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Association of dyslipidemia with vasospastic angina

Hong, Lifeng; Luo, Songhui; Li, Jianjun

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doi: 10.3760/cma.j.issn.0366-6999.20131949

Variant angina (VA) has been described the clinical entity whereby a sudden intense, spontaneous and reversible vasoconstriction of a coronary artery branch, subsequently resulted in subtotal or total occlusion during the duration of attack or provocative test. It is used to appear frequently at rest in the absence of any augment of myocardial oxygen demand and associated with ST-segment elevation on electrocardiography rather than with the usual ST-segment depression during the attack of exertional angina. Although the development of VA has been suggested to be associated with endothelial dysfunction and primary hyper-reactivity of vascular smooth muscle cells (VSMCs) triggered by some stimulating factors, such as smoking, the exact mechanism for this unique coronary disorder is largely unknown.

Dyslipidemia has been indisputably regarded as an important risk factor for atherosclerotic coronary artery disease (CAD). However, the association of dyslipidemia with VA has less been investigated. In fact, previous studies concerning the coronary angiography have demonstrated that VA mostly occurs in patients with mild atherosclerotic lesion or totally normal coronary segments and seldom links with pronounced lipid disorder.1 Several primary observations indicted that dyslipidemia was associated with the development of VA and the patients with VA was apparently characterized by low levels of high-density lipoprotein cholesterol (HDL-C) and apo-lipoprotein A-I (apoA-I) in addition to high concentration of lipoprotein (a), while elevated of plasma total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C) and triglyceride (TG) were not found, which is distinct from patients with organic CAD.2–5

Hence, we tried to review the current literatures regarding the pathogenesis of VA and its characteristics of lipid disorder in order to highlight the association of VA with dyslipidemia.

Pathogenic substrates of VA

The prevalence of VA displayed considerably ethnic variability and is clinically considered as rare contribution for admissions with a frequency limited to 1% to 1.5% in cohort of Caucasian for a long times, although it is much higher in east Asian population.6 Until recently the underestimated situation for incidence of VA has been increasingly recognized, especially in cases of atherosclerotic coronary lesions and out-hospitals of cardiac arrest.7 Moreover, as high as 30% to 35% subjects among those oriental patients with typical stable angina referred to diagnostic angiography have normal or “near” normal coronary (approximate to 40%-50%) might resort to a plausible explanation for their symptoms by pronounced focal or diffuse epicardial coronary spasm.7 In exceptional occasion, fatally left main trunk, multi-vessels or alternative vasospasm of the vital coronary segments can be catastrophic.8 Additionally, along with severe transmural ischemia secondary to occlusive coronary spasm, malignant arrhythmias, acute myocardial infarction (MI), syncope or even sudden cardiac death (SCD) can be complicated and has led to much therapeutic dilemmas.9–12 However, as a result of effective therapy of non-specific vasodilator such as the calcium channel blockers (CCB), the precise mechanisms, optimal treatment, and relevance of dyslipidemia with VA still remained poorly defined for the last six decades.13 Furthermore, almost 10%-20% patients of VA are refractory to conventional therapy and quantities of cardiac arrest due to severe vasospasm were neglected or misdiagnosis.14 Therefore, VA has never been a clinically benign entity and it is imperative to promote it with a deserved highlight.15

Although the precise mechanism of VA is still unclear, emerging evidence indicate that there are at least three fundamental pathogenic substrates involved in the development of VA, including endothelial dysfunction, primary hyper-reactivity of VSMCs and triggers or stimulating factors of coronary spasm (Figure 1).16–19 Dyslipidemia might bring into play through injured protective elements of coronary endothelia, increased oxidative stress effect, mediated inflammation, induced hypersensitivity of SMCs and contribute to the occurrences of VA (Figure 2).20

Figure 1.
Figure 1.:
Potential mechanism of association of variant angina with dyslipidemia.
Figure 2.
Figure 2.:
Available evidence of lipid parameters in the development of variant angina.

Endothelial dysfunction

The profile of endothelial function has a vital role in the physiological regulation of proper coronary vascular tone via mainly excretion of several vasodilators, the major type of which is nitric oxide (NO), to antagonize the various vasoconstrictors such as endothelin-1 (ET-1).21 Experimental studies, in vivo and in vitro, have indicated that vasoactive substance (e.g. acetylcholine, serotonin, histamine) reproduce vasodilative phenomenon, induced by release of NO from the normal endothelial cell.16,22 Whereas, in case of impairing endothelial function, above vessel response can be reversed due to failed release of NO and direct vasopastic reaction arisen from VSMCs.21 Meanwhile, emerging data suggested that inflammation and oxidative stress may facilitate the culprit vascular in the genesis of VA, superimposing an extra damage to dysfunctional endothelial cells.

Hyper-reactivity of VSMCs

However, subsequently clinical studies of VA related to the pathogenesis of endothelial dysfunction suggested that VA did not dependent on the presence of endothelial injury. Modified endothelial structures and function did not always directly lead to the attacks of vasospasm or VA as it was so common in subject with cardiovascular risk factors or atherosclerotic related diseases.17 Therefore, the injured endothelial function seems unlikely to be a pivotal element contributes to the occurrences of VA. Up to date, increased evidence suggest that a idiopathic or secondary hyper-reactivity of VSMCs of coronary artery wall is the determinant responsible for VA.17,18,23 The pathogenic role of predisposed VSMCs hyper-reactivity can be elicited by multiple stimuli that act through different receptors and cellular mechanisms, signified alterations of intracellular and post-receptor pathways, such as modification of pathways related Rho-kinase, protein kinase C, phospholipase C, G-proteins, ATP-dependent K+ channel, calmodulin or Calcium channel handling, and other ion channels, which were responsible for the hyperactivity of vulnerable VSMCs.17 Noteworthily, the most prominent finding among these factors was recently represented by an augment of Rho-kinase activity, an enzyme that facilitates to VSMC spasm favored by increasing sensitization to calmodulin of myosin light chains both through a directly, indirectly and through inhibition of myosin phosphatase.17,23 The expression of Rho-kinase in patient of VA, local and peripheral neutrophils, was significantly higher indeed than the reference group of healthy control (0.95±0.22 vs. 0.58±0.22, respectively, P <0.001) and could be antagonized by its specific inhibiter fasudil, effectively prevented the angina onset reproduced by acetylcholine.23 According to this cohort study, the positive and negative predictive value of noninvasive measurement of neutrophil Rho-kinase activity for VA was as high as 93% and 75% respectively.

Although the authors proposed neutrophil Rho-kinase activity to be a marker for active VA patients, evidence from previous studies indicated it was not an unique characteristic of VA populations.24 Clinically, Rho-kinase activity also can be also elevated in other cardiovascular diseases, such as systemic hypertension, pulmonary hypertension, acute stroke (included subarachnoid hemorrhage), stable angina and peripheral arterial disease.24 Therefore, there are other underlying substrates leading to the hypersensitivity of SMCs and the susceptibility of VA, involving in vasoconstrictors released by mast cells (e.g. histamine, prostaglandin D2, leukotriene), as well as over expressed of assorted growth factors (by VSMCs, endothelial cells and platelets).17 Besides, congenital or acquired abnormality of culprit vessel including vascular failure, fibromuscular hyperplasia, myocardial bridging and arterial aneurysm, deficiency of vitamin and magnesium, and modified ion channels or exchangers may also directly or indirectly lead to the hyperactivity of VSMCs and occurrences of VA.25

Triggers and stimulus

Although coronary artery VSMCs hypersensitivity seems to play a major role in the development of VA attack, it seldom can be done without various triggers and stimulus. Up to date, the triggers about VA attack remained extremely complicated and covered substantial ground. First of all, exposure to various exogenous stimulus, which included consumption or abuse of tobacco, alcohol, cocaine, marijuana, various therapeutic agents (e.g. Amphetamines, Methylphenidate, 5-Fluorouracil, Capecitabine, Losartan, stimulators or antagonist of adrenergic and cholinergic receptor), even cold atmosphere, pungent food such as cayenne pepper or soft drinks, sleeping disorder as well as emotional stimulations.26,27 Moreover, internal triggers such as disequilibrium of autonomic nervous activity, allergy mediators, abnormality of blood constituent and concentration (monocyte count, platelet, serum value of PH, cystatin C, ET-1, thromboxane A2, histamine and various constrictors), ethnic difference, genetic mechanisms and so on can also become important stimuli contributed to the episodes of VA.28 In addition, numbers of iatrogenic factors which covered various invasive operation, stress or provocative testing, interventional and implanted apparatus, hypothermia, over-ventilation and lower-ventilation might also lead to occurrences of VA.

Association of VA with lipid profile

Early in 1979, Rosendorff29 have demonstrated that some vasoconstrictors such as 5-hydroxytryptamine, normally has no effect on cerebral blood flow; in the presence of elevating plasma cholesterol concentration. However, it is a powerful vasoconstrictor. Meanwhile, in experimental dogs fed on a cholesterol-rich diet sufficient to reproduce a doubling of the serum cholesterol level, there was a tenfold increase in the sensitivity of both beta-receptor and alpha-receptor mediated vasoconstriction.29 The authors partially ascribed the mechanisms of this potentiation to chronic hypercholesterolemia in which would modify the noradrenaline adrenergic receptor binding characteristics and might even affect the ratio of alpha to beta receptors on the VSMCs membrane. As far as we known, this was the first study linking the VSMCs hyperactivity with lipid disorders. Following the study, other observations suggested that dyslipidemia on patients of VA was characterized by lower of HDL-C and apoA-I, as well as high concentration of lipoprotein(a), but without significant elevated of TC, LDL-C and TG. That's somehow distinct from scenario of CAD population and healthy control subjects.2–5

Changes of HDL-C, apoA-I, apoA-II, HDL-C/ apoA-I ratio and HDL-C particle in patients with VA

Early animal research failed to mimic occlusive coronary spasm in atherosclerotic rabbits with chronic hypercholesterolemia, as observed in patients with VA.30 However, multiple evidence from both animal and cohort investigations consistently suggested that the association of dyslipidemia with VA might be a real one. In animal experiment, it has been successfully established the VA model of miniature swine by removing its vessels endothelium and high cholesterol food feeding or by exposing to an inflammatory stimuli such as interleukin-1β.31 Meanwhile, Tasaki et al32 examined lipid profile in populations among VA, CAD, and healthy controlled subjects in 1989. In their study, they enrolled 108 male patients (22 cases of VA, 56 cases with obstructive CAD) and 30 cases of healthy controlled subjects. In comparison with lipid and apo-lipoprotein, their results indicated that LDL-C, apoA-I and apoA-II decreased significantly in the VA group. Additionally, stepwise discriminant analysis revealed that apoA-I was the best discriminator among the three groups or between group of VA or fixed CAD and the control group. However, Yoshida et al4 demonstrated that there were markedly differences of apoA-I and apoA-II compared with control group, but no difference discovered in plasma HDL-C value. Besides, Shirai et al33 inspected the lipid profile in patients with VA, patients with no angiographic coronary stenosis and absent of VA after intracoronary acetylcholine infusion. The plasma level of apoA-I in patients with VA (112 (plus or minus), 6 mg/dl) was obviously lower (P <0.05) than those without vasospasm (128 (plus or minus) 4 mg/dl). However, there were no difference between the two groups in the value of TC, TG, HDL-C, apoA-II and apoB.33

Afterwards, Miwa and its colleagues2 demonstrated that higher ratio of HDL-C/apoA-I, lower HDL-C and apoA-I were characteristic in subjects of VA, in whom HDL particles were large, cholesterol-rich and possibly malfunctioning. Series research by Miwa and his colleagues34 also suggested that high susceptibility of HDL to lipid per-oxidative modification might contribute to the genesis of coronary spasm, and oxidized HDL rather than oxidized LDL was more likely to be linked with VA.

Nobuyoshi et al26 initiated a prospective cohort study with 3 000 consecutive participants who referred to coronary cineangiography, attempting to determine which was the most significant risk factor for coronary spasm. According to the results of multiple regression analysis, there was a positive correlation between plasma HDL-C levels and VA (P <0.01).

Subsequently, prospective studies indicated that an increased HDL-C level improved the prognosis in patients with coronary vasospasm or VA.35,36 Besides, clinical study reported a positive correlation between HDL-C and acetylcholine-induced coronary reactivity in both angiographically smooth and diseased coronary segments.37 Zeiher et al38 reported that coronary segments in patients with relatively heighten HDL-C levels showed a significantly blunted response to both stimuli (acetylcholine and cold pressure test) compared with patients of lower HDL-C, suggesting that HDL-C exerts a beneficial effect on vascular reactivity.

However, recent evidence indicated that higher plasma HDL-C was not always inversely related to the risk of CAD and HDL-C/ApoA-I ratio might be a readily available biomarker for estimating HDL size and HDL particle concentration.39 Additionally, some data suggested that the functional domain of HDL-C to decrease oxidative stress and restore endothelial impairment consisted in apoA-I.40 Observational study also indicated large particle of HDL-C, which was cholesterol enriched, might be double-edged sword, and at some point to become cholesterol donors instead of acceptors hence contributed to atherogenic potency.41 Whereas, the prevailing view was that an increased concentration of large HDL particles conferred with lower CAD risk, and virtually absent in patients with overt CAD. Nevertheless, the precise role of HDL-C particle numbers, subclasses and other alternative metrics of HDL-C played in patients of VA were largely remained to be elucidated and deserved further researches.

Association of ox-LDL and LDL-particles with VA

Yamaguchi et al42 demonstrated that the plasma level of ox-LDL was equally increased in patients of VA and average CAD. However, compared with patients absent of coronary spasm, prior study suggested that plasma LDL-C in patients with active VA was highly susceptible to peroxidative modification.34 Recent study detected that higher levels of malonaldehyde LDL, a major epitope of oxidative modified LDL and a vital marker of atherothrombosis, were observed in the coronary circulation of patients with focal vasospasm than in those with diffuse vasospasm. It was suggested, under these conditions, the dramatically increased percent plaque volume in cases with focal vasoconstriction might play an important role in the development of acute coronary events.43 Miwa44 investigated LDL particle size in patients of VA. The study compared patients of effort angina with significant coronary stenosis (SEA), also in subjects without CAD (control) through the relative migratory distance of the predominant densitometric peak of LDL from that of very low-density lipoprotein (VLDL) to that of HDL in a 3% polyacrylamide gel electrophoresis. The detection rate of small, dense LDL (particle diameter <25.5 nm) or a relative migratory distance above 0.36 was significantly higher in VA group (57%) and SEA (39%) than in Control (20%). In SEA group, a higher value of TG was noted in the subgroup with the small, dense LDL as compared with the subgroup without. In contrast, in VA group, the level of TG was not significant difference between the subgroups with and without the small, dense LDL, although significantly lower serum levels of HDL-C and α-tocopherol were detected in the former. In 16 VA subjects, the concentrations of small, dense LDL was significantly decreased after an over 6-month angina-free period (from 69% to 31%). They thus led to the conclusion that patients with VA had smaller LDL particles, associated not with hypertriglyceridemia but low value of HDL-C and vitamin E.

In general, increased lipid oxidative stress has been implicated in the pathogenesis of coronary vasospasm and VA. The small, dense LDL with high susceptibility to oxidation and supersensitivity of the culprit vessel to vasoconstrictor via alteration of signal transduction in VSMCs may be associated to the genesis of VA.34,45

Connection of remnant lipoprotein particle and mid-band lipoprotein to VA

Miwa et al20 also confirmed that patients with active stage of VA had higher levels of remnant lipoprotein particle (RLP) than inactive patients with VA. High levels of RLP was regarded as a major risk factor of MI in patients with VA and connected to the disorder of TG enriched lipoprotein metabolism in which was considerably predisposed to oxidative stress.20,46 Similarly, patients’ population research suggested that RLP was also an major participating factor for SCD. Series studies verified that RLP unregulated Rho-kinase in coronary VSMCs, impaired endothelium-dependent vasorelaxation, highly vulnerable to oxidative modification and enhanced vasospastic response.47–49

Additionally, clinical study showed “the mid-band lipoprotein” observed between VLDL and LDL bands in the polyacrylamide disc gel electrophoretic analysis was frequently detected in patients with coronary vasospasm.50 The mid-band lipoproteins mainly consisted of VLDL remnant lipoproteins and impaired the effect of endothelium-dependent vasorelaxation, which was well-known to be atherogenic and easy to trigger spasm.48 Those studies were thus consistently underlined that disordered TG enriched lipoprotein metabolism with its convenience of increasing oxidative stress damage appears to be linked to the episodes of coronary vasospasm, suggesting a possible role in the pathogenesis of VA.51

Role of lipoprotein(a) in VA

Clinical study of small samples showed that the serum lipoprotein(a) levels in patients with coronary spasm (median of 17 mg/dl) was higher (P <0.01) than that control subjects (12 mg/dl) but lower (P <0.01) than that in patients with a fixed stenosis (23 mg/dl). The frequency of higher (>25 mg/dl) serum lipoprotein (a) levels was higher in patients with a fixed stenosis (46%, P <0.01) but not in patients with coronary spasm (27%), compared with control subjects (21%). Among the patients with coronary artery spasm, the incidence of higher lipoprotein(a) levels was higher in patients with prior MI than that in those without prior MI (56% vs. 21%, P <0.05). The patients with higher lipoprotein(a) levels had a higher incidence of prior MI than that those without (41% vs. 13%, P <0.05). The multivariate analysis confirmed that higher serum lipoprotein(a) level was an independent determinant for prior MI in these patients (odds ratio: 4.19: 95% confidence interval: 1.03 to 17.00). Thus, the relation of elevated lipoprotein(a) levels to coronary spasm appears to be weak, if any. The authors then led to conclusion that elevated lipoprotein(a) was associated with a history of MI in patients with coronary spasm, suggesting that lipoprotein(a) may play an important role in the genesis of thrombotic coronary occlusion and the occurrence of acute MI secondary to spasm. The author covered the underlying mechanism by the significant elevation of lipoprotein(a) in patients with coronary vasospasm might be acting synergistically with one or more other risk factors to produce the infarction.52

The recently study affirmed that lipoprotein(a) was significantly higher in the VA subject than in the control group (P <0.05). Multivariate regression analyses identified lipoprotein(a) as an independent marker for VA, and suggested that medical intervention to decrease lipoprotein(a) might be effective in controlling VA based on the hypothesis that lipoprotein(a) was correlated with endothelial damage and subsequently led to vasospasm.53,54

In summary, VA was either directly or indirectly associated with dyslipidemia through modified its capacity of preventing endothelial injury, oxidative stress, hypersensitivity of SMCs and inflammatory cascade.55 Lipid disorder especially a relatively lower plasma concentration and (or) malfunction of HDL-C and (or) apoA-I might be an independent determinant for the genesis of AV and its prognosis.4,36,55,56

Clinical implications

Dyslipidemia altered the underlying protective elements of native coronary endothelia, induced hyperactivity of SMCs and contributed to the occurrences of VA. As statins were prized at substantially improve endothelial function, antiinflammatory and inhibit oxidative stress effects, apart from direct effect of lipid intervention, prospective cohorts have confirmed that the additional statin to the conventional therapy significantly reduced the number of patients with reproduced coronary spasm as compared with the CCB therapy only.57 Thus, a standard therapeutic stratagem for VA should be included with statins on no contraindication due to the previous studies have indicated the intimate relevance of dyslipidemia and VA, as well as long-term nitrate therapy appended to CCBs cannot reduce cardiac events.

With the unraveling role of dyslipidemia in genesis of VA continues, further studies should be covered range from alteration of structure, function, concentration of lipids and lipoproteins to its precise mechanisms thus in favor of a more effective intervention for high-risk patient.


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vasospastic angina; dyslipidemia; therapy

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