BackgroundWomen with signs and symptoms of ischemia, no obstructive coronary artery disease (CAD) and preserved left ventricular ejection fraction (EF) often have diastolic dysfunction and experience elevated rates of major adverse cardiac events (MACE), including heart failure (HF) hospitalization with preserved ejection fraction (HFpEF). We evaluated the predictive value of inflammatory biomarkers for long-term HF hospitalization and all-cause mortality in these women.MethodsWe performed a cross-sectional analysis to investigate the relationships between inflammatory biomarkers [serum interleukin-6 (IL-6), C-reactive protein (hs-CRP) and serum amyloid A (SAA)] and median of 6 years follow-up for all-cause mortality and HF hospitalization among women with signs and symptoms of ischemia, non-obstructive CAD and preserved EF. Multivariable Cox regression analysis tested associations between biomarker levels and adverse outcomes.ResultsAmong 390 women, mean age 56 ± 11 years, median follow up of 6 years, we observed that there is continuous association between IL-6 level and HF hospitalization (adjusted hazard ratio [AHR] 2.5 [1.2–5.0], p = 0.02). In addition, we found significant association between IL-6, SAA levels and all-cause mortality AHR (1.8 [1.1–3.0], p = 0.01) (1.5 [1.0–2.1], p = 0.04), respectively.ConclusionIn women with signs and symptoms of ischemia, non-obstructive CAD and preserved EF, elevated IL-6 predicted HF hospitalization and all-cause mortality, while SAA level was only associated with all-cause mortality. These results suggest that inflammation plays a role in the pathogenesis of development of HFpEF, as well all-cause mortality.

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Background Coronary microvascular dysfunction (CMD) is prevalent in symptomatic women with ischemia but no obstructive coronary artery disease (INOCA). Urine albumin-creatinine ratio (UACR) is a measure of renal microvascular endothelial dysfunction. Both are predictors of adverse cardiovascular events. It is unknown if CMD could be a manifestation of a systemic process. We evaluated the relationship between renal microvascular dysfunction and CMD as measured by invasive coronary function testing (CFT). Methods and results We measured urine albumin and creatinine to provide UACR in 152 women enrolled in the Women’s Ischemia Syndrome Evaluation–Coronary Vascular Dysfunction (WISE-CVD) study (2008–2015) with suspected INOCA who underwent CFT. Invasive CFT measures of endothelial and non-endothelial dependent coronary microvascular function were obtained. Subjects were divided into those with detectable (≥20 mg/g) and undetectable urine albumin (<20 mg/g). The group mean age was 54 ± 11 years, with a moderate cardiac risk factor burden including low diabetes prevalence, and a mean UACR of 12 ± 55 mg/g (range 9.5–322.7 mg/g). Overall, coronary endothelial-dependent variables (change in coronary blood flow and coronary diameter in response to cold pressor testing) had significant inverse correlations with log UACR (r = -0.17, p = 0.05; r = -0.18, p = 0.03, respectively). Conclusions Among women with INOCA and relatively low risk factor including diabetes burden, renal microvascular dysfunction, measured by UACR, is related to coronary endothelial-dependent CMD. These results suggest that coronary endothelial-dependent function may be a manifestation of a systemic process. Enhancing efferent arteriolar vasodilatation in both coronary endothelial-dependent function and renal microvascular dysfunction pose potential targets for investigation and treatment. Clinical trial registration https://clinicaltrials.gov/ct2/show/NCT00832702.

BackgroundAssessment of coronary endothelial function with intracoronary acetylcholine (IC-Ach) provides diagnostic and prognostic data in patients with suspected coronary microvascular dysfunction (CMD), but is often not feasible due in part to the time and expertise needed for pharmacologic mixing. Cold pressor testing (CPT) is a simple and safe stimulus useful for either invasive or non-invasive endothelial function testing and myocardial perfusion imaging but has not been specifically evaluated among symptomatic women with signs of ischemic heart disease (IHD) who have no obstructive coronary artery disease (CAD).Methods163 women with signs and symptoms of IHD and no obstructive CAD from the NHLBI- Women’s Ischemia Syndrome Evaluation-Coronary Vascular Dysfunction (WISE-CVD) study underwent coronary reactivity testing with a Doppler flow wire (FloWire® Volcano, San Diego, CA) in the proximal left anterior descending artery. Coronary artery diameter and coronary blood flow (CBF) assessed by core lab using QCA before and after IC-Ach (18.2 μg/ml infused over 3 minutes) and during CPT.ResultsMean age was 55 ± 12 years. Rate pressure product (RPP) in response to IC-Ach did not change (baseline to peak, P = 0.26), but increased during CPT (363±1457; P = 0.0028). CBF in response to CPT was poorly correlated to IC-Ach CBF. Change in coronary artery diameter after IC-Ach correlated with change after CPT (r = 0.59, P<0.001). The correlation coefficient was stronger in subjects with coronary dilation to IC-Ach (r = 0.628, P<0.001) versus those without dilation (r = 0.353, P = 0.002), suggesting that other factors may be important to this relationship when endothelium is abnormal.ConclusionsIn women with no obstructive CAD and suspected CMD, coronary diameter changes with IC-Ach and CPT are moderately-well correlated suggesting that CPT testing may be of some use, particularly among patients with normal endothelial function, however, not an alternative to IC-Ach for diagnosis of coronary endothelial dysfunction.