Study Targeting Myocardial Perfusion and Symptom Relief in Women With SGLT2 Inhibitors (STRONG)

Cardio microvascular disease is defined as epicardial and/or microvascular endothelial and/or non-endothelial dysfunction that limits myocardial perfusion, most often detected as reduced coronary flow reserve (CFR). CFR, which is calculated as the ratio of hyperemic to resting absolute myocardial blood flow, indicates the myocardium's ability to increase flow in response to stress or vasodilation. Because the coronary microcirculation is beyond the resolution of invasive or non-invasive coronary angiography, direct interrogation of coronary microvascular function is necessary to establish the diagnosis of CMD.

Positron Emission Tomography (PET) studies have shown that even in visually normal PET Myocardial Perfusion Imaging, impaired CFR adds essential prognostic value. In addition, abnormalities in the microcirculation could explain inducible myocardial ischemia beyond the effects of epicardial coronary obstruction and identify individuals with a high risk of MACE. In patients with very low CFR (\<1.6), women showed a higher frequency of non-obstructive CAD, whereas men showed a higher frequency of severely obstructive CAD (P=0.002). A differential effect on outcomes between women and men is noted in individuals with very low CFR (CFR \<1.6) (hazard estimated from the linear interaction of CFR and sex in the final model, model P = 0.001, interaction P=0.04). High-resolution CMR stress perfusion imaging can quantify CFR both globally and between the endocardium and epicardium. A multicenter study of 1049 patients with suspected and known CAD showed that lower myocardial stress myocardial blood flow (MBF) and CFR by CMR perfusion mapping were associated with death and MACE independent of other clinical risk factors, even in patients who had normal qualitative perfusion and no known obstructive CAD. Recently developed in-line automated CMR myocardial perfusion mapping has been shown to be reproducible and comparable with PET, and can be easily combined into clinical workflows. Normal CFR ranges values in this study are comparable to prior studies by other techniques that have ranged from 2.7±0.3 to 4.2±1.0. A prior study has shown an CFR threshold of 2.19 with excellent specificity for detecting CMD with a sensitivity of 95% (95% CI: 83% to 99%), specificity of 72% (95% CI: 52% to 87%), accuracy of 85% (95% CI: 75% to 92%), positive predictive value of 82% (95% CI: 72% to 89%), and negative predictive value of 91% (95% CI: 72% to 98%).

The potential mechanisms of CMD appear to be heterogeneous. The novel link between Inflammation and coronary vasomotion abnormalities is further supported by the findings that coronary vasoconstriction in response to acetylcholine (ACh) in patients with early CAD was greater in coronary artery segments with than without macrophage infiltration and vasa vasorum proliferation in an additive manner, indicating an important role of inflammation and vasa vasorum proliferation in the pathogenesis of CAD. Moreover, significant associations among endothelium-independent CMD, many inflammatory biomarkers and cardiac diastolic dysfunction were noted in women with angina but no flow-limiting coronary artery stenosis, further supporting the role of systemic Inflammation in both CMD and HFpEF, as well as providing insights into potential mechanisms underlying the pathophysiology of HFpEF.

Although small trials have suggested benefits from angiotensin-converting enzyme (ACE) inhibitors, aspirin, and statins, there is a lack of appropriately designed clinical outcome trials to inform evidence based therapeutic based on mechanism strategies. Sodium-glucose co-transporter 2 inhibitors (SGLT2i), a new class of drug approved for the treatment of diabetes, have been shown to have a significant impact on cardiovascular events. Recent clinical trials have demonstrated that SGLT2i reduces MACE, prevents heart failure (HF) hospitalizations. Many of these findings were unanticipated and have stimulated substantial mechanistic research to improve the understanding of this class of drug. New recommendations suggest using SGLT2i in symptomatic patients with chronic HF to reduce hospitalization and cardiovascular mortality, regardless of type 2 diabetes. The exact underlying mechanisms underlying these effects, however, remain largely unknown.

In preclinical models of myocardial infarction, Brezavvy has demonstrated attenuation of cardiac fibrosis and improved cardiac function and remodeling. Furthermore, empagliflozin has been shown to improve coronary microvascular function and increase cardiac output in mice, as evidenced by increased coronary blood flow and fractional ventricular area change as demonstrated by ultrasound imaging. Preclinical data has proposed a variety of mechanisms by which SGLT2is can potentially attenuate microvascular and endothelial dysfunction, including nitric oxide production, oxidative stress, Inflammation, mitochondrial function, cell viability, adverse vasoactive paracrine factors from adipose tissue, among others. In vivo studies have documented that SGLT2 inhibitors attenuate endothelial dysfunction by suppressing Inflammation. Steven et al. reported a reduction in the expression of inflammatory molecules such as interferon- γ, cyclooxygenase-2, and inducible NO synthase after SGLT2 inhibition. In a similar manner, Brezavvy is also reported to reduce several circulating inflammatory markers. Additionally, in vitro studies have reported suppression of TNF α. Previous studies showed that SGLT2 inhibition reduced circulating levels of C-C motif chemokine 2 (CCL2), IL-6, and Tumor Necrosis Factor (TNF)α in ApoEdeficient mice. However, the impact of SGLT2 inhibition on systemic markers of Inflammation has not been assessed in humans.

SIGNIFICANCE AND IMPACT Women's ischemic heart disease (IHD) differs from men's, and women have a unique phenotype of less calcified lesions and more non-obstructive disease. A significant number of patients with symptoms do not have obstructive coronary artery stenosis. This condition is termed ANOCA. Patients with ANOCA have a high symptom burden and reduced quality of life. Patients with ANOCA report frequent time missed from work and work limitations, suggesting a substantial economic impact as reported by the group at UVA. One proposed mechanism contributing to ANOCA is CMD. There is an increasing recognition that CMD is more prevalent in women. There are no randomized, controlled outcome trials testing treatment strategies tailored to different pathways that have not been performed; therefore, the proposed studies are consistent with an unmet urgent need for new novel therapies to target the microcirculation, specifically in women with suspected or confirmed ischemic heart disease, especially when young, who have less atherosclerosis than men and less prevalence of obstructive CAD. Measuring myocardial blood flow quantitatively with stress CMR is a particular expertise of the Cardiovascular Imaging Center at the University of Virginia (UVA) and our research group.

SGLT2i are a class of drugs approved for treating diabetes. However, they have been shown to benefit cardiovascular events significantly. Many of these findings were unanticipated and have stimulated substantial mechanistic research to improve the understanding of this class. However, recent studies show that possible mechanisms of cardiovascular benefit are unlikely to be related to improved glycemic control. These benefits included reduced systemic inflammation. Therefore, in this proposal, the impact of SGLT2i on systemic Inflammation and how it improve coronary microvascular function seen in animal models will be studied.

INNOVATION This study will focus on a novel study population and a novel therapy. Women under investigation for myocardial ischemia are more likely to have non-obstructive CAD, and here, CMD is relevant. Targeting symptomatic women with ischemia and non obstructive CAD is clearly an urgent need. This group of patients with a disabling problem also incurs healthcare costs similar to many with obstructive CAD. CMD has historically been under-recognized and under-treated. Accordingly, in recent years, CMD has generated substantial interest in the clinical and basic science research community.

Innovative diagnostic method. Traditionally, the non-invasive diagnosis of CMD has been dominated by PET imaging. Quantitative high-resolution CMR to quantify coronary myocardial blood flow and myocardial resistance are being developed to diagnose CMD and add a novel additional component to our project and will allow us to explore a potential clinical indication to monitor possible therapies for CMD. At present, the management strategy for patients with ANOCA and CMD remains unclear due to the absence of randomized trials comparing therapies to reduce adverse cardiac events, and available data are limited to cohort studies. There are no therapeutic options specifically to treat CMD. Our study will test whether SGLT2i therapy improves coronary blood flow and quality of life in women with ANOCA. Results will also contribute to understanding this novel drug class's mechanistic effect in microvascular disease and other major disease states such as insulin resistance.

OVERALL STUDY DESIGN This single-center, randomized, double-blind, placebo-controlled study is designed to evaluate coronary flow reserve and quality of life after therapy with SGLT2i compared to placebo in symptomatic women with non-obstructive CAD (ANOCA) and CMD. Recruited women (n=150 total) will be clinically stable, with angina or equivalent symptoms, with no evidence of obstructive epicardial CAD (stenosis \< 50%) by invasive catheterization or coronary computed tomography angiography (CCTA) or FFR/CT-FFR \< 0.8 within the previous two years, and CMD diagnosis defined by CFR \<2 by CMR. They will meet the appropriate inclusion and exclusion criteria detailed in Table 1. The study population will include patients both with and without type 2 diabetes, as the benefits of SGLT2i appear to be independent of the glycemic effect. Figure 4. Overall study design. Study participants will receive background standard of care, with 75 receiving SGLT2i and 75 receiving placebo treatment for 12 weeks. Participants will undergo two stress CMR studies, including baseline, 12 weeks post-treatment, and three blood draws at baseline, at six and 12 weeks post-SGLT2i treatment. All 150 participants will undergo questionnaires to measure quality of life using the following questionnaires: Risk factors of Cardiovascular Disease in Women, EQ-5D-3L, Duke Activity Status Inventory, Modified Morisky Medicine Scale, Seattle Angina Questionnaires, Rose dyspnea score, GAD 7, and PHQ8 metrics at baseline, 6 weeks and at 12 weeks post-treatment.

After eligibility screening, informed consent, and randomization procedures by the study team, participants will follow up at 6, and 12 weeks and other testing as described later in the protocol.