Sex-Specific Factors in Microvascular Angina

Abstract

Among women presenting for evaluation of suspected ischemic symptoms, a diagnosis of normal coronary arteries is five times more common, as compared to men. These women are often labeled as cardiac syndrome X (CSX), a subset of which have microvascular angina (MA) due to microvascular coronary dysfunction (MCD). MCD is not benign and is associated with an annual 2.5% cardiac event rate. Non-invasive testing for MCD remains insensitive although newer imaging modalities such as adenosine cardiac magnetic resonance imaging (CMRI) appear promising. The gold standard for diagnosis of MCD is coronary reactivity testing (CRT), an invasive technique which is not available in many countries. With regard to treatment, large scale trials are lacking. While research is ongoing, the current platform of therapy consists of anti-anginal, anti-platelet and endothelial modifying agents (primarily angiotensin converting enzyme inhibitors and statins).

Introduction

Among women presenting for evaluation of suspected ischemic symptoms, a diagnosis of normal coronary arteries is five times more common, as compared to men.¹ Other studies demonstrate that women are less likely than age-matched men to have obstructive coronary artery disease (CAD).² These women are often labeled as cardiac syndrome X (CSX), defined as the triad of chest pain, abnormal stress testing consistent with ischemia and absence of obstructive CAD (i.e. ≥50% stenosis in ≥ 1 coronary artery) on coronary angiography.³

CSX is classically acknowledged as a female predominant disorder and nearly 70% of patients diagnosed as having CSX are women.⁴ Among subjects suspected to have myocardial ischemia and referred for clinically indicated coronary angiography, 41% of women versus only 8% of the men studied showed non-significant epicardial CAD.¹ The large Coronary Artery Surgery Study (CASS) of nearly 25,000 subjects evaluated after undergoing angiography, further points towards the female predominance of having chest pain with normal coronary arteries.⁵ More recently, similar results have been described with coronary computed tomographic angiography (CCTA).⁶

Symptom-driven care for women in the absence of obstructive CAD is substantial.⁷ For women with signs and symptoms of ischemia but no obstructive CAD the average lifetime cost for ischemic heart disease (IHD) is $ 767,288, comparable to the magnitude of more than $1 million dollars for women with obstructive CAD. Based on these data, we have estimated the societal economic burden for CAD care for women with angina could exceed $162 billion dollars annually in the US, with approximately half of this expenditure on women with no obstructive CAD.⁷ While some studies on ongoing in this area, there is a clear need for future research on microvascular angina and some suggestions for future research ideas are presented in Table 1.

Table 1.

Five Top Research Questions for Microvascular Coronary Dysfunction

Research Question	How Questions May Be Addressed
What is the best approach for noninvasive diagnosis?	Compare a non-invasive modality such as CMRI to invasive CRT to determine sensitivity and specificity
What is the best intervention for symptom management?	Clinical Trial in symptomatic MCD women of several different anti-anginals compared to placebo monitoring response with angina questionnaires
Do various interventions reduce major adverse cardiac events?	Clinical trial of medications such as statins, ACEI, aspirin compared to placebo to determine whether outcomes are improved
What are novel mechanistic pathways for MCD?	Pathophysiological study evaluating cardiac autonomic nervous system, smooth muscle regulation, endothelial progenitor cells, cytokine balance and vascular inflammation in MCD
What are novel treatment targets for MCD?	Pilot clinical trials with autonomic nervous system regulation, novel smooth muscle agents, stem cell therapy and autoimmune biologics in MCD subjects

Pathogenesis

A subset of patients with CSX have microvascular angina (MA)⁸ENREF 8 due to microvascular coronary dysfunction (MCD). The conditions of CSX and its subentity MA due to MCD, are increasingly investigated yet full elucidation of their pathogenesis remains lacking. Despite the considerable effort of research over the last 4 decades⁹, there is no universally accepted understanding of the pathogenesis of signs and symptoms of ischemia and no obstructive CAD.^9,10 Suggested mechanisms^9-11 of CSX include altered regulation of coronary microcirculation through autonomic dysregulatory and endothelial mechanisms, generalized vascular disorder and abnormal subendocardial perfusion. Other suggested contributing factors include inflammation, hyperinsulinemia, enhanced sodium-hydrogen exchange, hormonal deficiency, abnormal pain perception and lastly inherent pathogenetic pathways.

MA due to MCD appears to be a major etiologic mechanism underlying chest pain evoked by ischemia in patients with CSX (Figure 1). It refers to abnormalities in the vasomotor or metabolic regulators of the smaller resistance coronary arterioles (<500um), although structural abnormalities of the microcirculation (for example smooth muscle cell hypertrophy) have been described by some¹², but not all studies.¹³ Although small coronary arterioles are not visualized during coronary angiography, they are the major determinants of coronary vascular resistance.¹⁴ Experimental studies and clinical observations emphasize the role of sex differences in microvascular pathophysiology.¹⁵ Evidence from autopsy data suggests that women may have a higher frequency of coronary plaque erosion and microembolization¹⁶, which could result in greater MCD. Results from retinal photography implicate sex-specific dysfunction of the microvasculature. Retinal arterial narrowing, a measure of microvascular disease, is related to cardiovascular disease risk and mortality in women but not in men.¹⁷

Figure 1.

Model of Microvascular Angina in Women. HTN=hypertension, PCOS=polycystic ovary syndrome (reprinted with permission from Shaw LJ, Bugiardini R, Merz CN. Women and ischemic heart disease: evolving knowledge. Journal of the American College of Cardiology 2009;54:1561-75⁵⁹)).

Diagnosis

Non-invasive Testing

Non-invasive testing for MCD remains insensitive although newer imaging modalities such as adenosine cardiac magnetic resonance imaging (CMRI) appear promising as more sensitive for detection of the ischemic cascade (Figure 2).

Figure 2.

Cascade of Mechanisms and Manifestations of Ischemia Impacting IHD Risk in Women (reprinted with permission from Shaw LJ, Bugiardini R, Merz CN. Women and ischemic heart disease: evolving knowledge. Journal of the American College of Cardiology 2009;54:1561-75⁵⁹).

Exercise treadmill testing (ETT)

ST depression on standard ETT was the cornerstone to CSX diagnosis in the past. True microvascular pathology such as that seen in MCD, is not always captured on ETT however. In 1992, Camici et al. examined the correlation between the ECG during exercise stress and coronary vasodilator reserve by 13N-labeled ammonia and positron emission tomography in 45 patients with chest pain and normal coronary arteries.¹⁸ They reported good sensitivity (86%) in identifying patients with a blunted coronary flow reserve but poor specificity (45%).

Traditional stress imaging

Traditional cardiovascular imaging techniques are limited in their ability to image vessels <500um in diameter. Therefore, stress imaging techniques such as stress echocardiography and nuclear perfusion stress testing remain insensitive in diagnosing MCD. Kaski et al. studied 99 patients with angina and normal coronary arteries.⁴ While transient ST depression on ETT was observed in 65% of patients, only 22% had abnormalities on nuclear myocardial perfusion imaging. Further, Nihoyannopoulos et al. studied stress echo in a similar population and reported that all patients with ST depression on ETT had a normal stress echo.¹⁹

Cardiac Magnetic Resonance Imaging (CMRI)

CMRI offers several advantages over traditional imaging techniques in the diagnosis of MCD. CMRI allows evaluation of subendocardial perfusion, fibrosis and microinfarction, assessment of left ventricular function and mass and measurement of myocardial flow reserve using a myocardial perfusion reserve index (MPRI). Lanza et al. compared CMRI and invasive coronary reactivity testing with adenosine in 18 CSX patients and 10 healthy controls.²⁰ Reversible perfusion defects on CMRI were found in 56% of CSX patients and 0% of controls. Further, CSX patients with CMRI perfusion defects had a lower CFR by invasive testing than those without perfusion defects. A large-scale NHLBI funded trial comparing CMRI and CRT with regard to sensitivity and specificity is ongoing and will provide future insights into this promising modality.

Invasive Testing

Coronary reactivity testing (CRT)

CRT is the gold standard technique for the diagnosis of MCD. Intra-coronary infusion of adenosine, acetylcholine and nitroglycerin allows assessment of microvascular and macrovascular endothelial and nonendothelial pathways and provides therapeutic targets for patients with MCD. The normal response to intra-coronary infusion of adenosine is a ≥2.5 increase in coronary flow reserve (CFR). Therefore, a CFR of <2.5 defines MCD and examines the non-endothelial dependent microvascular pathway. Acetylcholine uniformly dilates both the microvasculature and macrovasculature in an endothelial-dependent fashion. The normal response to acetylcholine is an increase in coronary blood flow (CBF) of >50% above baseline and endothelial dysfunction may be manifest by a significant attenuation, no change or even a decrease in CBF. Finally, nitroglycerin tests the non-endothelial macrovascular pathway and lack of a response to nitroglycerin may indicate smooth muscle dysfunction. A recommended diagnostic and management approach for MCD including when to refer for coronary reactivity testing provided in Figure 3.

Figure 3.

Recommended algorithm for the management of patients with suspected microvacular coronary dysfunction.

CAD= coronary artery disease; MI= myocardial infraction

* Empiric therapy may include anti-anginals anti-platelets and/or endothelial modifying agents

Intravascular ultrasound

While MCD patients by definition will have minimal CAD on standard coronary angiography, several studies have demonstrated significant atherosclerosis by intravascular ultrasound (IVUS).^21,22 Khuddus et al. examined IVUS in 100 women with non-obstructive CAD (<50% stenosis in any epicardial artery). While 70% had no CAD on angiography, 79% had atherosclerosis on IVUS.²¹ This highlights one of the limitations of standard angiography in defining plaque burden in women.

Prognosis

Since the early 1970s, several studies have examined the prognosis of patients with angina symptoms suggestive of ischemia but without any evidence of obstructive CAD based on coronary angiography. The findings of these studies have been inconsistent, and to a large extent, not directly comparable due to a number of factors including, the differences in their patient populations under study (e.g. only including patients with no CAD or “normal” coronaries vs. including patients with nonobstructive CAD-mainly defined as <50% stenosis in any epicardial coronary artery), exclusion criteria (e.g. exclusion of patients with prior cardiovascular disease), follow-up time, or the differences in their outcome of interest (i.e. definition of major adverse cardiac event).

One of the earliest studies on the long-term outcome of CSX patients was based on the CASS registry, which included 4,051patients with normal or near normal (<50% stenosis) coronary arteries. Based on this study, Kemp et al. found that the prognosis of these patients was favorable with a 7-year survival rate of 96% and 92%, respectively.²³ Similarly, other earlier studies focusing only on patients with angiographically normal coronary arteries, have also reported good long-term prognosis with low rates of mortality and morbidity.^24,25 A meta-analysis comprised of 16 such studies, mainly with small sample sizes, has estimated a pooled rate of 1.5% per 5 years for major adverse cardiac events (death, myocardial infarction and revascularization).²⁶

However, more recent and larger studies have shown that the prognosis of patients with angina symptoms but without evidence of obstructive CAD is not as benign as it was once thought to be. Gulati et al. identified 540 women with stable angina but normal or nonobstructive CAD (< 50% stenosis), based on the Women’s Ischemia Syndrome Evaluation (WISE) study cohort, and compared their adverse cardiac outcomes to 1000 age- and race-matched asymptomatic women without any previous evidence of CAD.²⁷ The findings indicated that the 5-year rate of major adverse cardiovascular events (MACE) outcomes (i.e. hospitalization for myocardial infarction, heart failure, stroke, or cardiovascular death) were 3 fold higher in symptomatic women with normal coronary arteries and approximately 8 fold higher in symptomatic women with nonobstructive CAD, as compared to asymptomatic women without CAD (7.9% and 16.0% vs. 2.4%, respectively). This difference remained statistically significant even after adjusting for the baseline differences in patient’s risk profile. Of note, an age-stratified sub analysis of the findings, indicated that the difference in risk of MACE between women with normal coronaries and asymptomatic women without CAD, was only significant among younger patients, not among patients >62 years of age.

Furthermore, a Danish study by Jespersen et al. evaluated MACE outcomes (i.e. hospitalization for myocardial infarction, heart failure, stroke, or cardiovascular death) of 11,223 men and women with stable angina, as the indication for undergoing their first angiography, but with no evidence of obstructive CAD (< 50% stenosis).²⁸ The authors found that, regardless of sex, symptomatic patients with normal or nonobstructive CAD had elevated risk of MACE, as compared to a reference asymptomatic population selected from the Copenhagen City Heart study, with a pooled hazard ratio of 1.52 (95% CI: 1.27, 1.83) and 1.85 (95% CI: 1.51, 2.28), respectively. Similar to the findings of the study by Gulati et al., the increase in risk of MACE in symptomatic patients without obstructive CAD was driven primarily by re-hospitalization for heart failure.

Sex Differences in Adverse Outcomes

The current understanding of sex differences in outcomes of patients with angina and no evidence of obstructive CAD is limited. Although, the findings of the WISE study have greatly contributed to a better understanding of the pathophysiology as well as the risk and predictors of adverse outcomes of these patients, the WISE study population was comprised of women only. Subsequently, a few studies have extended the findings of the WISE study by highlighting important sex differences in this area of research.

A study by Humphries et al., in a large population-based setting, assessed the outcomes (re-hospitalization for ACS or chest pain) of 3,647 patients who underwent coronary angiography with an indication of stable angina or acute coronary syndrome but had angiographically normal coronaries.²⁹ The patients were identified using the BC Cardiac Registry, which collects information on all coronary angiography procedures performed in British Columbia, Canada. The authors found that, despite the overall favorable prognosis within the first year following initial angiography (1.0% died, 0.6% had stroke and 0.1% underwent revascularization), women were 4 times more likely to be re-hospitalized with a diagnosis of ACS or chest pain requiring angiography within the first 6 months. This difference remained significant even after adjusting for age and cardiac risk factors. Based on the same data source, Sedlak et al. evaluated the outcomes of 4,184 women and 9,511 men with chest pain and normal or nonobstructive coronary disease (<50% stenosis). Unlike the study by Humphries et al., this study was based on patients with stable angina as the indication for undergoing coronary angiography. Although the findings indicated that patients with normal coronaries had low 1- and 3-year MACE rates, Sedlak et al. found that the prognosis of those with nonobstructive CAD, particularly women, was not benign. As compared to patients with no CAD, women with nonobstructive CAD had a 3.5 times greater hazard of MACE (i.e. hospitalization for myocardial infarction, heart failure, stroke, or all-cause mortality) within the first year post angiography (HR=3.58; 95%CI: 1.87, 6.86) (Figure 4)³⁰. In contrast, the hazard of MACE in men with nonobstructive CAD was similar to men with no CAD (HR=0.82; 95%CI: 0.35, 1.93). With respect to sex differences in MACE outcomes, no difference was observed among patients with normal coronaries; in contrast, among patients with nonobstructive CAD, women had significantly higher risk of MACE as compared to men (HR=2.93; 95%CI: 1.30, 6.62).

Figure 4.

Freedom from Major Adverse Cardiac Events (MACE) Grouped by Sex and CAD Status (reprinted with permission from Sedlak TL, Lee M, Izadnegahdar M, Bairey Merz CN, Gao M, Humphries KH. Sex differences in clinical outcomes in patients with stable angina and no obstructive coronary artery disease. American Heart Journal. 2013 Jul;166(1):38-44³⁰)..

However, a recent study by Johnston et al., based on the Swedish Coronary Angiography and Angioplasty Register (SCARR), did not find any significant sex differences in adverse outcomes (i.e. any hospitalization for MI, any ischemic event, repeat coronary angiography and all-cause death) among stable angina patients with nonobstructive CAD.³¹ This inconsistency with prior findings may be explained by the differences in study outcomes. Specifically, this study did not include hospital readmission due to heart failure in their composite adverse outcome, while prior studies have indicated that the increased risk of MACE in patients with normal or non-obstructive CAD, particularly among women, is mainly driven by heart failure.

‘At-risk’ Populations with Elevated Risk of Adverse Outcomes

Among patients with chest pain but with nonobstructive CAD, in addition to female sex as independent predictor of elevated risk of adverse cardiac outcomes, emerging research suggests other contributing factors and ‘at-risk’ patient populations. These include patients with persistent chest pain and evidence for endothelial dysfunction. Based on the WISE study, Johnson et al. have shown that the 6-year incidence of MACE (readmission for MI, HF, stroke, and cardiac death) was twice as high in women with persistent chest pain (defined as chest pain symptoms still present at 1-year follow-up), as compared to women without persistent chest pain.³² Furthermore, several studies have shown that endothelial dysfunction in a setting of nonobstructive disease predicts the development of CAD in the long term and is associated with adverse cardiac outcomes.^33,34

Therapy

While a number of non-pharmacologic and pharmacological therapies have been tested in CSX and MA due to MCD subjects on the outcomes of angina, exercise performance and coronary blood flow (Table 2), no study has evaluated the impact on major adverse cardiac outcomes.

Table 2.

Evidence-based Treatment of Subjects with Angina, Evidence of Myocardial Ischemia, and No Obstructive CAD^*

A. Microvascular Coronary Dysfunction (MCD)

Coronary Endothelial Dysfunction

Angiotensin Converting Enzyme Inhibitors (ACE-I)50

Angiotensin Receptor Blockers (if ACE-I intolerant)

HMG CoA Reductase Inhibitors (Stating)43, 44

Anti-Platelet Agent (Aspirin)41

Enhanced External Counterpulsation (EECP)40

Diminished Coronary Blood Flow Reserve

Beta-blockers (including α-β blockers)45

L-arginine supplementation53

Coronary Smooth Muscle Dysfunction

Calcium Channel Blockers46

Nitrates

Anti-Anginal

Ranolazine56

Cognitive Behavioral Therapy/Autogenic training38

Tricyclic Medication52

Spinal Cord Stimulation (TENS unit)39

B. Coronary Vasopasm (Prinzmetal’s Angina)

Calcium Channel Blockers

C. Abnormal Cardiac Nociception

Tricyclic Medication52

Spinal Cord Stimulation (TENS unit)39

^*Proposed modification of existing ACC/AHA unstable angina and stable angina guidelines.

Treatment of Angina in Subjects with Evidence of Myocardial Ischemia and No Obstructive Coronary Artery A Chapter in Braunwald (8^th Edition) Disease. Puja K. Mehta MD, C. Noel Bairey Merz MD, FACC. In Press

Non-pharmacologic Therapies

Most lifestyle changes are beneficial in women for primary prevention of cardiovascular disease (CVD) and secondary prevention of ischemic heart disease. Specifically, the INTERHEART study, a global case-control study involving 52 countries, demonstrated that regular physical activity was strongly protective of a future acute myocardial infarction in women.³⁵ Data from the Nurses Health Study (NHS) demonstrated that women who adhered to a healthy diet, were nonsmoking, engaged in moderate-to-vigorous exercise >30 min/day, maintained a BMI <25 and had moderate alcohol consumption, their risk for future CVD events compared to non-adherent women was reduced by 83%, RR 0.17 (95% CI, 0.07 to 0.41).³⁶ In the MCD population, Eriksson et al. demonstrated that regular aerobic exercise (30 min, 3 times/week) decreased angina frequency and severity and improved endothelium-dependent blood flow in the brachial artery at 8 weeks however the number of patients studied was small and the level of significance was borderline (p=0.05).³⁷

With regard to other non-pharmacologic techniques, a recent study showed that an 8 week program of cognitive behavioral therapy (CBT) of autogenic training improved symptom frequency and severity in women with ischemia and non-obstructive coronary artery disease compared with controls (p<0.001).³⁸ Further, neurostimulation in the form of spinal cord stimulation has been shown to increase coronary blood flow, reduce duration and frequency of anginal attacks and reverse ST segment depression during stress testing compared to controls (p<0.001).³⁹ Patients with MCD and persistent angina have also been shown to benefit from Enhanced External Counterpulsation (EECP) therapy through reductions in angina and improvements in ischemia on traditional stress testing.⁴⁰ Specifically, in one study, at 12 months, 87% of patients had seen an improvement in angina by at least one Canadian Cardiovascular Society (CCS) class.

Pharmacologic Therapies

Anti-platelet agents

The 2011 effectiveness-based guidelines for the prevention of cardiovascular disease in women suggest a likely benefit from low dose aspirin in women >65 years particularly for stroke prevention.⁴¹ Since MCD patients are at elevated risk for future cardiovascular events compared to age and sex-matched controls, these guidelines can be extrapolated to recommend low dose aspirin in this group. Further, while coronary angiography often shows no significant CAD, IVUS has demonstrated significant coronary atherosclerosis in many MCD patients.²¹ Therefore, the CCS Guidelines for the use of antiplatelet therapy in the outpatient setting may be extrapolated to the use of low dose aspirin in MCD patients even in the <65 year old age category.⁴²

Statins

Most MCD patients will have plaque by IVUS and endothelial dysfunction on invasive CRT.²¹ Kayikcioglu et al. compared pravastatin 40 mg to placebo in 40 CSX women with an LDL < 4.0 mmol/L and reported significant improvements in both brachial artery flow mediated dilation (FMD), a marker for endothelial dysfunction, and in exercise-induced ischemia.⁴³ Further Pizzi et al. reported improved FMD and quality of life following 6 months of atorvastatin 40 mg (in addition to an angiotensin converting enzyme inhibitor) when compared to placebo.⁴⁴ In MCD patients, it is therefore reasonable to prescribe statins with a goal LDL of <2.0 in those who qualify by the presence of risk factors, evidence of atherosclerosis, and/or endothelial dysfunction.

Anti-ischemic Agents

Nitrates, beta-blockers, and calcium channel blockers are commonly used in MCD patients with ongoing angina. An observational study of 99 patients with CSX showed that nitrates were effective anti-anginal therapy in 40-50% of the patients.⁴ Nitrate tolerance is common however and it is important to advise the patient to take nitrate-free intervals to prevent escalating doses. Beta-blockers improve chest pain frequency and severity in MCD patients when compared to nitrates and/or calcium channel blockers.⁴⁵ While research is yet to be done, the newer generations of beta-blockers with alpha-blocking properties (carvedilol) and anti-oxidant properties (nebivolol) may offer additional benefits in the treatment of MCD in women. In women with coronary vasospasm, calcium channel blockers are first line therapy. In MCD patients however, diltiazem failed to improve CFR⁴⁶ and a meta-analysis by Heindenreich et al. found more patients on CCBs discontinued their medication due to side effects than those on beta-blockers (p<0.001).⁴⁷ Therefore, it is reasonable to conclude that beta-blockers should be used as first line therapy for anginal symptoms in MCD patients, reserving calcium channel blockers and nitrates for refractory cases and/or coronary vasospasm.

Angiotensin Converting Enzyme Inhibitors (ACEI)

Mechanistically, ACEI improve endothelial dysfunction through increasing endothelial nitric oxide bioavailability and reducing oxidative stress.^44,48,49 In MCD patients, the WISE compared quinapril 80 mg daily to placebo and reported improvements in both CFR by invasive coronary reactivity testing (p<0.019) and angina frequency (p=0.037) with ACEI over 16 weeks.⁵⁰ Therefore, ACEI are recommended in women with MCD particularly in patients with a reduced ejection fraction, uncontrolled risk factors, and/or endothelial dysfunction demonstrated on invasive testing.

Phosphodiesterase-5 Inhibition

Sildenafil, a phosphodiesterase-5 inhibitor, was examined in 23 women with MCD and a baseline CFR of <3.0 on invasive CRT.⁵¹ Ingestion of 100mg of oral sildenafil resulted in acute improvement in CFR, particularly in those women with a baseline CFR of ≤2.5 suggesting possible use of this medication in patients who have not responded to traditional medications. As phosphodiesterase-5 inhibitors interact with nitrates and can produce significant hypotension, specific counseling must be given around minimizing nitrate use while on these agents.

Low Dose Tricyclic Medication

Low dose tricyclic anti-depressants (TCAs) such as imipramine and amitriptyline have been shown to increase exercise tolerance and decrease chest pain in CSX patients.⁵² They are particularly useful in patients with cardiac nociceptive abnormality and uncontrolled chest pain despite traditional use of anti-anginals.

L-arginine

L-arginine is a precursor of nitric oxide, which mediates vascular smooth muscle cell relaxation and inhibits platelet aggregation. In patients with non-obstructive CAD and ongoing chest pain, 3g TID of L-arginine improved both symptoms and CBF response to acetylcholine over placebo.⁵³ Caution must be used in post-MI patients however as the Vascular Interaction With Age in Myocardial Infarction (VINTAGE-MI) trial demonstrated an increase in mortality with L-arginine supplementation.⁵⁴

Other agents not available in Canada and the US

Ranolazine is a relatively new anti-anginal agent that is available in the USA, but not in Canada. It alters late sodium current and reduces calcium overload in the myocyte.⁵⁵ A small trial in women with MCD demonstrated angina improvement measured by the Seattle Angina Questionnaire on ranolazine compared to placebo as well as trends towards improvement in myocardial perfusion abnormalities by cardiac magnetic resonance imaging.⁵⁶ Larger studies are currently ongoing. Nicorandil is a drug available only in Europe and has two mechanisms of action: venodilation and arterial dilation. In small studies, it improved angina symptoms in CSX patients.⁵⁷ Ivabradine, also available only in Europe, inhibits the If (so called “funny” channel) which is highly expressed in the sinoatrial node and therefore lowers heart rate. It has been shown to increase exercise duration in men and women with ischemic heart disease⁵⁸ but has not been examined specifically in the MCD population.

Conclusion

CSX and MA due to MCD are challenging medical conditions that predominantly impact women. New data improve our understanding of coronary vascular dysfunction and resultant myocardial ischemia that identifies the subgroup of MA due to MCD among patients with CSX. MCD has an adverse prognosis and health care cost expenditure comparable to obstructive CAD. The high prevalence of this condition, particularly in women, adverse prognosis and substantial health care costs, coupled with a lack of evidence regarding treatment strategies on prognosis, makes MA due to MCD an important research priority.