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Background Resistive reserve ratio (RRR), or the ratio of baseline to hyperemic microvascular resistance, has prognostic implications in predicting clinical outcomes in patients with obstructive coronary artery disease. However, its value in patients with angina or ischemia with nonobstructive coronary artery disease is unknown. Methods and Results We included 1692 patients with nonobstructive coronary artery disease who underwent invasive coronary vasoreactivity testing. Abnormal coronary flow reserve (CFR, the ratio of hyperemic and baseline resting flow velocities) and RRR were defined as <2.5 and <2.62, respectively. The mortality rate was marginally higher in patients with abnormal CFR (428 patients [25%]) than those with normal CFR (38 [9%] versus 81 [6%]; P =0.08), and was significantly higher in patients with abnormal RRR (716 patients [42%]) than those with normal RRR (70 [10%] versus 49 [5%], P =0.0002) over the median follow-up of 11.3 years. Patients with abnormal CFR had marginally lower survival than those with normal CFR (log-rank P =0.08). In contrast, patients with abnormal RRR had significantly lower survival than those with normal RRR (log-rank P =0.001). Abnormal RRR was associated with shorter time to death even after adjustment for other covariates (adjusted hazard ratio, 1.63; 95% CI, 1.11-2.38; P =0.01). Conclusions In patients with no obstructive coronary artery disease, RRR was superior to CFR in predicting long-term survival. An RRR <2.62 was associated with 1.6 times increased risk of death in patients with nonobstructive coronary artery disease. Indices of coronary microcirculatory resistive reserve comprising flow- and pressure-derived values may reflect underlying microvascular pathology more faithfully than flow-alone indices like CFR.

Previous studies in patients with Raynaud's phenomenon (RP) have found an association between microvascular abnormalities assessed by nail fold capillaroscopy and macrovascular peripheral endothelial dysfunction (PED), but the association between RP and nitric oxide related (NO) microvascular PED is not yet established. We performed a retrospective cross-sectional analysis of patients who were referred to Mayo Clinic between 2006 and 2014 for routine cardiovascular evaluation and who underwent evaluation of Reactive Hyperemia Peripheral Arterial Tonometry (index <2 consistent with PED). Identification of the presence of RP was determined by retrospective chart review. Six hundred sixty six individuals were included in this study (mean age 51.9 ± 13.5 years, 411 (61.3%) women), 637 (95.1%) individuals did not have RP (control group), and 29 (4.3%) had secondary RP. Only 4 patients had primary RP and were thus excluded from the final analyses. In a multivariate analysis adjusting for age, sex, smoking status, and use of statins we found a significant association between secondary RP and microvascular PED in all patients (Odds ratio: 2.45; 95% confidence interval 1.13-5.34; P = 0.0236) that remained significant in women after stratifying by sex. Secondary RP is associated with microvascular PED, detected using a non-invasive NO-dependent method. Early detection of microvascular PED could help in identifying individuals with secondary RP who are at risk for developing connective tissue disease as well as CVD., Competing Interests: Declaration of competing interest The authors have no conflicts of interest to disclose., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Background Peripheral microvascular endothelial dysfunction (PMED) has been linked to an increased risk of cardiovascular events, but there is a lack of information characterizing the predictive value of PMED for future risk of ischemic stroke (IS). Methods and Results This retrospective observational cohort study enrolled 637 patients who underwent non-invasive microvascular endothelial function assessment using reactive hyperemia peripheral arterial tonometry. Reactive hyperemia peripheral arterial tonometry index ≤2 was defined as PMED. Of 280 patients with PMED, 12 (4.3%) patients developed IS, compared with only 4 (1.1%) of 357 patients without PMED during a median follow-up of 5.3 years. Patients with PMED had lower IS-free survival compared with patients without PMED (log-rank P =0.03). Cox proportional hazard ratio (HR) analyses showed that PMED predicted the incidence of IS, with a HR of 3.43, 95% CI, 1.10-10.63 ( P =0.03); adjusted HR of 3.70, 95% CI, 1.18-11.59 ( P =0.02) after adjusting for sex, smoking history, and atrial fibrillation; adjusted HR of 3.45, 95% CI, 1.11-10.72 ( P =0.03) after adjusting for CHA 2 DS 2 -VASc score; adjusted HR of 5.70, 95% CI, 1.40-23.29 ( P =0.02) after adjusting for revised Framingham Stroke Risk Score. Reactive hyperemia peripheral arterial tonometry index improved discrimination of risk for IS after adding reactive hyperemia peripheral arterial tonometry index to CHA 2 DS 2 -VASc score and revised Framingham Stroke Risk Score. Conclusions PMED was associated with a >3-fold increased risk of IS. These findings underscore the concept of the systemic nature of endothelial dysfunction, which could act as a potential marker to predict future risk of IS.

Purpose of Review: The natural history of coronary atherosclerosis is complex and atherosclerotic plaques exhibit large morphologic and functional variability within the same individual as well as over time. The purpose of this article is to review the role of blood flow patterns and shear stress on the development of microvascular and epicardial endothelial dysfunction and atherosclerosis progression., Recent Findings: Recent breakthroughs in cardiovascular imaging have facilitated in-vivo characterization of the anatomic and functional characteristics of atherosclerotic plaques and have highlighted the role of endothelial shear stress and epicardial and microvascular endothelial dysfunction in the natural history of coronary atherosclerosis., Summary: There is an important need to identify individual lesions which may progress to vulnerable plaque in order to provide early therapeutic management. Evaluation of endothelial shear stress, local blood flow patterns, epicardial and microvascular endothelial dysfunction, as well as their complex associations might indicate those patients who have microvascular endothelial dysfunction and increased risk for upstream epicardial endothelial dysfunction and plaque progression. Such high-risk patients could potentially be targeted for more intensive therapeutic strategies to prevent the progression of both microvascular and epicardial atherosclerotic manifestations.

Background: Coronary microvascular dysfunction (CMD) is linked to adverse cardiovascular events. Definitive diagnosis of CMD requires invasive provocative testing during angiography. We developed and tested a novel computerized T wave analysis tool to identify electrocardiographic signatures of CMD., Methods: 1552 patients underwent an invasive assessment of coronary microvascular function. Patients with interpretable pre-procedural ECGs were divided into 2 age and sex matched groups (n=261 in each group, 75% female): normal microvascular function, CFR>2.5 (CFR+), and abnormal microvascular function, CFR ≤ 2.5 (CFR-). ECGs were evaluated using a novel T wave program that quantified subtle changes in T wave morphology., Results: T wave repolarization parameters were significantly different between patients with normal and abnormal microvascular function. The top 3 features in males comprised of T wave area in V6 (CFR+: 10091.4 mV(2) vs. CFR-: 8152.3 mV(2), p<0.05); T1 Y-center of gravity in lead II (CFR+: 17.8 mV vs. CFR-: 22.4, p<0.005) and T Peak-T End in lead II (CFR+: 97.6 msec vs. CFR-: 91.1 msec, p<0.05). These could identify the presence of an abnormal CFR with 74 ± 0.2% accuracy. In females, the top 3 features were T wave right slope lead V6 (CFR+: -2489.1 mV/msec vs. CFR-: -2352.3 mV/msec, p<0.005); Amplitude in V6 (CFR+: 190.4 mV vs. 172.7 mV, p=0.05) and Y-center of gravity in lead V1 (CFR+: 33.3 vs. CFR-: 40.0, p=0.001). These features could identify the presence of an abnormal CFR with 67 ± 0.3% accuracy., Conclusion: Our data demonstrates that a computer-based repolarization measurement tool may identify electrocardiographic signatures of CMD., (Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.)

Objectives: This study assessed the prevalence of coronary microvascular abnormalities in patients presenting with chest pain and nonobstructive coronary artery disease (CAD)., Background: Coronary microvascular abnormalities mediate ischemia and can lead to an increased risk of cardiovascular events., Methods: Using an intracoronary Doppler guidewire, endothelial-dependent microvascular function was examined by evaluating changes in coronary blood flow in response to acetylcholine, whereas endothelial-independent microvascular function was examined by evaluating changes in coronary flow velocity reserve in response to intracoronary adenosine. Patients were divided into 4 groups depending on whether they had a normal (+) or abnormal (-) coronary blood flow (CBF) in response to acetylcholine (Ach) and a normal (+) or abnormal (-) coronary flow velocity reserve (CFR) in response to adenosine (Adn): CBFAch+, CFRAdn+ (n = 520); CBFAch-, CFRAdn+ (n = 478); CBFAch+, CFRAdn- (n = 173); and CBFAch-, CFRAdn- (n = 268)., Results: Two-thirds of all patients had some sort of microvascular dysfunction. Women were more prevalent in each group (56% to 82%). Diabetes was uncommon in all groups (7% to 12%), whereas hypertension and hyperlipidemia were relatively more prevalent in each group, although rates for most conventional cardiovascular risk factors did not differ significantly between groups. There were no significant differences in the findings of noninvasive functional testing between groups. In a multivariable analysis, age was the only variable that independently predicted abnormal microvascular function., Conclusions: Patients with chest pain and nonobstructive CAD have a high prevalence of coronary microvascular abnormalities. These abnormalities correlate poorly with conventional cardiovascular risk factors and are dissociated from the findings of noninvasive functional testing., (Copyright © 2015 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Background: Coronary microvascular dysfunction (CMD) is associated with cardiovascular events in type 2 diabetes mellitus (T2DM). Optimal glycaemic control does not always preclude future events. We sought to assess the effect of the current target of HBA1c level on the coronary microcirculatory function and identify predictive factors for CMD in T2DM patients. Methods: We studied 100 patients with T2DM and 214 patients without T2DM. All of them with a history of chest pain, non-obstructive angiograms and a direct assessment of coronary blood low increase in response to adenosine and acetylcholine coronary infusion, for evaluation of endothelial independent and dependent CMD. Patients with T2DM were categorized as having optimal (HbA1c < 7 %) vs. suboptimal (HbA1c ≥ 7 %) glycaemic control at the time of catheterization. Results: Baseline characteristics and coronary endothelial function parameters differed significantly between T2DM patients and control group. The prevalence of endothelial independent CMD (29.8 vs. 39.6 %, p = 0.40) and dependent CMD (61.7 vs. 62.2 %, p = 1.00) were similar in patients with optimal vs. suboptimal glycaemic control. Age (OR 1.10; CI 95 % 1.04-1.18; p < 0.001) and female gender (OR 3.87; CI 95 % 1.45-11.4; p < 0.01) were significantly associated with endothelial independent CMD whereas glomerular filtrate (OR 0.97; CI 95 % 0.95-0.99; p < 0.05) was significantly associated with endothelial dependent CMD. The optimal glycaemic control was not associated with endothelial independent (OR 0.60, CI 95 % 0.23-1.46; p 0.26) or dependent CMD (OR 0.99, CI 95 % 0.43-2.24; p = 0.98). Conclusions: The current target of HBA1c level does not predict a better coronary microcirculatory function in T2DM patients. The appropriate strategy for prevention of CMD in T2DM patients remains to be addressed. [ABSTRACT FROM AUTHOR]