Microvascular dysfunction: what have we learned from WISE?

Keywords::

• angina
• coronary flow reserve
• microvascular dysfunction
• WISE
• women

Ischemic heart disease remains a leading contributor of morbidity and mortality among women. Although the link between epicardial coronary artery disease (CAD) and adverse outcomes established over past decades is well known, a subset of patients with signs and symptoms of ischemia have no obstructive epicardial CAD. Emerging data show that subsets of patients, most of whom are women, present without important epicardial obstruction but with ischemia markers, suggesting that other pathophysiological mechanisms contribute to ischemia-related adverse outcomes. Accumulating evidence supports microvascular dysfunction (MVD) as an important component of the explanation for ischemia and its relation to adverse outcomes.

Among women with signs and symptoms of ischemia and angiographically ‘normal’ coronary vessels, MVD was first suggested in 1967 [1], and in 1983 inappropriate coronary flow increases to vasomotor stimuli were described [2]. The term ‘microvascular angina’ was proposed for patients with documented MVD by a limited coronary flow response to stimuli, such as rapid atrial pacing, adenosine and/or acetylcholine.

Although evidence for MVD has been presented for both women and men, women appear disproportionately represented for reasons that are incompletely understood. Perhaps estrogen or other genetic and environmental milieu contribute to the stunted development of epicardial obstructive lesions, but not the underlying microvascular pathology. Alternatively, perhaps such milieu amplify microvascular abnormalities in women.

MVD is related to the disordered function of small (<100–200 µm) coronary vessels, and recently, structural differences in microvasculature in women compared with men have been documented [3]. MVD appears to underlie the atherosclerosis disease process, as documented in experimental models. Although gender differences in coronary reactivity were previously recognized, specific mechanisms underlying these differences and links with adverse outcomes are incomplete.

An aim of the Women’s Ischemia Syndrome Evaluation (WISE), a multicenter NHLBI-sponsored project, is to better understand the pathophysiological mechanisms underlying MVD in women. Clinical outcomes and mechanisms contributing to MVD were examined in this prospective cohort. In this article, we will summarize information that has emerged from WISE.

In the WISE, evaluation of coronary reactivity, including MVD by invasive coronary techniques, included assessment of coronary flow reserve (CFR) with Doppler flow wire measurements of blood flow and quantitative measures of coronary artery size with adenosine, acetylcholine and nitroglycerin. Results demonstrated that approximately 50% of cases had reduced CFR (<2.5) and measurements were similar in both the left anterior descending and circumflex arteries, indicating a diffuse process that was not limited to a myocardial region. These conclusions were confirmed by PET studies. We also observed that coronary velocity closely reflected absolute blood flow because endothelial dysfunction, frequent among such women, limited flow-mediated dilation [4].

Data from WISE documented a poor prognosis among women with chest pain but no evidence of obstructive CAD compared with asymptomatic women [5], and this has recently been confirmed by others [6–8]. However, the exact mechanisms underlying this increased risk are unclear. Recent work from WISE evaluated the association between CFR and adverse cardiovascular outcomes. At 5 years, a significant independent association was found between impaired CFR and major adverse outcomes, defined as first occurrence of death, nonfatal myocardial infarction, nonfatal stroke or heart failure hospitalization. A CFR <2.32 best discriminated the threshold for adverse outcomes. Low CFR was associated with an increased risk for major adverse outcomes and improved the ability to predict adverse outcomes over angiographic CAD severity and other risk conditions. In addition, this impaired prognosis, related to low CFR, persisted in the majority of women without obstructive CAD [9].

Although the association between MVD and epicardial CAD remains unclear, one hypothesis is that MVD may be a precursor to epicardial atherosclerotic disease progression later on, as has been proposed for diabetic patients. Using intravascular ultrasound (IVUS) in a consecutive sample of 100 women with ‘normal’ angiograms confirmed evidence for coronary artery plaque in approximately 80%. In many cases the plaque was concealed by positive remodeling. Considering the sampling limitations of IVUS, it seems reasonable that most, if not all women with CAD risk conditions as in the WISE, have coronary atherosclerosis. Another WISE substudy investigated the relationship between MVD and IVUS measures of macrovasculature. IVUS measures of conduit coronary artery size predicted microvasculature bed size (CFR) in women without obstructive CAD.

In addition to these invasive studies, several noninvasive techniques have previously investigated stress perfusion limitations in the absence of obstructive CAD. These included echocardiography and PET. Most recently, cardiac MRI, owing to superior spatial resolution, has emerged. A recent WISE substudy found global magnetic resonance myocardial perfusion imaging (MR-MPI) measures (average uptake slope, ratio of MR-MPI peak signal amplitude to uptake slope and ejection fraction) predictive of adverse events [10]. In addition, WISE and other investigators have documented a limited increase in subendocardial perfusion with adenosine.

Another substudy evaluated ³¹P nuclear magnetic resonance (P-NMR) spectroscopy, a noninvasive technique to assess metabolic evidence of ischemia in myocardium. Myocardial high-energy phosphates were measured with P-NMR spectroscopy before, during and after isometric handgrip exercise at 30% maximal voluntary grip strength. Approximately 20% of the women with chest pain and no obstructive CAD had decreases in the phosphocreatine:ATP ratio during exercise compared with controls. These results demonstrate direct evidence for myocardial ischemia in at least some women with chest pain but no obstructive CAD [11]. Such findings were also linked to adverse outcomes [12].

A particularly intriguing and only recently studied area of pathophysiology within the area of MVD is the role of stem and/or progenitor (S/P) cells. Many subsets of S/P cells are involved in the regulation of vascular function known to be disordered in MVD. Since coronary microvascular tone is regulated in part by the endothelium, it has been suggested that endothelial dysfunction may play a role in microangiopathy. Endothelial progenitor cells and circulating endothelial cells have the potential for endothelial repair. In a sample of WISE women, CFR and circulating S/P count and function were investigated: women with MVD had lower numbers of CD34⁺ cells compared with healthy controls. In addition, CD34⁺ cells from women with CFR ≤2.5 exhibited significantly decreased CD34⁺ cell function (nitric oxide production and migration to stromal cell-derived factor-1) compared with women without reduced CFR. Further study of the role of these cells should provide insight into the pathophysiology of MVD [13].

Compared with women with obstructive CAD, those with evidence of MVD should receive a tailored approach to therapy. Although symptom management remains a cornerstone of therapy, treatment should also target prevention. The underlying MVD leading to ischemia may be modified by statins and, more recently, angiotensin-converting enzyme inhibitors. In a randomized, placebo-controlled substudy of WISE, women with symptoms and signs of ischemic heart disease and limited CFR had improved CFR and reduced angina, as women with lower CFR gained the most benefit [14]. Another substudy recently showed that adding an aldosterone inhibitor to angiotensin-converting enzyme inhibitors improved coronary endothelial function among women with MVD [15].

Another potential therapy is the phosphodiesterase (PDE-5) inhibitors. In WISE, a subgroup of women without CAD had baseline CFR measurements and repeat CFR measurements 45 min after 100 mg of the PDE-5 inhibitor sildenafil was administered. CFR increased from 2.7 ± 0.6 to 2.9 ± 0.6, and this increase remained significant after controlling for age, menopausal status, hypertension, diabetes and systolic blood pressure–heart rate product. The lower the baseline CFR, the greater the response was to PDE-5 inhibition. Further studies are needed, but PDE-5 inhibition may be useful for the management of MVD in symptomatic women without obstructive CAD [16].

Although progress has been made in our understanding of MVD, a great deal remains unclear. Perhaps most important is further investigation of noninvasive assessment, as well as cellular mechanisms underlying this condition so that therapies can be tailored. Results from WISE have tied together the effect of renin–angiotensin–aldosterone system inhibition on coronary reactivity [14,15], and add to our understanding of MVD and treatment. As discussed earlier, endothelial progenitor cells appear to play some role, but a related area of cell study involves vascular smooth muscle cells. These cells play an important role in vascular reactivity, and other investigations have noted interactions between these cells and endothelial progenitor cells [17]. Further work is needed to continue to elucidate these cellular interactions and their importance within this condition.

Another area of interest is the role of serotonin in regulation of the coronary microcirculation. With an intact endothelium, serotonin causes coronary dilation while inducing constriction when the endothelium is damaged [18]. These results suggest that platelet-derived factors such as serotonin may play different roles in coronary microcirculation regulation in health and disease. Our recent work suggests an association between the genetic regulation of serotonin through a serotonin transporter polymorphism and adverse outcomes in WISE [19]. Further work will provide continued insight into the regulation of serotonin and its effects on MVD.

In summary, women (and men) with signs and symptoms of ischemic heart disease with nonobstructive CAD remain a challenge. While advancements have been made, we are just beginning to understand the pathophysiology underlying this condition as well as tailoring treatments. Many of these innovative findings have stemmed from the WISE, which is now recruiting its second cohort of women. Although these findings have focused on women, they also appear to be applicable to men [8,20].

Financial & competing interests disclosure

C Pepine has received research grants from WISE (NIH/NHLBI U01 HL64829 and 5 R01 HL090957) and the Clinical and Translational Science Institute (NIH/NHLBI 5UL1 RR025208). The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

No writing assistance was utilized in the production of this manuscript.