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Microvascular angina and systemic hypertension

Patients with systemic hypertension often experience chest pain despite the absence of obstructive coronary artery disease, which is caused by coronary microvascular dysfunction. Structural coronary microvascular abnormalities such as capillary rarefaction and functional mechanisms such as endothelial dysfunction are common causes for the development of angina pectoris in hypertensive individuals. In addition, in postmenopausal hypertensive women, oestrogen deficiency may also play a key pathogenetic role in microvascular angina. Treatment with ACE inhibitors and beta-blockers, in addition to aggressive tackling of all cardiovascular risk factors present in a given individual, often improves symptoms and reduces myocardial ischaemic events. Hormone replacement therapy with oestrogen should be considered in selected postmenopausal women. This treatment should be administered by specialist units, after careful characterisation of the patient’s hormonal status. Microvascular angina must be investigated in every patient with hypertension and chest pain not associated with obstructive coronary artery disease.



The clinical cluster of typical anginal chest pain, a positive response to stress testing and angiographically normal coronary arteries is relatively common in patients with systemic hypertension. Functional and structural mechanisms affecting the coronary microcirculation are often responsible for microvascular angina in patients with hypertension. Capillary rarefaction and left ventricular hypertrophy are common structural abnormalities responsible for microvascular dysfunction in hypertension. Among the functional abnormalities also contributing to microvascular angina, insulin resistance leading to endothelial dysfunction and oestrogen deficiency in post-menopausal women or women who have undergone hysterectomy are of particular relevance. The higher prevalence of microvascular angina in women than in men, and its relation to menopausal status (approximately 70% in large series) have led to the suggestion that oestrogen deficiency may play a pathogenetic role in the subgroup of peri- and post-menopausal women with angina and hypertension [1,2]. Similar considerations also apply to arterial hypertension, the incidence of which increases greatly in women after the menopause. The link between oestrogen deficiency and the development of microvascular angina and hypertension is complex and includes abnormal endothelial function, altered autonomic nervous system responses and the activation of the renin angiotensin aldosterone system (RAAS) [3].

Patients with arterial hypertension and microvascular angina [4,5] often show slow flow and tortuous coronary arteries, suggestive of small vessel “obstruction”.

Pathogenetic mechanisms

The mechanisms underlying angina pectoris in essential arterial hypertension patients without obstructive coronary artery disease are still largely unknown. Several functional pathophysiological abnormalities have been reported in these patients and have been postulated to represent the pathogenetic basis for angina in these patients, including endothelial dysfunction, increased sympathetic tone, microvascular spasm, oestrogen deficiency, psychological disorders, and increased pain sensitivity. Furthermore, hypertensive patients have a higher likelihood of presenting with features of the metabolic syndrome, e.g., hypertension, dyslipidaemia, obesity and insulin resistance, compared with the general population (30% versus 8%, respectively) [6]. This occurs more frequently in postmenopausal women. Insulin resistance, therefore, may represent an important mechanism for vascular dysfunction in this setting [7]. Structural abnormalities are also important, i.e., capillary rarefaction [8] as well as medial hypertrophy and/or fibrosis of arteriolar vessels.

Myocardial ischaemia triggered by functional and/or anatomical abnormalities in the coronary microcirculation has been documented in many studies using radionuclide myocardial perfusion techniques, coronary sinus oxygen saturation measurements and coronary sinus pH changes, and/or myocardial lactate production during pacing, as well as stress-induced alterations of cardiac high-energy phosphate, as assessed by magnetic resonance spectrometry. Both coronary microvascular spasm and/or a reduced microvascular vasodilator capacity have been demonstrated to cause myocardial ischaemia and anginal symptoms in patients with hypertension and microvascular angina [9].

Microvascular angina and endothelial dysfunction

The presence of endothelial dysfunction in patients with hypertension and microvascular angina has been suggested by a reduced coronary flow response to acetylcholine or atrial pacing and by inappropriate endothelial vasoconstrictor activity, mainly mediated by endothelin-1 (ET-1) production [10]. Indeed, increased plasma concentrations of ET-1 have been reported in patients with microvascular angina (cardiac syndrome X – CSX): these have been shown to correlate with coronary microvascular dysfunction. Moreover, ET-1 has been found to increase in the coronary circulation of patients with CSX in response to atrial pacing. However, other studies have shown an impairment of coronary microvascular dilation in response to endothelium-independent stimuli, such as adenosine, dipyridamole, and papaverine, suggesting primary abnormalities in the vascular smooth muscle cell that can lead to vasodilatory dysfunction and spasm [11].

Both coronary and peripheral microvascular dysfunction have been demonstrated in hypertensive patients with chest pain, normal-appearing coronary angiograms, and no left ventricular hypertrophy by echocardiography. Angina may occur in patients with arterial hypertension in the absence of epicardial coronary artery disease due to an abnormally elevated resistance of the coronary microvasculature [4].

Although impaired microvascular function and structure is generally considered to be the consequence of high blood pressure levels, there is evidence that microvascular changes, i.e., capillary rarefaction, and endothelial dysfunction may anticipate the clinical onset of arterial hypertension. This is supported by the finding of decreased capillary density in borderline hypertensive subjects and even in the normotensive offspring of hypertensive parents as well as the presence of endothelial dysfunction in the normotensive offspring of hypertensive patients.

Oestrogen deficiency

In the subgroup of peri- and post-menopausal women with hypertension, the cessation of ovarian function and the consequent oestrogen deficiency play a pathogenetic role [2,12]. Oestrogen deficiency negatively influences the cardiovascular system, favouring the development of cardiovascular disease. Oestrogen deficiency is associated with the loss of the direct protective effect of the hormone within the vessel wall and indirectly with negative changes in several other traditional risk factors for coronary artery disease, i.e., insulin resistance, blood cholesterol, body weight and insulin resistance. Oestradiol 17β has calcium channel blocking properties, thereby acting as an endothelium-independent vasodilator. Therefore, the loss of oestrogen negatively affects both endothelium-dependent and endothelium-independent vasodilatation with consequent effects on blood pressure, causing arterial hypertension and impairing coronary vasomotion. Oestrogen deficiency is one of the most important mechanisms leading to the development of arterial hypertension in postmenopausal women acting through several mechanisms [3].

Of interest, oestrogen deficiency has negative effects on the occurrence of chest pain in women with CSX, as low oestrogen levels are associated with an impaired function of the endogenous opioid system and of the gamma-aminobutyric acid (GABA) system. Indeed, low oestrogen concentrations reduce or suppress the production or release of endorphins and enkephalins, leading to increased pain perception [12]. This mechanism has been confirmed by the fact that oestrogen administration improves chest pain in patients with CSX. However, hyperreactivity of cardiac pain receptors, abnormal transmission and/or modulation of pain signals at subcortical level(s), or a variable combination of all these abnormalities, might equally account for the abnormal activation of specific cerebral areas, a lower pain threshold and psychological instability.

Management of microvascular angina in hypertensive patients

Evidence-based guidelines for treating CSX are still lacking. This due partly to the lack of a clear understanding of the pathophysiology of the syndrome and partly to the lack of sufficiently powered randomised controlled trials conducted in these patients. Traditionally, the prognosis of patients with CSX was considered to be benign. However, the Women’s Ischaemia Syndrome Evaluation (WISE) study showed that women with persistent chest pain had twice the rate of composite cardiovascular events, including non-fatal myocardial infarction, stroke, congestive heart failure, and cardiovascular deaths, compared with those without [13].

A comprehensive prevention program includes recommendations on lifestyle modification (diet, exercise, body weight reduction, quitting smoking, behavioural and psychosocial issues) that may positively improve endothelial function and microvascular dysfunction. In particular, reduction of body weight in postmenopausal women with hypertension and microvascular angina is an important aim due to the positive effects of weight loss on both blood pressure and insulin resistance. ACE inhibitors are the therapy of choice in this setting, given their beneficial effects on blood pressure, endothelial function and exercise-induced ischaemia in CSX.

In addition, ACE inhibitors may counteract the hyperactivity of the RAAS observed in patients with arterial hypertension, particularly in the subgroup of postmenopausal women, and in those with CSX, as first shown by Kaski et al [14].

Interestingly, drugs working on a similar pathway, i.e., the angiotensin II receptor, type I, antagonist irbesartan, did not show significant subjective or objective improvement in patients with CSX [15]. The activation of the bradikynin axis by ACE inhibitors may be the reason for the different responses to these agents.

Beta-blockers have been shown to reduce the frequency and severity of angina and to improve exercise tolerance in patients with CSX. Newer beta-blockers with a positive effect on NO release, such as carvedilol and nebivolol, are likely to be more effective in this context [16].


Systemic hypertension is often associated with microvascular angina. Several pathogenetic mechanisms have been identified which represent suitable targets for treatment. Microvascular dysfunction needs to be investigated (and treated if present) in patients with systemic hypertension, angina and angiographically normal coronary arteries.


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Notes to editor


Dr Cristiana Vitale, MD, PhD

Department of Medical Sciences, IRCCS San Raffaele Pisana, Rome, Italy

Professor Juan Carlos Kaski, DSc, MD, DM (Hons), FRCP, FESC, FACC, FAHA

Cardiovascular and Cell Sciences Research Institute, St George’s, University of London, London, United Kingdom

Author for correspondence:

Prof. Juan Carlos Kaski

Cardiovascular and Cell Sciences Research Institute,

St George’s, University of London,

Cranmer Terrace,


SW17 0RE,

United Kingdom

Tel. no. + 44 208 725 6879

Fax no. + 44 208 725 3416


Conflict of interest:

Regarding this manuscript, the authors declare having no conflicts of interest

The content of this article reflects the personal opinion of the author/s and is not necessarily the official position of the European Society of Cardiology.