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.

Symptomatic women with INOCA have elevated native T1 compared to matched reference controls and there is a significant association between elevated native T1 and impaired MPRI, considered a surrogate measure of ischemia severity in this cohort. Future studies in a larger cohort are needed to elucidate the mechanism underlying this inverse relationship.

BackgroundCoronary endothelial function testing using acetylcholine is not routinely available, while non-pharmacological cold pressor testing (CPT) is considered an endothelial stressor. Noninvasive cardiac magnetic resonance imaging (CMRI) myocardial perfusion reserve index (MPRI) can detect coronary microvascular dysfunction (CMD). We evaluated if CPT stress CMRI MPRI could detect invasive coronary endothelial dysfunction.MethodsCoronary reactivity testing was performed in 189 women with symptoms and signs of ischemic but no obstructive coronary artery disease as previously described plus CPT stress. Subjects also underwent pharmacologic and CPT stress during CMRI (1.5 T). Statistical analysis comparing CPT MPRI between groups was performed by Welch`s t-test and Mann-Whitney where appropriate. Anderson-Darling test and Levene test were considered to verify the normality and homogeneity of variances assumptions. Correlation analyses between CPT MPRI and both invasive and noninvasive measures of CMD were performed using Spearman correlation.ResultsWhile CPT MPRI correlated with pharmacological stress MPRI, it did not correlate with invasive measures of CMD including invasively measured responses to intracoronary (IC) adenosine, IC acetylcholine, CPT, or IC nitroglycerin. Additionally CPT MPRI was not significantly different between subjects with normal compared to abnormal pharm stress MPRI or normal compared to abnormal invasive CMD parameters.ConclusionDespite correlation with pharmacological stress MPRI, non-invasive CPT MPRI does not appear to be useful for detecting CMD in symptomatic women.

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Background:Cardiovascular magnetic resonance imaging (CMRI) derived myocardial perfusion reserve index (MPRI) has recently been shown to detect coronary microvascular dysfunction (CMD) in women with signs and symptoms of ischemia and no obstructive coronary artery disease (CAD). The aim of this study was to determine the inter-scan reproducibility of MPRI in this patient group in order to assess its diagnostic robustness in serial scans and assess its utility as a marker of potential therapies for CMD.Methods:Rest/stress perfusion CMR was performed at 1.5T using a standardized protocol in 17 women with signs and symptoms of ischemia and no obstructive CAD on two separate days (within 90 days of each other). The same pharmacological stress agent (adenosine/regadenoson) was used for both scans. MPRI was calculated from time-intensity curves of the whole myocardium and blood pool at stress and rest. One experienced observer, blinded to clinical data, performed all measurements. Intra-class correlation coefficients (ICC), coefficient of variation (CoV), and Bland-Altman plots were determined.Results:Mean age was 53±10 years old and BMI 28±7 kg/m2; 47% had hypertension, 4% diabetes, 9% hyperlipidemia and 10% family history of CAD. Mean MPRI for the 17 women was higher for scan 2 compared to scan 1 (1.98±0.3 vs. 1.65±0.78, respectively, p<0.001); and this relationship persisted even when corrected for resting rate pressure product (RPP) (2.42±0.81 vs. 1.97±0.92, respectively, 0.002), The mean bias for MPRI between sequential scans was 0.34 (95% CI: 0.18 to 0.49, limits of agreement: −0.31, 0.98 and when corrected for resting RPP it was 0.45 (95% CI: 0.21 to 0.68, limits of agreement: −0.52, 1.41), ICC and CoV also indicated modest inter-scan reproducibility (ICC 0.57; CoV 20.3%), but both measures were comparable to values seen in prior studies in CAD populations and healthy volunteers.Conclusion:Inter-scan reproducibility of CMRI-derived MPRI in women with suspected CMD is modest, with relatively wide limits of agreement. This variability is similar to that seen in other populations, suggesting that some caution must be exercised when using absolute MPRI cut-offs in isolation for the diagnosis of CMD or repeated measures of MPRI to track response to therapy. Additional work is ongoing to improve reproducibility from both biological and technological standpoints.