Resistive Reserve Ratio Research Articles

Traditional cardiovascular risk factors and coronary microvascular disease in women and men- a single center study

Abstract Introduction Coronary microvascular dysfunction (CMD) is a common, often missed, cause for effort intolerance and angina symptoms, and is associated with adverse clinical outcomes. Risk factors for the development of CMD have not been fully elucidated, and studies examining sex associated differences in traditional cardiovascular risk factors (TCRs) for obstructive coronary artery disease (CAD) in patients with CMD have yielded conflicting results. Although several non-invasive methods for the evaluation of CMD exist, currently, catheter-based invasive assessment is the gold standard for the diagnosis of coronary microvascular dysfunction. Purpose To examine the association between TCR and CMD and sex associated differences in TCR, in a prospective cohort of patients undergoing invasive microvascular function evaluation in a large tertiary medical center. Methods In this single center, prospective registry, we enrolled patients with non-obstructive CAD undergoing clinically indicated invasive assessment of coronary microvascular function between November 2019 and March 2023. Measurements of microvascular function included CFR, IMR, RRR as well as FFR. Pathologic CFR was defined as <2.5 or <2. Associations between coronary microvascular dysfunction, traditional cardiovascular risk factors, and sex were assessed using univariate and multivariate regression models. Results Overall, 245 patients with non-obstructive CAD were included in the analysis (62.9% female; median age 68 (interquartile range [IQR]: 59,75). Microvascular dysfunction was diagnosed in 141 patients (57.5%). The prevalence of microvascular dysfunction was similar in women and men in the entire cohort (59.0% vs. 57.0%; p=0.77). In 41 patients diagnosed with functional microvascular dysfunction there were more women than men (70.7% vs. 29%). When using a threshold of CFR<2.5 no association was found between traditional risk factors for coronary atherosclerosis and CMD regardless of whether CMD was structural or functional. In women, but not in men, older age and the presence of previous ischemic heart disease were associated with lower coronary flow reserve (CFR) (β=-0.29; p<0.01 and β=-0.15; p=0.05, respectively) and lower resistive reserve ratio (RRR) (β=-0.28; p<0.01 and β=-0.17; p=0.04, respectively). When using a threshold of <2.0 for CFR similar results were found. Conclusion The prevalence of TCRs was similar in patients with and without CMD. In women, older age and previous IHD were associated with lower CFR and RRR values while no association between TCRs and indices of CMD was found in men. It is likely that there are other, currently unknown risk factors for CMD as well as unique risk factors for each of its endotypes, beyond TCRs. It is unclear which parameter of microvascular dysfunction is the most accurate, and whether different parameters should be used in women and men. Large-scale multi-center studies to further evaluate these issues are needed.Variables associated with CMDStudy inclusion process

Hyperemic vs non-hyperemic indexes discordance: Role of epicardial and microvascular resistance (HyperDisco Study)

BackgroundLiterature reports a 20 % discordance between hyperemic (FFR) and non-hyperemic indexes (NHi) of coronary stenosis lesions. This work aims to develop and test clinically, a formula relating FFR and NHi (including iFR, RFR and Pd/Pa) to study their discordance. MethodsWe conducted a prospective, single-center, clinical study enrolling all patients undergoing full coronary physiology assessment with Coroventis CoroFlow Cardiovascular System (Abbott Vascular, St. Paul, Minnesota) to validate the developed formula:FFR/NHi=IMR/BMRBSR+BMR/HSR+IMRwhere IMR(BMR) is the hyperemic (basal) microvascular resistance and HSR(BSR) is the hyperemic (basal) stenosis resistance. ResultsA total of 51 patients were enrolled, 72 % male, average age 67.4 ± 8.9. Mean hemodynamic data were: FFR 0.87 ± 0.07, iFR 0.93 ± 0.05, RFR 0.91 ± 0.05, Pd/Pa 0.92 ± 0.05, BMR 76.6 ± 51.6 mmHg*s, IMR 28.4 ± 22.8 mmHg*s, BSR 5.5 ± 4.7 mmHg, HSR 3.8 ± 2.9 mmHg*s, coronary flow reserve (CFR) 2.9 ± 1.6, resistive reserve ratio (RRR) 3.3 ± 2.0. Lin's Concordance and Bland Altman analysis showed an optimal correlation between measured and estimated data. Sensitivity analysis showed that: (1) FFR can underestimate epicardial stenosis severity leading to FFR- vs NHi + discordance in case of elevated IMR, (2) NHi can overestimate epicardial stenosis severity leading to FFR- vs NHi + in the case of low BMR, (3) if BSR > HSR, FFR- vs NHi + discordance can occur, while if BSR < HSR, FFR+ vs NHi- discordance can occur. Conclusion(1) NHi can be more reliable in case of elevated IMR; (2) FFR-CFR combination can be more reliable for low BMR occurring to compensate an epicardial stenosis; (3) NHi-CFR combination can be more reliable when BSR > HSR, while FFR-CFR combination can be more reliable when BSR < HSR. The combination between pressure and flow indexes (FFR-CFR or NHi-CFR) is more reliable when compensatory mechanisms occur.

Prognostic Implications of Resistive Reserve Ratio in Patients With Nonobstructive Coronary Artery Disease With Myocardial Bridging.

Myocardial bridging (MB) is accompanied by the dynamic extravascular compression of epicardial coronary arteries, leading to intracoronary hemodynamic disturbance with abnormal coronary flow profiles. We aimed to evaluate the prognostic implications of resistive reserve ratio (RRR), a composite measure of flow and pressure parameters that represents the vasodilatory capacity of the coronary arteries, in patients with angina with nonobstructive coronary artery disease (ANOCA) and MB, in comparison with coronary flow reserve (CFR). In this retrospective cohort study, we included patients with ANOCA who underwent coronary reactivity testing, where MB was identified by transient constriction in coronary artery segments between systole and diastole. Abnormal CFR and RRR were defined as <2.5 and <2.62, respectively. Major adverse cardiac events, including cardiovascular death, stroke, myocardial infarction, heart failure, and late revascularization, served as outcomes. Among 1251 patients with ANOCA, 191 (15.3%) had MB. The prevalence of abnormal CFR or RRR was not significantly different between patients with and without MB (P=0.144 and P=0.398, respectively). Over a median follow-up time of 6.9 years, abnormal RRR predicted major adverse cardiac events in patients with MB (hazard ratio [HR], 4.38 [95% CI, 1.71-11.21]; P=0.002) and without MB (HR, 1.91 [95% CI, 1.38-2.64]; P<0.001). Abnormal CFR predicted major adverse cardiac events in patients without MB (HR, 2.15 [95% CI, 1.54-3.00]; P<0.001), whereas it was not predictive of major adverse cardiac events in patients with MB (HR, 2.29 [95% CI, 0.93-5.65]; P=0.073). In patients with ANOCA and MB, impaired RRR was superior to impaired CFR in distinguishing patients at a higher risk of future adverse events, suggesting that RRR may serve as a risk stratification tool in patients with MB and ANOCA.

Coronary microvascular dysfunction in patients with Takotsubo syndrome

BackgroundThe pathophysiology of Takotsubo syndrome (TTS) remains incompletely understood. While coronary microvascular dysfunction (CMD) is a potential pathophysiologic mechanism, evidence is limited. ObjectivesWe sought to evaluate CMD in patients with TTS. MethodsConsecutive patients diagnosed with TTS were included and underwent coronary angiography with invasive microvascular function evaluation, including fractional flow reserve, Coronary Flow Reserve (CFR), Index of Microcirculatory Resistance (IMR), and Resistive Reserve Ratio (RRR). Patients had an echocardiography evaluation during their index admission and at approximately 6 weeks. ResultsThirty patients were included (mean age 74 ±9, 90 % female). Twenty-five patients (83 %) had at least one abnormal coronary microvascular function parameter. Abnormal parameters included CFR<2.5 in 20 patients (67 %), IMR>25 in 18 patients (60 %), and RRR<3.5 in 25 (83 %). Longer time from symptoms to angiography correlated with a higher CFR (r = 0.51, P<0.01), and had an area under the receiver operating characteristic curve of 0.793 (95 % CI 0.60-0.98) for pathologic CFR. Patients with emotional trigger had a lower rate of pathologic IMR compared with non-emotional trigger (36 % vs 81 %, p = 0.01). Follow up echocardiography performed at a median of 1.5 months (IQR 1.15-6) showed an improvement in left ventricular ejection fraction for all patients (from mean of 40 % to 57 %). ConclusionCMD was present in most patients with TTS. The role of microvascular function in TTS may vary according to the clinical presentation and RRR may be more sensitive for the diagnosis of CMD in TTS.

Impaired coronary flow reserve in patients with poor type 2 diabetes control: Preliminary results from prospective microvascular dysfunction registry.

Type 2 diabetes (DM) is a common comorbidity associated with cardiovascular disease, especially when poor glucose control is present. Extracardiac microcirculatory complications prevalence is well documented, however coronary microcirculatory dysfunction (CMD) seem to be underreported in this group. The present study analyzed coronary physiology measurements (coronary flow reserve [CFR], index of microcirculatory resistance [IMR], resistance reserve ratio [RRR]) in 47 diabetic patients (21 subjects with poor glycemia control defined as fasting glucose levels > 7.2 mmol/L and 26 with normal fasting glucose), and compared to 54 non-diabetic controls, who had undergone coronary angiography due to symptoms of chronic coronary syndrome. The median age of patients was 65.5 [59.0; 73.0] years old, 74% male, similar in terms of cardiovascular risk factors and prior myocardial infarction. Insulin was used by 19% of diabetic patients with poor glucose control and by 15% of those with DM and low fasting glucose. Prevalence of CMD was 38% in poor glycemia control patients, 27% in DM-patients with proper glucose control and 31% of non-diabetics. Median CFR values were the lowest in poor DM control patients compared to both, normal fasting glucose (1.75 [1.37; 2.32] vs. 2.30 [1.75; 2.85], p = 0.026) and to non-diabetics (1.75 [1.37; 2.32] vs. 2.15 [1.50; 2.95], p = 0.045). Levels of IMR, RRR and MRR did not differ significantly between compared groups (p > 0.05 for all comparisons). Poor glycemia control in type 2 DM might be associated with a higher prevalence of CMD driven by decreased coronary flow reserve, however, further research in larger groups of patients should be performed to confirm this observation.

Traditional Cardiovascular Risk Factors and Coronary Microvascular Dysfunction in Women and Men: A Single-Center Study

Introduction: Coronary microvascular dysfunction (CMD) is common in patients with and without obstructive epicardial coronary artery disease (CAD). Risk factors for the development of CMD have not been fully elucidated, and data regarding sex-associated differences in traditional cardiovascular risk factors for obstructive CAD in patients with CMD are lacking. Methods: In this single-center, prospective registry, we enrolled patients with nonobstructive CAD undergoing clinically indicated invasive assessment of coronary microvascular function between November 2019 and March 2023. Associations between coronary microvascular dysfunction, traditional cardiovascular risk factors, and sex were assessed using univariate and multivariate regression models. Results: Overall, 245 patients with nonobstructive CAD were included in the analysis (62.9% female; median age 68 (interquartile range: 59, 75). Microvascular dysfunction was diagnosed in 141 patients (57.5%). The prevalence of microvascular dysfunction was similar in women and men (59.0% vs. 57.0%; p = 0.77). No association was found between traditional risk factors for coronary atherosclerosis and CMD regardless of whether CMD was structural or functional. In women, but not in men, older age and the presence of previous ischemic heart disease were associated with lower coronary flow reserve (β = −0.29; p < 0.01 and β = −0.15; p = 0.05, respectively) and lower resistive reserve ratio (β = −0.28; p < 0.01 and β = −0.17; p = 0.04, respectively). Conclusion: For the entire population, no association was found between coronary microvascular dysfunction and traditional risk factors for coronary atherosclerosis. In women only, older age and previous ischemic heart disease were associated with coronary microvascular dysfunction. Larger studies are needed to elucidate risk factors for CMD.

Smoking and Respiratory Diseases in Patients with Coronary Microvascular Dysfunction

BackgroundCoronary microvascular disease (CMD) is common in patients with and without obstructive coronary artery disease, and is associated with adverse clinical outcomes. Respiratory-related variables are associated with pulmonary and systemic microvascular dysfunction, while evidence about their relationship with CMD is limited. We aim to evaluate respiratory-related variables as risk factors of CMD. MethodsThis is an observational, single-center study enrolling consecutive patients undergoing invasive evaluation of coronary microvascular function in the catheterization laboratory. Patients with evidence of obstructive coronary artery disease or with missing data were excluded. Associations between respiratory-related variables and indices of CMD were assessed using univariate and multivariate regression models. ResultsOverall, 266 patients (mean age 67 ± 11 years, 59% females) were included in the current analysis. Of those, 155 (58%) had evidence of CMD. Among the respiratory variables, independent predictors of CMD were current smoking (adjusted odds ratio [AOR] 2.5; 95% confidence interval [CI], 1.2-5; P = .01) and obstructive sleep apnea (AOR 5.7; 95% CI, 1.2-26; P = .03), while chronic obstructive pulmonary disease was not. Among ever-smokers, higher smoking pack-years was an independent risk factor for CMD (median 35 vs 25 pack-years, AOR 1.09; 95% CI, 1.04-1.13; P < .01), and was associated with higher rates of pathologic index of microcirculatory resistance and resistive reserve ratio. ConclusionIn patients undergoing invasive coronary microvascular evaluation, current smoking and obstructive sleep apnea are independently associated with CMD. Among smokers, higher pack-years is a strong predictor for CMD. Our findings should raise awareness for prevention and possible treatment options.

Catheter-based examination for pulmonary microcirculatory function in patients with pulmonary hypertension.

A device that can evaluate human pulmonary microcirculation is currently unavailable. This study aimed to establish a novel approach for assessing pulmonary microcirculation in patients with pulmonary hypertension (PH). We used a guidewire embedded with temperature and pressure sensors to measure the following pulmonary microcirculatory function indicators: pulmonary flow reserve, pulmonary index of microcirculatory resistance (PIMR), and pulmonary resistive reserve ratio. Adenosine was administered to patients to induce hyperemia in the pulmonary artery for assessment. The correlation between these indicators and various parameters, including serum biomarkers, hemodynamic and respiratory functions, and exercise capacity, were examined. The procedure was performed in 19 patients with moderate PH, without major complications. The minimum effective adenosine dosage for maximal hyperemia, without severe side effects, was 150 μg∙kg-1∙min-1. Multivariate stepwise analysis revealed a positive correlation between the hyperemic PIMR and serum uric acid (p < 0.001) and N-terminal probrain natriuretic peptide levels (p = 0.014). Therefore, this catheter-based method offers an effective means to assess pulmonary microcirculatory function in patients with PH, and the optimal dose of adenosine for this evaluation was 150 μg∙kg-1∙min-1.

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.

Factors Associated with Impaired Resistive Reserve Ratio and Microvascular Resistance Reserve

Coronary microvascular dysfunction (CMD) is described as an important subset of ischemia with no obstructive coronary artery disease. Resistive reserve ratio (RRR) and microvascular resistance reserve (MRR) have been proposed as novel physiological indices evaluating coronary microvascular dilation function. The aim of this study was to explore factors associated with impaired RRR and MRR. Coronary physiological indices were invasively evaluated in the left anterior descending coronary artery using the thermodilution method in patients suspected of CMD. CMD was defined as a coronary flow reserve <2.0 and/or index of microcirculatory resistance ≥25. Of 117 patients, 26 (24.1%) had CMD. RRR (3.1 ± 1.9 vs. 6.2 ± 3.2, p < 0.001) and MRR (3.4 ± 1.9 vs. 6.9 ± 3.5, p < 0.001) were lower in the CMD group. In the receiver operating characteristic curve analysis, RRR (area under the curve 0.84, p < 0.001) and MRR (area under the curve 0.85, p < 0.001) were both predictive of the presence of CMD. In the multivariable analysis, previous myocardial infarction, lower hemoglobin, higher brain natriuretic peptide levels, and intracoronary nicorandil were identified as factors associated with lower RRR and MRR. In conclusion, the presence of previous myocardial infarction, anemia, and heart failure was associated with impaired coronary microvascular dilation function. RRR and MRR may be useful to identify patients with CMD.

The change of angina levels in patients with chronic coronary syndromes and coronary microcirculatory dysfunction - a prospective study with 24 months follow-up.

A substantial proportion of patients with chronic coronary syndromes suffer from angina even after medical treatment and revascularization. Coronary microvascular dysfunction (CMD) is discussed as a potential mechanism. To assess angina status in patients with chronic coronary syndromes undergoing functional assessment of coronary circulation regarding the presence of coronary microcirculatory dysfunction. The study included 101 consecutive patients referred for coronary angiography requiring functional stenosis assessment, with median age of 66 years, 74% male, diagnosed or treated for dyslipidemia (91%) and diabetes type 2 (42%), 20% with a history of prior non-ST myocardial infarction. Fractional flow reserve (FFR), coronary flow reserve (CFR), resistive reserve ratio (RRR), and index of microcirculatory resistance (IMR) were measured. The diagnosis of CMD was defined by either IMR ≥ 25 units or CFR ≤ 2.0 in case of no significant stenosis. A change of one CCS class over 24 months follow-up was considered clinically significant. In patients without CMD diagnosis, there was a significant decrease in angina intensity (p < 0.001). Lack of angina improvement was associated with lower median RRR (2.30 (1.70, 3.30) vs. 3.05 (2.08, 4.10), p = 0.004) and lower median CFR (1.90 (1.40, 2.50) vs. 2.30 (IQR: 1.60, 3.00), p = 0.021), as compared to patients with angina improvement. The presence of CMD is a risk factor for no angina improvement. Impaired coronary resistive reserve ratio and lower microvascular reactivity may be one of the pathomechanisms leading to the lack of angina improvement in patients with chronic coronary syndromes.

Proof of concept study on coronary microvascular function in low flow low gradient aortic stenosis

ObjectivesWe hypothesised that low flow low gradient aortic stenosis (LFLGAS) is associated with more severe coronary microvascular dysfunction (CMD) compared with normal-flow high-gradient aortic stenosis (NFHGAS) and that CMD is...

Validation of pressure-bounded coronary flow reserve using invasive coronary physiologic assessment.

Coronary flow reserve (CFR) represents entire coronary compensatory capacity. While CFR assessment is recommended to identify patients at an increased risk of cardiovascular events and coronary microvascular dysfunction, invasive CFR measurement is often technically challenging. Although not well validated yet, pressure-bounded CFR (pbCFR) has been proposed as a simple surrogate to estimate impaired CFR. In this study, we evaluated coronary physiological characteristics of low pbCFR using detailed invasive assessment. Invasive physiological assessment including resting ratio of distal coronary pressure to aortic pressure (Pd/Pa), fractional flow reserve (FFR), resting and hyperemic mean transit time, index of microcirculatory resistance (IMR), CFR, resistive reserve ratio, and microvascular resistance reserve (MRR) was performed in 107 patients in the left anterior descending coronary artery. pbCFR was calculated only with resting Pd/Pa and FFR. Patients were divided into low pbCFR and non-low pbCFR groups. Of 107 patients, 50 (46.7%) had low pbCFR. FFR (0.90 ± 0.05 vs. 0.83 ± 0.05, p < 0.001), hyperemic mean transit time (0.27 ± 0.17 vs. 0.21 ± 0.12, p = 0.04), and IMR (20.4 ± 13.2 vs. 15.0 ± 9.1, p = 0.01) were significantly higher in the low pbCFR group than their counterpart. While directly measured CFR did not differ significantly (4.4 ± 2.3 vs. 5.1 ± 2.8, p = 0.18), MRR was lower in the low pbCFR group (5.4 ± 3.0 vs. 6.8 ± 3.8, p = 0.047). The rates of CFR < 2.0 and IMR ≥ 25 were not significantly different between the 2 groups. In conclusion, although CFR did not differ significantly, IMR and MRR were impaired in patients with low pbCFR, suggesting pbCFR as a potential surrogate of coronary microvascular function in clinical practice.

Abstract 11403: Systemic Administration of High Mobility Group Box 1 Fragment Improves Cardiac Functions via Activating Tissue Healing Pathway of Bone-Marrow Mesenchymal Stem Cell in a Porcine Ischemic Cardiomyopathy Model

Introduction : Regenerative therapy for heart failure (HF) points to bone marrow mesenchymal stem cell (BM-MSC) as a promising cell source. High mobility group box 1 (HMGB1) is a nuclear protein involved in tissue homeostasis. In this study, we developed an HMGB1 fragment containing a BM-MSC mobilization domain. Hypothesis: We hypothesize that the HMGB1 fragment improves cardiac function by activating a tissue healing pathway of BM-MSC within a porcine ischemic cardiomyopathy (ICM) model as a pre-clinical study. Methods: Gottingen mini pigs weighing 15-25 kg were used. An ICM model was generated by placing an ameroid constrictor ring (internal diameter; 3.5 mm) on the left anterior descending artery (LAD). After 4 weeks, either the HMGB1 fragment (HMGB1 group; 3 mg/kg, n=6) or normal saline (control group; n=5) was administered intravenously with one dose every 48 h for five times. We examined cardiac function before and 8 weeks post treatment through echocardiography, cardiac magnetic resonance imaging (cMRI) with late gadolinium enhancement (LGE), and a fluoroscopy-guided pressure wire study. Then, histological analysis was performed. Results: In echocardiography, ejection fraction significantly improved in the HMGB1 group compared with the control (+11.1% vs -4.8%, p=0.0003). cMRI with LGE demonstrated that the areas of damaged myocardium (core infarct zone + border zone) in the LAD region was reduced in the HMGB1 group compared with the control group (-11.9% vs +17.9%, p=0.0090). Coronary flow reserve (CFR) and resistive reserve ratio (RRR) were evaluated through pressure wire study; they improved in the HMGB1 group compared with the control group (ΔCFR; +0.38 vs +0.01, p=0.0249, ΔRRR; +0.42 vs +0.07, p=0.0275). Histological analysis showed that cardiomyocyte size (26.6 μm vs 38.0 μm, p=0.0339) and areas of fibrosis were smaller (9.8% vs 11.6%, p=0.1649), and the density of CD31-positive endothelial cells was higher (1033/mm 2 vs 640/mm 2 , p=0.0339) in the HMGB1 group than in the control group. Conclusions: Systemic administration of the HMGB1 fragment improved cardiac function, coronary flow reserve, and reduced cardiac fibrosis in an ICM model. This drug-induced activation of inner tissue repair and regeneration is a novel approach to treat HF.

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 microvascular dysfunction is associated with reduced cardiac performance in low flow low gradient aortic stenosis

Abstract Background Little is known about coronary microvascular function of patients with low-flow low-gradient aortic stenosis (LFLGAS). We hypothesized that LFLGAS is associated with more severe coronary microvascular dysfunction (CMD) compared with normal-flow high-gradient aortic stenosis (NFHGAS) and that CMD is related to reduced cardiac efficiency. Purpose To perform a prospective invasive assessment of CMD in patients with LFLGAS undergoing TAVI and to compare it with patients with NFHGAS. Moreover, we aimed to assess the possible acute impact of TAVI on coronary microvascular function and the interactions between CMD and of cardiac performance at speckle tracking echocardiography (STE). Methods Invasive thermodilution-based assessment was systematically performed in 41 consecutive patients with isolated severe AS with angiographic unobstructed coronary arteries undergoing TAVI. The index of microcirculatory resistance (IMR), resistive reserve ratio (RRR) and coronary flow reserve (CFR) were derived to assess coronary microcirculatory function before and after TAVI. Advanced echocardiographic imaging, including STE, was performed to assess cardiac function. Results IMR was significantly higher in patients with LFLGAS compared with patients with NFHGAS (24.1 [14.6–39.1] vs 12.8 [8.6–19.2] p=0.002). Similarly, RRR was significantly lower in LFLGAS compared with NFHGAS (1.4 [1.1–2.1] vs 2.6 [1.5–3.3] p=0.020). No significant differences were observed in CFR between the two groups. High IMR was associated with low stroke volume index (rho=−0.427, p=0.005), low cardiac output (rho=−0.517, p=0.001), reduced peak atrial longitudinal strain (PALS) (rho=−0.610, p≤0.001) and presence of atrial fibrillation (54.6% vs 21.1%, p=0.036). Conversely, IMR was only modestly associated with the mean pressure aortic valve gradient (rho=−0.304, p=0.054). Notably, the mean gradient was significantly associated with IMR in the NFHGAS group (rho=0.632, p=0.003) but not in the LFLGAS (rho=−0.222, p=0.333). Similarly, high IMR was associated with the AVA in the NFHGAS group (rho=−0.50, p=0.025) but not in patients with LFLGAS (rho=0.157, p=0.497). Paradoxical LFLGAS emerged as a phenotype associated with CMD, poor left ventricular longitudinal systolic function and left atrial dysfunction. TAVI determined no significant variation in microvascular function (IMR: 16.0 [10.4–26.1] vs 16.6 [10.2–25.6], p=0.403) and in PALS (15.9 [9.9–26.5] vs 20.1 [12.3–26.7], p=0.222). Conversely, left ventricular global longitudinal strain increased overall after TAVI (−13.2 [8.4–16.6] vs −15.1 [9.4–17.8], p=0.047). Conclusions LFLGAS is associated with impaired coronary microvascular function compared with NFHGAS. Combined invasive assessment of microvascular function and advanced non-invasive imaging contributed to define different AS phenotypes. CMD was associated with low-flow state, left atrial dysfunction and reduced cardiac efficiency in patients with AS. Funding Acknowledgement Type of funding sources: Private company. Main funding source(s): Abbott Vascular

COlchicine to Prevent PeriprocEdural Myocardial Injury in Percutaneous Coronary Intervention (COPE-PCI): Coronary Microvascular Physiology Pilot Substudy.

Aim In this randomized pilot trial, we aimed to assess the anti-inflammatory effect of preprocedural colchicine on coronary microvascular physiology measurements before and after PCI. Methods Patients undergoing PCI for stable angina (SA) or non-ST-elevation myocardial infarction (NSTEMI) were randomized to oral colchicine or placebo, 6- to 24-hours before the procedure. Strict prespecified inclusion/exclusion criteria were set to ensure all patients were given the study medication, had a PCI, and had pre- and post-PCI culprit vessel invasive coronary physiology measurements. Fractional flow reserve (FFR), Index of Microvascular Resistance (IMR), Coronary Flow Reserve (CFR), and Resistive Reserve Ratio (RRR) were measured immediately before and after PCI. CMVD was defined as any one of post-PCI IMR >32 or CFR <2 or RRR <2. High-sensitive-(hs)-troponin-I, hsCRP, and leucocyte count were measured before and 24 hours after PCI. Results A total of 50 patients were randomized and met the strict prespecified inclusion/exclusion criteria: 24-colchicine and 26-placebo. Pre-PCI coronary physiology measurements, hs-troponin-I, and hsCRP were similar between groups. Although numerically lower in patients given colchicine, the proportion of patients who developed CMVD was not significantly different between groups (colchicine: 10 (42%) vs placebo: 16 (62%), p=0.16). Colchicine patients had higher post-PCI CFR and RRR vs placebo (respectively: 3.25 vs 2.00, p=0.03 & 4.25 vs 2.75, p < 0.01). Neutrophil count was lower after PCI in the colchicine arm (p=0.02), and hsCRP post-PCI remained low in both treatment arms (1.0 mg/L vs 1.7 mg/L, p=0.97). Patients randomized to colchicine had significantly less PCI-related absolute hs-troponin-I change (46 ng/L vs 152 ng/L, p=0.01). Conclusion In this pilot randomized substudy, colchicine given 6 to 24 hours before PCI did not statistically impact the post-PCI CMVD definition used in this study, yet it did improve post-PCI RRR and CFR measurements, with less procedure-related troponin release and less inflammation.

Impact of Ticagrelor Versus Clopidogrel on Coronary Microvascular Function After Non-ST-Segment-Elevation Acute Coronary Syndrome.

Coronary microvascular dysfunction after acute coronary syndrome is an important predictor of long-term prognosis. Data is lacking on the effects of oral P2Y12-inhibitors on coronary microvascular function in non-ST-segment-elevation acute coronary syndrome. The aim of this study was to compare the acute effects of ticagrelor versus clopidogrel pretreatment on coronary microvascular function in non-ST-segment-elevation acute coronary syndrome patients. Hospitalized non-ST-segment-elevation acute coronary syndrome patients were randomized (1:1) to ticagrelor or clopidogrel. The index of microcirculatory resistance, coronary flow reserve, and resistive reserve ratio were obtained using an intracoronary pressure-temperature sensor-tipped wire. In total, 128 patients were randomized between March 2018 and July 2020. Mean age 59.2±11.8 years, 84% were male, mean Global Registry of Acute Coronary Events score was 93.7±24.5. Intracoronary physiological measurements were obtained in 118 patients (60 ticagrelor, 58 clopidogrel). In the infarct-related artery, the ticagrelor group had lower baseline index of microcirculatory resistance (22.0 [13.0-34.9] versus 27.7 [19.3-29.8]; P=0.02) and higher baseline resistive reserve ratio (3.0 [2.3-4.4] versus 2.4 [1.7-3.4]; P=0.01) compared with the clopidogrel group. A total of 88 patients underwent percutaneous coronary intervention (PCI; 45 ticagrelor, 43 clopidogrel). The ticagrelor group had lower post-PCI index of microcirculatory resistance (22.0 [15.0-29.0] versus 27.0 [18.5-47.5]; P=0.02) and higher post-PCI resistive reserve ratio (3.0 [1.8-3.8] versus 1.8 [1.5-3.4]; P=0.006) compared with the clopidogrel group. The coronary flow reserve was not significantly different between the 2 groups at baseline or post-PCI. No between-group differences were seen in any of the indices in the non-infarct-related artery. In non-ST-segment-elevation acute coronary syndrome patients, ticagrelor significantly improved coronary microvascular function before and after PCI compared with clopidogrel. URL: https://www.anzctr.org.au; Unique identifier: ACTRN12618001610224.

Resistive reserve ratio and microvascular resistance reserve in patients with coronary vasospastic angina.

Patients with epicardial coronary vasospastic angina (VSA) may be likely to have coronary microvascular dysfunction, although mixed results have been reported. The aim of this study was to evaluate coronary microvascular function in detail using novel invasive physiologic indices, such as resistive reserve ratio (RRR) and microvascular resistance reserve (MRR). A total of 45 patients undergoing intracoronary acetylcholine (ACh) provocation test and invasive coronary circulatory evaluation using a thermodilution method were prospectively included. VSA was diagnosed as angiographic vasospasm accompanied by chest pain and/or ischemic electrocardiographic changes by intracoronary injection of ACh. Coronary circulation was assessed with physiologic indices including fractional flow reserve, resting and hyperemic mean transit time (Tmn), coronary flow reserve (CFR), basal resistance index, index of microcirculatory resistance (IMR), RRR, and MRR. Of 45 patients, 23 (51.1%) were diagnosed as having VSA. Patients with positive ACh test had longer resting Tmn (slower coronary flow velocity), higher basal resistance index, and greater RRR and MRR than those without, while fractional flow reserve, CFR, and IMR did not differ significantly between the two groups. In conclusion, although conventional measures such as CFR and IMR failed to show significant differences, RRR and MRR, novel invasive coronary physiologic indices, provided counterintuitive insights that coronary microvascular dilation function was better preserved in patients with VSA than those without.

Interventional Diagnostic Procedure: A Practical Guide for the Assessment of Coronary Vascular Function

Approximately 40% of patients undergoing invasive coronary angiography for investigation of angina are found to have no obstructive coronary artery disease (ANOCA). Abnormal coronary function underlies coronary vasomotion syndromes including coronary endothelial dysfunction, microvascular angina, vasospastic angina, post-PCI angina and myocardial infarction with no obstructive coronary arteries (MINOCA). Each of these endotypes are distinct subgroups, characterized by specific disease mechanisms. Diagnostic criteria and linked therapy for these conditions are now established by expert consensus and clinical guidelines. Coronary function tests are performed as an adjunctive interventional diagnostic procedure (IDP) in appropriately selected patients during coronary angiography. This aids differentiation of patients according to endotype. The IDP includes two distinct components: a diagnostic guidewire test and a pharmacological coronary reactivity test. The tests last approximately 5 minutes for the former and 10-15 minutes for the latter. Patient safety and staff education are key. The diagnostic guidewire test measures parameters of coronary flow limitation (fractional flow reserve [FFR], coronary flow reserve [CFR], microvascular resistance [index of microvascular resistance (IMR)], basal resistance index, and vasodilator function [CFR, resistive reserve ratio (RRR)]). The pharmacological coronary reactivity test measures the vasodilator potential and propensity to vasospasm of both the main coronary arteries and the micro-vessels. It involves intra-coronary infusion of acetylcholine and glyceryl trinitrate (GTN). Acetylcholine is not licensed for parenteral use and is therefore prescribed on a named-patient basis. Vasodilatation is the normal, expected response to infusion of physiological concentrations of acetylcholine. Vascular spasm represents an abnormal response, which supports the diagnosis of vasospastic angina. The purpose of this practical guide is to provide information on the preparation and administration of the IDP in clinical practice. It discusses some key preparation and safety considerations, as well as tips for procedural success. The IDP supports stratified medicine for a personalized approach to health and wellbeing.