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Background: Bolus thermodilution and intravenous adenosine are established methods for coronary microcirculatory assessment. Yet, its adoption remains low, partly due to procedural time and patient discomfort associated with intravenous adenosine. We investigated differences between intracoronary and intravenous adenosine using bolus thermodilution in terms of microcirculatory indices, procedural time, and side effects associated with adenosine in patients with myocardial ischemia and nonobstructive coronary arteries., Methods and Results: In this prospective, observational study, 102 patients with suspected myocardial ischemia and nonobstructive coronary arteries underwent measurements of mean transit time, coronary flow reserve, index of microcirculatory resistance, procedure time and patient tolerability with low-dose intracoronary adenosine, high-dose intracoronary adenosine (HDIC), and intravenous adenosine. HDIC induced greater hyperemia compared with low-dose intracoronary IC adenosine and intravenous adenosine with a shorter hyperemic mean transit time, P <0.0001. Coronary flow reserve was higher and index of microcirculatory resistance lowest with HDIC, compared with low-dose intracoronary IC adenosine and intravenous adenosine, P <0.05. Low coronary flow reserve was downgraded from 21% with intravenous adenosine to 10% with HDIC adenosine ( P =0.031); high index of microcirculatory resistance was downgraded from 23% with intravenous adenosine to 14% with HDIC ( P =0.098). Intracoronary adenosine was associated with lower procedural times ( P <0.0001). More patients experienced chest pain with intravenous adenosine ( P <0.01) and the chest pain intensity was higher compared with intracoronary adenosine ( P <0.0001)., Conclusions: In patients with suspected myocardial ischemia and nonobstructive coronary arteries undergoing coronary microcirculatory assessment with bolus thermodilution, the use of HDIC compared with intravenous adenosine was associated with enhanced induction of hyperemia. The use of intracoronary adenosine allowed for a shorter procedure time and was better tolerated., Registration+: URL: clinicaltrials.gov; Unique Identifier: NCT04827498.

Competing Interests: None declared.

Introduction: Periprocedural anxiety is common in pediatric patients and is characterized by tension, anxiety, irritability, and autonomic activation. Periprocedural anxiety increases during certain events including admission to the preoperative area, separation from caregivers, induction of anesthesia, and IV placement. A study of children aged 2-12 showed that perioperative anxiety in children may be influenced by high parental anxiety and low sociability of the child. While these are nonmodifiable variables in the perioperative setting, there are numerous ways to ameliorate both parental and patient anxiety including the use of certified child life specialists (CCLSs) to aid in child comfort. In this study, our objective was to evaluate the integration of CCLS in our perioperative setting on the rate of benzodiazepine use., Methods: We used a prospectively maintained database to identify patients undergoing outpatient elective surgical and radiologic procedures from July 2022 to September 2023 and January 2023 to September 2023 respectively. CCLSs were used to work with appropriately aged children in order to decrease the use of benzodiazepines and reduce possible adverse events associated with their use., Results: A total of 2175 pediatric patients were seen by CCLS in same day surgery from July 2022 to September 2023. During this period, midazolam use decreased by an average of 11.4% (range 6.2%-19.3%). An even greater effect was seen in the radiologic group with 73% reduction. No adverse events were reported during this period., Conclusions: CCLSs working with age-appropriate patients in the periprocedural setting is a useful adjunct in easing anxiety in pediatric patients, reducing the need for periprocedural benzodiazepine administration and the risk of exposure to unintended side effects., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Background: The microvascular resistance reserve (MRR) is an innovative index to assess the vasodilatory capacity of the coronary circulation while accounting for the presence of concomitant epicardial disease. The MRR has shown to be a valuable diagnostic and prognostic tool in the general coronary artery disease (CAD) population. However, considering the fundamental aspects of its assessment and the unique hemodynamic characteristics of women, it is crucial to provide additional considerations for evaluating the MRR specifically in women., Aim: The aim of this study was to assess the diagnostic and prognostic applicability of the MRR in women and assess the potential differences across different sexes., Methods: From the ILIAS Registry, we enrolled all patients with a stable indication for invasive coronary angiography, ensuring complete physiological and follow-up data. We analyzed the diagnostic value by comparing differences between sexes and evaluated the prognostic value of the MRR specifically in women, comparing it to that in men., Results: A total of 1494 patients were included of which 26% were women. The correlation between MRR and CFR was good and similar between women (r = 0.80, p < 0.005) and men (r = 0.81, p < 0.005). The MRR was an independent and important predictor of MACE in both women (HR 0.67, 0.47-0.96, p = 0.027) and men (HR 0.84, 0.74-0.95, p = 0.007). The optimal cut-off value for MRR in women was 2.8 and 3.2 in men. An abnormal MRR similarly predicted MACE at 5-year follow-up in both women and men., Conclusion: The MRR seems to be equally applicable in both women and men with stable coronary artery disease., (Copyright © 2024 The Author(s). Published by Elsevier B.V. All rights reserved.)

Prostate cancer is the second most common malignancy in men worldwide, with a good prognosis when is detected and treated in early stages, but, when it presents progression to castration-resistant metastatic prostate cancer, most of the cases will have bone metastasis, decreasing the quality of life and life expectancy. For the evaluation of the disease in the routinary clinical practice, 68 Ga-PSMA PET/CT, among others is a valuable tool for the evaluation of the disease extension. 68 Ga-PSMA PET/CT detects the presence of PSMA receptor in the tumoral tissue, but also has physiologic uptake in certain organs, such as liver, spleen, intestine, kidneys, lacrimal and salivary glands. Total or partial absence of uptake in those organs is rare and may be due to a high metastatic tumor burden, a phenomenon originally described in bone scintigraphy as super scan. We describe a case series of seven patients with prostate cancer from the National Institute of Cancerology in Colombia, in which a super scan pattern was found in the evaluation with 68 Ga-PSMA PET/CT, proposing the suppression of uptake in the intestine, liver, spleen, lacrimal and salivary glands as the main criteria for its definition, and showing that renal uptake persists in most cases, considering that, unlike the super scan in conventional bone scintigraphy, this is not a criterion necessary for its definition in the study with 68 Ga-PSMA., Competing Interests: The authors declare no conflicts of interest.

Background: Microvascular resistance (MR) has prognostic value in acute and chronic coronary syndromes following percutaneous coronary intervention (PCI), however anatomic and physiologic determinants of the relative changes of MR and its association to target vessel failure (TVF) has not been investigated previously. This study aims to evaluate the association between changes in MR and TVF., Methods: This is a sub-study of the Inclusive Invasive Physiological Assessment in Angina Syndromes (ILIAS) registry which is a global multi-centre initiative pooling lesion-level coronary pressure and flow data., Results: Paired pre-post PCI haemodynamic data were available in n = 295 vessels out of n = 828 PCI treated patients and of these paired data on MR was present in n = 155 vessels. Vessels were divided according to increase vs. decrease % in microvascular resistance following PCI (ΔMR % ≤ 0 vs. ΔMR > 0%). Decreased microvascular resistance ΔMR % ≤ 0 occurred in vessels with lower pre-PCI fractional flow reserve (0.67 ± 0.15 vs. 0.72 ± 0.09 p = 0.051), coronary flow reserve (1.9 ± 0.8 vs. 2.6 ± 1.8 p < 0.0001) and higher hyperemic microvascular resistance (2.76 ± 1.3 vs. 1.62 ± 0.74 p = 0.001) and index of microvascular resistance (24.4 IQ (13.8) vs. 15. 8 IQ (13.2) p = 0.004). There was no difference in angiographic parameters between ΔMR % ≤ 0 vs. ΔMR > 0%. In a cox regression model ΔMR % > 0 was associated with increased rate of TVF (hazard ratio 95% CI 3.6 [1.2; 10.3] p = 0.018)., Conclusion: Increased MR post-PCI was associated with lesions of less severe hemodynamic influence at baseline and higher rates of TVF at follow-up., Competing Interests: Declaration of Competing Interest There are no conflicts of interests., (Copyright © 2023 The Author(s). Published by Elsevier B.V. All rights reserved.)

In current clinical practice, commissural alignment of the transcatheter heart valve (THV) during transcatheter aortic valve implantation (TAVI) is seldom achieved. Orientation of the THV within the aortic root and the subsequent influence upon leaflet haemodynamic function, coronary blood flow, and ease of access to the coronary ostia are gaining significant interest. Herein, we review the incidence and clinical implications of commissural misalignment in TAVI and offer thorough descriptions of how optimal alignment can be achieved with several different contemporary THV devices.

Introduction: Sodium-glucose type 2 cotransporter inhibitors (SGLT2-I) have shown solid benefits in reducing cardiovascular mortality and admissions for heart failure in patients with type 2 diabetes mellitus (T2DM) and cardiovascular disease. However, no specific studies exist in patients with high-risk coronary artery disease (CAD)., Methods: Single-center, retrospective, observational study including patients with T2DM and a new diagnosis of extensive CAD (defined as left main disease or three main coronary vessel disease). Patients were recruited from 2015 until 2020, with a follow-up of at least 12 months. The primary outcome was to compare all-cause mortality in patients treated with or without SGLT2-I at discharge and adjusted by inverse probability of treatment weighting (IPTW) propensity score., Results: A total of 420 patients were included: 104 (24.7%) were treated with SGLT2-I and 316 (75.3%) were not (non-SGLT2-I group). The presentation was acute coronary syndrome in 44.3%. The mean age was 71.2 ± 10.5 years. The mean left ventricular ejection fraction was 51.5 ± 12.5%, and the mean estimated glomerular filtration rate was 73.9 ± 22 ml/min. After a mean follow-up of 3 ± 1.6 years, all-cause mortality was 16.4%, and cardiovascular mortality was 9.5%. After IPTW, the risk of all-cause death was lower in the SGLT2-I group with a hazard ratio of 0.32 (95% confidence interval 0.12-0.81), p = 0.016. With regard to secondary outcomes, patients in the SGLT2-I group were associated with less renal function deterioration but an increase in unplanned revascularizations., Conclusions: In patients with T2DM and extensive CAD, treatment with SGLT2-I after discharge was associated with a reduced risk of all-cause death., (© 2023. The Author(s).)

Background and Aims: The management of chronic coronary syndrome (CCS) is informed by studies predominantly including men. This study investigated the relationship between patients sex and different endotypes of CCS, including sex-specific clinical outcomes., Methods: In patients with CCS undergoing coronary angiography, invasive Fractional Flow Reserve (FFR) and Coronary Flow Reserve (CFR) were measured. Patients were stratified into groups: 1) obstructive coronary artery disease (oCAD) (FFR≤0.80, no revascularization), 2) undergoing revascularization, 3) non-obstructive coronary artery disease with coronary microvascular dysfunction (CMD) (FFR>0.80, CFR≤2.5), and 4) non-obstructive coronary artery disease without CMD (FFR>0.80 and CFR>2.5)., Results: 1836 patients (2335 vessels) were included, comprising 1359 (74.0%) men and 477 (26.0%) women. oCAD was present in 14.1% and was significantly less prevalent in women than in men (10.3% vs 15.5%, respectively p < 0.01). Revascularization was present in 30.9% and was similarly prevalent in women and men (28.2% vs. 31.9%, respectively p = 0.13). CMD was present in 24.2% and was significantly more prevalent in women than men (28.6% vs 22.6%, respectively p < 0.01). Normal invasive measurements were found in 564 patients (33.0% women vs 30.0% men, p = 0.23). Male sex was associated with an increased risk of target vessel failure compared to women (HR.1.89, 95% CI 1.12-3.18, p = 0.018), regardless of CCS-endotype., Conclusions: Sex differences exist in the prevalence and outcomes of different endotypes of CCS in symptomatic patients undergoing invasive coronary angiography. In particular, oCAD (and subsequent revascularization) were more prevalent in men. Conversely, CMD was more prevalent in women. Overall, men experienced a worse cardiovascular outcome compared to women, independent of any specific CCS endotype., (Copyright © 2023 The Authors. Published by Elsevier B.V. All rights reserved.)

Aims: The microvascular resistance reserve (MRR) was introduced as a means to characterize the vasodilator reserve capacity of the coronary microcirculation while accounting for the influence of concomitant epicardial disease and the impact of administration of potent vasodilators on aortic pressure. This study aimed to evaluate the diagnostic and prognostic performance of MRR., Methods and Results: A total of 1481 patients with stable symptoms and a clinical indication for coronary angiography were included from the global ILIAS Registry. MRR was derived as a function of the coronary flow reserve (CFR) divided by the fractional flow reserve (FFR) and corrected for driving pressure. The median MRR was 2.97 [Q1-Q3: 2.32-3.86] and the overall relationship between MRR and CFR was good [correlation coefficient (Rs) = 0.88, P < 0.005]. The difference between CFR and MRR increased with decreasing FFR [coefficient of determination (R2) = 0.34; Coef.-2.88, 95% confidence interval (CI): -3.05--2.73; P < 0.005]. MRR was independently associated with major adverse cardiac events (MACE) at 5-year follow-up [hazard ratio (HR) 0.78; 95% CI 0.63-0.95; P = 0.024] and with target vessel failure (TVF) at 5-year follow-up (HR 0.83; 95% CI 0.76-0.97; P = 0.047). The optimal cut-off value of MRR was 3.0. Based on this cut-off value, only abnormal MRR was significantly associated with MACE and TVF at 5-year follow-up in vessels with functionally significant epicardial disease (FFR <0.75)., Conclusion: MRR seems a robust indicator of the microvascular vasodilator reserve capacity. Moreover, in line with its theoretical background, this study suggests a diagnostic advantage of MRR over other indices of vasodilatory capacity in patients with hemodynamically significant epicardial coronary artery disease., (© The Author(s) 2023. Published by Oxford University Press on behalf of the European Society of Cardiology.)

Objectives: We aimed to evaluate the diagnostic accuracy of quantitative flow ratio (QFR) in left main (LM) coronary stenoses, using Fractional Flow Reserve (FFR) as reference., Background: QFR has demonstrated a high accuracy in determining the functional relevance of coronary stenoses in non-LM. However, there is an important paucity of data regarding its diagnostic value in the specific anatomical subset of LM disease., Methods: This is a retrospective, observational, multicenter, international, and blinded study including patients with LM stenoses. Cases with significant ostial LM disease were excluded. QFR was calculated from conventional angiograms at blinded fashion with respect to FFR., Results: Sixty-seven patients with LM stenoses were analyzed. Overall, LM had intermediate severity, both from angiographic (diameter stenosis [%DS] 43.8 ± 11.1%) and functional perspective (FFR 0.756 ± 0.105). Mean QFR was 0.733 ± 0.159. Correlation between QFR and FFR was moderate (r = 0.590). Positive and negative predictive value, sensitivity and specificity were 85.4%, 64%, 85.4%, and 69.6% respectively. Classification agreement of QFR and FFR in terms of functional stenosis severity was 78.1%. Area under the receiver operating characteristics of QFR using FFR as reference was 0.82 [95% confidence interval [CI], 0.71-0.93], and significantly better than angiographic evaluation including %DS (area under the receiver-operating characteristic curve [AUC] 0.45 [95% CI, 0.32-0.58], p < 0.001) and minimum lumen diameter (AUC 0.60 [95% CI, 0.47-0.74], p < 0.001)., Conclusions: Compared with FFR, QFR has acceptable diagnostic performance in determining the functional relevance of LM stenosis, being better than conventional angiographic assessment. Nonetheless, caution should be taken when applying functional angiography techniques for the assessment of LM stenosis given its particular anatomical characteristics., (© 2023 The Authors. Catheterization and Cardiovascular Interventions published by Wiley Periodicals LLC.)

Background: The optimal duration of dual antiplatelet therapy (DAPT) ought to be determined taking into account individual ischaemic or bleeding events risks. To date, studies have provided inconclusive evidence on the effects of prolonged DAPT. We sought to evaluate the long-term outcomes of this strategy following percutaneous revascularization in the context of acute coronary syndrome (ACS)., Methods: Retrospectively from four centers in Madrid, we identified 750 consecutive ACS patients, divided in two groups of DAPT duration: <13 months and >13 months, with a mean follow-up of 48 months., Results: Patients with DAPT > 13 months had a higher non-adjusted incidence of Major Adverse Cardiovascular Events (11.6% vs. 17.3%) and new revascularization (3.7% vs. 8.7%). Differences in all-cause death, cardiac death, myocardial infarction, stent thrombosis and stroke were non-significant. There was no difference in the incidence of major bleeding (7.4% vs. 6.3%). Multivariable Cox regression analysis showed that the independent risk predictors of MACE were age (HR: 1.04, 95% CI: 1.02-1.06, p  < 0.001) and multivessel disease (HR: 2.29, 95% CI: 1.32-3.95, p  = 0.003), whereas the independent protective predictor was normal hemoglobin (HR: 0.88, 95% CI: 0.78-0.98, p  = 0.022)., Conclusions: In this real-world registry cohort of ACS patients treated with PCI and 1 year of DAPT in Spain, we report a trend of increased rate of MACE and new revascularization not associated with TVR in patients with longer DAPT. Our findings support the need for future randomized controlled trials to confirm or refute these results., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (© 2023 Vergara-Uzcategui, Moreno, Hennessey, Sánchez-del-Hoyo, Donis, Gonzalez-Rojas, Salinas, Nombela-Franco, Gonzalo, Jimenez-Quevedo, Mejia-Renteria, Escaned, Fernández Ortiz, Macaya Miguel and Núñez-Gil.)

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. (NCT04485234) 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., (© 2023. The Author(s).)

Background: It remains unknown whether the presence of coronary microcirculatory dysfunction (CMD) correlates with its equivalent condition in the brain, cerebral small vessel disease (CSVD). The cerebral-coronary connection (C3), a prospective blinded study, investigated the prevalence of CMD in patients with coronary artery disease (CAD) and its association with CSVD and cognitive function., Methods and Results: Patients with documented CAD fulfilling inclusion criteria underwent physiological assessment of epicardial vessels and the microcirculation using intracoronary pressure and Doppler. Coronary microcirculation-related indices included coronary flow reserve (CFR) and hyperaemic microvascular resistance. Brain magnetic resonance imaging, transcranial Doppler (TCD), and neurocognitive examination were performed. Overall, 67 patients were included in the study (mean age 66 years, 73% female). Patients with abnormal CFR (<2.0) (55.2%) showed higher burden of white-matter hyperintensities: 43.2 vs. 20.0% (P = 0.044). After statistical adjustment, low CFR was associated with lower grey matter volume (P = 0.024) and with parameters of white-matter microstructural damage in diffusion-tensor imaging (lower fractional anisotropy and higher mean diffusivity, P = 0.029 and P = 0.032, respectively). Low CFR was associated with higher resistive (P = 0.027) and pulsatility (P = 0.043) values on TCD, and worse neurocognitive test scores (lower mini mental state examination, P = 0.025, and slower Trail Making Test A, P = 0.034)., Conclusions: Coronary microcirculatory dysfunction is frequent in patients with CAD and correlates with CSVD, abnormal cerebral flow haemodynamics, and significant cognitive impairment. These findings support the hypothesis that microvascular dysfunction in the heart and the brain are part of a single pathological process affecting microcirculation in patients with CAD., Clinical Trial Registration: ClinicalTrials.gov NCT04131075., Competing Interests: Conflict of interest: A.T. has received unrestricted educational grants from Philips. H.M.-R. has received consultancy fees from Medis Medical Imaging and speaking honoraria from Philips and Abbott. C.E.-P. received a Rio Hortega grant (CM20/00013) from Instituto de salud Carlos III (Madrid, Spain). J.E. reports advisory board and speaker fees from Philips and Abbott., (© The Author(s) 2022. Published by Oxford University Press on behalf of the European Society of Cardiology.)

Objective: The aim of this study is to evaluate the diagnostic and prognostic value of non-hyperaemic Pd/Pa and to determine its additional value when combined with the gold standard hyperaemic pressure ratio (FFR) to guide revascularization., Methods: In a large, multi-center, retrospective registry, we included a total of 2141 patients with a clinical indication for coronary angiography providing physiological data in 2726 vessels. A classification was made based on the FFR (cut-off value: 0.80) and non-hyperaemic Pd/Pa (cut-off value: 0.92) values and the primary outcome was target-vessel failure (TVF) at 5-year follow-up., Results: Mean age was 63 ± 10.0 and 75% of the study population were men. Regression analysis showed an overall good correlation between FFR and non-hyperaemic Pd/Pa (r = 0.73, p < 0.005) and discordance was present in 17% of the vessels. Resting Pd/Pa was independently associated with TVF at 5-year follow-up (HR 0.08, 95%CI: 0.02-0.27; p < 0.005). The risk for TVF was the lowest in vessles with concordant normal pressure ratio's, with the highest risk in vessels with any abnormal pressure ratio in which revascularization was deferred. In these vessels, there was no difference in risk for TVF between the discordant and concordant abnormal values., Conclusion: Abnormal pressure ratios in both non-hyperemic and hyperemic conditions portend important prognostic value. Combined application of FFR and non-hyperemic Pd/Pa efficiently identifies those vessels with concordant normal resting and hyperemic pressure ratios of which long-term clinical outcomes are excellent. These data lead to hypothesize that the decision to defer revascularization should potentially be based on combined non-hyperemic and hyperemic pressure ratios., Clinical Trial Registration: Inclusive Invasive Physiological Assessment in Angina Syndromes Registry (ILIAS Registry), NCT04485234., Competing Interests: Conflict of Interest Tvdh has received speaker fees and institutional research grants from Abbott and Philips. JML received research grants from Abbott and Philips. MEP has received speaker fees from Abbott and Philips. BKK has received institutional research grants from Abbott Vascular and Philips Volcano. JJP has received support as consultant for Philips/Volcano, and has received institutional research grants from Philips. The other authors report no relationship with industry related to this work., (Copyright © 2022 The Author(s). Published by Elsevier B.V. All rights reserved.)

Objectives: Investigate age-related changes in coronary microvascular function, its effect on hyperemic and non-hyperemic indices of stenosis relevance, and its prognostic implications., Background: Evidence assessing the effect of age on fractional flow reserve (FFR), resting mean distal intracoronary pressure/mean aortic pressure (Pd/Pa), and microcirculatory function remains scarce., Methods: This is a post hoc study of a large prospective international registry (NCT03690713) including 1134 patients (1326 vessels) with coronary stenoses interrogated with pressure and flow guidewires. Age-dependent correlations with functional indices were analyzed. Prevalences of FFR, resting Pd/Pa, and coronary flow reserve (CFR) classification agreement were assessed. At 5 years follow-up, the relation between resting Pd/Pa, CFR, and their age-dependent implications on FFR-guided percutaneous coronary intervention (PCI) deferral (deferred if FFR > 0.80) were investigated using vessel-oriented composite outcomes (VOCO) composed of death, myocardial infarction, and repeated revascularization., Results: Age correlated positively with FFR (r = 0.08, 95% confidence interval [CI]: 0.03 to 0.13, p =  0.005), but not with resting Pd/Pa (r = -0.03, 95% CI:-0.09 to 0.02, p = 0.242). CFR correlated negatively with age (r = -0.15, 95% CI: -0.21 to -0.10, p < 0.001) due to a significant decrease in maximal hyperemic flow in older patients. Patients over 60 years of age with FFR-guided deferred-PCI abnormal resting Pd/Pa or abnormal CFR had increased risk of VOCO (hazard ratio [HR]: 2.10, 95% CI: 1.15 to 4.36, p = 0.048; HR: 2.46, 95% CI:1.23 to 4.96, p = 0.011; respectively)., Conlusions: Aging is associated with decrease in microcirculatory vasodilation, as assessed with adenosine-based methods like CFR. In patients older than 60 years in whom PCI is deferred according to FFR > 0.80, CFR and resting Pd/Pa have an incremental value in predicting future vessel-oriented patient outcomes., (© 2022 The Authors. Catheterization and Cardiovascular Interventions published by Wiley Periodicals LLC.)

Background: Coronary microvascular dysfunction (CMD) is an important contributor to angina syndromes. Recently, two distinct endotypes were identified using combined assessment of coronary flow reserve (CFR) and minimal microvascular resistance (MR), termed structural and functional CMD., Aims: We aimed to assess the relevance of the combined assessment of CFR and MR in patients with angina and no obstructive coronary arteries., Methods: Patients with chronic coronary syndromes (CCS) and non-obstructive coronary artery disease (fractional flow reserve [FFR] ≥0.80) were selected (N=1,102). Functional CMD was defined as abnormal CFR in combination with normal MR and structural CMD as abnormal CFR with abnormal MR. Clinical endpoints were the incidence of major adverse cardiac events (MACE) and target vessel failure (TVF) at 5-year follow-up., Results: Abnormal CFR was associated with an increased risk of MACE and TVF at 5-year follow-up. Microvascular resistance parameters were not associated with MACE or TVF at 5-year follow-up. The risk of MACE and TVF at 5-year follow-up was similarly increased for patients with structural or functional CMD compared with patients with normal microvascular function. There were no differences between both endotypes (p=0.88 for MACE, and p=0.55 for TVF)., Conclusions: Coronary microvascular dysfunction, identified by an impaired CFR, was unequivocally associated with increased MACE and TVF rates over a 5-year follow-up period. In contrast, impaired MR was not associated with 5-year adverse clinical events. Moreover, there was no significant difference in the risk of MACE and TVF between a low CFR accompanied by pathologically increased MR (structural CMD) or not (functional CMD)., Clinicaltrials: gov: NCT04485234.

Coronary microvascular dysfunction (CMD) is a prevalent cause of ischemic heart disease and is associated with poorer quality of life and worse patient outcomes. Both functional and structural abnormalities of the microcirculation can generate ischemia in the absence of epicardial stenosis or worsen concomitant obstructive coronary artery disease (CAD). The invasive assessment of CMD allows for the evaluation of the entirety of the coronary vascular tree, from the large epicardial vessels to the microcirculation, and enables the study of vasomotor function through vasoreactivity testing. The standard evaluation of CMD includes vasomotor assessment with acetylcholine, as well as flow- and resistance-derived indices calculated with either thermodilution or Doppler guidewires. Tailored treatment based upon the information gathered from the invasive evaluation of CMD has been demonstrated to reduce the burden of angina; therefore, a thorough understanding of these procedures is warranted with the aim of improving the quality of life of the patient. This review summarizes the most widespread approaches for the invasive evaluation of CMD, with a focus on patients with ischemia and non-obstructive CAD., (© 2022. The Author(s).)

Background and Objectives: There is clinical and phenotypic heterogeneity in LRRK2 G2019S Parkinson disease (PD), including loss of smell. Olfactory scores have defined subgroups of LRRK2 PD at baseline. We now extend this work longitudinally to better determine features associated with olfactory classes and to gain further insight into this heterogeneity., Methods: Evaluation of 162 patients with LRRK2 PD and 198 patients with idiopathic PD (IPD) from the LRRK2 Ashkenazi Jewish Consortium was performed, with follow-up available for 92 patients with LRRK2 PD and 74 patients with IPD. Olfaction (University of Pennsylvania Smell Identification Test [UPSIT]), motor function (Unified Parkinson Disease Rating Scale), and cognition (Montreal Cognitive Assessment), as well as sleep, nonmotor, and mood, were measured. Gaussian mixture models were applied on the UPSIT percentile score to determine subgroups based on olfactory performance. Linear mixed effects models, using PD duration as the time scale, assessed the relationship between UPSIT subgroup membership and motor/cognitive change., Results: Baseline olfaction was better in LRRK2 PD compared with IPD (mean UPSIT ± SD: 24.2 ± 8.8 vs 18.9 ± 7.6), with higher mean percentile scores (difference: 15.3 ± 11.6) ( p < 0.001) and less frequent hyposmia (55.6% vs 85.4%; p < 0.001). Analysis suggested 3 classes among LRRK2 PD. Age at onset in LRRK2 PD was earlier in the worst olfaction group (group 1), compared with groups 2 and 3 (54.5 ± 11.1 vs 61.7 ± 9.3) ( p = 0.012), and separately in the hyposmic group overall (55.0 ± 11.3 vs 61.7 ± 9.1) ( p < 0.001). Longitudinal motor deterioration in LRRK2 PD was also significantly faster in the worst UPSIT group than the best UPSIT group (group 3 vs group 1: B = 0.31, SE = 0.35 vs B = 0.96, SE = 0.28) (rate difference = -0.65, SE = 0.29) ( p = 0.03). However, olfactory group membership was not significantly associated with cognitive decline., Discussion: In this large LRRK2 cohort with longitudinal analysis, we extend prior work demonstrating subgroups defined by olfaction in LRRK2 G2019S PD and show that the worst olfaction group has earlier age at PD onset and more rapid motor decline. This supports a subgroup of LRRK2 PD that might show more rapid change in a clinical trial of LRRK2 -related agents and highlights the need to integrate careful phenotyping into allocation schema in clinical trials of LRRK2 -related agents., Classification of Evidence: This study provides Class II evidence that worse olfactory scores were associated with an earlier age at symptomatic onset and a faster rate of motor deterioration in patients with LRRK2 PD., (© 2022 American Academy of Neurology.)

Background Intracoronary 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 Results A 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. Conclusions CFR 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. Registration URL: https://www.clinicaltrials.gov; Unique identifier: NCT04485234.

Background: Coronary pressure indices such as fractional flow reserve are the standard for guiding elective revascularization. However, considering additional coronary flow parameters could further individualize and optimize the decision on revascularization. We aimed to investigate the potentially differential prognostic associations of elective percutaneous coronary intervention (PCI) according to coronary flow properties represented by coronary flow reserve (CFR), coronary flow capacity (CFC), and baseline CFC (bCFC)., Methods: From the ILIAS Registry (Inclusive Invasive Physiological Assessment in Angina Syndromes) composed of 16 hospitals globally from 7 countries, patients with obstructive coronary artery disease who underwent invasive coronary physiological assessment were included (N=2370 vessels). We assessed effect measure modifications of the association of PCI and 5-year target vessel failure according to CFR, CFC, and bCFC either assessed by Doppler-technique or thermodilution-method., Results: The mean age of the population was 63.3 years, and there were 1322 (73.6%) males. Median fractional flow reserve was 0.85, and PCI was performed in 600 (25.3%) vessels. Reduced CFR, CFC, and abnormal bCFC were defined in 988 (41.7%), 542 (22.9%), and 600 (25.3%) vessels, respectively. Significant effect measure modifications were observed by CFC either in odds ratio ( P =0.0018), additive ( P =0.029), and hazard ratio scale ( P =0.0002). The absolute risk of 5-year target-vessel failure was higher if treated by PCI in vessels with normal CFC by 1.8 (-1.7 to 5.3) percent, while that was lower by -5.9 (-12 to -0.1) percent in those with reduced CFC. CFR and bCFC were not significant effect modifiers in any scales. Similar associations were observed in per-patient analyses, whereas the findings were less robust., Conclusions: We observed qualitative effect measure modification of PCI and 5-year clinical outcomes according to CFC status in additive scale. CFR and bCFC were not robust effect modifiers. Therefore, CFC could be potentially used to optimize the patient selection for elective PCI treatment combined with fractional flow reserve.

Objectives: The authors sought to evaluate comparative prognosis between deferred versus performed percutaneous coronary intervention (PCI) according to coronary flow reserve (CFR) values of patients with intermediate fractional flow reserve (FFR)., Background: For coronary stenosis with intermediate FFR, the prognostic value of PCI remains controversial. The prognostic impact of PCI may be different according to CFR in patients with intermediate FFR., Methods: From the ILIAS Registry (Inclusive Invasive Physiological Assessment in Angina Syndromes Registry, N = 2,322), 400 patients (412 vessels) with intermediate FFR (0.75-0.80) were selected. Patients were stratified into preserved CFR (>2.0, n = 253) and depressed CFR (≤2.0, n = 147) cohorts. Per-vessel clinical outcomes during 5 years of follow-up were compared between deferred versus performed PCI groups in both cohorts. The primary outcome was target vessel failure (TVF), a composite of cardiac death, target vessel myocardial infarction, or target vessel revascularization., Results: Among the study population, PCI was deferred for 210 patients (219 vessels, 53.2%) (deferred group) and performed for 190 patients (193 vessels, 46.8%) (performed group). The risk of TVF was comparable between the deferred and performed groups (12.8% vs 14.2%; adjusted HR: 1.403; 95% CI: 0.584-3.369; P = 0.448). When stratified by CFR, PCI was performed in 39.1% (100/261 vessels) of the preserved CFR cohort and 61.9% (93/151 vessels) of the depressed CFR cohort. Within the preserved CFR cohort, the risk of TVF did not differ significantly between the deferred and performed groups (11.0% vs 13.9%; adjusted HR: 0.770; 95% CI: 0.262-2.266; P = 0.635). However, in the depressed CFR cohort, the deferred group had a significantly higher risk of TVF than the performed group (17.2% vs 14.2%; adjusted HR: 4.932; 95% CI: 1.312-18.53; P = 0.018). A significant interaction was observed between CFR and the treatment decision (interaction P = 0.049). Results were consistent after inverse probability weighting adjustment., Conclusions: In patients with intermediate FFR of 0.75 to 0.80, the prognostic value of PCI differed according to CFR, with a significant interaction. PCI was associated with a lower risk of TVF compared with the deferral strategy when CFR was depressed (≤2.0), but there was no difference when CFR was preserved (>2.0). CFR could be used as an additional risk stratification tool to determine treatment strategies in patients with intermediate FFR. (Inclusive Invasive Physiological Assessment in Angina Syndromes Registry [ILIAS Registry]; NCT04485234)., Competing Interests: Funding Support and Author Disclosures Dr Joo Myung Lee has received research grants from Abbott and Philips. Dr Mejia-Renteria has received speaker fees from Philips, Abbott, and Medis. Dr Echavarria-Pinto has received speaker fees from Abbott and Philips. Dr van de Hoef has received speaker fees and institutional research grants from Abbott and Philips. Dr van Royen has received speaker fees and institutional research grants from Abbott and Philips. Dr Koo has received institutional research grants from Abbott Vascular and Philips Volcano. Dr Piek has received support as a consultant for Philips/Volcano; and has received institutional research grants from Philips. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose., (Copyright © 2022 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Background In the absence of obstructive coronary stenoses, abnormality of noninvasive stress tests (NIT) in patients with chronic coronary syndromes may indicate myocardial ischemia of nonobstructive coronary arteries (INOCA). The differential prognosis of INOCA according to the presence of coronary microvascular dysfunction (CMD) and incremental prognostic value of CMD with intracoronary physiologic assessment on top of NIT information remains unknown. Methods and Results From the international multicenter registry of intracoronary physiologic assessment (ILIAS [Inclusive Invasive Physiological Assessment in Angina Syndromes] registry, N=2322), stable patients with NIT and nonobstructive coronary stenoses with fractional flow reserve >0.80 were selected. INOCA was diagnosed when patients showed positive NIT results. CMD was defined as coronary flow reserve ≤2.5. According to the presence of INOCA and CMD, patients were classified into 4 groups: group 1 (no INOCA nor CMD, n=116); group 2 (only CMD, n=90); group 3 (only INOCA, n=41); and group 4 (both INOCA and CMD, n=40). The primary outcome was major adverse cardiovascular events, a composite of all-cause death, target vessel myocardial infarction, or clinically driven target vessel revascularization at 5 years. Among 287 patients with nonobstructive coronary stenoses (fractional flow reserve=0.91±0.06), 81 patients (38.2%) were diagnosed with INOCA based on positive NIT. By intracoronary physiologic assessment, 130 patients (45.3%) had CMD. Regardless of the presence of INOCA, patients with CMD showed a significantly lower coronary flow reserve and higher hyperemic microvascular resistance compared with patients without CMD ( P <0.001 for all). The cumulative incidence of major adverse cardiovascular events at 5 years were 7.4%, 21.3%, 7.7%, and 34.4% in groups 1 to 4. By documenting CMD (groups 2 and 4), intracoronary physiologic assessment identified patients at a significantly higher risk of major adverse cardiovascular events at 5 years compared with group 1 (group 2: adjusted hazard ratio [HR adjusted ], 2.88; 95% CI, 1.52-7.19; P =0.024; group 4: HR adjusted , 4.00; 95% CI, 1.41-11.35; P =0.009). Conclusions In stable patients with nonobstructive coronary stenoses, a diagnosis of INOCA based only on abnormal NIT did not identify patients with higher risk of long-term cardiovascular events. Incorporating intracoronary physiologic assessment to NIT information in patients with nonobstructive disease allowed identification of patient subgroups with up to 4-fold difference in long-term cardiovascular events. Registration URL: https://www.clinicaltrials.gov; Unique identifier: NCT04485234.

Objectives: To investigate the effect of aging on coronary stenosis functional assessment with fractional flow reserve (FFR) and instantaneous wave-free ratio (iFR)., Background: Limited data exist regarding the impact of patient age on these coronary pressure indices., Methods: We analyzed 514 patients with coronary stenosis interrogated with intravascular physiology. The influence of patient age on FFR, iFR, and microcirculation-related indices was investigated. Vessel-oriented composite outcome (VOCO) was assessed in the FFR-based deferred population according to iFR, coronary flow reserve (CFR), and age., Results: FFR increased (r = 0.128, p = 0.004), iFR remained unchanged (r = -0.001, p = 0.980), and CFR decreased (r = -0.095, p = 0.001) with patient age. Relationship between FFR and CFR differed across age groups (r = 0.263 in <60 years old vs. r = 0.124 in ≥60 years old, p = 0.0056), whereas iFR correlated to CFR similarly regardless age (r = 0.283 in <60 years old vs. r = 0.219 in ≥60 years old, p = 0.3781). No differences were found on angiographic stenosis severity (%DS 47.4 in <60 years old and 49.8 in ≥60 years old, p = 0.317). At 5 years, FFR-based revascularisation deferral in patients ≥60 years old was associated with more VOCO when either iFR (25%) or CFR (16.9%) were abnormal, compared to patients with normal iFR (6.3%) or normal CFR (4.6%) (log-rank p < 0.001). This difference in clinical outcomes was not observed in younger patients., Conclusions: FFR values increased progressively with patient age, potentially associated with age-related changes in the coronary microcirculation. Conversely, iFR values remained unchanged across the patient age spectrum. In ≥60 years old patients with revascularisation deferral based on FFR, both abnormal iFR and CFR values were associated with worse long-term patient outcomes., (© 2022 Wiley Periodicals LLC.)

Background: The safety of revascularization deferral according to pressure wire examination in patients with chronic kidney disease (CKD) has not been fully established., Methods: From a retrospective cohort of 439 patients in whom revascularization was deferred after physiological assessment, we examined the incidence of patient-oriented composite endpoint (POCE: all-cause death, myocardial infarction [MI] and unplanned revascularization) in patients with CKD (estimated glomerular filtration rate [eGFR] < 60 mL/min/1.73 m²) and without it., Results: At 4 years of follow-up, the primary endpoint was met by 25.0% of patients with CKD and by 14.4% of patients without CKD (hazard ratio [HR] 1.56, 95% confidence interval [CI] 0.96-2.53, p = 0.071). The incidence of POCE was even higher in patients with an eGFR < 30 mL/min/1.73 m²: 43.8% (HR 3.10, 95% CI 1.08-8.92, p = 0.036). However, no differences were observed in the incidence of MI (4.2% vs. 4.4% in non-CKD), target vessel revascularization (5.8% vs. 5.9%), and target vessel MI (0.8% vs. 4.6%)., Conclusions: Patients with CKD in whom pressure-wire evaluation led to deferral of coronary revascularization develop more POCE in the long term, compared to patients with normal renal function. However, the increase in POCE in patients with CKD was seldom related to deferred vessels, thus suggesting an epiphenomenon of an intrinsically higher cardiovascular risk of CKD patients.

Background: Endothelial dysfunction is one of the underlying mechanisms to vascular and cardiac complications in patients with COVID-19. We sought to investigate the systemic vascular endothelial function and its temporal changes in COVID-19 patients from a non-invasive approach with reactive hyperemia peripheral arterial tonometry (PAT)., Methods: This is a prospective, observational, case-control and blinded study. The population was comprised by 3 groups: patients investigated during acute COVID-19 (group 1), patients investigated during past COVID-19 (group 2), and controls 1:1 matched to COVID-19 patients by demographics and cardiovascular risk factors (group 3). The natural logarithmic scaled reactive hyperemia index (LnRHI), a measure of endothelium-mediated dilation of peripheral arteries, was obtained in all the participants and compared between study groups., Results: 144 participants were enrolled (72 COVID-19 patients and 72 matched controls). Median time from COVID-19 symptoms to PAT assessment was 9.5 and 101.5 days in groups 1 and 2, respectively. LnRHI was significantly lower in group 2 compared to both group 1 and controls (0.53 ± 0.23 group 2 vs. 0.72 ± 0.26 group 1, p = 0.0043; and 0.79 ± 0.23 in group 3, p < 0.0001). In addition, within group 1, it was observed a markedly decrease in LnRHI from acute COVID-19 to post infection stage (0.73 ± 0.23 vs. 0.42 ± 0.26, p = 0.0042)., Conclusions: This study suggests a deleterious effect of SARS-CoV-2 infection on systemic vascular endothelial function. These findings open new venues to investigate the clinical implication and prognostic role of vascular endothelial dysfunction in COVID-19 patients and post-COVID syndrome using non-invasive techniques., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Background: No data are currently available on the process of vessel healing and long-term physiological results after implantation of resorbable magnesium-made scaffold (RMS) in human coronary arteries., Objectives: To investigate after percutaneous coronary intervention (PCI) and at 12 months follow-up (a) RMS resorption process and vessel healing, as judged by optical coherence tomography (OCT) imaging; and (b) physiological result of RMS implantation evaluated by quantitative flow ratio (QFR)., Methods: All patients successfully treated with at least one RMS from July 2016 to August 2018 at 2 Italian centers were evaluated. All cases with OCT pullback and/or coronary angiography suitable for QFR analysis performed after PCI and at 12 months were included. Resorption process was analyzed at OCT in each frame reporting presence of residual struts in the vessel., Results: Forty-four patients/forty-nine lesions were included. 12-months mean lumen area (LA; 7.54 ± 3.04 mm 2 ) significantly decreased compared to mean LA recorded immediately after PCI (8.12 ± 1.89 mm 2 ; p < .01). However, LA changes did not affect the functional result of PCI with a non-ischemic QFR value (>0.80) in 98% of cases at 12-months follow-up. Protruding struts were detectable in more than half of cases and their presence was correlated with an increase in mean LA (+0.73mm 2 [95% CI 0.51-0.94], p < .001)., Conclusions: RMS implantation in a real-world population lead to significant decrease in mean LA without significant functional impairment. Two different patterns of RMS resorption were recorded, whose clinical significance remains to be investigated., (© 2020 Wiley Periodicals LLC.)

Objectives: We aimed to develop a novel wire- and adenosine-free microcirculatory resistive index from functional angiography (angio-IMR) to estimate coronary microcirculatory resistance, and to investigate how this method can improve clinical interpretation of physiological stenosis assessment with quantitative flow ratio (QFR)., Background: Hyperemic index of coronary microcirculatory resistance (IMR) is a widely used tool to assess microcirculatory dysfunction. However, the need of dedicated intracoronary wire and hyperemia limits its adoption in clinical practice., Methods: We performed our study in two separate stages: (1) development of a formula (angio-IMR) to estimate IMR from resting angiograms and aortic pressure (Pa), and (2) validation of the method in a clinical population using invasively measured IMR as reference. Additionally, QFR diagnostic performance was assessed considering angio-IMR values., Results: We developed the formula: angio-IMR = (Pa-[0.1*Pa])*QFR*e-Tmn (where e-Tmn is an estimation of hyperaemic mean transit time) and validated it in 115 vessels (104 patients). Angio-IMR correlated well with IMR (Spearman's rho = 0.70, p < 0.001). Sensitivity, specificity, positive and negative predictive value, accuracy and area under the curve of angio-IMR to predict IMR were 87.5% (73.2-95.8), 85.3% (75.3-92.4), 76.1% (64.5-84.8), 92.8% (84.9-96.7), 85% and 0.90 (0.83-0.95), respectively. False positive QFR measurements decreased from 19.5% to 8.5% when angio-IMR was incorporated into the QFR interpretation workflow., Conclusions: Estimation of IMR without physiology wire and adenosine is feasible. Coronary microcirculatory dysfunction causing high IMR can be ruled-out with high confidence in vessels with low angio-IMR. Awareness of angio-IMR contributes to a better clinical interpretation of functional stenosis assessment with QFR., (© 2021 Wiley Periodicals LLC.)

Aims: Several novel low-dose fluoroscopic systems (LDS) developed recently, but real practice information of the net benefit for the patient and professionals is scarce. We evaluated separately patient and operator radiation exposure during percutaneous interventions of chronic total occlusions (CTO)., Methods: A total of 116 consecutive CTOs were analyzed (60 in LDS and 56 in standard-dose fluoroscopic system [SDS]). Digital dosimetry of patient and occupational (operator and scatter dose) exposure was prospectively recorded., Results: Biometrics, demographics, CTO variables, and operators were distributed evenly. Patient radiation exposure was effectively decreased in LDS (dose area product [DAP] by 36%, Air Kerma [AK] by 47%). However, occupational data showed no statistical differences between LDS and SDS. The LDS uses less radiation amount but with higher energy (due to additional filtration) compared to SDS, therefore increasing the scatter dose. When comparing the C-arm scatter dose to the DAP we found higher scatter dose with the LDS (0.0139 mSv/gray (Gy)*cm2 vs. 0.0082 mSv/Gy*cm2, p < .001). This was confirmed in a larger dataset comprising 5,221 coronary procedures., Conclusions: LDS was safer for patients reducing DAP and AK compared to SDS. However, occupational doses were not lower and scatter dose higher. Radiological protection measures must be kept maximized even in LDS., (© 2020 Wiley Periodicals LLC.)

Vascular inflammation causes endothelial barrier disruption and tissue edema. Several inflammatory mediators act through G protein–coupled receptors (GPCRs), including protease-activated receptor-1 (PAR1), to elicit inflammatory responses. The activation of PAR1 by its ligand thrombin stimulates proinflammatory, p38 mitogen-activated protein kinase (MAPK) signaling that promotes endothelial barrier disruption. Through mass spectrometry phosphoproteomics, we identified heat shock protein 27 (HSP27), which exists as a large oligomer that binds to actin, as a promising candidate for the p38-mediated regulation of barrier integrity. Depletion of HSP27 by siRNA enhanced endothelial cell barrier permeability and slowed recovery after thrombin stimulation. We further showed that two effector kinases of p38 MAPK, MAPKAPK2 (MK2) and MAPKAPK3 (MK3), differentially phosphorylated HSP27 at Ser 15 , Ser 78 , and Ser 82 . Whereas inhibition of thrombin-stimulated p38 activation blocked HSP27 phosphorylation at all three sites, inhibition of MK2 reduced the phosphorylation of only Ser 15 and Ser 78 . Inhibition of both MK2 and MK3 was necessary to attenuate Ser 82 phosphorylation. Thrombin-stimulated p38-MK2-MK3 signaling induced HSP27 oligomer disassembly. However, a phosphorylation-deficient mutant of HSP27 exhibited defective oligomer disassembly and altered the dynamics of barrier recovery after thrombin stimulation. Moreover, blocking HSP27 oligomer reassembly with the small-molecule inhibitor J2 enhanced endothelial barrier permeability in vitro and vascular leakage in vivo in response to PAR1 activation. These studies reveal the distinct regulation of HSP27 phosphorylation and function induced by the GPCR-stimulated p38-MK2-MK3 signaling axis that controls the dynamics of endothelial barrier recovery in vitro and vascular leakage in vivo.

Objective: The aim of this study was to search for genes/variants that modify the effect of LRRK2 mutations in terms of penetrance and age-at-onset of Parkinson's disease., Methods: We performed the first genomewide association study of penetrance and age-at-onset of Parkinson's disease in LRRK2 mutation carriers (776 cases and 1,103 non-cases at their last evaluation). Cox proportional hazard models and linear mixed models were used to identify modifiers of penetrance and age-at-onset of LRRK2 mutations, respectively. We also investigated whether a polygenic risk score derived from a published genomewide association study of Parkinson's disease was able to explain variability in penetrance and age-at-onset in LRRK2 mutation carriers., Results: A variant located in the intronic region of CORO1C on chromosome 12 (rs77395454; p value = 2.5E-08, beta = 1.27, SE = 0.23, risk allele: C) met genomewide significance for the penetrance model. Co-immunoprecipitation analyses of LRRK2 and CORO1C supported an interaction between these 2 proteins. A region on chromosome 3, within a previously reported linkage peak for Parkinson's disease susceptibility, showed suggestive associations in both models (penetrance top variant: p value = 1.1E-07; age-at-onset top variant: p value = 9.3E-07). A polygenic risk score derived from publicly available Parkinson's disease summary statistics was a significant predictor of penetrance, but not of age-at-onset., Interpretation: This study suggests that variants within or near CORO1C may modify the penetrance of LRRK2 mutations. In addition, common Parkinson's disease associated variants collectively increase the penetrance of LRRK2 mutations. ANN NEUROL 2021;90:82-94., (© 2021 The Authors. Annals of Neurology published by Wiley Periodicals LLC on behalf of American Neurological Association.)

Objective: The heart team (HT) approach plays a key role in selecting the optimal treatment strategy for patients with aortic stenosis (AS). However, little is known about the HT decision process and its impact on outcomes. The aim of this study was to identify the factors associated with the HT decision and evaluate clinical outcomes according to the treatment choice., Methods: The study included a total of 286 consecutive patients with AS referred for discussion in the weekly HT meeting in a cardiovascular institute over 2 years. Patients were stratified according to the selected therapeutic approach: medical treatment (MT), surgical (SAVR), or transcatheter (TAVR) aortic valve replacement. Baseline characteristics involved in making a therapeutic choice were identified and a decision-making tree was built using classification and regression tree methodology., Results: Based on HT discussion, 53 patients were assigned to SAVR, 210 to TAVR, and 23 to MT. Older patients (≥88 years old) were mainly assigned to TAVR or MT according to the logistic EuroSCORE (

Aims: To establish the value of the SYNTAX Score-II (SS-II) in predicting long-term mortality of patients treated with left main PCI (LM-PCI) using second-generation drug-eluting stents (DES)., Methods and Results: The SYNTAX score (SS) and the SS-II were calculated in 804 patients included in the FAILS-2 registry (failure in left main study with 2nd generation stents). Patients were classified in low (SS-II ≤33; n = 278, 34.6%), intermediate (SS-II 34-43; n = 260, 32.3%) and high (SS-II ≥44; n = 266, 33.1%) SS-II tertiles. Primary endpoint was all-cause mortality. A significant difference in long-term mortality was noted (5.2 ± 3.6 years): 4.1, 7.5, and 16.7% in low, mid and high SS-II tertiles respectively (p < .001). SS-II score was more accurate in predicting mortality than SS (AUC = 0.73; 95%CI: 0.67-0.79 vs. AUC = 0.55; 95%CI: 0.48-0.63, respectively; p < .001). SS-II led to a reclassification in the risk of all-cause mortality re-allocating 73% of patients from the CABG-only indication to PCI or equipoise PCI-or-CABG indication. Using multiple Cox regression analysis, SS-II (HR: 1.07; 95%CI: 1.05-1.09; p < .001), along with Acute coronary syndrome (ACS) (HR: 1.66; 95%CI: 1.03-2.66; p = .07) and Cardiogenic shock (CS) (HR: 2.82 (95%CI: 1.41-5.64; p = .003) were independent predictors of long-term mortality. SS-II (HR: 1.05; 95%CI: 1.04-1.06; p < .001) along with Insulin dependent Type 2 DM (HR: 1.58, 95%CI: 1.09-2.30.; p < .05), ACS (HR: 1.58, 95%CI: 1.16-2.14; p < .001) and CS (HR: 2.02 95%CI 1.16-3.53; p < .05), were independent predictors of long-term MACE., Conclusion: The SS-II was superior to the SS in predicting outcomes associated with contemporary LM-PCI. In this real-world population, two clinical variables not included in the SS-II, ACS and T2DM, were identified as additional markers of poor outcome., (© 2019 Wiley Periodicals, Inc.)

Background Off-target properties of ticagrelor might reduce microvascular injury and improve clinical outcome in patients with ST-segment-elevation myocardial infarction. The REDUCE-MVI (Evaluation of Microvascular Injury in Revascularized Patients with ST-Segment-Elevation Myocardial Infarction Treated With Ticagrelor Versus Prasugrel) trial reported no benefit of ticagrelor regarding microvascular function at 1 month. We now present the follow-up data up to 1.5 years. Methods and Results We randomized 110 patients with ST-segment-elevation myocardial infarction to either ticagrelor 90 mg twice daily or prasugrel 10 mg once a day. Platelet inhibition and peripheral endothelial function measurements including calculation of the reactive hyperemia index and clinical follow-up were obtained up to 1.5 years. Major adverse clinical events and bleedings were scored. An intention to treat and a per-protocol analysis were performed. There were no between-group differences in platelet inhibition and endothelial function. At 1 year the reactive hyperemia index in the ticagrelor group was 0.66±0.26 versus 0.61±0.28 in the prasugrel group ( P =0.31). Platelet inhibition was lower at 1 month versus 1 year in the total study population (61% [42%-81%] versus 83% [61%-95%]; P <0.001), and per-protocol platelet inhibition was higher in patients randomized to ticagrelor versus prasugrel at 1 year (91% [83%-97%] versus 82% [65%-92%]; P =0.002). There was an improvement in intention to treat endothelial function in patients randomized to ticagrelor ( P =0.03) but not in patients randomized to prasugrel ( P =0.88). Major adverse clinical events (10% versus 14%; P =0.54) and bleedings (47% versus 63%; P =0.10) were similar in the intention-to-treat analysis in both groups. Conclusions Platelet inhibition at 1 year was higher in the ticagrelor group, without an accompanying increase in bleedings. Endothelial function improved over time in ticagrelor patients, while it did not change in the prasugrel group. Clinical Trial Registration URL: https://www.clinicaltrials.gov/. Unique Identifier: NCT02422888.

Introduction: The Montreal Cognitive Assessment (MoCA), an instrument widely used for cognitive screening in Parkinson's disease (PD), is validated in Hebrew and English. However, it remains unknown whether the scores are comparable., Methods: The MoCA was analyzed in 483 Ashkenazi Jewish PD patients in Tel-Aviv and New York who had MoCA ≥21. Each section of the MoCA was compared between English and Hebrew. Linear regression models were used to test the association between MoCA performance and language., Results: Total MoCA scores were lower in Hebrew than in English (25.4 versus 26.1; P = 0.007), even after adjustment for age, sex, PD duration, genotype, levodopa equivalent dose, the Unified Parkinson's Disease Rating Scale (UPDRSIII), and Geriatric Depression Scale score in a linear model (P < 0.001). However, when language sections were removed from the total, scores were similar between the languages (Hebrew 23.7 versus English 23.4, P = 0.111)., Conclusion: The language section of the MoCA may be more difficult in Hebrew. The comparability of MoCA in different languages requires further evaluation., Competing Interests: Conflict of interest: None.

Background: Increased cancer risk has been reported in Parkinson's disease (PD) patients carrying the leucine rich repeat kinase 2 (LRRK2) G2019S mutation (LRRK2-PD) in comparison with idiopathic PD (IPD). It is unclear whether the elevated risk would be maintained when compared with unaffected controls., Methods: Cancer outcomes were compared among 257 LRRK2-PD patients, 712 IPD patients, and 218 controls recruited from 7 LRRK2 consortium centers using mixed-effects logistic regression. Data were then pooled with a previous study to examine cancer risk between 401 LRRK2-PD and 1946 IPD patients., Results: Although cancer prevalence was similar among LRRK2-PD patients (32.3%), IPD patients (27.5%), and controls (27.5%; P = 0.33), LRRK2-PD had increased risks of leukemia (odds ratio [OR] = 4.55; 95% confidence interval [CI], 1.46-10.61) and skin cancer (OR = 1.61; 95% CI, 1.09-2.37). In the pooled analysis, LRRK2-PD patients had also elevated risks of leukemia (OR = 9.84; 95% CI, 2.15-44.94) and colon cancer (OR = 2.34; 95% CI, 1.15-4.74) when compared with IPD patients., Conclusions: The increased risks of leukemia as well as skin and colon cancers among LRRK2-PD patients suggest that LRRK2 mutations heighten risks of certain cancers. © 2019 International Parkinson and Movement Disorder Society., (© 2019 International Parkinson and Movement Disorder Society.)

Bioresorbable scaffolds (BRS) have been advocated as the 'fourth revolution' in interventional cardiology because they could provide temporary scaffolding and then 'disappear' (resorb) potentially significantly improving coronary artery disease treatment. BRS technology has gradually matured, and there are many devices available worldwide, which are currently undergoing preclinical or clinical testing. Due to the concerns related to polylactide scaffolds, magnesium alloy is now one of the most promising resorbable technologies despite available evidences on its performances in vivo are limited to small observational studies. In this state-of-art review we present Magmaris™ (Biotronik AG, Buelach, Switzerland) magnesium-based BRS from bench to bedside, reviewing to date available clinical trial data and current recommendations for its optimal use in clinical practice.

Endothelial dysfunction is induced by inflammatory mediators including multiple G protein-coupled receptor (GPCR) agonists. However, the GPCR signaling pathways that promote endothelial dysfunction are incompletely understood. We previously showed that thrombin promotes endothelial barrier disruption through autophosphorylation and activation of p38 mitogen-activated protein kinase (MAPK) via a non-canonical transforming growth factor-β-activated protein kinase-1-binding protein-1 (TAB1) and TAB2-dependent pathway rather than the canonical three-tiered kinase cascade. Here, we sought to determine whether other GPCR agonists stimulate p38 MAPK activation via this non-canonical pathway in human endothelial cells derived from different vascular beds. Using primary human umbilical vein endothelial cells (HUVECs), HUVEC-derived EA.hy926 cells, and human dermal microvascular endothelial cells (HDMECs), we found that both non-canonical and canonical p38 activation pathways components are expressed in these various endothelial cell types, including TAB3, a structurally-related TAB2 homolog. Moreover, multiple GPCRs agonists, including thrombin, histamine, prostaglandin E 2 , and ADP, stimulated robust p38 autophosphorylation, whereas phosphorylation of the upstream MAPKs MAP kinase kinase 3 (MKK3) and MKK6, was virtually undetectable, indicating that non-canonical p38 activation may exist for other GPCRs. Indeed, in EA.hy926 cells, thrombin- and histamine-stimulated p38 activation depended on TAB1-TAB2, whereas in primary HUVECs, both TAB1-TAB2 and TAB1-TAB3 were required for p38 activation. In HDMECs, thrombin-induced p38 activation depended on TAB1-TAB3, but histamine-induced p38 activation required TAB1-TAB2. Moreover, thrombin- and histamine-stimulated interleukin-6 production required both TAB1-TAB2 and TAB1-TAB3 in HUVEC. We conclude that multiple GPCR agonists utilize non-canonical TAB1-TAB2 and TAB1-TAB3-dependent p38 activation to promote endothelial inflammatory responses., (© 2019 Grimsey et al.)

Background: Quantitative flow ratio (QFR) is a novel modality for physiological lesion assessment based on 3-dimensional vessel reconstructions and contrast flow velocity estimates. We evaluated the value of online QFR during routine invasive coronary angiography for procedural feasibility, diagnostic performance, and agreement with pressure-wire-derived fractional flow reserve (FFR) as a gold standard in an international multicenter study., Methods and Results: FAVOR II E-J (Functional Assessment by Various Flow Reconstructions II Europe-Japan) was a prospective, observational, investigator-initiated study. Patients with stable angina pectoris were enrolled in 11 international centers. FFR and online QFR computation were performed in all eligible lesions. An independent core lab performed 2-dimensional quantitative coronary angiography (2D-QCA) analysis of all lesions assessed with QFR and FFR. The primary comparison was sensitivity and specificity of QFR compared with 2D-QCA using FFR as a reference standard. A total of 329 patients were enrolled. Paired assessment of FFR, QFR, and 2D-QCA was available for 317 lesions. Mean FFR, QFR, and percent diameter stenosis were 0.83±0.09, 0.82±10, and 45±10%, respectively. FFR was ≤0.80 in 104 (33%) lesions. Sensitivity and specificity by QFR was significantly higher than by 2D-QCA (sensitivity, 86.5% (78.4-92.4) versus 44.2% (34.5-54.3); P <0.001; specificity, 86.9% (81.6-91.1) versus 76.5% (70.3-82.0); P =0.002). Area under the receiver curve was significantly higher for QFR compared with 2D-QCA (area under the receiver curve, 0.92 [0.89-0.96] versus 0.64 [0.57-0.70]; P <0.001). Median time to QFR was significantly lower than median time to FFR (time to QFR, 5.0 minutes [interquartile range, -6.1] versus time to FFR, 7.0 minutes [interquartile range, 5.0-10.0]; P <0.001)., Conclusions: Online computation of QFR in the catheterization laboratory is clinically feasible and is superior to angiographic assessment for evaluation of intermediary coronary artery stenosis using FFR as a reference standard., Clinical Trial Registration: URL: https://www.clinicaltrials.gov. Unique identifier: NCT02959814., (© 2018 The Authors. Published on behalf of the American Heart Association, Inc., by Wiley.)

Background: In 2015, the International Parkinson and Movement Disorder Society Task Force recommended research criteria for the estimation of prodromal PD., Objectives: We aimed to evaluate, for the first time, the criteria in first-degree relatives of Ashkenazi Jewish G2019S-LRRK2 PD patients, who are considered a population at risk for developing PD, and assess the sensitivity and specificity of the criteria in identifying phenoconverters., Methods: Participants were evaluated longitudinally over a period of 5 years (average follow-up: 49.2 ± 12.3 months). Likelihood ratios and probability estimations were calculated based on the International Parkinson and Movement Disorder Society Research Criteria for Prodromal Parkinson's Disease markers and examined for each assessment point., Results: One hundred twenty healthy carriers (49.53 ± 13.4 years; 54% female) and 111 healthy noncarriers (48.43 ± 15.79 years; 49% female) participated in this study. Probability scores were significantly higher in healthy carriers than healthy noncarriers (P < 0.0001). Of the 20 participants (8.6%) who met criteria for probable prodromal PD at baseline, 17 were healthy carriers. Participants who reached the threshold were older (P < 0.0001), had higher UPDRS-III (P < 0.001), lower cognitive function (P = 0.001), and more nonmotor symptoms (P < 0.0001), compared to those who did not. Ten participants were diagnosed with incident PD within 5 years from baseline resulting in a specificity of 91.82% (95% confidence interval: 86.69-96.94), sensitivity of 80% (95% confidence interval: 55.21-100), positive predictive value of 47.06% (95% confidence interval: 23.33-70.79), and negative predictive value of 98.06% (95% confidence interval: 95.39-100). All 10 phenoconvertors were G2019S-LRRK2 carriers., Conclusions: The results showed the utility of using the criteria and high sensitivity and specificity in identifying prodromal PD in this high-risk unique cohort. These results may be valuable for future disease modification clinical trials. © 2018 International Parkinson and Movement Disorder Society., (© 2018 International Parkinson and Movement Disorder Society.)

Importance: Few prospective longitudinal studies have evaluated the progression of Parkinson disease (PD) in patients with the leucine-rich repeat kinase 2 (LRRK2 [OMIM 609007]) mutation. Knowledge about such progression will aid clinical trials., Objective: To determine whether the longitudinal course of PD in patients with the LRRK2 mutation differs from the longitudinal course of PD in patients without the mutation., Design, Setting, and Participants: A prospective comprehensive assessment of a large cohort of patients from 3 sites with LRRK2 PD or with nonmutation PD was conducted from July 21, 2009, to September 30, 2016. All patients of Ashkenazi Jewish ancestry with PD were approached at each site; approximately 80% agreed to an initial visit. A total of 545 patients of Ashkenazi Jewish descent with PD who had 1 to 4 study visits were evaluated. A total of 144 patients (26.4%) had the LRRK2 G2019S mutation. Patients with GBA (OMIM 606463) mutations were excluded from the analysis., Main Outcomes and Measures: Linear mixed-effects models for longitudinal motor scores were used to examine the association of LRRK2 mutation status with the rate of change in Unified Parkinson's Disease Rating Scale III scores using disease duration as the time scale, adjusting for sex, site, age, disease duration, cognitive score, and levodopa-equivalent dose at baseline. Mixed-effects models were used to assess change in cognition, as measured by Montreal Cognitive Assessment scores., Results: Among the 545 participants, 233 were women, 312 were men, and the mean (SD) age was 68.2 (9.1) years for participants with the LRRK2 mutation and 67.8 (10.7) years for those without it. Seventy-two of 144 participants with the LRRK2 mutation and 161 of 401 participants with no mutation were women. The estimate (SE) of the rate of change in the Unified Parkinson's Disease Rating Scale III motor score per year among those with the LRRK2 mutation (0.689 [0.192] points per year) was less than among those without the mutation (1.056 [0.187] points per year; difference, -0.367 [0.149] points per year; P = .02). The estimate (SE) of the difference in the rate of change of the Montreal Cognitive Assessment score between those with the LRRK2 mutation (-0.096 [0.090] points per year) and those without the mutation (-0.192 [0.102] points per year) did not reach statistical significance (difference, 0.097 [0.055] points per year; P = .08)., Conclusions and Relevance: Prospective longitudinal follow-up of patients with PD with or without the LRRK2 G2019S mutation supports data from a cross-sectional study and demonstrates a slower decline in motor Unified Parkinson's Disease Rating Scale scores among those with LRRK2 G2019S-associated PD.

OBJECTIVE To measure blood lead concentrations (BLCs) in dogs living in Flint, Mich, following a declared water crisis and to assess potential associations of BLCs with demographic data, water sources, and clinical signs in these dogs. DESIGN Cross-sectional study. ANIMALS 284 dogs residing in Flint, Mich (test population), and 47 dogs residing in East Lansing, Mich (control population), and immediately adjacent areas. PROCEDURES Blood samples were collected at free screening clinics in Flint (test population) and at the Michigan State University College of Veterinary Medicine Veterinary Medical Center (control population). Owners of test population dogs completed questionnaires providing demographic and clinical information. Hematologic evaluations were performed; BLCs were measured by inductively coupled plasma-mass spectrometry. RESULTS 4 of 284 test population dogs had BLCs > 50 ppb; an additional 20 had BLCs > 20 ppb. Overall, BLCs of test population dogs were higher than those of control dogs. Within the test population, young dogs (≤ 2 years of age) had higher BLCs than old dogs (≥ 6 years of age). Only 7.2% of test population dogs were drinking unfiltered tap water at the time of screening; however, dogs that had been receiving filtered or bottled water for ≤ 3 months before screening had higher BLCs than did those that received such water for > 3 months. CONCLUSIONS AND CLINICAL RELEVANCE Taken together, findings suggested that the impact of the Flint water crisis extended to companion animals. Results highlighted the importance of maintaining awareness of lead exposure and considering both human and animal well-being in cases of environmental toxicant exposures.

Background: Penetrance estimates of the leucine-rich repeat kinase 2 (LRRK2) p.G2019S mutation for PD vary widely (24%-100%). The p.G2019S penetrance in individuals of Ashkenazi Jewish ancestry has been estimated as 25%, adjusted for multiple covariates. It is unknown whether penetrance varies among different ethnic groups. The objective of this study was to estimate the penetrance of p.G2019S in individuals of non-Ashkenazi Jewish ancestry and compare penetrance between Ashkenazi Jews and non-Ashkenazi Jews to age 80., Methods: The kin-cohort method was used to estimate penetrance in 474 first-degree relatives of 69 non-Ashkenazi Jewish LRRK2 p.G2019S carrier probands at 8 sites from the Michael J. Fox LRRK2 Cohort Consortium. An identical validated family history interview was administered to assess age at onset of PD, current age, or age at death for relatives in different ethnic groups at each site. Neurological examination and LRRK2 genotype of relatives were included when available., Results: Risk of PD in non-Ashkenazi Jewish relatives who carry a LRRK2 p.G2019S mutation was 42.5% (95% confidence interval [CI]: 26.3%-65.8%) to age 80, which is not significantly higher than the previously estimated 25% (95% CI: 16.7%-34.2%) in Ashkenazi Jewish carrier relatives. The penetrance of PD to age 80 in LRRK2 p.G2019S mutation carrier relatives was significantly higher than the noncarrier relatives, as seen in Ashkenazi Jewish relatives., Conclusions: The similar penetrance of LRRK2 p.G2019S estimated in Ashkenazi Jewish carriers and non-Ashkenazi Jewish carriers confirms that p.G2019S penetrance is 25% to 42.5% at age 80 in all populations analyzed. © 2017 International Parkinson and Movement Disorder Society., (© 2017 Internationalnternational Parkinson and Movement Disorder Society.)