Introduction
Coronary vascular dysfunction causes microvascular angina and vasospastic angina, which are prevalent clinical endotypes of myocardial ischaemia with no obstructive coronary arteries (INOCA). INOCA impairs quality of life and confers an increased likelihood of cardiovascular events and health resource utilization.
Contemporary advances in non-invasive and invasive testing facilitate an accurate diagnosis and linked therapy. New guideline recommendations and patient advocacy are also relevant. Nonetheless, a lack of disease-modifying therapy for INOCA perpetuates the medical need.
This viewpoint focuses on the emerging therapy for INOCA. We initially describe the pathophysiology and clinical endotypes of INOCA. We then review novel therapeutic strategies, including ongoing clinical trials and future therapeutic possibilities.
Pathophysiology of ischaemia with no obstructive coronary arteries
Bairey Merz et al. proposed the now widely accepted term ‘INOCA’. These myocardial ischaemic syndromes are caused by distinct mechanisms leading to abnormal coronary vasomotion. Non-invasive imaging and invasive tests of coronary vascular function provide mechanistic information to diagnose clinical endotypes, that is, angina caused by a specific mechanism. The endotypes include microvascular angina, vasospastic angina, in the presence or absence of coronary atherosclerosis, and non-coronary, systemic disorders, e.g. anaemia.
Vasospastic angina
Vasospastic angina is caused by epicardial coronary vasospasm. Coronary vascular smooth muscle cell constriction is stimulated by inflammation, hypertension, and vascular risk factors, notably smoking. Functional genetic variants may individualize an enhanced susceptibility to coronary vasoconstriction. Coronary vasospasm often localizes with atheroma. During acetylcholine provocation testing, the coronary spasm may be diffuse or focal.
Microvascular angina
Coronary microvascular dysfunction involves structural and functional mechanisms which should inform stratified therapy.
Structural vascular remodelling involves cell hypertrophy enhancing media thickness, wall stiffness, and lumen loss. Interstitial remodelling involves an enhanced extracellular matrix. Rarefaction involves the loss of capillaries and microvessels, resulting in increased microvascular resistance. Endothelial dysfunction, clinically demonstrated by impaired coronary artery dilatation or even vasoconstriction to acetylcholine, associates with atherosclerosis and cardiovascular events in the longer term. Coronary microvascular spasm is diagnosed by the reproduction of symptoms, and electrocardiographic changes, without epicardial spasm during acetylcholine testing.
Contemporary management of ischaemia with no obstructive coronary arteries
Current evidence-based treatments for INOCA are summarized in the Graphical Abstract. Several of these medicines are repurposed for coronary heart disease. Polypharmacy is prevalent and burdensome to patients, potentially leading to nonadherence with therapy.
Coronary microvascular and epicardial spasm involve similar therapeutic approaches. Calcium channel blockers are recommended and beta-1 adrenoceptor blockers are contra-indicated, however, symptoms may be difficult to control, curtailing quality of life. A personalised approach to medical management should involve a care plan with an elective schedule of outpatient assessments to control cardiovascular risk factors, assess for measures of efficacy (and adherence) e.g. heart rate, and side-effects, and relieve angina.
Novel therapeutic strategies for ischaemia with no obstructive coronary arteries
Coronary vasomotion disorders involve distinct and overlapping mechanisms, posing a challenge to the design of clinical trials. This underscores the need for the use of specific eligibility criteria to define disease endotypes, objective measures of myocardial ischaemia, validated patient-reported outcome measures, and surrogate outcomes that reflect disease activity.
Stratified medicine
Stratified medicine holds promise for mechanistically targeted therapy. The CorMicA trial was the first to investigate stratified medicine in angina. The study population included outpatients with angina undergoing clinically indicated coronary angiography. The intervention involved a ‘functional’ coronary angiogram, including the index of microvascular resistance, coronary flow reserve (CFR), and coronary reactivity. The treatment decisions were linked to the test results and mechanistically targeted to the underlying problem. At six months, compared with standard angiography-guided management, angina severity, and quality of life improved significantly in the stratified medicine group compared to the standard angiography-guided group. Stratified medicine is now being evaluated in other populations.
Intensive preventive therapy
The WARRIOR trial is a multicentre, prospective, randomized, clinical outcome trial involving a PROBE design in 4422 women with INOCA (NCT03417388). The intervention involves intensive preventative therapy using low-dose anti-platelet therapy with aspirin, high-dose statins, and maximally tolerated renin-angiotensin-aldosterone system blockade.
Precision medicine
Precision medicine involves a targeted therapeutic approach informed by genetic testing with the potential to reduce empirical polypharmacy.
Endothelin-1 (ET-1), a 21-amino acid peptide produced primarily by the endothelium, mediates coronary vasoconstriction and vasodilation. The minor G allele (population prevalence ∼36%) of the non-coding single nucleotide polymorphism rs9349379 enhances the expression of the ET-1 (EDN1) gene in human vascular cells, increasing circulating concentrations of ET-1 and appears to be more prevalent in patients with microvascular angina.
The Precision Medicine with Zibotentan in Microvascular Angina (PRIZE) trial is a randomized, double-blind, placebo-controlled, cross-over study of zibotentan, an oral endothelin A receptor-selective antagonist, in patients with microvascular angina (NCT04097314). The hypothesis is that in a population of patients with microvascular angina enriched with carriers of rs9349379 (minor G allele), zibotentan will be an effective treatment.
Hormone replacement therapy
The onset of microvascular angina is associates with menopause when circulating concentrations of 17β-oestradiol (the main physiologically active form of oestrogen) have naturally declined. Several trials have demonstrated that oestrogen-containing hormone replacement therapy (HRT) might be helpful to post-menopausal women with microvascular angina.
However, research on HRT in microvascular angina was limited by safety concerns prompted by the Women’s Health Initiative trial. Encouragingly, longer-term follow-up data found no association of conjugated equine oestrogens with all-cause, cardiovascular, or cancer mortality during 18 years of follow-up. The risk of breast cancer is increased during and after the use of all types of HRT, except vaginal oestrogens. Prescribers should discuss the risks and benefits of HRT with their patients, and a multidisciplinary approach is recommended. HRT merits further investigation in post-menopausal women with INOCA.
Future therapeutic possibilities for ischemia with no obstructive coronary arteries
Fatty acid oxidation inhibition
Trimetazidine selectively inhibits the fatty acid beta-oxidation enzyme 3-keto-acyl-CoA dehydrogenase, which increases carbohydrate oxidation, resulting in reduced lactate production and a higher cell pH during ischaemia. In 2006, Topal et al. conducted a randomized, double-blind, placebo-controlled, cross-over trial of trimetazidine in patients with coronary ‘slow flow’ phenomenon. Trimetazidine improved exercise time before the onset of angina and the number of angina-free patients at four weeks compared to placebo. The case for trimetazidine in INOCA merits further study.
Rho-kinase inhibition
Rho-kinase is an intracellular enzyme that mediates excitation-contraction coupling in vascular smooth muscle cells. Intracoronary fasudil is a non-selective rho-kinase inhibitor which antagonizes coronary vasospasm, with potential disease-modifying effects in patients with vasospastic angina and microvascular spasm. However, since fasudil is not available as an oral preparation, novel oral rho-kinase inhibitors should be a priority for pharmaceutical research and development.
Phosphodiesterase inhibitors
Phosphodiesterase (PDE) enzyme inhibitors attenuate the hydrolysis of the intracellular second messengers, cyclic adenosine monophosphate and cyclic guanine monophosphate. Depending on the PDE family targeted, outcomes include inhibition of inflammation and smooth muscle relaxation, which may improve coronary microvascular function.
PDE3 inhibition increases intracellular cyclic adenosine monophosphate concentrations producing anti-platelet, anti-inflammatory, and vasodilatory effects. Shin et al. performed a randomized, double-blinded, placebo-controlled, multicentre trial of the PDE3 inhibitor cilostazol in 50 patients with vasospastic angina. Compared to placebo, treatment with cilostazol (200 mg daily for 4 weeks) improved angina, but more patients experienced headaches (40% vs. 20.8%).
In the WISE study, 23 women with INOCA and a baseline CFR ≤3.0, were treated with 100 mg of oral sildenafil (a PDE5 inhibitor) with repeat coronary function testing 45 min after dosing. The CFR post-PDE5 inhibition was significantly higher (P = 0.008). This initial improvement was more pronounced in women with a CFR <2.5. If the acute effects of oral sildenafil are sustainable, then a larger clinical trial of sildenafil or one of the longer-acting PDE5 inhibitors may be warranted.
Cell and gene-based therapies
The cluster of differentiation-34 (CD34) was the original cell marker of endothelial progenitor cells, which are vasculogenic. In the open-label Intracoronary Autologous CD34+ Cell Therapy for the Treatment of Coronary Endothelial Dysfunction in Patients With Angina and Nonobstructive Coronary Arteries (IMPROvE-CED) trial, 20 patients with INOCA and in coronary endothelial dysfunction followed a protocol that involved exercise stress testing, granulocyte colony stimulating factor-mediated CD34 + cell mobilization, leukapheresis and infusion of 1 × 105 CD34 + cells/kg into the left anterior descending coronary artery. At 6 months, cell therapy was associated with improvements in coronary microvascular function, Seattle Angina Questionnaire scores, and reduced sublingual nitroglycerin use.
Neuromodulation therapy
Neuromodulation therapy with spinal cord stimulation (invasive) or transcutaneous electrical nerve stimulation (non-invasive) may be helpful for patients with refractory symptoms, although trial evidence is limited. Lanza et al. undertook a randomized cross-over trial of spinal cord stimulation in ten patients with refractory microvascular angina who had received an internal pulse generator device 17 ± 16 months before enrolment. Spinal cord stimulation was associated with improvements in angina, ST-segment depression on both ambulatory monitoring and dobutamine stress echocardiography. There may be a role for non-invasive transcutaneous electrical nerve stimulation and a future trial seems warranted.
Coronary sinus reducer
Increased coronary sinus pressure may reduce myocardial ischaemia by redistributing blood to ischaemic territories. The Coronary Sinus Reducer (Neovasc Medical, Inc., Or Yehuda, Israel) is a percutaneous implantable, hour-glass stent designed to establish a coronary sinus narrowing and elevate proximal coronary venous pressure, thereby redistributing coronary microvascular blood flow to under perfused myocardium. Pre-clinical, open-label studies provided favourable results on safety and anti-ischaemic effects. The COSIMA (NCT04606459) pilot trial is investigating the Coronary Sinus Reducer to treat microvascular angina.
Conclusion
Over the past three decades, multiple studies have clarified the health impact of INOCA, however, disease-modifying therapy is lacking. Clinical guidelines prioritize stratified medicine. Novel therapy development is a key priority.
Acknowledgement
The authors thank George Bailie, Tom Ford, Carl Pepine, and Harmony Reynolds for their contribution to this manuscript.
Declarations
Disclosure of Interest
Colin Berry is employed by the University of Glasgow which holds consultancy and research agreements for his work with Abbott Vascular, AstraZeneca, Boehringer Ingelheim, Causeway Therapeutics, Coroventis, Genentech, GSK, HeartFlow, Menarini, Neovasc, Novartis, Servier, Siemens Healthcare, and Valo Health. Colin Berry receives research funding from the British Heart Foundation grant (RE/18/6134217), Chief Scientist Office, EPSRC (EP/R511705/1, EP/S030875/1), European Union (754946-2), Medical Research Council (MR/S018905/1), and UKRI (MC/PC/20014). The University of Glasgow has submitted a patent on using Zibotentan for microvascular angina. Dr. Morrow and McFarlane have no disclosures.
