Download the full program announcement here.
One out of every three women dies of cardiovascular disease1. It is the number one cause of death for women. Approximately 100 million* women, globally, live with stable chest pain†. Each year, a subset of these women — an estimated 700,000 women in the United States and Europe alone — undergo invasive coronary angiography and leave without a diagnosis. They are told their arteries look “normal.” That their hearts are healthy. That it might be anxiety.
These women, in addition to having debilitating symptoms, carry an up to 4-fold higher risk of major cardiovascular events including cardiovascular death, heart attack, stroke, or hospitalization for heart failure, than women without these symptoms2. The condition they have is increasingly recognized as angina, the clinical term for chest pain, with no obstructive coronary arteries (ANOCA)‡.
Of the women with stable angina who undergo coronary angiography, two out of three do not have a blockage in their heart arteries3-5— the cause of heart disease medicine has spent decades learning to find and fix. In most of ANOCA, the underlying abnormality lies in coronary function, which remains largely invisible to current diagnostic pathways. The most common abnormality, present in up to 70% of patients, is coronary microvascular dysfunction6,7.
The coronary microvasculature consists of the smallest blood vessels of the heart. Although invisible on coronary angiography, these vessels comprise the vast majority of the vascular network and, under normal conditions, control more than 80% of the blood flow to the heart muscle8. Coronary microvascular disease reflects failure of this regulatory system, leading to restricted or abnormal blood flow that can result in a mismatch between oxygen supply and demand (ischemia) even in the absence of upstream blockages.
The result of a system optimized to find focal blockages is a diagnostic odyssey and a population, predominantly women, left unseen. Many, in search of answers, endure years of repeated stress tests, repeated angiograms, and repeated dismissals before anyone names what is wrong.
The consequences are profound. Seven in ten women with ANOCA report adverse effects on work, with at least half reducing hours or retiring early; approximately 40% apply for disability, and 30% move into lower-paid roles9. Seven in ten report adverse effects on mental health, and eight in ten report impacts on their social lives.
The economic cost is equally staggering. Healthcare systems spend thousands of dollars per patient on tests designed to detect a disease pattern that is not present. Lifetime healthcare costs associated with ANOCA are estimated at $750,000 per patient10.
What are the limits of current practice?
Unlike the larger heart arteries that run along the surface of the heart, the coronary microvasculature consists of vessels mostly embedded within the heart muscle itself. These vessels are difficult to assess not only because of their small size, but also because they are in constant motion with each heartbeat.
As a result, evaluation of microvascular function relies on indirect measurements of coronary blood flow and vascular resistance, requiring — for comprehensive assessment — an invasive approach similar to coronary angiography, but with specialized equipment, pharmacologic agents, and expertise that is not available in most catheterization laboratories.
Further, clinical guidelines for stable ischemic heart disease, informed by decades of research conducted predominantly in male populations, have historically centered diagnosis on obstructive coronary artery disease. Although coronary function testing is included in most recent guidelines, the recommendations are based on the weakest level of evidence, reflecting the lack of robust clinical research11,12.
The result is a diagnostic gap for millions of women globally, with likely fewer than 1% of women with ANOCA undergoing coronary function testing.
Even for the small number of women who receive a diagnosis of coronary microvascular disease, robust evidence to guide treatment pathways and improve long-term outcomes is absent. Significant deficits in knowledge persist regarding the detailed mechanisms of coronary microvascular disease and how they relate to clinical manifestations.
Multiple mechanisms have been investigated to identify treatment targets. However, attempts to selectively target individual pathways have yielded inconsistent improvements in coronary microvascular function or symptoms13,14. While these largely negative findings may in part reflect heterogeneous study populations and inconsistent outcome assessment, they also point to a deeper problem: coronary microvascular disease represents dysfunction of a complex regulatory system with multiple, partially redundant pathways, such that targeting a single component in isolation may be insufficient.
To address upstream drivers, current clinical management targets traditional cardiovascular risk factors. However, at least within ANOCA populations, traditional risk factors have explained only a limited proportion of coronary microvascular dysfunction15,16. These observations raise critical questions about additional upstream drivers of coronary microvascular disease that must be identified to advance treatment and improve care.
Why women?
Coronary microvascular structure and function are shaped by adaptation to changing physiological demands. In women, this adaptation is uniquely dynamic across a woman’s life course22. The microvasculature continuously responds to hormonal fluctuations and to profound physiological transitions, such as pregnancy, during which blood volume increases by up to 50%17,18.
The requirement for a highly adaptive regulatory system and/or the cumulative effects of repeated microvascular remodeling may increase susceptibility to dysregulation, injury, and maladaptive structural change. Adverse pregnancy outcomes, such as preeclampsia, are increasingly recognized as early markers of vascular vulnerability, with arterial stiffness and endothelial dysfunction proposed as potential links to future cardiovascular risk19,20. Whether preeclampsia acts as a vascular stressor, represents ‘demasking’ of inherent risk, or both, remains unknown.
Importantly, the menopausal transition represents a major inflection point in vascular biology. Declining estrogen levels have been linked to adverse changes in endothelial function, arterial elasticity, autonomic regulation, and inflammatory signaling that appear to extend beyond the effects of chronological aging alone21.
Goal of the program
The goal of VISIBLE is to increase the proportion of women presenting with stable angina who receive effective diagnosis and treatment for coronary microvascular disease from less than 1% to more than 80%, without increasing the risk of missed diagnosis or treatment of obstructive coronary artery disease. In so doing, the program aims to demonstrate advances capable of reducing the burden of cardiovascular disease for millions of women worldwide.
Central to the program is the recognition that coronary microvascular disease encompasses multiple endotypes with distinct, yet overlapping, pathophysiological mechanisms, including functional and structural abnormalities. By refining and validating these endotypes, the program aims to move beyond empiric care toward mechanism-informed diagnosis and treatment.
Download the full program announcement here.
Thrust 1: Develop scalable approaches for diagnosis and monitoring of coronary microvascular disease.
Thrust 1 aims to develop scalable diagnostics to detect coronary microvascular disease with >80% sensitivity and >80% specificity.
Considering that coronary microvascular disease is at least as prevalent as obstructive coronary artery disease among women presenting with stable angina, proposed diagnostic approaches must be deployable early in the diagnostic workup at a scale comparable to current non-invasive testing for obstructive coronary artery disease.
Promising novel approaches include strategies using artificial intelligence or machine learning to identify signatures of coronary microvascular disease from data already acquired in routine care, or those accessing microvascular beds outside of the heart to obtain markers of the disease. Biomarkers and other patient characteristics (e.g., symptom patterns) linked to coronary microvascular disease may also be used to support risk stratification, diagnosis, or monitoring of disease activity and treatment response.
Thrust 2: Identify risk factors and evaluate prognosis of coronary microvascular disease endotypes.
Thrust 2 seeks to identify upstream risk factors for coronary microvascular disease and define the prognostic significance of distinct endotypes.
2A: Identify risk factors for coronary microvascular disease (effect sizes ≥1.5) to define treatment targets.
Altering the disease trajectory of coronary microvascular disease will require targeting upstream drivers rather than focusing solely on downstream mechanisms of the disease. To better characterize upstream drivers of coronary microvascular disease in women, Thrust 2 seeks to identify risk factors (including sex-specific risk factors) using clinical and biological data. Associations should be quantified using adjusted odds ratios, hazard ratios, or relative risks, with effect sizes ≥1.5 considered indicative of a meaningful impact on risk.
2B: Define prognosis of coronary microvascular disease endotypes.
In parallel, the program seeks to leverage existing ANOCA datasets with comprehensive invasive coronary function testing and follow-up to define the prognostic significance of distinct coronary microvascular disease endotypes.
Outcomes of interest include, but are not limited to, angina burden and quality of life, and major adverse cardiovascular events, including cardiovascular death, myocardial infarction, stroke, and heart failure.
Thrust 3: Build and validate multiscale human-relevant models of the coronary microvasculature to interrogate causal mechanisms of coronary microvascular disease.
Definitive pathophysiological causes of coronary microvascular dysfunction remain poorly understood, in part because existing experimental systems do not permit controlled, causal interrogation of microvascular function in a human-relevant environment. Recent advances in biomedical engineering provide new opportunities to address these gaps. For example, microphysiological systems have enabled controlled modeling of flow-mediated endothelial dysfunction under coronary-relevant mechanical conditions, with quantitative characterization of endothelial structural, barrier, and inflammatory responses to defined mechanical perturbations22. In parallel, integrative approaches that combine in vitro microvascular networks with in silico modeling have been applied to simulate hemodynamic changes and perfusion impairment in coronary microvascular disease, providing a framework for linking local microvascular perturbations to tissue- and organ-level functional consequences23.
Thrust 3 seeks to develop and apply integrated, multiscale models, coupling human cell-based systems with computational frameworks, to establish causal relationships between upstream drivers, proposed disease mechanisms, and resulting changes in coronary microvascular function.
Thrust 4: Develop treatment strategies that improve both coronary microvascular function and patient-centered outcomes.
To date, studies of interventions intended to improve symptoms and/or coronary microvascular function have yielded inconsistent results. However, many of these studies enrolled heterogeneous populations without accounting for disease endotypes or incorporating coronary microvascular function testing at all13. To overcome this limitation, it is essential that studies move beyond the use of umbrella diagnoses such as ANOCA or coronary microvascular disease and instead use coronary function testing to explicitly match distinct disease endotypes to specific treatments. Thrust 4, therefore, focuses on proof-of-concept studies testing existing interventions in well-characterized patient populations that most likely will benefit.
Successful interventions are expected to demonstrate statistically significant improvement (p < 0.05) in prespecified coronary microvascular function domains, with effect sizes appropriate to the targeted mechanism, and specific treatment goals for coronary flow reserve and angina burden defined by the program.
Download the full program announcement here.
*Estimates range from 60-140 million24,25.
†Stable chest pain is the most common symptom of ischemic heart disease, a condition caused by reduced blood flow to the heart muscle.
‡ or ischemia with no obstructive coronary artery disease (INOCA), when objective evidence of ischemia is present
Program Director.
Call for abstracts and proposals.
We are soliciting abstracts and proposals for work over three (3) years in one or more of the following thrust areas (see Thrust areas in full program announcement). Proposers should clearly relate work in these thrust areas to one or more of the program goals.
It is not necessary to form a large consortium or teams to address all facets of the program. The strength of this approach will manifest through program-level integration of efforts from individuals and small agile teams with deep (and sometimes narrow) expertise. Across all projects, Wellcome Leap will facilitate iterative and collaborative integration of findings to refine models and improve and validate predictive measures and adapt approaches as teams make progress towards shared goals.
Process and timeline
30 DAYS FOR PREPARATION AND SUBMISSION OF ABSTRACT
15-Day Abstract review round
30 DAYS FOR PREPARATION OF FULL PROPOSALS AFTER ABSTRACT FEEDBACK
30-Day Full proposal review round
25-page full proposals including technical approach, milestones, costs, and key personnel submitted. Proposals should specifically address abstract feedback.
All submissions will receive a ‘selected for funding’ or ‘not selected for funding’ decision. Those selected will proceed to contract signature as the final gate with work expected to commence within approximately 30 days.
Who is eligible?
Performers from universities and research institutions: small, medium, and large companies (including venture-backed); and government or non-profit research organizations are invited to propose.
Wellcome Leap accepts project proposals from any legal entity, based in any legal jurisdiction, including academic, non-profit, for-profit, and regulatory/professional organizations. Applicants are encouraged to contact Wellcome Leap about joining its Health Breakthrough Network by executing its MARFA (or CORFA for commercial entities) agreement. Full execution of the Wellcome Leap MARFA is not required for application submission but is required for any award.
I understand that the information being disclosed will be reviewed and evaluated independently on behalf of Leap. I am submitting information with the intention that it imposes no confidentiality obligations on Leap. Furthermore, my submission does not breach any confidentiality obligations that I owe to others; there is no legal reason why I cannot submit information; and I am not underage or otherwise legally incompetent. By submitting, I am not granting, other than for the purpose of evaluation, any rights in relation to any patent, copyright, or design. I am not relying upon Leap in any way for legal advice, including (but not limited to) whether the contents of my submission can be protected under IP law. I recognize that Leap may already be aware of or funding the same or related efforts as described by my submission. I agree that no contractual obligation or working relationship is being created between myself and Leap by submitting this information. If the submission is deemed of interest, I may be required to sign a further Agreement with Leap so that any confidential information, that is subsequently shared, is protected.
I acknowledge and consent to the use of AI systems operated by third parties to process such data. These systems may generate summaries, insights or other recommendations based on the content of the application. You waive any claims against Wellcome Leap related to the use of AI for summarization, provided that complies with applicable laws and internal policies.
Applicants submitting a full proposal may provide proprietary or confidential information. The applicant agrees that they have all necessary rights to make the submission, including rights to disclose all included data and any confidential or proprietary information. If any third party information is included, it is the Applicant’s obligation to ensure that the third party has agreed to these terms.
For information designated as confidential in a submitted full proposal, Wellcome Leap agrees to the following:
- Purpose Limitation: Wellcome Leap will use the confidential information solely for the purpose of reviewing and evaluating the proposal. Such information will not be used for Wellcome Leap’s direct or indirect personal or financial benefit, nor made available for the direct or indirect benefit of any other organization or individual. The applicant acknowledges that any feedback or review received from Wellcome Leap is not legal advice and the applicant will not rely on the same for any action, including on whether or not any IP filings could be made.
- Access Controls and Confidentiality Commitments: Wellcome Leap will not disclose confidential information to anyone except individuals who: (i) have been formally designated by Wellcome Leap to participate in the proposal review; and (ii) are bound by appropriate confidentiality obligations. Wellcome Leap will take reasonable measures at least equivalent to those used to protect its own confidential information to safeguard designated confidential information. Wellcome Leap will promptly notify the applicant of any actual or suspected misuse, misappropriation, or unauthorized disclosure that comes to its attention.
- Exceptions: Wellcome Leap shall have no obligation or liability with respect to information that it can demonstrate:
(i) was in the public domain at the time of disclosure or enters the public domain through no fault of Wellcome Leap;
(ii) was known to Wellcome Leap, without restriction, prior to disclosure;
(iii) is disclosed with the applicant’s prior written consent;
(iv) becomes known to Wellcome Leap, without restriction, from a source not in breach of any confidentiality obligation; or
(v) is required to be disclosed by law, regulation, or court/administrative order, provided that Wellcome Leap will give prompt notice to the applicant to allow the applicant to seek protective measures to limit such disclosure. - Acknowledgment of Similar Efforts: As acknowledged at the abstract stage, the applicant understands that Wellcome Leap may already be aware of, considering, or funding programs or proposals similar to, or overlapping with, the submitted work. Confidentiality obligations under this section do not restrict Wellcome Leap’s ability to pursue such existing or independent efforts so long as Wellcome Leap does not use the applicant’s designated confidential information in doing so.
- Duration
Wellcome Leap’s obligations with respect to designated confidential information will continue for three (3) years from the date the proposal is received. - Use of AI Systems
Consistent with the abstract-stage acknowledgment, the applicant agrees that Wellcome Leap may use third-party AI systems to assist in processing, summarization, or other assessments of proposal materials. The results of processing may be used by Wellcome Leap as part of its evaluation processes. Any confidential information processed will remain subject to the protections described in this section. To the extent consistent with applicable laws and policies, the applicant waives any claims against Wellcome Leap related to use of AI for these purposes.
No contractual obligation or working relationship is being created between the applicant and Wellcome Leap due to this submission. Any engagement between Wellcome Leap and the applicants will be through separately executed contracts, including master agreements that have been or will be entered into between the parties. Other than the right for Wellcome Leap and its agents to store, copy and modify the submissions for the purpose of evaluation, no rights in relation to any patent, copyright, or design are granted by virtue of this submission.
Abstract application steps.
- Download guidelines
- Download abstract template (and cost and schedule template)
- We’ll remind you when the application portal opens on 2 March 2026 at 11:59pm ET.
- Upload your abstract and submit your application before 9 March 2026 at 11:59pm ET.
More details will be provided for the proposal round of submissions.
If you have questions, please review our FAQ section here – current version, updated 6 February 2026.
Send inquiries to visible@wellcomeleap.org
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