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Available online at www.sciencedirect.com

www.elsevier.com/locate/tcm

Seeing is believing: New updates on coronary microvascular dysfunction “Seeing is believing.” This idiom certainly holds true when it comes to the topic of the coronary circulation. The epicardial vasculature has always captured widespread attention; after all, it is the site of acute coronary syndromes. It has also been considered to be the main culprit of abnormal stress tests and anginal symptoms. Reflections of myocardial ischemia such as these, however, are the consequence of a mismatch between oxygen/nutrient supply and demand, and this could be for various reasons, far beyond the scope of epicardial coronary artery disease. Indeed, the myocardial cells are intertwined with the coronary microcirculation, and functional or structural compromise on this level would lead to the same ischemic end result as functional or structural obstruction of the epicardial circulation. Yet, our inability to visualize the microcirculation with standard imaging techniques has left us with a lack of concrete evidence commonly required to convince us. Thus, the coronary microcirculation has remained as mysterious now as it always has been and likely always will [1]. Against this background, one can respond in no other way but in appreciation of how this topic is presented in an updated manner by Drs. Petersen and Pepine [2] in this edition of Trends in Cardiovascular Medicine. Indeed, one might want to take note of a number of very important points as they arise. First of all, they do recommend abandoning the term “cardiac syndrome X” as they see no definition consensus. The most commonly used definition has been the triad of angina, positive stress testing, and normal coronary arteries on angiography [3]. Certainly, cardiac syndrome X is not synonymous with microvascular dysfunction or even microvascular angina. However, for some providers, this terminology allowed them to provide a working diagnosis without any further testing. Deserting this terminology may thus leave patients referred to the cardiac catheterization laboratory with signs and symptoms of ischemia but without evidence of obstructive coronary artery disease (CAD) on

angiography with descriptive terms such as “angina with normal coronaries.” Importantly, these case scenarios are not infrequent; in fact, they apply to approximately 50% of patients undergoing coronary angiography [1]. Furthermore, these individuals consume medical resources that “rival” those of patients with obstructive CAD, as elegantly phrased by Drs. Petersen and Pepine [4]. Having made the point that additional testing in these patients is pertinent to their care, the question arises which techniques should be used. A preconceived notion is that resources would be required that are not readily available or desirable in many hospitals. With the widespread use of fractional flow reserve (FFR), however, there is now a level of familiarity with adenosine that could be leveraged upon. Even more, there is a level of synergism that could be utilized in using both a pressure sensor for FFR and a Doppler probe for coronary flow velocity reserve (CFVR) assessment. The former will address first and foremost epicardial disease severity, whereas the latter will extend the evaluation to the entire coronary circulation including the microvasculature. Indeed, a recent study utilizing this approach noted discordant results of FFR and CFVR in approximately onethird of the patients [5]. An abnormal CVFR reserve in the presence of a normal FFR was less common (only 6–14% depending on FFR cutoffs), but these patients had the worst prognosis with 80% experiencing major adverse cardiac events (including cardiac death, myocardial infarction, and need for revascularization) by 5 years. Studies such as these do offer insight into scenarios that are encountered and contended in clinical practice, e.g., cases of “positive” noninvasive stress test and “negative” coronary angiogram. They also underscore the fact that a not insubstantial burden of microvascular disease is even present in (nearly half of) patients with significant CAD [6]. This may explain why approximately 20% of CAD patients still continue to have angina even after complete epicardial revascularization [7].

This work was in part supported by funding from the National Institutes of Health, National Heart Lung and Blood Institute, USA (1K08HL116952-01A1). The authors have indicated there are no conflicts of interest. http://dx.doi.org/10.1016/j.tcm.2014.10.009 1050-1738/& 2014 Published by Elsevier Inc.

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Additional testing of the functional status of the coronary circulation based on the response to adenosine, which acts on the very end of the functional cascade and thus tests the integrity of the entire coronary artery system, is therefore an adjunctive assessment that is of great clinical value and can be easily and safely implemented as a deviation from present day FFR assessments. Other additional testing modalities such as intracoronary acetylcholine testing are useful to define the endothelium-dependent component of microvascular dysfunction in any given patient as well as the presence and extent of epicardial endothelial dysfunction [8]. Profound vasoconstriction, i.e., vasospasm, can also be the consequence of and thus be provoked by other constricting stimuli for vascular smooth muscle such as those acting via the 5-hydroxytryptamine (5-HT) receptors, e.g., methylergonovine (Methergines) [9]. Both, acetylcholine and methylergonovine are relatively safe. Studies in Japan outlined an incidence of bradycardia and ventricular tachycardia/fibrillation events of 2% and 3%, respectively [10]. Of note, these arrhythmic events were several times more common with acetylcholine than ergonovine. This is in the context of more extensive, even multi-vessel vasoconstrictive responses to acetylcholine that were noted in this population. Vasoreactivity studies as performed in the WISE trial and limited to the LAD with local injection and infusion of adenosine and acetylcholine carries a risk of only 0.7% of major complications (coronary artery dissection and myocardial infarction) and less than 1% of arrhythmias [11,12]. The yield from such testing is that at least 50% of patients referred to the catheterization laboratory but found to have normal coronary arteries would be noted to have coronary vascular dysfunction on epicardial and/or microvascular level, capable of causing ischemia with provocative testing [13]. Interestingly, a similar proportion of patients who were “ruled out” for CAD by positron emission tomography (PET) rest/stress testing had evidence of reduced coronary flow reserve [14]. Importantly, the proportion was the same in men and women, and thus microvascular disease is no longer solely a “women's heart disease.” While PET remains the best non-invasive modality for the assessment of this population, its availability likely remains a limiting factor for many hospitals [1]. Moreover, this modality carries even further from the “seeing is believing” reality, and the ability to visually demonstrate epicardial coronary vasoconstriction and coronary slow flow is an advantage for the invasive assessment in addition to direct measurements of flow and flow velocity in the coronary artery. Once altered coronary vasofunction is confirmed, even more challenging questions arise, e.g., how this information will impact prognosis. Indeed, this question is at the core of the clinical significance of this entire topic, has generated a fair amount of debate, and has been subject to a number of recent studies. The major update provided by these studies is that coronary microvascular dysfunction is a powerful predictor for adverse outcomes [15]. It is present even before the development of epicardial CAD in diabetic patients and portrays a 11 times higher annual risk of death or nonfatal myocardial infarction [16]. Even in patients with established CAD, microvascular dysfunction alone was associated with a more than 3-times higher mortality risk [6]. Furthermore,

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coronary microvascular dysfunction predisposes to the development of heart failure, and as pointed out by Drs. Petersen and Pepine, a link to heart failure with preserved ejection fraction (HFpEF) is of particular interest. Indeed, a novel paradigm has emerged in that comorbidities would drive HFpEF though coronary microvascular endothelial dysfunction [17]. Almost to be viewed as an overlap of cardiomyopathy and acute coronary syndrome, apical ballooning syndrome has its own stand, with microvascular dysfunction having been implied as a contributing mechanism. One of the most supporting pieces of evidence resides in the fact that coronary microvascular dysfunction is impaired in the acute stage and improves before the resolution of regional wall motion abnormalities [18]. As impairment of microvascular function has been noted in acutely decompensated heart failure as well and improves with heart failure treatment, one may wonder how unique this mechanism truly is to apical ballooning syndrome [19]. Furthermore, a very recent report indicates that coronary microvascular dysfunction is still evident in 90% of patients, days to years out from presentation and recovery from apical ballooning syndrome [20]. Thus, rather than relying on reverse reversibility dynamics of microvascular and cardiac function, one would have to note the opposite and ideally prove that coronary microvascular dysfunction is the primary cause and not a secondary phenomenon. The other challenging question in response to the diagnosis of microvascular dysfunction is how much it relates to the presenting symptoms of the patient and how it could be treated to improve symptoms and prognosis. Drs. Petersen and Pepine point out ivabradine and ranolazine as new developments for symptom control. Otherwise, standard anti-anginal agents continue to be the mainstay of therapy with beta-blockers as a preferable choice for patients with a high sympathetic tone. Beyond symptom control, some authors have suggested that treatment with “anti-anginals” such as calcium channel blockers may even curtail cardiovascular events [21]. However, as Drs. Petersen and Pepine point out, the impact of therapy on a potential reduction of future events remains to be studied. Statins are to be considered, as they may not only improve coronary microvascular function but also any concomitant CAD [22]. In fact, CAD is frequently present in these patients, and this is a point well made by Drs. Petersen and Pepine in their article as well. In the WISE trial alone, 80% of women with socalled normal coronary arteries had evidence of atherosclerosis by intravascular ultrasound. How much of the unfavorable prognosis of patients with microvascular disease relates to unrecognized macrovascular disease is unknown and is subject to future studies.

Summary In 2014, we have realized that coronary microvascular dysfunction is a complex clinical scenario generated by many different mechanisms and leading to various presentations (Fig.). Therapy is to be directed to all of these aspects to improve not only the quality of life but also prognosis. Recognizing the potential prognostic implications of this entity may be one of the biggest advances, and it should provide sufficient momentum to more routinely evaluate

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Angina, chronic stable

Posive Stress Test

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Fig – Conceptual illustration of coronary microvascular dysfunction (MVD): mechanism and consequences. EF denotes ejection fraction.

the functional status of the coronary microcirculation in clinical practice.

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re fe r en ces [16] [1]

Herrmann J, Kaski JC, Lerman A. Coronary microvascular dysfunction in the clinical setting: from mystery to reality. Eur Heart J 2012;33:2771–81. [2] Petersen JW, Pepine CF. Microvascular coronary dysfunction and ischemic heart disease—where are we in 2014? Trends Cardiovasc Med 2014;24. [3] Lanza GA. Cardiac syndrome X: a critical overview and future perspectives. Heart 2007;93:159–66. [4] Jespersen L, Abildstrom SZ, Hvelplund A, Galatius S, Madsen JK, Pedersen F, et al. Symptoms of angina pectoris increase the probability of disability pension and premature exit from the workforce even in the absence of obstructive coronary artery disease. Eur Heart J 2013;34:3294–303. [5] van de Hoef TP, van Lavieren MA, Damman P, Delewi R, Piek MA, Chamuleau SA, et al. Physiological basis and long-term clinical outcome of discordance between fractional flow reserve and coronary flow velocity reserve in coronary stenoses of intermediate severity. Circ Cardiovasc Interv 2014;7:301–11. [6] van de Hoef TP, Bax M, Damman P, Delewi R, Hassell ME, Piek MA, et al. Impaired coronary autoregulation is associated with long-term fatal events in patients with stable coronary artery disease. Circ Cardiovasc Interv 2013;6:329–35. [7] Tonino PA, De Bruyne B, Pijls NH, Siebert U, Ikeno F, van' t Veer M, et al. Fractional flow reserve versus angiography for guiding percutaneous coronary intervention. N Engl J Med 2009;360:213–24. [8] Herrmann J, Wohlert C, Saguner AM, Flores A, Nesbitt LL, Chade A, et al. Primary proteasome inhibition results in cardiac dysfunction. Eur J Heart Fail 2013;15:614–23. [9] Hamilton KK, Pepine CJ. A renaissance of provocative testing for coronary spasm? J Am Coll Cardiol 2000;35:1857–9. [10] Takagi Y, Yasuda S, Takahashi J, Tsunoda R, Ogata Y, Seki A, et al. Clinical implications of provocation tests for coronary artery spasm: safety, arrhythmic complications,

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and prognostic impact: multicentre registry study of the Japanese Coronary Spasm Association. Eur Heart J 2013; 34:258–67. Wei J, Mehta PK, Johnson BD, Samuels B, Kar S, Anderson RD, et al. Safety of coronary reactivity testing in women with no obstructive coronary artery disease: results from the NHLBI-sponsored WISE (Women's Ischemia Syndrome Evaluation) study. JACC Cardiovasc Interv 2012;5:646–53. Ong P, Athanasiadis A, Borgulya G, Vokshi I, Bastiaenen R, Kubik S, et al. Clinical usefulness, angiographic characteristics, and safety evaluation of intracoronary acetylcholine provocation testing among 921 consecutive white patients with unobstructed coronary arteries. Circulation 2014;129:1723–30. Ong P, Athanasiadis A, Borgulya G, Mahrholdt H, Kaski JC, Sechtem U. High prevalence of a pathological response to acetylcholine testing in patients with stable angina pectoris and unobstructed coronary arteries. The ACOVA Study (Abnormal Coronary Vasomotion in patients with stable angina and unobstructed coronary arteries). J Am Coll Cardiol 2012;59:655–62. Murthy VL, Naya M, Taqueti VR, Foster CR, Gaber M, Hainer J, et al. Effects of sex on coronary microvascular dysfunction and cardiac outcomes. Circulation 2014;129:2518–27. Nakanishi K, Fukuda S, Shimada K, Miyazaki C, Otsuka K, Maeda K, et al. Impaired coronary flow reserve as a marker of microvascular dysfunction to predict long-term cardiovascular outcomes, acute coronary syndrome and the development of heart failure. Circ J 2012;76:1958–64. Cortigiani L, Rigo F, Gherardi S, Galderisi M, Bovenzi F, Sicari R. Prognostic meaning of coronary microvascular disease in type 2 diabetes mellitus: a transthoracic Doppler echocardiographic study. J Am Soc Echocardiogr 2014;27:742–8. Paulus WJ, Tschope C. A novel paradigm for heart failure with preserved ejection fraction: comorbidities drive myocardial dysfunction and remodeling through coronary microvascular endothelial inflammation. J Am Coll Cardiol 2013;62:263–71. Jain M, Upadaya S, Zarich SW. Serial evaluation of microcirculatory dysfunction in patients with Takotsubo cardiomyopathy by myocardial contrast echocardiography. Clin Cardiol 2013;36:531–4. Lauten A, Ferrari M, Goebel B, Rademacher W, Schumm J, Uth O, et al. Microvascular tissue perfusion is impaired in acutely decompensated heart failure and improves following standard treatment. Eur J Heart Fail 2011;13:711–7. Patel SM, Lerman A, Lennon RJ, Prasad A. Impaired coronary microvascular reactivity in women with apical ballooning syndrome (Takotsubo/stress cardiomyopathy). Eur Heart J Acute Cardiovasc Care 2013;2:147–52. Ohba K, Sugiyama S, Sumida H, Nozaki T, Matsubara J, Konishi M, et al. Microvascular coronary artery spasm presents distinctive clinical features with endothelial dysfunction as nonobstructive coronary artery disease. J Am Heart Assoc 2012;1:e002485. Eshtehardi P, McDaniel MC, Dhawan SS, Binongo JN, Krishman SK, Golub L, et al. Effect of intensive atorvastatin therapy on coronary atherosclerosis progression, composition, arterial remodeling, and microvascular function. J Invasive Cardiol 2012;24:522–9.

Joerg Herrmann, MD Division of Cardiovascular Diseases Department of Internal Medicine Mayo Clinic, Rochester, MN 55905

Seeing is believing: new updates on coronary microvascular dysfunction.

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