Author + information
- Filippo Crea, MD⁎ ( and )
- Gaetano Antonio Lanza, MD
- ↵⁎Reprint requests and correspondence
: Dr. Filippo Crea, Istituto di Cardiologia, Università Cattolica del Sacro Cuore, Largo A. Gemelli, 8, 00168 Rome, Italy
Six decades ago Prinzmetal et al. (1) described a particular form of angina that occurred at rest, in the absence of any increase of myocardial oxygen demand, and was associated with ST-segment elevation on electrocardiography rather than with the usual ST-segment depression observed during effort angina. The investigators suggested that this “variant form of angina” was caused by a primary reduction of coronary blood flow consequent to an increased “tonus” of stenotic coronary arteries (1). Some years later, coronary angiographic studies showed that variant angina was indeed caused by coronary artery spasm (CAS) (2). Accordingly, it is now often referred as vasospastic angina (VSA).
CAS is defined as a sudden, intense, reversible vasoconstriction of a coronary artery branch resulting in subtotal or total occlusion. It can occur in stenotic or angiographically normal coronary segments, can be focal or diffuse, and can involve 1 or multiple epicardial coronary arteries.
VSA occurs frequently at night or in the early morning, but in some patients it prevails in the afternoon. Angina episodes may be sporadic or present in clusters and may spontaneously subside and then recur after a variable period of time. Triggers of CAS also differ among patients, with exercise, for example, inducing CAS in about 25% of patients with VSA. Importantly, CAS can cause life-threatening arrhythmias and sudden death, and prolonged CAS is a cause of acute myocardial infarction (3). Accordingly, a prompt diagnosis is mandatory to prevent these serious complications; yet, the diagnosis of VSA is often missed for months after symptom onset (4).
Of note, progress in this area has been limited, for 2 main reasons. First, the prevalence of VSA is low (1% to 1.5% of admissions for angina in Caucasian populations) (4), thus making the enrollment of large numbers of patients difficult. Second, calcium-channel blockers (CCBs) prevent CAS in the majority of patients, thus limiting the need for new forms of treatment. Yet, 10% to 20% of patients with VSA are refractory or develop poorly tolerated side effects to CCBs. Thus, elucidating the mechanisms of CAS might be important, as it might lead to development of new forms of treatment.
Pathogenesis of CAS
The pathogenetic substrate of CAS is constituted by a nonspecific hyper-reactivity to vasoconstrictor agents of smooth muscle cells (SMCs) in spastic coronary artery segments (5). Local SMC hyper-reactivity is suggested by the evidence that vasoconstrictor stimuli trigger CAS in patients with VSA but not in patients with other forms of angina and that, in patients with VSA, they trigger CAS in the spastic but not in the remaining coronary segments. Of note, CAS can be elicited in the same patient by several constrictor stimuli that act through different receptors. Accordingly, a specific receptor blocker is usually unable to prevent CAS, likely because it contrasts a single trigger, leaving the others unopposed. These observations suggest an intracellular, post-receptor localization of the alteration responsible for SMC hyper-reactivity (3).
In a porcine model of CAS, Shimokawa et al. (6) showed, for the first time, that a possible major intracellular determinant of SMC hyper-reactivity is increased activity of Rho-kinase, an enzyme that favors SMC fiber contraction through sensitization of myosin light chains to Ca2+. In this model, SMC Rho-kinase was indeed overexpressed, and a Rho-kinase inhibitor, hydroxyfasudil, prevented CAS induced by several vasoconstrictors (7).
The possible role of Rho-kinase in VSA was subsequently confirmed by the observation that pre-treatment with fasudil, a Rho-kinase inhibitor, prevented acetylcholine-induced CAS in these patients (8).
Rho-Kinase Activity in Peripheral Neutrophils and CAS
In this issue of the Journal, Kikuchi et al. (9) report exciting new data on the possible involvement of Rho-kinase in patients with VSA. They enrolled 53 consecutive patients with chest pain who showed nonsignificant (<50%) coronary stenoses on angiography. Patients underwent intracoronary acetylcholine testing and were then allocated to 2 groups: patients who developed CAS (VSA group, n = 33) and patients who did not develop CAS (non-VSA group, n = 20). Rho-kinase activity was measured in circulating neutrophils as the ratio of phosphorylated to total myosin-binding subunit of myosin phosphatase.
Neutrophil Rho-kinase activity was significantly higher in the VSA group than in the non-VSA group. In 21 patients with VSA, followed up after 3 months of CCB treatment, neutrophil Rho-kinase activity decreased significantly, and this was correlated with a significant reduction in symptoms.
The novel data provided by Kikuchi et al. (9) have important pathogenetic and clinical implications and, at the same time, raise some new stimulating questions in the still foggy area of CAS.
The demonstration that neutrophil Rho-kinase activity is increased in VSA patients (9) lends further support to the notion that enhanced Rho-kinase activity in SMCs may contribute to the pathogenesis of CAS.
Importantly, evidence from this and other studies that neutrophil Rho-kinase activity is also increased in other cardiovascular diseases, such as systemic and pulmonary hypertension, acute stroke, and stable angina, may have far-reaching consequences. This increase might well reflect the enhanced vasoconstriction that, in these diseases, is detectable in the systemic, pulmonary, cerebral, and epicardial coronary circulation, respectively. Accordingly, measurement of neutrophil Rho-kinase activity might open the way to new studies aimed at investigating the contributory role of SMC dysfunction in cardiovascular diseases. Indeed, although there are a great deal of data on the importance of endothelial dysfunction, very little is known about the role of SMC dysfunction.
With regard to VSA, however, the demonstration of systemic enhancement of Rho-kinase activity fails to explain the observation that CAS is usually localized to a specific coronary segment or branch, suggesting the presence of yet unknown local factors that cause local SMC hyper-reactivity by further enhancement of SMC Rho-kinase activity and/or by involvement of other constrictor pathways.
Kikuchi et al. (9) show that in patients with chest pain, a simple, noninvasive measurement such as neutrophil Rho-kinase activity might help identify those with VSA.
The investigators report, however, that neutrophil Rho-kinase activity was similarly increased in patients with chronic stable angina. Thus, although enhanced Rho-kinase activity seems able to identify patients in whom chest pain is caused by anatomic or functional alterations of epicardial coronary arteries, a careful assessment of clinical features remains crucial to discriminate patients with VSA from those with stable angina.
The positive predictive power for VSA of neutrophil Rho-kinase activity in the study by Kikuchi et al. (9) was 93%, using the cutoff value of phosphorylated myosin-binding subunit/total myosin-binding subunit ratio of 1.18, suggesting that this new biomarker might be particularly helpful in patients in whom VSA is suspected but 24-h ambulatory electrocardiographic monitoring fails to demonstrate transient episodes of ST-segment elevation. In these patients, the only way, at present, to demonstrate CAS is noninvasive ergonovine testing or invasive ergonovine or acetylcholine testing. If the data of Kikuchi et al. (9) are confirmed in future studies, assessment of neutrophil Rho-kinase activity might reduce the need for provocative tests, which can be performed only by experienced teams.
It should be observed, however, that the negative predictive power of the test was only 75%; thus, Rho-kinase activity below the best cutoff value identified in the study would not allow confident exclusion of a diagnosis of VSA.
Importantly, Kikuchi et al. (9) also found that a reduction of neutrophil Rho-kinase activity during CCB treatment paralleled symptomatic improvement. This finding suggests that this new biomarker might be useful to monitor disease activity. It also suggests that Rho-kinase might represent a valid therapeutic target for CAS prevention and that CCBs may in part act by reducing Rho-kinase activity (10). It remains to be established, however, whether Rho-kinase activity measurement improves the approach currently used to monitor VSA activity, based on symptom assessment and on ambulatory electrocardiographic monitoring (4).
A last interesting aspect of the study by Kikuchi et al. (9) concerns the group of non-VSA patients. Indeed, neutrophil Rho-kinase activity in these patients was significantly higher compared with that of a reference group of healthy controls (0.95 ± 0.22 vs. 0.58 ± 0.22, respectively, p < 0.001 by t test). This observation might suggest that at least some patients without VSA had microvascular angina, in which SMC hyper-reactivity is confined to coronary microcirculation. This working hypothesis deserves assessment in future studies.
Drs. Crea and Lanza have reported that they have no relationships relevant to the contents of this paper to disclose.
↵⁎ Editorials published in the Journal of the American College of Cardiology reflect the views of the authors and do not necessarily represent the views of JACC or the American College of Cardiology.
- American College of Cardiology Foundation
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