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Women's health: making cardiovascular disease real

Wei, Janet; Shufelt, Chrisandra; Bairey Merz, C. Noel

doi: 10.1097/HCO.0000000000000544
PREVENTION: Edited by Andrew Pipe

Purpose of review When patients are seen for persistent chest pain in the absence of obstructive coronary artery disease, the physician must decide if the symptoms are due to myocardial ischemia in order to guide treatment.

Recent findings Recent findings indicate that ischemia due to coronary microvascular dysfunction (CMD) is associated with subclinical coronary atherosclerosis and an adverse prognosis. Therapeutic probe trials suggest that antiatherosclerotic and anti-ischemic therapeutic strategies may be useful. A large randomized clinical trial of high-intensity statin, maximally tolerated angiotensin-converting-enzyme inhibitor or angiotensin receptor blocker and low-dose aspirin (WARRIOR NCT#03417388) is in progress.

Summary The diagnosis of CMD should be considered in patients with persistent angina, evidence of myocardial ischemia and normal coronary angiogram. Because of the associated adverse prognosis of CMD , conservative empiric treatment or further diagnostic evaluation of the coronary microvasculature can be performed. Diagnosis involves the measurement of coronary blood blow in response to a vasodilator agent invasively or noninvasively. Treatment of CMD can include the use of traditional antianginal and antiatherosclerotic medications. Clinical trials are needed to assess therapeutic strategies on the outcomes of cardiovascular disease and quality of life, in order to develop evidence-based guidelines.

Barbra Streisand Women's Heart Center, Cedars-Sinai Smidt Heart Institute, Los Angeles, California, USA

Correspondence to C. Noel Bairey Merz, MD, FAHA, FACC, Barbra Streisand Women's Heart Center, Cedars-Sinai Smidt Heart Institute, 127 S. San Vicente Blvd, Suite A3206, Los Angeles, CA 90048, USA. Tel: +1 310 423 9680; fax: +1 310 423 9681; e-mail: Noel.BaireyMerz@cshs.org

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INTRODUCTION

When patients are seen for persistent chest pain in the absence of obstructive coronary artery disease (CAD), the physician must decide if the symptoms are due to myocardial ischemia. The concern is that myocardial ischemia due to coronary microvascular dysfunction (CMD) may be present, which is associated with an adverse prognosis [1–4]. Current evidence shows that a significant portion of these patients have nonobstructive coronary atherosclerosis and CMD, not evident on coronary angiography (Fig. 1) [5,6].

Box 1

Box 1

FIGURE 1

FIGURE 1

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PROGNOSIS

Studies now have consistently shown that CMD is associated with adverse cardiovascular outcomes including death, myocardial infarction, stroke, hospitalization for angina and heart failure [7–9] (Table 1) [2,7,10▪,11–19]. Both endothelial-dependent and nonendothelial-dependent CMD predict adverse prognosis [4,20]. In the Women's Ischemia Syndrome Evaluation (WISE) study of 189 women with signs and symptoms of ischemia and no obstructive CAD, endothelial independent dysfunction characterized by reduced coronary flow reserve (CFR) is also associated with major adverse outcomes at 5-year mean follow-up (Fig. 2) [2].

Table 1

Table 1

FIGURE 2

FIGURE 2

The unexpectedly high heart failure hospitalizations at 4-year follow-up in these WISE individuals with preserved left ventricular (LV) ejection fraction and no obstructive CAD combined with our frequent findings of resting diastolic dysfunction (impaired LV relaxation [13,21–23] and elevated LV end-diastolic pressure (LVEDP) [13]) have led to the hypothesis that CMD represents a preheart failure with preserved ejection fraction (HfpEF) stage, contributes to diastolic dysfunction and may lead to subsequent clinical HFpEF; a condition which also preferentially impacts women. HFpEF is currently poorly understood and also lacks evidence-based therapy. Ongoing WISE study is investigating this pathophysiology.

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PATHOPHYSIOLOGY

CMD encompasses various pathophysiological changes that lead to functional and structural abnormalities in the coronary microvasculature (Fig. 3) [24]. These changes disrupt the ability to vasodilate and augment blood flow in response to increased myocardial oxygen demand, causing angina and myocardial ischemia [25].

FIGURE 3

FIGURE 3

Prior WISE work has also demonstrated adverse LV remodeling in our WISE women with elevated LVEDP [26▪]. Most recently, we have demonstrated that this does not appear to be related to blood pressure or blood pressure treatment per se, but possibly related to anti-ischemic therapy associated with improvement in angina (measured by the Seattle Angina Questionnaire) and CMD-induced ischemia measured by cardiac magnetic resonance imaging (cMRI) myocardial perfusion reserve index [27].

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PATIENT CHARACTERISTICS

Patient characteristics that suggest the potential CMD should be carefully considered. Exclusion of patients with LV hypertrophy, hypertrophic cardiomyopathy, heart failure or valvular heart disease, as well as comorbidities such as anemia or thyroid dysfunction is the first step. These patients likely have secondary CMD due to obstructive CAD and should be evaluated and treated with etiologic-specific existing therapies [25].

The patients to consider evaluation for CMD include: symptoms thought by the clinician to be ischemia; evidence of ischemia by functional capacity, ECG, noninvasive stress testing or ST-segment or non-ST-segment myocardial infarction (STEMI/NSTEMI); and no obstructive CAD by invasive or noninvasive coronary angiography [28]. The vast majority of patients have CVD risk factors and evidence of nonobstructive coronary atherosclerosis. Additional risk factors may include autoimmune conditions, cancer treatment including radiation to the chest and/or chemotherapy [29,30,31▪].

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DIAGNOSTIC STRATEGIES

Diagnostic approaches include conservative, noninvasive and invasive strategies which should involve shared decision because of the absence of guidelines in this area.

The conservative strategy includes the use of optimal medical therapy in patients at least 65 years with risk factors, including high-intensity statin, angiotensin-converting-enzyme inhibitor (ACE-I)/angiotensin receptor blocker (ARB), low-dose ASA and antianginal/anti-ischemia therapy, as well as therapeutic lifestyle change and cardiac rehabilitation [32,33]. The benefit of this strategy includes deployment of therapies known to reduce CVD risk, where the risk includes possible unnecessary overtreatment.

The noninvasive strategy involves advanced imaging using cMRI or PET to document myocardial blood flow reserve abnormality [34–36]. This strategy can be used for patients who are relatively lower risk or unable/unwilling to undergo invasive coronary reactivity testing. Because only nonendothelial function can be assessed, documentation of an abnormal flow reserve would typically be followed by nonselective optimal medical therapy and antianginal/anti-ischemic strategies [35]. The benefit of this strategy is documentation of abnormal CFR, whereas the risks are potential false negative results because of nonresponse to pharmacologic stress and lack of specific coronary pathway to direct therapy [37].

The gold-standard test to diagnose MCD involves invasive strategies with coronary reactivity testing using intracoronary adenosine, acetylcholine and nitroglycerin to determine nonendothelial and endothelial microvascular and macrovascular coronary dysfunction pathways [38]. This strategy allows for specific pathway therapy for patients who are at higher risk because of prior STEMI, NSTEMI or resuscitated sudden cardiac death [2,3,12,37,39–42]. Other considerations for this diagnostic strategy can include lack of recognition/treatment of persistent chest pain by community physicians, repeated emergency department visits and/or coronary angiograms, lack of response to empiric therapy or uncertainty regarding the utility of optimal medical therapy in women of reproductive age [43]. The benefits of the invasive strategy include specific coronary nonendothelial, endothelial, smooth muscle and nociception pathway identification for specific therapy, whereas the risks are minimal and include traditional coronary angiography risks [38].

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THERAPEUTIC STRATEGIES

Therapeutic approaches can include optimal medical therapy and therapeutic lifestyle change, and should be considered because of the presence of subclinical coronary atherosclerosis. Optimal medical therapy can consist of high-intensity statin, maximally tolerated ACE-I or ARB, β-blockers and low-dose aspirin combined with physical activity and nutrition counseling [32,33,44–46]. Antianginal/anti-ischemic therapy can include those listed in Table 2 [44]. Pharmacologic probe and intermediate outcomes trials further support specific pathway therapies, including endothelial pathway (statins, ACE-I/ARB, aerobic exercise and external counter-pulsation therapy) [47–53], nonendothelial pathway (α-β blockers/β-blockers and ranolazine) [54–62], smooth muscle pathway [calcium channel blockers, nitrates, xanthine derivatives (aminophylline)] [63–67], cardiac nociception pathway (low-dose tricyclic medication, spinal cord stimulation and cognitive behavioral therapy) [68–72] and elevated LV filling pathway (aldosterone inhibitor, phospho-diesterase 5 inhibitors) [73–76].

Table 2

Table 2

Clinical trials are needed to assess therapeutic strategies on the outcomes of CVD and quality of life, in order to develop evidence-based guidelines [10▪]. Pharmacologic probe trials support an antiatherosclerotic and anti-ischemic therapeutic approach and our ongoing clinical trial (WARRIOR NCT#03417388) is testing the impact of high-intensity statin and maximally tolerated ACE-I/ARB in 4422 CMD individuals for reduction of major adverse cardiac events (results available in 2021).

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CONCLUSION

The diagnosis of CMD should be considered in patients with persistent angina, evidence of myocardial ischemia and normal coronary angiogram. Because of the associated nonobstructive coronary atherosclerosis and adverse prognosis, conservative empiric optimal medical therapy or evaluation of coronary microvasculature for the presence of CMD can be used. Diagnosis involves the measurement of CFR in response to a vasodilator agent invasively or noninvasively. Treatment of CMD can include the use of traditional antianginal and antiatherosclerotic medications. Clinical trials are needed to assess therapeutic strategies on the outcomes of CVD and quality of life, in order to develop evidence-based guidelines.

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Acknowledgements

None.

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Financial support and sponsorship

This work was supported by contracts from the National Heart, Lung and Blood Institutes: N01-HV-68161, N01-HV-68162, N01-HV-68163, N01-HV- 68164, R01-HL-089765 and grant K23-HL-127262-01A1; a GCRC grant MO1-RR-00425 from the National Center for Research Resources; grant UL1RR033176, the NIH/National Center for Advancing Translational Sciences (NCATS); UCLA CTSI grant UL1TR000124 and UF CTSI grant UL1TR001427; DoD contract number W81XWH-17-2-0030; and grants from the Gustavus and Louis Pfeiffer Research Foundation, Denville, New Jersey; the Women's Guild of Cedars-Sinai Medical Center, Los Angeles, California; the Edythe L. Broad Women's Heart Research Fellowship, Cedars-Sinai Medical Center, Los Angeles, California; the Constance Austin Women's Heart Research Fellowship; the Barbra Streisand Women's Cardiovascular Research and Education Program, Cedars-Sinai Medical Center, Los Angeles; and the Erika J. Glazer Women's Heart Research Initiative, Cedars-Sinai Medical Center, Los Angeles.

This work was supported by grants from the Edythe L. Broad Women's Heart Research Fellowship, the Constance Austin Women's Heart Health Fellowship, the Barbra Streisand Women's Cardiovascular Research and Education Program, and the Erika J. Glazer Women's Heart Research Initiative, Cedars-Sinai Medical Center, Los Angeles.

B.M. reports personal honoraria and consulting from ACRWH (NIH Advisory Council), NIH-CASE (grant review study section), Springer International (book honorarium), Decision Support in Medicine LLC (book honorarium) and NHLBI Research Triangle Institute (RTI) International, as well as personal research grants for WISE HFpEF (Sponsor: Cedars-Sinai Medical Center, NCT02582021), RWISE (Sponsor: Cedars-Sinai Medical Center, NCT01342029), FAMRI (Sponsor: University of California, San Francisco, NCT01639235), WARRIOR Trial (Sponsor: University of Florida, NCT03417388) and California Institute for Precision Medicine (Sponsor: Cedars-Sinai Medical Center, NCT03064360). J.W. and C.S. have no disclosures to report.

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Conflicts of interest

There are no conflicts of interest.

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REFERENCES AND RECOMMENDED READING

Papers of particular interest, published within the annual period of review, have been highlighted as:

  • ▪ of special interest
  • ▪▪ of outstanding interest
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Keywords:

cardiovascular disease; coronary microvascular dysfunction; myocardial ischemia; women

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