.0001. On oral L-arginine (9.2 g/d) to increase production of NO for a median of 4.7 months in 16 PVA patients with symptomatic angina despite conventional nitrate-calcium channel blockers, using the Seattle Angina Questionnaire, satisfaction with symptom remission rose (median) from 50% to 100% (P = 0.004), satisfaction with angina frequency reduction rose from 65% to 80% (P = 0.02), satisfaction with treatment for symptoms rose from 38% to 88% (P = 0.001), and perception of overall life status rose from 25 to 71% (P = 0.0002). On L-arginine (median 4.7 months), in 20 patients, none had worsening of angina, and of 7 patients whose angina totally resolved, eNOS T-786C homozygosity was over-represented, P = 0 .04. The eNOS T-786C mutation appears to be a reversible etiology of PVA in patients whose angina may be ameliorated by L-arginine.
Adherence to the Mediterranean Diet Association with Serum Levels of Nitric Oxide, Prostacyclin, and Thromboxane B<inf>2</inf> among Prinzmetal Angina Patients and Healthy Persons
2023, Nutrients
Priapism in sickle cell disease: Associations between NOS3 and EDN1 genetic polymorphisms and laboratory biomarkers
2021, PLoS ONE

View all citing articles on Scopus

: This study was supported by grants from the Medical Research Council, London, United Kingdom, and the Lipoprotein Research Fund of the Jewish Hospital, Cincinnati, Ohio.

View full text

Coronary artery diseaseEndothelial Nitric Oxide Synthase T-786C Mutation, A Reversible Etiology of Prinzmetal's Angina Pectoris

Section snippets

Methods

Results

Discussion

Am J Cardiol

Thromb Res

J Cardiol

Atherosclerosis

J Am Coll Cardiol

Kidney Int

J Nutr Biochem

A −786T>C polymorphism in the endothelial nitric oxide synthase gene reduces serum nitrite/nitrate levels from the heart due to an intracoronary injection of acetylcholine

Pharmacogenet Genomics

Genetic risk factors for coronary artery spasm: significance of endothelial nitric oxide synthase gene T-786→C and missense Glu298Asp variants

J Investig Med

Coronary artery spasm and the polymorphisms of the endothelial nitric oxide synthase gene

Circ J

The endothelial nitric oxide synthase gene −786T/C polymorphism is a predictive factor for reattacks of coronary spasm

Pharmacogenet Genomics

T-786→C mutation in the 5′-flanking region of the endothelial nitric oxide synthase gene is associated with coronary spasm

Circulation

Synergistic interaction of T-786→C polymorphism in the endothelial nitric oxide synthase gene and smoking for an enhanced risk for coronary spasm

Pharmacogenetics

Coronary artery spasm in patients with normal or near normal coronary arteries: long-term follow-up of 277 patients

Eur Heart J

Prinzmetal's angina

Am J Crit Care

The relationship of mutations in the MTHFR, prothrombin, and PAI-1 genes to plasma levels of homocysteine, prothrombin, and PAI-1 in children and adults

Thromb Haemost

Coronary artery disease
Endothelial Nitric Oxide Synthase T-786C Mutation, A Reversible Etiology of Prinzmetal's Angina Pectoris