Table 6. Future research to address INOCA.

	Gaps in knowledge	Future research
1	Lack of large studies on the prevalence of INOCA.	Prospective national/international registries as well as surveys in the general population in different countries.
2	Few studies evaluating the pathophysiology of INOCA.	Mechanistic studies to understand the pathophysiology of INOCA.
3	Few diagnostic tools to evaluate microvascular dysfunction.	Improved tools to facilitate the diagnosis of microvascular dysfunction with invasive and non-invasive means.
4	Few studies using non-invasive techniques to diagnose INOCA.	Non-invasive diagnostic studies with the newest techniques aimed at identifying alternate origins of cardiac ischaemia, including endothelial dysfunction, coronary vasospasm, or coronary microvascular dysfunction.
5	Few invasive studies to diagnose INOCA.	Prospective studies on diagnostic evaluation during coronary angiography using novel catheter-based techniques and intracoronary drug testing (ACh).
6	Few studies evaluating tailored therapy in INOCA.	Prospective studies to evaluate the impact of a tailored therapy on the angina class and quality of life as well as the occurrence of major adverse cardiac events at clinical follow-up.
7	Treatment of anginal symptoms in patients with INOCA is challenging as the patients represent a heterogeneous group and randomized trials are lacking.	Large randomized studies evaluating existing (statin ACEi/ARB) and new medications such as ETa receptor antagonist and Rho kinase inhibitors.
8	Lack of awareness among clinicians regarding INOCA.	Surveys to evaluate the awareness of cardiologists/clinicians of INOCA and of its diagnosis and treatment.
		Immediate action points should include launching educative campaigns to generate awareness regarding the causes and pathophysiology of INOCA, emphasizing that the diagnosis and management of patients with anginal symptoms should go beyond the identification and treatment of flow-limiting stenoses.
		Education should address therapeutic nihilism regarding INOCA by disseminating available evidence regarding the beneficial effect that objective documentation of the cause of chest pain and tailored treatment has on quality of life of these patients.
9	Lack of studies evaluating the cost effective diagnostic approaches in INOCA.	Cost effectiveness study to evaluate the cost effectiveness of the various diagnostic approaches in the management of INOCA.
10	Few studies on lifestyle interventions in INOCA. The ability of specific diets, such as anti-inflammatory, vegan, or Mediterranean, to improve symptomatic coronary vascular dysfunction is unknown.	Studies on lifestyle interventions, in particular dietary and stress reducing programmes.
11	Few studies to clarify the clinical significance of micro-vascular dysfunction in non-cardiac organs.	Studies evaluating the association of INOCA with microvascular pathology in other vascular beds for example the brain.
12	Prevalence of INOCA among women with prior history of pregnancy-related conditions is insufficiently studied.	Studies evaluating INOCA and its association with HFpEF, pregnancy-related conditions.
All these actions should be promoted by national and international scientific societies, as well as the pharma and biomedical industries, in the firm belief that, once INOCA is acknowledged as a major unmet need in clinical practice, a virtuous cycle of progress in science and technology will be initiated, ultimately improving the quality of life and prog.nosis of these patients. ACEi: angiotensin-converting enzyme inhibitor; Ach: acetycholine; ARB: angiotensin receptor blocker; HFpEF: heart failure with preserved ejection fraction.