Lower Coronary Flow Reserve Research Articles

Impact of stenosis resistance and coronary flow capacity on fractional flow reserve and instantaneous wave-free ratio discordance: acombined analysis of DEFINE-FLOW and IDEAL.

The pressure-derived parameters fractional flow reserve (FFR) and the emerging instantaneous wave-free ratio (iFR) are the most widely applied invasive coronary physiology indices to guide revascularisation. However, approximately 15-20% of intermediate stenoses show discordant FFR and iFR, and therapeutical consensus is lacking. We sought to associate hyperaemic stenosis resistance index, coronary flow reserve (CFR) and coronary flow capacity (CFC) to FFR/iFR discordance. We assessed pressure and flow measurements of 647 intermediate lesions (593patients) of two multi-centre international studies. FFR and iFR were discordant in 15% of all lesions (97 out of 647). FFR+/iFR- lesions had similar hyperaemic average peak velocity (hAPV), CFR and CFC as FFR-/iFR- lesions, whereas FFR-/iFR+ lesions had similar hAPV, CFR and CFC as FFR+/iFR+ lesions (p > 0.05 for all). FFR+/iFR- lesions were associated with lower baseline stenosis resistance, but not hyperaemic stenosis resistance, compared with FFR-/iFR+ lesions (p < 0.001). Discordance with FFR+/iFR- is characterised by maximal flow values, CFR, and CFC patterns similar to FFR-/iFR- concordance that justifies conservative therapy. Discordance with FFR-/iFR+ on the other hand, is characterised by low flow values, CFR, and CFC patterns similar to iFR+/FFR+ concordance that may benefit from percutaneous coronary intervention.

Particularities of coronary physiology in patients with atrial fibrillation: insights from combined pressure and flow indices measurements.

Symptoms suggestive of myocardial ischemia are frequently encountered in patients with atrial fibrillation (AF) even in the absence of obstructive coronary artery disease. Nevertheless, an in-depth characterisation of coronary physiology in patients with AF is currently lacking. We aim to provide an insight into the characteristics of coronary physiology in AF, by performing simultaneous invasive measurements of coronary flow- and pressure- indices in a real-life population of patients with AF and indication of coronary angiography. This is a prospective open label study including patients with permanent or persistent AF and indication of coronary angiography showing intermediate coronary stenosis requiring routine physiological assessment (n = 18 vessels from 14 patients). We measured FFR (fractional flow reserve), and Doppler-derived coronary flow indices, including CFR (coronary flow reserve) and HMR (hyperaemic microvascular resistance). From the analysed vessels, 18/18 vessels (100%) presented a pathological CFR (<2.5), indicative of coronary microvascular dysfunction (CMD), and 3/18 (17%) demonstrated obstructive epicardial coronary disease (FFR ≤ 0.8). A large proportion of vessels (15/18; 83%) showed discordant FFR/CFR with preserved FFR and low CFR. 47% of the coronary arteries in patients with AF and non-obstructive epicardial coronary disease presented structural CMD (HMR ≥ 2.5 mmHg/cm/s), and were associated with high BMR and an impaired response to adenosine. Conversely, vessels from patients with AF and non-obstructive epicardial coronary disease with functional CMD (HMR < 2.5 mmHg/cm/s) showed higher bAPV. The permanent AF subpopulation presented increased values of HMR and BMR compared to persistent AF, while structural CMD was more often associated with persistent symptoms at 3 months, taking into account the limited sample size of our study. Our findings highlight a systematically impaired CFR in patients with AF even in the absence of obstructive epicardial coronary disease, indicative of CMD. In addition, patients with AF presented more prevalent structural CMD (HMR ≥ 2.5 mmHg/cm/s), characterized by reduced hyperaemic responses to adenosine, possibly interfering with the FFR assessment.

The relationship between combat-related traumatic amputation and subclinical cardiovascular risk

BackgroundThe relationship between acute combat-related traumatic injury (CRTI) to coronary flow reserve (CFR) and subclinical cardiovascular risk have not been examined and was the primary aim of this study. Methods and resultsUK combat veterans from the ADVANCE cohort study (UK-Afghanistan War 2003–14) with traumatic limb amputations were compared to injured non-amputees and to a group of uninjured veterans from the same conflict. Subclinical cardiovascular risk measures included fasted blood atherogenic index of plasma (AIP), triglyceride-glucose index (TyG; insulin resistance), the neutrophil-lymphocyte ratio (NLR) and high-sensitivity C-reactive protein (hs-CRP; vascular inflammation), body mass index (BMI) and visceral fat volume (dual-energy X-ray absorptiometry) and 6-min walk distance (6MWD; physical performance). The subendocardial viability ratio (SEVR), to estimate CFR, was calculated using arterial pulse waveform analysis (Vicorder device). In total 1144 adult male combat veterans were investigated, comprising 579 injured (161 amputees, 418 non-amputees) and 565 uninjured men. AIP, TyG, NLR, hs-CRP, BMI, total body fat and visceral fat volume were significantly higher and the SEVR and 6MWD significantly lower in the amputees versus the injured-non-amputees and uninjured groups. The SEVR was lowest in those with above knee and multiple limb amputations. CRTI (ExpB 0.96; 95% CI 0.94–0.98: p < 0.0001) and amputation (ExpB 0.94: 95% CI 0.91–0.97: p < 0.0001) were independently associated with lower SEVR after adjusting for age, rank, ethnicity and time from injury. ConclusionCRTI, traumatic amputation and its worsening physical deficit are associated with lower coronary flow reserve and heightened subclinical cardiovascular risk.

Coronary microvascular dysfunction in Takotsubo syndrome and associations with left ventricular function.

Coronary microvascular dysfunction (CMD) has been proposed as an important pathophysiological mechanism in Takotsubo syndrome (TTS). Our aims were (i) to evaluate and compare levels of CMD in patients with TTS and patients with ischaemia and no obstructive coronary arteries (INOCA) and (ii) to investigate associations between CMD and clinical parameters, left ventricular function, and coronary atherosclerosis in TTS. We conducted a prospective study of 27 female TTS patients and an equally sized, age- and gender-matched, cohort of INOCA patients. Coronary microvascular function was quantified invasively using the index of microcirculatory resistance (IMR), coronary flow reserve (CFR), and resistive reserve ratio (RRR). CMD was defined as IMR≥25 and/or CFR≤2. In the TTS patients, left ventricular function was assessed with echocardiography and cardiovascular magnetic resonance (CMR) imaging, and coronary atherosclerosis was visualized with intravascular ultrasound with near-infrared spectroscopy (IVUS-NIRS). The incidence of CMD was higher in the TTS patients than in the INOCA cohort (78% vs. 44%, P=0.01), with higher IMR (30 vs. 14, P=0.002), lower CFR (1.8 vs. 2.8, P=0.009), and lower RRR (2.1 vs. 3.5, P=0.003). In apical compared with midventricular TTS, IMR was numerically higher (50 vs. 28, P=0.20), whereas CFR and RRR were lower (1.5 vs. 2.5, P=0.003 and 1.6 vs. 2.7, P=0.01, respectively). Global longitudinal strain and global circumferential strain, assessed with CMR imaging, were more impaired in apical than in midventricular TTS (-11 vs. -14, P<0.001 and -12 vs. -15, P=0.049, respectively). In the TTS patients, CFR and RRR correlated with echocardiography-derived (R2 =0.15, P=0.002 and R2 =0.18, P=0.007, respectively) and CMR-derived (R2 =0.09, P=0.025 and R2 =0.10, P=0.038, respectively) ejection fraction. CFR and RRR correlated inversely with CMR-derived end-diastolic volume index, end-systolic volume index, and left ventricular mass index. IMR, CFR, and RRR were not associated with measures of coronary atherosclerosis derived by IVUS-NIRS. Coronary microvascular dysfunction is common in patients with TTS and more frequent than in patients with INOCA. CMD in TTS is more severe in the apical compared with the midventricular phenotype of the syndrome, is associated with left ventricular function, but is unrelated to coronary atherosclerosis. Our results support the notion of CMD as a key mediator in TTS.

Clinical implications of coronary microvascular dysfunction in patients with non-obstructive coronary artery disease and role of the thermodilution method.

More than 60% of patients undergoing coronary angiography present no coronary artery disease (CAD). Angina and myocardial ischemia are classically determined by epicardial vascular obstruction, but coronary microvascular dysfunction (CMD) may also represent a possible cause for these phenomena. Two endotypes of CMD have been recognized, with two different pathophysiological mechanisms: structural CMD, characterized by low coronary flow reserve (CFR) and high microvascular resistance (MVR) values; and functional CMD, characterized by low CFR and normal MVR values. According to the present data, almost half of patients with non-obstructive CAD have shown signs of CMD. For this reason, further investigations for microvascular function assessment should be considered when evaluating no-CAD patients complaining of angina or presenting signs of myocardial ischemia. The thermodilution method is currently becoming a widespread invasive technique due to its feasibility and high reproducibility for coronary physiology evaluation. Furthermore, a recently introduced technique - called continuous thermodilution - allows for direct measurement of absolute coronary flow and resistances. The role of this brand-new technique in the clinical scenario is however still to be fully investigated and its use is at present limited to research purposes only. Among no-CAD patients, both structural and functional CMD are related to a worse prognosis in term of mortality and major adverse cardiovascular events (MACE). In this review, we will discuss the present evidence supporting the definition, prevalence and clinical implication of the different forms of CMD and the technical aspects of its invasive assessment.

Anxiety is associated with coronary microvascular dysfunction: Results from the CAMADA study.

Coronary microvascular dysfunction (CMD) is an important component of ischemic heart disease. Here, we assessed the associations between anxiety/depression and CMD using coronary microvascular function indicators. The study included 81 patients (26 males and 55 females) with nonobstructive coronary artery disease. The symptoms of anxiety and depression were measured with Self-rating Anxiety Scale and Self-rating Depression Scale. Coronary microvascular function was assessed using coronary flow reserve (CFR) measured by transthoracic Doppler echocardiography. The anxiety group had significantly lower CFR than that in the no-anxiety group (2.97 ± 0.63 vs. 3.40 ± 0.61, p=.029). In bivariate correlation analysis, anxiety was negatively associated with CFR (r=-.333, p=.002). In the multiple linear regression model, after adjusting for age, sex, BMI, hypertension, dyslipidemia, smoking status, and family history of premature coronary heart disease, anxiety was negatively associated with CFR (β=-.314, p=.008). When both anxiety and depression were included in the multiple linear regression model, anxiety was also negatively associated with CFR (β=-.345, p=.012). Anxiety patients had lower CFR, anxiety was independently associated with CFR. Psychological disorders may play an important role in coronary microvascular dysfunction.

Abnormal physiological findings after FFR-based revascularisation deferral are associated with worse prognosis in women

The prognostic value of abnormal resting Pd/Pa and coronary flow reserve (CFR) after fractional flow reserve (FFR)-guided revascularisation deferral according to sex remains unknown. From the ILIAS Registry composed of 20 hospitals globally from 7 countries, patients with deferred lesions following FFR assessment (FFR > 0.8) were included. (NCT 04485234) The primary clinical endpoint was target vessel failure (TVF) at 2-years follow-up. We included 1392 patients with 1759 vessels (n = 564 women, 31.9%). Although resting Pd/Pa was similar between the sexes (p = 0.116), women had lower CFR than men (2.5 [2.0–3.2] vs. 2.7 [2.1–3.5]; p = 0.004). During a 2-year follow-up period, TVF events occurred in 56 vessels (3.2%). The risk of 2-year TVF was significantly higher in women with low versus high resting Pd/Pa (HR: 9.79; p < 0.001), whereas this trend was not seen in men. (Sex: P-value for interaction = 0.022) Furthermore, resting Pd/Pa provided an incremental prognostic value for 2-year TVF over CFR assessment only in women. After FFR-based revascularisation deferral, low resting Pd/Pa is associated with higher risk of TVF in women, but not in men. The predictive value of Pd/Pa increases when stratified according to CFR values, with significantly high TVF rates in women in whom both indices are concordantly abnormal.Clinical Trial Registration: Inclusive Invasive Physiological Assessment in Angina Syndromes Registry (ILIAS Registry), NCT04485234.

Impact of core laboratory assessment on treatment decisions and clinical outcomes using combined fractional flow reserve and coronary flow reserve measurements – DEFINE-FLOW core laboratory sub-study

ObjectiveThe role of combined FFR/CFR measurements in decision-making on coronary revascularization remains unclear. DEFINE-FLOW prospectively assessed the relationship of FFR/CFR agreement with 2-year major adverse cardiac event (MACE) and target vessel failure (TVF) rates, and uniquely included core-laboratory analysis of all pressure and flow tracings. We aimed to document the impact of core-laboratory analysis on lesion classification, and the relationship between core-laboratory fractional flow reserve (FFR) and coronary flow reserve (CFR) values with clinical outcomes and angina burden during follow-up. MethodsIn 398 vessels (348 patients) considered for intervention, ≥1 coronary pressure/flow tracing was approved by the core-laboratory. Revascularization was performed only when both FFR(≤0.80) and CFR(<2.0) were abnormal, all others were treated medically. ResultsMACE was lowest for concordant normal FFR/CFR, but was not significantly different compared with either discordant group (low FFR/normal CFR: HR:1.63; 95%CI:0.61–4.40; P = 0.33; normal FFR/low CFR: HR:1.81; 95%CI:0.66–4.98; P = 0.25). Moreover, MACE did not differ between discordant groups treated medically and the concordant abnormal group undergoing revascularization (normal FFR/low CFR: HR:0.63; 95%CI:0.23–1.73;P = 0.37; normal FFR/low CFR: HR:0.70; 95%CI:0.22–2.21;P = 0.54). Similar findings applied to TVF. ConclusionsPatients with concordantly normal FFR/CFR have very low 2-year MACE and TVF rates. Throughout follow-up, there were no differences in event rates between patients in whom revascularization was deferred due to preserved CFR despite reduced FFR, and those in whom PCI was performed due to concordantly low FFR and CFR. These findings question the need for routine revascularization in vessels showing low FFR but preserved CFR.Clinical trial registration: http://ClinicalTrials.govNCT02328820

Abstract 11968: Association Between Reduction in Inflammation and Change in Cardiovascular Risk: Results From the Liira Study

Background: Coronary microvascular disease (CMD) is associated with increased cardiovascular (CV) risk in rheumatoid arthritis (RA). Studies suggest that higher RA disease activity is associated with a higher degree of CMD, as measured by coronary flow reserve (CFR). However, it is not known whether reducing inflammation results in improvement in CMD or other CV correlates. The objective of this study was to determine the association between reducing inflammation with changes in CV risk. Methods: The Lipids, Inflammation and CV risk in RA (LiiRA) study recruited RA patients age ≥18 yrs with active RA about to initiate a TNFi as part of clinical care. All subjects underwent a stress myocardial perfusion PET scan to quantify CFR at baseline and after 24 weeks. A lower CFR in the absence of obstructive CAD is indicative of CMD, CFR&lt; 2.5 defined CMD. Inflammatory markers and hs-cTnT were performed at baseline and 24 weeks. Primary and secondary outcomes was change in CFR and hs-cTnT, respectively, and tested by Spearman correlations. Results: A total of 66 subjects completed the study, 80% female, mean RA duration 7.7 yrs. Baseline estimated ASCVD risk was 5.6%, yet 47% had evidence of CMD. We observed a significant reduction in all inflammatory markers between baseline and follow-up, along with improvements in RA disease activity; however, no change in the mean CFR or hs-cTnT was observed. A reduction in hsCRP and IL-1beta was associated with a reduction in hs-cTnT. A non-significant trend for correlation of reduced IL-1beta with higher CFR was observed among subjects with CMD at baseline (Figure). Conclusion: There was a high prevalence of CMD at baseline, but CFR did not significantly improve. Reducing inflammation was correlated with improvements in measures of CV risk, mainly in the subset of patients with detectable hs-cTnT, particularly via the IL-1beta pathway. These data suggest that hs-cTnT may be a useful marker when considering targeting inflammation to reduce CV risk in RA.

Abstract 9764: Simultaneous Assessment of Coronary Flow Reserve and Left Ventricular Strain During Vasodilator Stress Measured by 13 N-ammonia Positron Emission Tomography/Magnetic Resonance Imaging

Introduction: Hybrid positron emission tomography (PET)/magnetic resonance imaging (MRI) is able to yield important information regarding molecular and functional imaging in a one-stop examination. The aim of this study was to investigate the relationship between coronary flow reserve (CFR) and left ventricular longitudinal strain (LVLS) using simultaneous acquisitions on hybrid 13 N-ammonia PET/MRI. Methods: Thirty-eight patients with suspected coronary artery disease (CAD) who underwent 13 N-ammonia PET/MRI were enrolled. Vasodilator stress was induced by intravenous injection of adenosine. CFR was calculated from dynamic acquisition of 13 N-ammonia PET. LVLS was evaluated by feature-tracked MRI. Myocardial flow reserve (MFR) and LVLS values were based on a 17-segment model and three coronary territories, left anterior descending artery (LAD), left circumflex artery (LCx), and right coronary artery (RCA). Results: We analyzed 577 myocardial segments in the left ventricle. LVLS under vasodilator stress was significantly increased compared with LVLS at rest in myocardial segments with MFR ≥2.0 (P&lt;0.01), whereas there were no changes between LVLS under stress and LVLS at rest in the segments with MFR &lt; 2.0 (P=0.24). Similarly, regional values of LVLS under vasodilator stress were significantly increased compared with those measured at rest in the coronary territories of LAD (P&lt;0.01), LCx (P&lt;0.01), and RCA (P&lt;0.01) with MFR ≥ 2.0, whereas there were no differences between LVLS at rest and LVLS under stress in those territories with CFR &lt; 2.0 (P=0.45). These data revealed that left ventricular strain under vasodilator stress was impaired in segments with lower CFR. Conclusion: Simultaneous assessment of regional CFR and LV strain was feasible using by 13 N-ammonia PET/MRI. 13 N-ammonia PET/MRI was able to detect not only impaired CFR but also morphological abnormalities, which may improve diagnostic and predictive capacity in patients with CAD.

Prognostic Impact of Coronary Flow Reserve in Patients With CKD

Both coronary flow reserve (CFR) and chronic kidney disease (CKD) are known to be associated with adverse cardiac events. However, it is unclear how these prognostic factors are interrelated. This study evaluated the association between intracoronary physiologic indexes and CKD and their prognostic implications. A total of 351 patients without left ventricular systolic dysfunction (ejection fraction≥ 40%) and not on dialysis whose revascularization was deferred based on fractional flow reserve (FFR) > 0.80 were analyzed. Depressed CFR was defined as CFR≤ 2.0. The primary outcome was a composite of cardiac death or hospitalization for heart failure at 3 years. Patients with CKD showed lower CFR than the non-CKD population (3.28 ± 1.77 vs. 2.60 ± 1.09, P< 0.001), mainly driven by increased resting coronary flow. There was no significant difference in hyperemic coronary flow, FFR, and index of microvascular resistance between the 2 groups. CFR was significantly associated with estimated glomerular filtration rate (eGFR) (P= 0.045), and the proportion of depressed CFR was significantly increased with higher CKD stages (P= 0.011). The risk of cardiac death or hospitalization for heart failure was the lowest in the non-CKD and preserved CFR group (11.9%) and the highest in the CKD and depressed CFR group (60.0%, overall log rank P< 0.001). Both CKD (adjusted hazard ratio [HRadj] 2.614, 95% confidence interval [CI] 1.505-4.539, P< 0.001) and depressed CFR (HRadj 3.237, 95% CI 2.015-5.199, P< 0.001) were independently associated with the risk of the primary outcome. There was a significant association between severity of CKD and CFR. Both CKD and depressed CFR showed independent association with higher risk of cardiac death or hospitalization for heart failure.

The impact of coronary microvascular dysfunction on the discordance between fractional flow reserve and resting full-cycle ratio in patients with chronic coronary syndromes.

BackgroundResting full-cycle ratio (RFR) is an alternative to fractional flow reserve (FFR) for the evaluation of borderline coronary artery lesions. Although FFR and RFR results are discordant in some cases, factors associated with the discordance remain unclear. The role of coronary microvascular dysfunction (CMD) is discussed as a potential mechanism to explain these discrepancies.AimThe study aimed to assess concordance between RFR and FFR in a real-life cohort from a high-volume center regarding the role of CMD.MethodsConsecutive patients with borderline coronary lesions undergoing coronary functional testing for chronic coronary syndromes were included in the study. Measurements of RFR and FFR were performed alongside additional coronary flow reserve (CFR), resistance reserve ratio (RRR), and an index of microcirculatory resistance (IMR) measurements. CMD was defined according to the current guideline by either IMR ≥25 or CFR ≤2.0 in vessels with no significant stenosis.ResultsMeasurements were performed in 157 coronary arteries, in 101 patients, with a median age of 66 y., 74% male, with prior history of arterial hypertension (96%), dyslipidaemia (91%), and diabetes (40%). The median value of vessel diameter stenosis was 45% according to QCA.Overall, FFR and RFR values were significantly correlated (r = 0.66, p < 0.001), where positive FFR/negative RFR and negative FFR/positive RFR were observed in 6 (3.8%) and 38 (24.2%) of 157 vessels. The RFR/FFR discrepancy was present in 44 (28%) of measurements. CMD was confirmed in 28 (64%) of vessels with discrepant RFR/FFR and in 46 (41%) of vessels with concordant results (p = 0.01). In discordant RFR/FFR vessels, as compared to concordant ones, significantly lower values of CFR [median 1.95 (IQR: 1.37, 2.30) vs. 2.10 (IQR: 1.50, 3.00), p = 0.030] and RRR [median 2.50 (IQR: 1.60, 3.10) vs. 2.90 IQR (1.90, 3.90), p = 0.048] were observed.Main predictors of RFR/FFR discrepancy in a univariate regression analysis were: higher age of patients [OR = 1.06 (1.01; 1.10), p = 0.010], presence of CMD [OR = 2.51 (1.23; 5.25), p = 0.012], lower CFR [OR = 1.64 (1.12; 2.56), p = 0.018], and lower RRR values [OR = 1.35 (95% CI: 1.03; 1.83), p = 0.038].ConclusionIn discrepant RFR/FFR vessels, CMD is more prevalent than in concordant RFR/FFR measurements, which can be driven by lower CFR or RRR values. Further research is needed to confirm this observation.

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.

Long-standing persistent atrial fibrillation with low coronary flow reserve is associated with unnecessary coronary angiography

Abstract Background/Introduction Atrial fibrillation (AF) is associated with an increased risk of myocardial infarction. Myocardial perfusion imaging (MPI) is well-established for the diagnosis of coronary artery disease (CAD) and risk-stratification in sinus rhythm (SR) patients. Purpose The aim of this study was to determine the impact of AF and coronary flow reserve (CFR) on revascularization in patients undergoing positron emission tomography (PET) MPI. Methods 680 patients without a known history of CAD were included. 226 paroxysmal AF (PAF) and 114 long-standing persistent AF (LSPAF) patients were identified from a single-center prospective PET MPI registry and propensity matched in a 1:1 ratio to SR patients. The main indications for PET MPI were chest pain and dyspnea. Follow-up was obtained for downstream referral for invasive coronary angiography (CAG) and the occurrence of myocardial infarction (MI) or coronary revascularization. Results Compared with PAF, LSPAF patients were older (p=0.011) and more frequently male (p=0.031), with no significant differences in prior medical history and cardiac risk factors. The number of abnormal scans (infarction or ischemia) did not differ significantly between SR and AF, respectively 22.1% and 18.5% (p=0.253). The frequency of downstream CAG was comparable between the groups (p=0.298), with a significantly higher yield of obstructive CAD in the SR group as compared to PAF and LSPAF groups (63% vs 42% vs 36%, p=0.007). A low CFR (defined as CFR below the median of 2.4) in patients with SR showed significantly more revascularization compared with PAF and LSPAF (p&amp;lt;0.001), although more patients with LSPAF and low CFR underwent CAG (p&amp;lt;0.001). In patients with low CFR referred for CAG, the overall prevalence of obstructive coronary artery disease on CAG was 62%, with 30% for LSPAF, 52% for PAF and 78% for SR. There were no significant differences between SR, PAF and LSPAF in the occurrence of MI during a mean follow-up of 36 months (p=0.256). Conclusion A low CFR was only associated with a higher incidence of revascularization in patients with SR. Among patients with low CFR, LSPAF patients have the highest number of unnecessary CAGs as compared with SR and PAF. Funding Acknowledgement Type of funding sources: None.

Assessment of absolute coronary flow and microvascular resistance reserve in patients with severe aortic stenosis

Abstract Introduction The development of left ventricular hypertrophy in patients with severe aortic stenosis (AS) is accompanied by adaptive coronary flow regulation, both in epicardial and microvascular compartment, which ultimately lead to a chronic ischemic insult even in the absence of obstructive coronary artery disease. Intracoronary continuous thermodilution of saline through a dedicated infusion catheter is a novel tool that allows to measure absolute coronary flow and microvascular resistance at rest and during hyperemia and to calculate both coronary flow reserve (CFR) and Microvascular Resistance Reserve (MRR) Purpose We aimed to assess absolute coronary flow, microvascular resistance, CFR and MRR in patients with AS, by continuous intracoronary thermodilution, comparing these hemodynamic findings with a propensity-score matched contemporary cohort of patients without AS. Methods Absolute coronary blood flow and microvascular resistance were measured by continuous thermodilution in 29 patients with AS and compared to 15 controls matched for age, gender, diabetes mellitus and functional severity of epicardial coronary lesions. Myocardial work, total myocardial mass and LAD-specific mass were quantified by echocardiography and cardiac-CT. Results Patients with AS presented a significantly positive LV remodeling with lower global longitudinal strain and higher global work index compared to controls (p&amp;lt;0.02). Total LV myocardial mass and LAD-specific myocardial mass were significantly higher in patients with AS. Compared to matched controls, absolute resting flow in the LAD was significantly higher in the AS cohort (86 [66–107] ml/min vs 68 [52–75] ml/min, p=0.036), resulting, in lower CFR (2.30±0.69 vs 2.89±0.77, p=0.005) and MRR (2.73±0.74 vs 3.53±0.95, p=0.005) in the AS cohort compared to controls (Figure 1). No differences were found in hyperemic flow and resting and hyperemic resistances. Interestingly, hyperemic myocardial perfusion (calculated as the ratio between the absolute coronary flow in the LAD and the mass subtended by the vessel, expressed in mL/min/g), but not resting, was significantly lower in the AS group (1.9 [1.5–2.5] ml/min/g vs 2.3 [2–3.1] ml/min/g p=0.036). Conclusions In patients with severe aortic stenosis and non-obstructive coronary artery disease, with the progression of LVH, the compensatory mechanism of increased resting flow maintains an adequate perfusion at rest, but not during hyperemia (Figure 2). As consequence, both CFR and MRR are significantly impaired. Funding Acknowledgement Type of funding sources: None.

Differences in coronary flow reserve and flow-mediated dilation between plaque psoriasis and psoriatic arthritis

Abstract Background/Introduction Psoriatic disease is associated with increased cardiovascular risk through mechanisms of inflammation and oxidative stress. Purpose We aimed to investigate endothelial glycocalyx, coronary microcirculatory function and flow-mediated dilation in patients with plaque psoriasis and psoriatic arthritis. Methods In 311 patients (mean age: 52±12 years) with psoriatic disease (185 with plaque psoriasis and 126 with psoriatic arthritis) and 150 controls with similar age, sex and atherosclerotic risk factors, we assessed: (1) Perfused boundary region (PBR) of the sublingual microvessels with a diameter 5–25μm using Sidestream Dark Field camera (Microscan, Glycocheck). Increased PBR indicates impaired glycocalyx integrity. (2) Coronary flow reserve (CFR) in the distal left anterior descending coronary artery, (3) Flow-mediated dilation (FMD) of the brachial artery, and (4) LV global longitudinal strain (GLS) using speckle-tracking echocardiography. Results Compared with controls, patients with psoriatic disease had higher PBR (2.14±0.29 versus 1.78±0.25μm, p&amp;lt;0.001) and lower CFR (2.86±0.93 versus 3.39±0.68, p&amp;lt;0.001), FMD (6.97±3.9 versus 9.1±2.1, p&amp;lt;0.001) and GLS (−17.4±3.8 versus −21.9±1.5%, p&amp;lt;0.001). There was not significant difference between the two study groups (plaque psoriasis and psoriatic arthritis) in PBR (2.14±0.28 versus 2.14±0.31μm, p=0.990) and GLS (−17.2±3.9 versus −17.6±3.8%, p=0.297). Patients with psoriatic arthritis had more impaired CFR (2.75±0.85 versus 2.96±0.99, p=0.045) and FMD (5.45±3.2 versus 7.76±4, p=0.003) compared to patients with plaque psoriasis. Conclusions Patients with psoriatic disease have impaired endothelial, vascular and myocardial function compared with controls. Coronary microcirculatory function and flow-mediated dilation are more affected in psoriatic arthritis compared with plaque psoriasis. Funding Acknowledgement Type of funding sources: None.

Prognostic value of PET derived coronary flow reserve: should we correct for resting perfusion product?

Abstract Introduction Positron emission tomography (PET) myocardial perfusion imaging (MPI) derived coronary flow reserve (CFR) is an important risk-stratifying tool to tailor management of patients with coronary artery disease. Resting myocardial blood flow (MBF) is positively correlated to the product of resting heart rate and systolic blood product (resting pressure product – RPP), and can in turn lead to lower CFR in the setting of normal stress MBF. Purpose We aimed to assess the comparative incremental prognostic value of uncorrected to RPP-corrected CFR in predicting incident events. Methods Consecutive patients who had clinically indicated PET MPI were included. Patients were followed from the date of imaging to incident major adverse cardiovascular event (MACE: inclusive of all-cause death, myocardial infarction, admission for heart failure and late revascularization – percutaneous coronary intervention (PCI) or coronary artery bypass graft (CABG) &amp;gt;90 days after imaging). Results The study population consisted of 2,893 patients with clinically indicated PET MPI (mean age 67 (±12), 53% male, 41% Caucasian). Cardiovascular risk factors were prevalent (88% hypertensive, 80% dyslipidemic, 47% diabetics, 18% ever smoking). After a mean follow-up of 8±7 months, 250 patients (8.6%, 10.7 per 1000 person-year) experienced MACE (90 D/38 MI/51 PCI/11 CABG/113 HF). Both uncorrected and corrected CFR were independently associated with incident MACE (HR 0.38, 95% CI 0.29–0.51, p&amp;lt;0.001 and 0.61, 95% CI 0.50–0.76, p&amp;lt;0.001 respectively). A comparison of model incremental prognostic value showed the model with uncorrected CFR had a statistically higher Harrell's C (0.76 vs 0.77, p=0.23). Conclusion Our findings showed that the prognostic value of CFR was preserved even in the setting of high resting blood pressure or heart rate. This suggests that correction for RPP should be selective. Funding Acknowledgement Type of funding sources: None.

Trans-myocardial Extraction of Endothelin-1 Correlates with Increased Microcirculatory Resistance following Percutaneous Coronary Intervention.

Objective Coronary microvascular dysfunction (CMD) can complicate successful percutaneous coronary intervention (PCI). The potent endogenous vasoconstrictor peptide Endothelin-1 (ET-1) may be an important mediator. To investigate the mechanism, we sought to define the peri-procedural trans-myocardial gradient (TMG-coronary sinus minus aortic root levels) of ET-1 and its precursor peptide – Big ET-1. We then assessed correlation with pressure-wire indices of CMD: coronary flow reserve (CFR) and index of microvascular resistance (IMR). Methods Paired blood samples from the guide catheter and coronary sinus were collected before and after pressure-wire-guided PCI from patients with stable angina. Plasma was analysed using a specific enzyme-linked immunosorbent assay for quantification of ET-1 peptides and correlated with pressure-wire data. Non normally distributed continuous variables are presented as median [IQR]. Results ET-1 and Big ET-1 increased post-PCI in the aorta (ET-1: 0.98 [0.76–1.26] pg/ml to 1.20 [1.03–1.67] pg/ml, P < 0.001 and Big ET-1: 2.74 [1.78–2.50] pg/ml to 3.36 [2.33–3.97] pg/ml, P < 0.001) and coronary sinus (ET-1: 1.00 [0.81–1.28] pg/ml to 1.09 [0.91–1.30] pg/ml, P = 0.03 and Big ET-1: 2.89 [1.95–3.83] pg/ml to 3.56 [2.66–4.83] pg/ml, P = 0.01). TMG of ET-1 shifted negatively compared with baseline following PCI reflecting significantly increased extraction (0.03 [−0.12–0.17] pg/ml pre-PCI versus −0.16 [−0.36–0.07] pg/ml post-PCI, P = 0.01). Increased ET-1 trans-myocardial extraction correlated with higher IMR (Pearson's r = 0.293, P = 0.02) and increased hyperemic transit time (Pearson's r = 0.333, P < 0.01). In subgroup analysis, mean ET-1 trans-myocardial extraction was higher amongst patients with high IMR compared with low IMR (0.73 pg/ml, SD:0.78 versus 0.17 pg/ml, SD:0.42, P = 0.02). There was additionally a numerical trend towards increased ET-1 trans-myocardial extraction in subgroups of patients with low CFR and in patients with Type 4a Myocardial Infarction, albeit not reaching statistical significance. Conclusions Circulating ET-1 increases post-PCI and upregulated ET-1 trans-myocardial extraction contributes to increased microcirculatory resistance.

Prognostic Impact of Coronary Flow Reserve in Patients With Reduced Left Ventricular Ejection Fraction.

BackgroundIntracoronary physiologic indexes such as coronary flow reserve (CFR) and left ventricular ejection fraction (LVEF) have been regarded as prognostic indicators in patients with coronary artery disease. The current study evaluated the association between intracoronary physiologic indexes and LVEF and their differential prognostic implications in patients with coronary artery disease.Methods and ResultsA total of 1889 patients with 2492 vessels with available CFR and LVEF were selected from an international multicenter prospective registry. Baseline physiologic indexes were measured by thermodilution or Doppler methods and LVEF was recorded at the index procedure. The primary outcome was target vessel failure, which was a composite of cardiac death, target vessel myocardial infarction, or clinically driven target vessel revascularization over 5 years of follow‐up. Patients with reduced LVEF <50% (162 patients [8.6%], 202 vessels [8.1%]) showed a similar degree of epicardial coronary artery disease but lower CFR values than those with preserved LVEF (2.4±1.2 versus 2.7±1.2, P<0.001), mainly driven by the increased resting coronary flow. Conversely, hyperemic coronary flow, fractional flow reserve, and the degree of microvascular dysfunction were similar between the 2 groups. Reduced CFR (≤2.0) was seen in 613 patients (32.5%) with 771 vessels (30.9%). Reduced CFR was an independent predictor for target vessel failure (hazard ratio, 2.081 [95% CI, 1.385–3.126], P<0.001), regardless of LVEF.ConclusionsCFR was lower in patients with reduced LVEF because of increased resting coronary flow. Patients with reduced CFR showed a significantly higher risk of target vessel failure than did those with preserved CFR, regardless of LVEF.RegistrationURL: https://www.clinicaltrials.gov; Unique identifier: NCT04485234.

Increased expression of miR-224-5p in circulating extracellular vesicles of patients with reduced coronary flow reserve

BackgroundEndothelial and microvascular dysfunction are pivotal causes of major adverse cardiac events predicted by coronary flow reserve (CFR). Extracellular Vesicles (EVs) have been studied extensively in the pathophysiology of coronary artery disease. However, little is known on the impact of the non-coding RNA content of EVs with respect to CFR.MethodsWe carried out a study among 120 patients divided by high-CFR and low-CFR to profile the miRNA content of circulating EVs.ResultsA multiplex array profiling on circulating EVs revealed mir-224-5p (p-value ≤ 0.000001) as the most differentially expressed miRNA in the Low-CFR group and showed a significantly independent relationship to CFR. Literature survey indicated the origin of the miR from liver cells and not of platelet, leukocyte, smooth muscle or endothelial (EC) origin. A q-PCR panel of the conventional cell type-EVs along with hepatic EVs showed that EVs from liver cells showed higher expression of the miR-224-5p. FACS analysis demonstrated the presence of liver-specific (ASGPR-1+/CD14−) EVs in the plasma of our cohort with the presence of Vanin-1 required to enter the EC barrier. Hepatic EVs with and without the miR-224-5p were introduced to ECs in-vitro, but with no difference in effect on ICAM-1 or eNOS expression. However, hepatic EVs elevated endothelial ICAM-1 levels per se independent of the miR-224-5p.ConclusionThis indicated a role of hepatic EVs identified by the miR-224-5p in endothelial dysfunction in patients with Low CFR.