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