Reduction In Coronary Flow Reserve Research Articles

CORONARY FLOW AT REST AND CLINICAL OUTCOMES IN DILATED CARDIOMYOPATHY

Abstract Background/Objectives Reduced coronary flow reserve (CFR) was described in dilated cardiomyopathy (DCM). To match increased metabolic demand from the myocardium, resting coronary flow (rCF) increases with CFR consumption. Whether an increased rCF causing a reduction of CFR is associated with worse clinical outcomes in DCM remains debated. RCF is inversely correlated to the resting mean transit time (mtt) required for blood to pass through the coronary artery (rCF=1/mtt). A reliable surrogate of mtt is the ratio n frames/frame rate where n frames are the number of frames required for the dye to reach standard distal landmarks of coronary arteries during invasive coronary angiography (ICA) and frame rate is the frame rate acquisition. We aim to assess the prognostic role of rCF evaluated at the ICA performed as standard clinical practice at the time of diagnosis at long–term follow–up in DCM. Methods This is a retrospective analysis of a prospective cohort of patients with idiopathic DCM under medical management enrolled in the Verona Heart Failure registry between 01/2012 and 12/2022. RCF was evaluated at the ICA performed at the time of diagnosis as 1/(n frames/frame rate). The primary endpoint was a composite of cardiovascular death, rehospitalization for heart failure, resuscitated cardiac arrest, hemodynamically unstable ventricular arrhythmias, implanted cardiac defibrillator intervention and cardiac transplantation due to advanced heart failure. Results 110 patients were enrolled in the final cohort. 15 patients (13.6%) suffered the primary endpoint at a median follow–up time of 42 months (IQR 18–71). At the ROC curve analysis rCF predicts the primary endpoint at a cut–off of 2.32 with an AUC of 0.728 (0.599–0.858, p=0.005) with sensitivity, specificity, negative and positive predictive value of 73.3%, 69.5%, 94.3% and 27.5% respectively. Patients suffering the primary endpoint tended to be older (66 years [60–74] vs 59 years [51–69], p=0.060) and were characterized by an increased rCF (3 [1.87–3.75] vs 1.87 [1.36–2.5]). Patients with rCF<2.32 suffered the primary endpoint more frequently when compared to those with rCF≥2.32 (27.5% vs 5.7%, log rank test p=0.007). Conclusions Increased rCF leading to a consumption of CFR is associated with worse clinical outcomes at long term follow–up in idiopathic DCM. Whether coronary microvascular dysfunction can play a prognostic role in this setting remains to be explored by proper prospective studies.

Accelerated stenotic flow in the left anterior descending coronary artery explains the causes of impaired coronary flow reserve: an integrated transthoracic enhanced Doppler study.

Accelerated stenotic flow (AsF) in the entire left anterior descending coronary artery (LAD), assessed by transthoracic enhanced color Doppler (E-Doppler TTE), can reveal coronary stenosis (CS) and its severity, enabling a distinction between the microcirculatory and epicardial causes of coronary flow reserve (CFR) impairment. Eighty-four consecutive patients with a CFR <2.0 (1.5 ± 0.4), as assessed by E-Doppler TTE, scheduled for coronary angiography (CA) and eventually intracoronary ultrasounds (IVUS), were studied. CFR was calculated by the ratio of peak diastolic flow velocities: during i.v. adenosine (140 mcg/Kg/m) over resting; AsF was calculated as the percentage increase of localized maximal velocity in relation to a reference velocity. CA showed ≥50% lumen diameter narrowing of the LAD (critical CS) in 68% of patients (57/84) vs. non-critical CS in 32% (27/84). Based on the established CA/IVUS criteria, the non-critical CS subgroup was further subdivided into 2 groups: subcritical/diffuse [16/27 pts (57%)] and no atherosclerosis [11/27 pts (43%)]. CFR was similar in the three groups: 1.4 ± 0.3 in critical CS, 1.5 ± 0.4 in subcritical/diffuse CS, and 1.6 ± 0.4 in no atherosclerosis (p = ns). Overall, at least one segment of accelerated stenotic flow in the LAD was found in 73 patients (87%), while in 11 (13%) it was not. The AsF was very predictive of coronary segmental narrowing in both angio subgroups of atherosclerosis but as expected with the usage of different cutoffs. On the basis of the ROC curve, the optimal cutoff was 109% and 16% AsF % increment to successfully distinguish critical from non-critical CS (area under the curve [AUC] = 0.99, p < 0.001) and diffuse/subcritical from no CS (AUC = 0.91%, p < 0.001). Sensitivity and specificity were 96% and 100% and 82% and 100%, respectively. E-Doppler TTE is highly feasible and reliable in detecting the CS of any grade of severity, distinguishing epicardial athero from microvascular causes of a severe CFR reduction.

Dynamic Assessments of Coronary Flow Reserve after Myocardial Ischemia Reperfusion in Mice.

After cardiac ischemia, there is often insufficient myocardial perfusion, even if flow has been successfully and completely restored in an upstream artery. This phenomenon, known as the "no-reflow phenomenon," is attributed to coronary microvascular dysfunction and has been associated with poor clinical outcomes. In clinical practice, a reduction in coronary flow reserve (CFR) is frequently used as an indicator of coronary artery disease. CFR is defined as the ratio of the peak flow velocity induced by pharmacologic or metabolic factors to the resting flow velocity. This protocol focused on assessing the dynamic changes in CFR before and after ischemia-reperfusion (IR) using pulse wave Doppler measurements. In this study, normal mice exhibited the ability to increase the peak velocity of coronary blood flow up to two times higher than the resting values under isoflurane stimulation. However, after ischemia-reperfusion, the CFR at 1 h significantly decreased compared to the pre-operation baseline. Over time, the CFR showed gradual recovery, but it remained below the normal level. Despite the preservation of systolic function, early detection of microvascular dysfunction is crucial, and establishing a practical guide could aid doctors in this task, while also facilitating the study of cardiovascular disease progression over time.

OR02-5 Coronary Microvascular Dysfunction is Present Among Well-Treated Asymptomatic Persons with HIV, Similar to Those with Diabetes

Abstract Persons with HIV (PWH) who are well-treated on antiretroviral therapies (ART) have a 1.5-2.0 fold increased risk of cardiovascular disease (CVD) compared to persons without HIV (PWOH). A unique cardiovascular phenotype is seen in HIV such that traditional cardiovascular risk factors alone to do not account for this excess CVD risk. Coronary microvascular dysfunction may promote subendocardial ischemia and cardiomyocyte injury and provide a potential underlying mechanism for the atherosclerotic and myocardial disease prevalent in HIV. We assessed coronary microvascular function among those with HIV, comparing to those without HIV and with diabetes (DM). 39 PWH with no known history of CVD or DM, required to be on stable ART and virologically controlled (HIV viral load &amp;lt;200 copies/mL), underwent coronary 13N-ammonia PET/CT to evaluate coronary flow reserve (CFR)—a measure of microvascular dysfunction calculated by the ratio of peak coronary flow during regadenoson stress to rest. CFR was corrected using the rate pressure product, which integrates resting blood pressure and heart rate. A 0.1 unit reduction in CFR is associated with a 8% increase in hazard of CV events. Comparisons of CFR were made to PWOH from a database of higher risk clinical referrals who were matched approximately 2: 1 based on demographics and traditional risk factors and to those with diabetes and no known history of CVD recruited as part of a prior study evaluating CFR. Overall group comparisons for CFR were analyzed with the Wilcoxon/Kruskal-Wallis test, and if significant, the Mann-Whitney U test was employed for two-group comparisons. PWH(74% male, age 55±7years, BMI 32±6kg/m2, duration HIV 20±8years, duration ART 16±7years, CD4+ count 801±333cells/ul) were similar to PWOH(n=69, 74% male, age 55±8years, BMI 32±6kg/m2) and persons with DM(n=63, 63% male, age 55±8years, BMI 32±5kg/m2). CFR was significantly different among groups: PWOH 2.76(2.37,3.36), PWH 2.47(1.92,2.93), DM 2.31(1.98,2.84), overall P=.003. CFR was significantly reduced when comparing to PWH to PWOH(P=.02) as was DM to PWOH(P=.001) and did not differ when comparing PWH to DM(P=.68). Total cholesterol 182(168,205)mg/dL, LDL 108(77,127)mg/dL, triglycerides 159(88,219)mg/dL, and current tobacco use 23% were overall significantly higher among PWH (overall P&amp;lt;.03 for each comparison). Controlling for group status (PWH vs. PWOH) and either total cholesterol or current tobacco use, only group status remained significantly and independently related to CFR (group status P=.02 and .01, respectively). Subclinical coronary microvascular dysfunction is present among asymptomatic, chronically infected PWH on ART who demonstrate good immunological control. This study demonstrates for the first time CFR is reduced compared to higher risk PWOH and comparable to those with DM, regardless of traditional CVD risk factors, and further highlights well-treated HIV as a CVD-risk enhancing factor similar to diabetes. The implications of reduced CFR in HIV warrants further investigation. Presentation: Saturday, June 11, 2022 12:30 p.m. - 12:45 p.m.

Mechanism of exercise intolerance in heart diseases predicted by a computer model of myocardial demand‐supply feedback system

Background and objectiveThe myocardial demand-supply feedback system plays an important role in augmenting blood supply in response to exercise-induced increased myocardial demand. During this feedback process, the myocardium and coronary blood flow interact bidirectionally at many different levels. MethodsTo investigate these interactions, a novel computational framework that considers the closed myocardial demand-supply feedback system was developed. In the framework coupling the systemic circulation of the left ventricle and coronary perfusion with regulation, myocardial work affects coronary perfusion via flow regulation mechanisms (e.g., metabolic regulation) and myocardial-vessel interactions, whereas coronary perfusion affects myocardial contractility in a closed feedback system. The framework was calibrated based on the measurements from healthy subjects under graded exercise conditions, and then was applied to simulate the effects of graded exercise on myocardial demand-supply under different physiological and pathological conditions. ResultsWe found that the framework can recapitulate key features found during exercise in clinical and animal studies. We showed that myocardial blood flow is increased but maximum hyperemia is reduced during exercise, which led to a reduction in coronary flow reserve. For coronary stenosis and myocardial inefficiency, the model predicts that an increase in heart rate is necessary to maintain the baseline cardiac output. Correspondingly, the resting coronary flow reserve is exhausted and the range of heart rate before exhaustion of coronary flow reserve is reduced. In the presence of metabolic regulation dysfunction, the model predicts that the metabolic vasodilator signal is higher at rest, saturates faster during exercise, and as a result, causes quicker exhaustion of coronary flow reserve. ConclusionsModel predictions showed that the coronary flow reserve deteriorates faster during graded exercise, which in turn, suggests a decrease in exercise tolerance for patients with stenosis, myocardial inefficiency and metabolic flow regulation dysfunction. The findings in this study may have clinical implications in diagnosing cardiovascular diseases.

Coronary flow abnormalities in chronic kidney disease: A systematic review and meta-analysis.

Coronary vasomotion abnormalities have been described in small studies but not studied systematically. We aimed to review the present literature and analyze it to improve our understanding of chronic kidney disease (CKD) related-coronary microvascular dysfunction. Coronary flow reserve (CFR) is a well-known measure of coronary vasomotion. We aimed to assess the difference in CFR among participants with and without CKD. PubMed, Embase, and Cochrane CENTRALwere systematically reviewed to identify studies that compared CFR in participants with and without CKD. We estimated standardized mean differences in mean CFR reported in these studies. We performed subgroup analyses according to imaging modality, and the presence of significant epicardial coronary artery disease. In 14 observational studies with 5966 and 1410 patients with and without CKD, the mean estimated glomerular filtration rate (eGFR) was 29±04 and 87±25ml/min/1.73m2 , respectively. Mean CFR was consistently lower in patients with CKD in all studies and the cumulative mean difference was statistically significant (2.1±.3vs. 2.7±.5, standardized mean difference -.8, 95% CI -1.1, -.6, p<.05). The lower mean CFR was driven by both significantly higher mean resting flow velocity (.58cm/s, 95% CI .17, .98) and lower mean stress flow velocity (-.94cm/s, 95% CI -1.75, -.13) in studies with CKD. This difference remained significant across diagnostic modalities and even in absence of epicardial coronary artery disease. In meta-regression, there was a significant positive relationship between mean eGFR and mean CFR (p<.05). Patients with CKD have a significantly lower CFR versus those without CKD, even in absence of epicardial coronary artery disease. There is a linear association between eGFR and CFR. Future studies are required to understand the mechanisms and therapeutic implications of these findings. In this meta-analysis of observational studies, there was a significant reduction in coronary flow reserve in studies with chronic kidney disease versus those without. This difference was seen even in absence of epicardial coronary artery disease. In meta-regression, a lower estimate glomerular filtration rate was a significant predictor of lower coronary flow reserve. Coronary microvascular dysfunction, rather than atherosclerosis-related epicardial disease may underly increase cardiovascular risk in a patient with chronic kidney disease.

Endothelial dysfunction due to decreased nitric oxide bioavailability in dysglycaemic subjects and first-degree relatives of type 2 diabetic patients

Abstract Background/Introduction Oxidative stress plays an important role in the pathogenesis of type 2 diabetes mellitus. Purpose We aimed to investigate oxidative stress and nitrites/nitrates concentrations at baseline and during postprandial hyperglycaemia in 40 first-degree relatives (FDR) of type 2 diabetic patients with normal oral glucose test (OGTT), 40 subjects with abnormal OGTT (dysglycaemic) and 20 subjects with normal OGTT without parental history of diabetes (normoglycaemic). Methods Perfused boundary region (PBR) of the sublingual microvessels with a diameter 5–25μm (Microscan, Glycocheck), a marker of endothelial glycocalyx integrity, coronary flow reserve (CFR) in the distal left anterior descending coronary artery, left ventricular global longitudinal strain (GLS), malondialdehyde (MDA), protein carbonyls (PC) and nitrites/nitrates plasma levels were assessed at 0 and 120 min of a 2-hour OGTT. Insulin sensitivity was evaluated using Matsuda and insulin sensitivity index (ISI). Results In all subjects, there were no significant changes in MDA and PC at 120 min after OGTT (p&amp;gt;0.05). Compared with normoglycaemic subjects, in FDR and dysglycaemic subjects, nitrites/nitrates levels were significantly decreased at 120 min (−24% versus −30% versus −3%, respectively) with a parallel increase in PBR (+7% versus +10% versus −3%) and a reduction in CFR (−11% versus −14% versus −6%) and GLS (−4% versus −4% versus +0.1%) (p&amp;lt;0.05 for all comparisons). The percent reduction of nitrites/nitrates levels was associated with abnormal values of Matsuda and ISI, reversely related with the percent increase of PBR (r=−0.60, p=0.001) and positively related with the percent decrease of CFR (r=0.39, p=0.038) and GLS (r=0.48, p=0.008). Conclusion Insulin resistance determines acute endothelial responses during OGTT leading to reduced nitric oxide production with resultant coronary and myocardial dysfunction in FDR and dysglycaemic subjects. Funding Acknowledgement Type of funding sources: None.

The diagnosis and prognosis of coronary microvascular disease using PET/CT.

This study aimed to evaluate the diagnostic and prognostic value of 13N-NH3·H2O positron emission tomography combined with computed tomography (PET/CT) for non-obstructive coronary microvascular disease (CMVD). A retrospective analysis was conducted on 70 patients with clinically suspected non-obstructive CMVD (35 males, 35 females) between March 2017 and August 2019. The average age of the patients was 53.32±7.82 years. The patients underwent 13N-NH3·H2O PET/CT and were divided into two groups based on diagnostic criteria: a CMVD group and a non-CMVD group. They were then followed up for 180-1,095 days. Data were analyzed using an χ2 test, the logistic regression model, the multiple linear regression model, the Kaplan-Meier method, the Cox proportional hazards regression model, and a receiver operating characteristic (ROC) curve. (1) The incidence of cardiovascular family history and a high calcification score (11-400) was higher in the CMVD group than in the non-CMVD group (58.8% vs. 20.8% and 29.4% vs. 5.7%, respectively; P < 0.05 for all), stress myocardial blood flow (MBF) and coronary flow reserve (CFR) values were lower in the CMVD group than in the non-CMVD group (2.280±0.693 vs. 3.641±1.365 and 2.142±0.339 vs. 3.700±1.123, respectively), and calcification score was higher in the CMVD group than in the non-CMVD group (110.18±165.07 vs. 13.21±41.68, respectively; P < 0.05 for all). Gender and diabetes were risk factors for stress MBF reduction (β= 1.287 and β= -0.636, respectively), calcification score and hypertension were risk factors for CFR reduction (β= -0.004 and β= -0.654, respectively), and hypertension, family history, and calcification score were risk factors in the CMVD group (OR = 7.323, OR = 5.108, OR = 1.012, respectively; P < 0.05 for all). (2) The prognosis of patients with CFR < 2.5 was worse than that of patients with CFR≥2.5 (x2 value: 27.404, P < 0.001). The risk of adverse cardiovascular events in diabetic patients was also increased (β= 0.328, P < 0.001). When CFR was set to 2.595, the prognostic sensitivity was 94% and the specificity was 80%. The technology of 13N-NH3·H2O PET/CT can be used for the diagnosis and prognosis of non-obstructive CMVD. Cardiovascular risk factors are related to the occurrence and prognosis of CMVD.

An update on the coronary calcium score: a review for clinicians.

The clinical manifestation of coronary artery atherosclerosis is coronary artery disease (CAD) with symptoms ranging from exertional chest pain due to reduction of coronary flow reserve to acute coronary syndrome due to rupture of usually a nonobstructive plaque with abrupt coronary blood flow reduction. CAD is the leading cause of morbidity and mortality worldwide. Therefore, identifying asymptomatic people at risk of CAD is pivotal to guide decision-making for primary prevention. Coronary artery calcium (CAC) is a hallmark of coronary artery atherosclerosis. It can be detected using cardiac computed tomography and quantified by the Agatston method. CAC examination is a cheap, fast and low radiation dose test, without injecting a contrast agent. It provides prognostic information over other traditional cardiovascular risk markers and established scoring systems, especially for low-risk subgroups such as women and younger adults, and indicates the appropriate moment to implement primary prevention, including acetylsalicylic acid and statins. In this review, we discuss the methods of CAC evaluation, the meaning of a zero CAC score (CACS), its conversion to CACS > 0 and the impact of this fact on cardiovascular risk, the effect of statins and proprotein convertase subtilisin/kexin type 9 inhibitor on CAC progression, interpretation of CACS results, and CACS prognostic value in both asymptomatic and symptomatic patients.

Coronary flow reserve and cardiovascular outcomes: a systematic review and meta-analysis.

AimsThis meta-analysis aims to quantify the association of reduced coronary flow with all-cause mortality and major adverse cardiovascular events (MACE) across a broad range of patient groups and pathologies.Methods and resultsWe systematically identified all studies between 1 January 2000 and 1 August 2020, where coronary flow was measured and clinical outcomes were reported. The endpoints were all-cause mortality and MACE. Estimates of effect were calculated from published hazard ratios (HRs) using a random-effects model. Seventy-nine studies with a total of 59 740 subjects were included. Abnormal coronary flow reserve (CFR) was associated with a higher incidence of all-cause mortality [HR: 3.78, 95% confidence interval (CI): 2.39–5.97] and a higher incidence of MACE (HR 3.42, 95% CI: 2.92–3.99). Each 0.1 unit reduction in CFR was associated with a proportional increase in mortality (per 0.1 CFR unit HR: 1.16, 95% CI: 1.04–1.29) and MACE (per 0.1 CFR unit HR: 1.08, 95% CI: 1.04–1.11). In patients with isolated coronary microvascular dysfunction, an abnormal CFR was associated with a higher incidence of mortality (HR: 5.44, 95% CI: 3.78–7.83) and MACE (HR: 3.56, 95% CI: 2.14–5.90). Abnormal CFR was also associated with a higher incidence of MACE in patients with acute coronary syndromes (HR: 3.76, 95% CI: 2.35–6.00), heart failure (HR: 6.38, 95% CI: 1.95–20.90), heart transplant (HR: 3.32, 95% CI: 2.34–4.71), and diabetes mellitus (HR: 7.47, 95% CI: 3.37–16.55).ConclusionReduced coronary flow is strongly associated with increased risk of all-cause mortality and MACE across a wide range of pathological processes. This finding supports recent recommendations that coronary flow should be measured more routinely in clinical practice, to target aggressive vascular risk modification for individuals at higher risk.

Adenosine-Induced Coronary Steal Is Observed in Patients Presenting With ST-Segment-Elevation Myocardial Infarction.

BackgroundAdenosine is used to treat no‐reflow in the infarct‐related artery (IRA) during ST‐segment–elevation myocardial infarction intervention. However, the physiological effect of adenosine in the IRA is variable. Coronary steal—a reduction of blood flow to the distal coronary bed—can occur in response to adenosine and this is facilitated by collaterals. We investigated the effects of adenosine on coronary flow reserve (CFR) in patients presenting with ST‐segment–elevation myocardial infarction to better understand the physiological mechanism underpinning the variable response to adenosine.Methods and ResultsPressure‐wire assessment of the IRA after percutaneous coronary intervention was performed in 93 patients presenting with ST‐segment–elevation myocardial infarction to calculate index of microvascular resistance, CFR, and collateral flow index by pressure. Modified collateral Rentrop grade to the IRA was recorded, as was microvascular obstruction by cardiac magnetic resonance imaging. Coronary steal (CFR <0.9), no change in flow (CFR=0.9–1.1), and hyperemic flow (CFR >1.1) after adenosine occurred in 19 (20%), 15 (16%), and 59 (63%) patients, respectively. Patients with coronary steal had higher modified Rentrop score to the IRA (1 [0, 1.75] versus 0 [0, 1], P<0.001) and a higher collateral flow index by pressure (0.25±0.10 versus 0.15±0.10, P=0.004) than the hyperemic group. The coronary steal group also had significantly higher index of microvascular resistance (61.68 [28.13, 87.04] versus 23.93 [14.67, 37.00], P=0.006) and had more disease (stenosis >50%) in the donor arteries (52.63% versus 22.03%, P=0.02) than the hyperemic group.ConclusionsAdenosine‐induced coronary steal may be responsible for a reduction in coronary flow reserve in a proportion of patients presenting with ST‐segment–elevation myocardial infarction.RegistrationURL: https://www.clinicaltrials.gov; Unique identifier: NCT03145194. URL: https://www.isrctn.com; Unique identifier: ISRCTN3176727.

Coronary microvascular function is impaired in patients with cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL)

Abstract Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL; OMIM 125310) is a rare inherited disease, caused by NOTCH3 gene mutations. Main clinical manifestations of CADASIL include recurrent subcortical ischemic events, migraine, cognitive impairment and psychiatric disturbances. CADASIL is a systemic microangiopathy and cardiac involvement has been observed in a series of Dutch patients, presenting higher frequency of myocardial infarction compared to non-mutated relatives and general population. In particular, electron microscopic examination of myocardial tissue of a study participant demonstrated CADASIL characteristics. We sought to investigate the relationship between CADASIL and microvascular dysfunction (MVD). Seventeen patients with genetically-confirmed CADASIL, aged &amp;lt;60 years, with ≤1 cardiovascular risk factor (current smoke, diabetes, hypertension, dyslipidemia), recent (&amp;lt;3 months) neurological evaluation with neuropsychological tests and 3 Tesla brain magnetic resonance imaging (MRI) underwent 12-lead ECG, echocardiography, and measurement of maximal myocardial blood flow following Regadenoson infusion (Reg-MBF) by 13NH3positron emission tomography (PET), to investigate the presence of coronary microvascular dysfunction (CMD). Coronary flow reserve (CFR) was defined as Reg-MBF/resting MBF. PET results were compared to those of 15 healthy controls matched for age and sex recruited among a historical cohort of healthy patients. The study was approved by the institutional review board and all the subjects gave informed consent. Mean age was 40±9 years (range 28–57 years); 6 patients (35%) were male. One was a current smoker and 3 ex-smokers; 1 patient was on aspirin, 1 on acetazolamide and 2 on escitalopram, none was taking statins. 12 patients (71%) presented with migraine, 9 (53%) had psychiatric disturbances and 1 (6%) had a previous stroke. Brain MRI showed mild-moderate and severe leukoencephalopathy in 11 (65%) and 5 (29%) patients respectively, lacunes were present in 14 patients and microbleeds in 1; one patient had normal findings. Both Reg-MBF and CFR were blunted in CADASIL patients compared with controls (Reg-MBF 2.46±0.54 versus 3.09±0.44 ml/gr/min respectively, p&amp;lt;0.001; CFR 2.74±0.36 vs. 3.28±0.66, respectively, p&amp;lt;0.01). In 3 male patients (17%), CFR reduction was severe (&amp;lt;2). Segmental Reg-MBF analysis of left ventricular flow showed diffuse hypoperfusion, excluding preferential regional involvement. No correlations were found between Reg-MBF values and neuropsychological performance or cerebral lesion burden, suggesting that neurological and cardiac involvement might be independent in CADASIL. These data represent the first documentation of coronary microvascular involvement in a group of young and mildly symptomatic CADASIL patients, confirming the systemic nature of the disease. This proof of concept study expands our understanding of genetically-driven CMD. Funding Acknowledgement Type of funding source: None

Microvascular dysfunction and sympathetic hyperactivity in women with supra-normal left ventricular ejection fraction (snLVEF).

Recently, a new disease phenotype characterized by supra-normal left ventricular ejection fraction (snLVEF) has been suggested, based on large datasets demonstrating an increased all-cause mortality in individuals with an LVEF > 65%. The underlying mechanisms of this association are currently unknown. A total of 1367 patients (352 women, mean age 63.1 ± 11.6years) underwent clinically indicated rest/adenosine stress ECG-gated 13N-ammonia positron emission tomography (PET) between 1995 and 2017 at our institution. All patients were categorized according to LVEF. A subcohort of 698 patients (150 women) were followed for major adverse cardiac events (MACEs), a composite of cardiac death, non-fatal myocardial infarction, cardiac-related hospitalization, and revascularization. The prevalence of a snLVEF (≥ 65%) was higher in women as compared to that in men (31.3% vs 18.8%, p < 0.001). In women, a significant reduction in coronary flow reserve (CFR, p < 0.001 vs normal LVEF) and a blunted heart rate reserve (% HRR, p = 0.004 vs normal LVEF) during pharmacological stress testing-a surrogate marker for autonomic dysregulation-were associated with snLVEF. Accordingly, reduced CFR and HRR were identified as strong and independent predictors for snLVEF in women in a fully adjusted multinomial regression analysis. After a median follow-up time of 5.6years, women with snLVEF experienced more often a MACE than women with normal (55-65%) LVEF (log rank p < 0.001), while such correlation was absent in men (log rank p = 0.76). snLVEF is associated with an increased risk of MACE in women, but not in men. Microvascular dysfunction and an increased sympathetic tone in women may account for this association.

P3108Microcirculation injury is involved in anthracycline-induced cardiac toxicity

Abstract Background/Introduction Cardiotoxicity (CT) is a major concern for cancer patients receiving anthracyclines. While the effect of anthracyclines on cardiomyocytes is well established, its impact on myocardial microcirculation has not been characterized. Purpose To evaluate the effect of low and high cumulative doses of doxorubicin (doxo) on anatomical and functional vasculature status evaluated by serial invasive Coronary Flow Reserve (CFR) and Cardiac Magnetic Resonance (CMR)-based quantitative perfusion in a large animal model. Methods Large-white male pigs (n=15, 30 kg) were distributed in 2 doxo regimes: Group 1) high cumulative dose (5 biweekly intracoronary (i.c) injections of 0.45 mg/kg of doxo) followed-up until week 16 (a time when severe left ventricular systolic dysfunction is present) and then sacrificed (N=5); Group 2) low cumulative dose of doxo (3 biweekly i.c. doses) followed-up until week 16 and then sacrificed (N=5)). Group 3) pigs sacrificed at 6 weeks (2 weeks after third doxo dose), N=5. Invasive catheter-based CFR was evaluated after i.c papaverine (0.5 mg/kg) while CMR quantitative rest perfusion maps were obtained after intravenous injection of gadolinium. CFR and CMR were performed before doxo, and at 0, 2, 4, 6 and 16 weeks thereafter. Cardiac vessels were evaluated ex vivo with trichrome staining. Statistical analysis was performed using one-way ANOVA with multiple pairwise comparisons (vs. baseline) and Bonferroni corrected p-value. Results CFR and CMR-quantitative myocardial perfusion were non-significantly reduced after 3 doxo doses despite myocardial vasculature was overtly injured on histology at this timepoint. Animals receiving 5 doxo doses suffered a progressive deterioration of CFR and CMR-perfusion until week 16 (1.41±0.23 vs 3.71±0.94 at baseline [p=0.014] and 65.4±18.2 ml/100g/min vs 154.9±56.3 ml/100g/min at baseline [p=0.046], respectively). At 16 weeks histology revealed extensive microvascular damage with media layer involvement and perivascular fibrosis. Pigs receiving 3 doxo doses showed less pronounced CFR reduction on long-term follow-up (3.13±0.82 vs 3.69±1.57 at baseline [p&gt;0.05] but overt CMR-perfusion reduction (138.3±11.9 vs 197.8±37.1 at baseline [p=0.045]). On histology, damage of vasculature including arterioles was evidenced to a lesser extent than in the high cumulative doxo dose group with mild microvascular disruption and smooth muscle vacuolization. Conclusions Doxorubicin results in a progressive damage of the myocardial microcirculation. Even low cumulative doxo doses (resulting in no overt left ventricular dysfunction) results in vascular damage. The microcirculation status may serve as an early marker of doxorubicin cardiotoxicity.

Abstract P180: Deficiency of Sirtuin 3 Sensitizes Angiotensin II-Induced Cardiac Pericyte-Fibroblast Transition and Diastolic Dysfunction via Iron Overloading

Hypertension is the key factor for the development of cardiac fibrosis and diastolic dysfunction. Our previous study showed that knockout of SIRT3 resulted in diastolic dysfunction in mice. In present study, we aim to explore the role of SIRT3 in pericyte recruitment and cardiac fibrosis in response to hypertension. NG2 + tracing reporter NG2DsREDBAC mouse was crossed with SIRT3KO mice. Mice were infused with Ang-II (1000ng/kg/min) for 28 days, blood pressure, coronary flow reserve (CFR) and diastolic function (IVRT and MPI) were measured pre- and post- Ang-II treatment. Cardiac fibrosis and iron content were measured by Masson and Prussian staining. Pericytes and fibroblasts were measured by co-immunostaining. The expression of heme oxygenase-1 (HO-1), ferroportin (FPN), p47 phox , and transforming growth factor-β1(TFG-β1) was analyzed by western blots. Infusion of Ang-II resulted in a significant increase in blood pressure compared to basal levels in WT mice (MAP 94± 2 mHg vs 130±1.7 mHg, n=7, p&lt;0.05); whereas knockout of SIRT3 exacerbated Ang-II-induced increase in blood pressure (MAP WT 130±1.7 mHg vs SIRT3KO 145 ± 2.1 mHg, n=7, p&lt;0.05). Furthermore, knockout of SIRT3 sensitized Ang-II-induced reduction of CFR and elevation of IVRT and MPI in mice. Using NG2 pericyte tracing reporter mice, we found that mice infusion with Ang-II resulted in a significant increase in NG2 + pericyte recruitment in the heart. Knockout of SIRT3 enhanced Ang-II-induced NG2 + pericyte recruitment. Knockout of SIRT3 further enhanced Ang-II-induced cardiac fibrosis as well as fibrotic markers FSP1 and a-SMA staining. To examine whether pericytes differentiate into fibroblast, NG2 + pericytes were co-stained with FSP-1 + . Ang-II infusion led to a significant increase in NG2 + /FSP-1 + ; while knockout of SIRT3 further increased numbers of NG2 + /FSP-1 + in the heart. Mechanistically, knockout of SIRT3 increased iron staining in the heart. This was accompanied by a significant increase in the expression of HO-1, FPN, p47 phox , ROS, and TGF-β as compared to Ang-II treatment. Our study suggests that deficiency of SIRT3 may promote Ang-II-induced cardiac fibrosis via pericyte-fibroblast transition and by Fe2 + -ROS-TGF-β pathway.

Recognition and treatment of ischemic heart diseases in women.

Heart disease is the leading cause of death among women in the industrialized world. However, women after myocardial infarctions (MIs) are less likely to receive preventive medications or revascularization and as many as 47% experience heart failure, stroke or die within 5 years. Premenopausal women with MIs frequently have coronary plaque erosions or dissections. Women under 50 years with angina and nonobstructive epicardial coronary artery disease often have coronary microvascular dysfunction (CMD) with reductions in coronary flow reserve that may require nontraditional therapies. In women with coronary artery disease treated with stents, the 3-year incidence of recurrent MI or death is 9.2%. Coronary bypass surgery operative mortality averages 4.6% for women compared with 2.4% in men. Addition of internal mammary artery and radial artery coronary grafts in women does not increase operative survival but improves 5-year outcome to greater than80%.

Serial Assessment of Coronary Flow Reserve by Rubidium-82 Positron Emission Tomography Predicts Mortality in Heart Transplant Recipients

ObjectivesThis study aimed to evaluate the long-term prognostic value of serial assessment of coronary flow reserve (CFR) by rubidium Rb 82 (82Rb) positron emission tomography (PET) in heart transplantation (HT) patients. BackgroundCardiac allograft vasculopathy is a major determinant of late mortality in HT recipients. The long-term prognostic value of serial CFR quantification by PET imaging in HT patients is unknown. MethodsA total of 89 patients with history of HT (71% men, 7.0 ± 5.7 years post-HT, age 57 ± 11 years) scheduled for dynamic rest and stress (dipyridamole) 82Rb PET between March 1, 2008 and July 31, 2009 (PET-1) were prospectively enrolled in a single-center study. PET myocardial perfusion studies were reprocessed using U.S. Food and Drug Administration–approved software (Corridor 4DM, version 2017) for calculation of CFR. Follow-up PET (PET-2) imaging was performed in 69 patients at 1.9 ± 0.3 years following PET-1. Patients were categorized based on CFR values considering CFR ≤1.5 as low and CFR >1.5 as high CFR. ResultsForty deaths occurred during the median follow-up time of 8.6 years. Low CFR at PET-1 was associated with a 2.77-fold increase in all-cause mortality (95% confidence interval [CI]: 1.34 to 5.74; p = 0.004). CFR decreased over time in patients with follow-up imaging (PET-1: 2.11 ± 0.74 vs. PET-2: 1.81 ± 0.61; p = 0.003). Twenty-five patients were reclassified based on PET-1 and PET-2 (high to low CFR: n = 18, low to high CFR: n = 7). Overall survival was similar in patients reclassified from high to low as patients with low to low CFR, whereas patients reclassified from low to high had similar survival as patients with high to high CFR. In multivariate Cox regression of patients with PET-2, higher baseline CFR (hazard ratio [HR] for a 0.73 unit (one SD) increase: 0.36, 95% CI: 0.16 to 0.82) and reduction in CFR from PET-1 to PET-2 (HR for a 0.79 unit (one SD) decrease: 1.50 to 7.84) were independent predictors of all-cause mortality. ConclusionsSerial assessment of CFR by 82Rb PET independently predicts long-term mortality in HT patients.

Heart or Mind? Unexplained Chest Pain in Patients with and Without Coronary Disease

Patients with unexplained chest pain continue to present a difficult challenge for clinicians, especially for cardiologists. Approximately 20% of patients undergoing diagnostic coronary arteriography for acute or chronic cardiac ischemia have angiographically normal coronary arteries. In these cases, patients with chest pain are usually reassured by their physician and other causes of substernal chest pain are searched. However, apart from a sizeable proportion of patients with gastroesophageal disorders, the remaining patients remain symptomatic without apparent reasons. The mechanism behind this phenomenon is likely to be the result of a combination of functional or anatomical abnormalities in the coronary microcirculation, a metabolic disorder which affects the handling of energy substrates by the heart, insulin resistance and neuropsychological components affecting pain perception. These patients often exhibit an increase in sympathetic outflow to the cardiovascular system, which might account for the reduction in coronary flow reserve, changes in metabolic utilization and development of insulin resistance that are seen in some of these patients. Therapeutically, beta-blockers appear to be most effective in controlling the symptoms associated with this condition, although those calcium antagonists which do not affect the neurohormonal system may be of some utility in patients with primary microvascular angina, in which microvascular spasm is operating or in whom excessive constriction of the distal component of the coronary circulation limits the vasodilatory reserve. This article reviews the clinical presentation, differential diagnosis, and approach to evaluation and therapy of this complex group of patients.

Abstract P296: Deletion of Endothelial Sirt3 Causes Diastolic Dysfunction

The morbidity of heart failure with preserved ejection fraction (HFpEF) increases with advanced age and is associated with endothelial dysfunction. In the present study, we analyzed the cardiac function and coronary microvascular function in endothelial specific SIRT3 knockout (ECKO) mice and global SIRT3 KO mice, as well as endothelial glycolytic metabolism and angiogenesis in vitro . We found that SIRT3 ECKO mice developed left ventricle (LV) diastolic dysfunction, as evidenced by prolonged isovolumic relaxation time (IVRT) and reduction of coronary flow reserve. Western blot analysis revealed a significant decrease in glycolytic enzyme PFKFB3 in SIRT3 KO-ECs, accompanied by a dramatic reduction in basal glycolysis, glycolytic reserve and glycolytic capacity. Moreover, SIRT3 KO-ECs exhibited higher oxygen consumption rate and more prominent production of reactive oxygen species (ROS) than WT-ECs. SIRT3 KO-ECs exhibited less potent angiogenic capabilities as indicated by decreased network formation and migration. In contrast, global knockout of SIRT3 in mice resulted in progressive deterioration of LV function, as evidenced by a decrease in ejection fraction and fraction shortening at 12 months of age. SIRT3 KO mice also exhibited reduction of ANP and ERK-1/2, and increased ROS production, gp91(phox), caspase-3 and Wnt7 in the heart. In conclusion, we demonstrated that ablation of SIRT3 in ECs caused an HFpEF phenotype with impaired glucose metabolism and angiogenesis. Global SIRT3 KO mice, however, exhibited an HFrEF phenotype. Our data suggest cell-specific effects of SIRT3 deletion on cardiac function.

(528) - The Clinical Application of Non-Invasive Assessment of Coronary Flow Reserve via Rubidium PET in Heart Transplant Patients

Coronary flow reserve (CFR) has been measured through a flow wire and more recently with the use of nuclear imaging. The advantage of nuclear imaging is that the entire heart is being assessed as opposed to a single coronary artery through the use of the flow wire. Reduction of CFR has implied an abnormal microcirculation in the donor heart due to small vessel transplant coronary artery disease. We have been assessing our patients in a cross-sectional study using Rubidium PET scans to assess CFR. It is not known whether an abnormal CFR (<2.0) is correlated to cardiac function and hemodynamics. Between 2010 and 2014 we assessed 93 heart transplant patients who had undergone Rubidium PET scanning to exclude significant transplant coronary artery disease (TCAD). Patients with abnormal CFR (<2.0) and normal CFR (≥2.0) were compared for the presence of coronary ischemia, LVEF at rest and with stress, end diastolic volume index (EDVI) at rest and stress and % left ventricular (LV) enlargement. Subsequent 1-year survival and development of new cardiac allograft vasculopathy (CAV) were also recorded. Those patients with abnormal CFR (<2.0) compared to those with normal CFR (≥2.0) had lower LVEF at rest and with stress, higher average end diastolic volume index (EDVI) at rest and stress and increased % left ventricular (LV) enlargement (see table). There was no difference in 1-year subsequent survival and development of new CAV. (See table) Patients with abnormal CFR (<2.0) have abnormal cardiac function and hemodynamics and may be at risk for poor outcome. Longer follow-up is required to assess for prognostic significance of an abnormal CFR.Tabled 1EndpointsCFRCFR > 2.0 (n=66)P-Value1-Year Subsequent Actual Survival96.2%97.6%0.5321-Year Subsequent Actual Freedom from CAV100.0%96.8%0.517Average LVEF Rest, Mean ± SD56.4 ± 15.8862.9 ± 11.180.028Average LVEF Post Stress, Mean ± SD60.5 ± 17.1067.4 ± 11.830.029Average EDVI Rest, Mean ± SD50.8 ± 30.3741.4 ± 14.060.044Average EDVI Post Stress, Mean ± SD55.3 ± 34.5145.2 ± 13.760.045% LV Enlargement (%)14.8% (4/27)1.5% (1/66)0.024 Open table in a new tab