Ultrasound-guided versus fluoroscopy-guided large-bore femoral access in PCI of complex coronary lesions: the international, multicentre, randomised ULTRACOLOR Trial.

BACKGROUND: Transfemoral access is often used when large-bore guide catheters are required for percutaneous coronary intervention (PCI) of complex coronary lesions, especially when large-bore transradial access is contraindicated. Whether the risk of access site complications for these procedures may be reduced by ultrasound-guided puncture is unclear. AIMS: We aimed to show the superiority of ultrasound-guided femoral puncture compared to fluoroscopy-guided access in large-bore complex PCI with regard to access site-related Bleeding Academic Research Consortium 2, 3 or 5 bleeding and/or vascular complications requiring intervention during hospitalisation. METHODS: The ULTRACOLOR Trial is an international, multicentre, randomised controlled trial investigating whether ultrasound-guided large-bore femoral access reduces clinically relevant access site complications compared to fluoroscopy-guided large-bore femoral access in PCI of complex coronary lesions. RESULTS: A total of 544 patients undergoing complex PCI mandating large-bore (≥7 Fr) transfemoral access were randomised at 10 European centres (median age 71; 76% male). Of these patients, 68% required PCI of a chronic total occlusion. The primary endpoint was met in 18.9% of PCI with fluoroscopy-guided access and 15.7% of PCI with ultrasound-guided access (p=0.32). First-pass puncture success was 92% for ultrasound-guided access versus 85% for fluoroscopy-guided access (p=0.02). The median time in the catheterisation laboratory was 102 minutes versus 105 minutes (p=0.43), and the major adverse cardiovascular event rate at 1 month was 4.1% for fluoroscopy-guided access and 2.6% for ultrasound-guided access (p=0.32). CONCLUSIONS: As compared to fluoroscopy-guided access, the routine use of ultrasound-guided access for large-bore transfemoral complex PCI did not significantly reduce clinically relevant bleeding or vascular access site complications. A significantly higher first-pass puncture success rate was demonstrated for ultrasound-guided access. CLINICALTRIALS: gov identifier: NCT04837404.

Fractional Flow Reserve-Guided PCI or Coronary Bypass Surgery for 3-Vessel Coronary Artery Disease: 3-Year Follow-Up of the FAME 3 Trial.

BACKGROUND: Previous studies comparing percutaneous coronary intervention (PCI) with coronary artery bypass grafting (CABG) in patients with multivessel coronary disease not involving the left main have shown significantly lower rates of death, myocardial infarction (MI), or stroke after CABG. These studies did not routinely use current-generation drug-eluting stents or fractional flow reserve (FFR) to guide PCI. METHODS: FAME 3 (Fractional Flow Reserve versus Angiography for Multivessel Evaluation) is an investigator-initiated, multicenter, international, randomized trial involving patients with 3-vessel coronary artery disease (not involving the left main coronary artery) in 48 centers worldwide. Patients were randomly assigned to receive FFR-guided PCI using zotarolimus drug-eluting stents or CABG. The prespecified key secondary end point of the trial reported here is the 3-year incidence of the composite of death, MI, or stroke. RESULTS: A total of 1500 patients were randomized to FFR-guided PCI or CABG. Follow-up was achieved in >96% of patients in both groups. There was no difference in the incidence of the composite of death, MI, or stroke after FFR-guided PCI compared with CABG (12.0% versus 9.2%; hazard ratio [HR], 1.3 [95% CI, 0.98-1.83]; P=0.07). The rates of death (4.1% versus 3.9%; HR, 1.0 [95% CI, 0.6-1.7]; P=0.88) and stroke (1.6% versus 2.0%; HR, 0.8 [95% CI, 0.4-1.7]; P=0.56) were not different. MI occurred more frequently after PCI (7.0% versus 4.2%; HR, 1.7 [95% CI, 1.1-2.7]; P=0.02). CONCLUSIONS: At 3-year follow-up, there was no difference in the incidence of the composite of death, MI, or stroke after FFR-guided PCI with current-generation drug-eluting stents compared with CABG. There was a higher incidence of MI after PCI compared with CABG, with no difference in death or stroke. These results provide contemporary data to allow improved shared decision-making between physicians and patients with 3-vessel coronary artery disease. REGISTRATION: URL: https://www. CLINICALTRIALS: gov; Unique identifier: NCT02100722.

Subcellular localization of hippocampal ryanodine receptor 2 and its role in neuronal excitability and memory.

Ryanodine receptor 2 (RyR2) is abundantly expressed in the heart and brain. Mutations in RyR2 are associated with both cardiac arrhythmias and intellectual disability. While the mechanisms of RyR2-linked arrhythmias are well characterized, little is known about the mechanism underlying RyR2-associated intellectual disability. Here, we employed a mouse model expressing a green fluorescent protein (GFP)-tagged RyR2 and a specific GFP probe to determine the subcellular localization of RyR2 in hippocampus. GFP-RyR2 was predominantly detected in the soma and dendrites, but not the dendritic spines of CA1 pyramidal neurons or dentate gyrus granular neurons. GFP-RyR2 was also detected within the mossy fibers in the stratum lucidum of CA3, but not in the presynaptic terminals of CA1 neurons. An arrhythmogenic RyR2-R4496C+/- mutation downregulated the A-type K+ current and increased membrane excitability, but had little effect on the afterhyperpolarization current or presynaptic facilitation of CA1 neurons. The RyR2-R4496C+/- mutation also impaired hippocampal long-term potentiation, learning, and memory. These data reveal the precise subcellular distribution of hippocampal RyR2 and its important role in neuronal excitability, learning, and memory.

Impact of opioids on P2Y12 receptor inhibition in patients with ST-elevation myocardial infarction who are pre-treated with crushed ticagrelor: Opioids aNd crushed Ticagrelor In Myocardial infarction Evaluation (ON-TIME 3) trial.

AIMS: Platelet inhibition induced by P2Y12 receptor antagonists in patients with ST-elevation myocardial infarction (STEMI) can be affected by concomitant use of opioids. The aim of this trial was to examine the effect of intravenous (iv) acetaminophen compared with iv fentanyl on P2Y12 receptor inhibition in patients with STEMI. METHODS AND RESULTS: The Opioids aNd crushed Ticagrelor In Myocardial infarction Evaluation (ON-TIME 3) trial randomized 195 STEMI patients who were scheduled to undergo primary percutaneous coronary intervention (PCI) and were pre-treated with crushed ticagrelor to iv acetaminophen (N = 98) or iv fentanyl (N = 97) in the ambulance. The primary endpoint, consisting of the level of platelet reactivity units (PRU) measured immediately after primary PCI, was not significantly different between the study arms [median PRU 104 (IQR 37-215) vs. 175 (63-228), P = 0.18]. However, systemic levels of ticagrelor were significantly higher in the acetaminophen arm at the start of primary PCI [151 ng/mL (32-509) vs. 60 ng/mL (13-206), P = 0.007], immediately after primary PCI [326 ng/mL (94-791) vs. 115 ng/mL (38-326), P = 0.002], and at 1 h after primary PCI [488 ng/mL (281-974) vs. 372 ng/mL (95-635), P = 0.002]. Acetaminophen resulted in the same extent of pain relief when compared with fentanyl [reduction of 3 points on 10-step-pain scale before primary PCI (IQR 1-5)] in both study arms (P = 0.67) and immediately after PCI [reduction of 5 points (3-7); P = 0.96]. CONCLUSION: The iv acetaminophen in comparison with iv fentanyl was not associated with significantly lower platelet reactivity in STEMI patients but resulted in significantly higher ticagrelor plasma levels and was effective in pain relief.

Fractional Flow Reserve-Guided PCI as Compared with Coronary Bypass Surgery.

BACKGROUND: Patients with three-vessel coronary artery disease have been found to have better outcomes with coronary-artery bypass grafting (CABG) than with percutaneous coronary intervention (PCI), but studies in which PCI is guided by measurement of fractional flow reserve (FFR) have been lacking. METHODS: In this multicenter, international, noninferiority trial, patients with three-vessel coronary artery disease were randomly assigned to undergo CABG or FFR-guided PCI with current-generation zotarolimus-eluting stents. The primary end point was the occurrence within 1 year of a major adverse cardiac or cerebrovascular event, defined as death from any cause, myocardial infarction, stroke, or repeat revascularization. Noninferiority of FFR-guided PCI to CABG was prespecified as an upper boundary of less than 1.65 for the 95% confidence interval of the hazard ratio. Secondary end points included a composite of death, myocardial infarction, or stroke; safety was also assessed. RESULTS: A total of 1500 patients underwent randomization at 48 centers. Patients assigned to undergo PCI received a mean (±SD) of 3.7±1.9 stents, and those assigned to undergo CABG received 3.4±1.0 distal anastomoses. The 1-year incidence of the composite primary end point was 10.6% among patients randomly assigned to undergo FFR-guided PCI and 6.9% among those assigned to undergo CABG (hazard ratio, 1.5; 95% confidence interval [CI], 1.1 to 2.2), findings that were not consistent with noninferiority of FFR-guided PCI (P = 0.35 for noninferiority). The incidence of death, myocardial infarction, or stroke was 7.3% in the FFR-guided PCI group and 5.2% in the CABG group (hazard ratio, 1.4; 95% CI, 0.9 to 2.1). The incidences of major bleeding, arrhythmia, and acute kidney injury were higher in the CABG group than in the FFR-guided PCI group. CONCLUSIONS: In patients with three-vessel coronary artery disease, FFR-guided PCI was not found to be noninferior to CABG with respect to the incidence of a composite of death, myocardial infarction, stroke, or repeat revascularization at 1 year. (Funded by Medtronic and Abbott Vascular; FAME 3 ClinicalTrials.gov number, NCT02100722.).

Kidney Function in Patients With Neuromuscular Disease: Creatinine Versus Cystatin C.

Background: Accurate measurement of kidney function in patients with neuromuscular disorders is challenging. Cystatin C, a marker not influenced by skeletal muscle degradation, might be of clinical value in these patients. Methods: We consecutively enrolled 39 patients with neuromuscular disorders. We investigated the association of the eGFR, based on plasma creatinine and Cystatin C, with clinical and biochemical variables associated with kidney function, namely age and galectin-3. Results: Creatinine-based eGFR was 242 (±80) and Cystatin C-based eGFR was 110 (±23) mL/min/1.73 m2. Cystatin C-based eGFR was associated with age (ß -0.63 p < 0.0001) and galectin-3 levels (ß -0.43 p < 0.01), while creatinine-based eGFR was not (ß -0.22 p = 0.20; ß -0.28 p = 0.10). Sensitivity analyses in Duchenne and Becker patients revealed the same results: Cystatin C-based eGFR was associated with age (ß -0.61 p < 0.01) and galectin-3 levels (ß -0.43 p = 0.05), while creatinine-based eGFR was not (ß -0.32 p = 0.13; ß -0.34 p = 0.14). Conclusions: These data indicate that estimation of renal function in patients with neuromuscular disorders cannot reliably be achieved with creatinine, while Cystatin C appears a reasonable alternative. Since a large proportion of patients with neuromuscular disorders develops heart failure, and requires heart failure medication, adequate monitoring of renal function is warranted.

NT-proBNP level before primary PCI and risk of poor myocardial reperfusion: Insight from the On-TIME II trial.

BACKGROUND: N-terminal fragment of the brain natriuretic peptide prohormone (NT-proBNP), a marker for neurohumoral activation, has been associated with adverse outcome in patients with myocardial infarction. NT-proBNP levels may reflect extensive ischemia and microvascular damage, therefore we investigated the potential association between baseline NT-proBNP level and ST-resolution (STR), a marker of myocardial reperfusion, after primary percutaneous coronary intervention (pPCI). METHODS: we performed a post-hoc analysis of the On-TIME II trial (which randomized ST-elevation myocardial infarction (STEMI) patients to pre-hospital tirofiban administration vs placebo). Patients with measured NT-proBNP before angiography were included. Multivariate logistic-regression analyses was performed to investigate the association between baseline NTproBNP level and STR one hour after pPCI. RESULTS: Out of 984 STEMI patients, 918 (93.3%) had NT-proBNP values at baseline. Patients with STR <70% had higher NT-proBNP values compared to patients with complete STR (>70%) [Mean ±SD 375.2 ±1021.7 vs 1007.4 ±2842.3, Median (IQR) 111.7 (58.4-280.0) vs 168.0 (62.3-601.3), P <.001]. At multivariate logistic regression analysis, independent predictors associated with higher risk of poor myocardial reperfusion (STR <70%) were: NT-proBNP (OR 1.17, 95%CI 1.04-1.31, P = .009), diabetes mellitus (OR 1.87, 95%CI 1.14-3.07, P = .013), anterior infarct location (OR 2.74, 95% CI 2.00-3.77, P <.001), time to intervention (OR 1.06, 95%CI 1.01-1.11, P = .021), randomisation to placebo (OR 1.45, 95%CI 1.05-1.99, P = .022). CONCLUSIONS: In STEMI patients, higher baseline NT-proBNP level was independently associate with higher risk of poor myocardial reperfusion, supporting the potential use of NT-proBNP as an early marker for risk stratification of myocardial reperfusion after pPCI in STEMI patients.

Impaired myosin isoform shift and calcium transients contribute to cellular pathogenesis of rat cirrhotic cardiomyopathy.

BACKGROUND & AIMS: Cirrhotic cardiomyopathy is a recently recognized entity, but detailed cellular and molecular mechanisms remain unclarified. We aimed to elucidate the role of myosin heavy chain isoform shifts and their relation to calcium transients in the contractile kinetics of cirrhotic rats. METHODS: Cirrhosis was induced in male Lewis Brown-Norway rats by bile duct ligation (BDL). Myosin heavy chain (MHC) isoform distribution was evaluated by gel electrophoresis. Contractile force, Ca2+ transients and cell shortening were studied at varied frequency and extracellular [Ca2+ ]. T-tubular integrity was analysed by power spectrum analysis of images of myocytes stained with di-8-ANEPPS. RESULTS: Compared with sham controls, the phenotypes of cirrhotic rats were as follows: (a) alpha-myosin heavy chain shifted to beta-MHC isoform; (b) mild loss of T-tubular integrity in myocytes; (c) a reduced maximum and rate of rise of the Ca2+ transient (max F/Fo ); (d) a reduction in both the rate of rise and fall of contraction; (e) decreased maximal force-generating capacity; (f) loss of the inotropic effect of increased stimulus frequency; (g) unchanged sensitivity of force development to varied extracellular [Ca2+ ] and (h) increased spontaneous diastolic sarcomere length fluctuations. CONCLUSION: Cardiomyocytes and ventricular trabeculae in a cirrhotic rat model showed features of typical heart failure including systolic and diastolic prolongation, impaired force-frequency relation and decreased force-generating capacity. Impaired myosin isoform shift and calcium transients are important contributory mechanisms underlying the pathogenesis of the heart failure phenotype seen in cirrhosis.

Complex Large-Bore Radial percutaneous coronary intervention: rationale of the COLOR trial study protocol.

INTRODUCTION: The radial artery has become the standard access site for percutaneous coronary intervention (PCI) in stable coronary artery disease and acute coronary syndrome, because of less access site related bleeding complications. Patients with complex coronary lesions are under-represented in randomised trials comparing radial with femoral access with regard to safety and efficacy. The femoral artery is currently the most applied access site in patients with complex coronary lesions, especially when large bore guiding catheters are required. With slender technology, transradial PCI may be increasingly applied in patients with complex coronary lesions when large bore guiding catheters are mandatory and might be a safer alternative as compared with the transfemoral approach. METHODS AND ANALYSIS: A total of 388 patients undergoing complex PCI will be randomised to radial 7 French access with Terumo Glidesheath Slender (Terumo, Japan) or femoral 7 French access as comparator. The primary outcome is the incidence of the composite end point of clinically relevant access site related bleeding and/or vascular complications requiring intervention. Procedural success and major adverse cardiovascular events up to 1 month will also be compared between both groups. ETHICS AND DISSEMINATION: Ethical approval for the study was granted by the local Ethics Committee at each recruiting center ('Medisch Ethische Toetsing Commissie Isala Zwolle', 'Commissie voor medische ethiek ZNA', 'Comité Medische Ethiek Ziekenhuis Oost-Limburg', 'Comité d'éthique CHU-Charleroi-ISPPC', 'Commission cantonale d'éthique de la recherche CCER-Republique et Canton de Geneve', 'Ethik Kommission de Ärztekammer Nordrhein' and 'Riverside Research Ethics Committee'). The trial outcomes will be published in peer-reviewed journals of the concerned literature. TRIAL REGISTRATION NUMBER: NCT03846752.

Selecting interventions to improve patient-relevant outcomes in health care for aortic valve disease - the Intervention Selection Toolbox.

BACKGROUND: Measuring and improving outcomes is a central element of value-based health care. However, selecting improvement interventions based on outcome measures is complex and tools to support the selection process are lacking. The goal was to present strategies for the systematic identification and selection of improvement interventions applied to the case of aortic valve disease and to combine various methods of process and outcome assessment into one integrated approach for quality improvement. METHODS: For this case study a concept-driven mixed-method approach was applied for the identification of improvement intervention clusters including: (1) benchmarking outcomes, (2) data exploration, (3) care delivery process analysis, and (4) monitoring of ongoing improvements. The main outcome measures were long-term survival and 30-day mortality. For the selection of an improvement intervention, the causal relations between the potential improvement interventions and outcome measures were quantified followed by a team selection based on consensus from a multidisciplinary team of professionals. RESULTS: The study resulted in a toolbox: the Intervention Selection Toolbox (IST). The toolbox comprises two phases: (a) identifying potential for improvement, and (b) selecting an effective intervention from the four clusters expected to lead to the desired improvement in outcomes. The improvements identified for the case of aortic valve disease with impact on long-term survival in the context of the studied hospital in 2015 include: anticoagulation policy, increased attention to nutritional status of patients and determining frailty of patients before the treatment decision. CONCLUSIONS: Identifying potential for improvement and carefully selecting improvement interventions based on (clinical) outcome data demands a multifaceted approach. Our toolbox integrates both care delivery process analyses and outcome analyses. The toolbox is recommended for use in hospital care for the selection of high-impact improvement interventions.

Pharmacist-led medication reviews in pre-dialysis and dialysis patients.

BACKGROUND: Pre-dialysis and dialysis patients are at risk for drug related problems (DRPs) due to a high incidence of comorbidities. Pharmacist-led medication reviews might reduce the number of DRPs. OBJECTIVES: The aim of this study was to evaluate pharmacist-led medication reviews in pre-dialysis and dialysis patients by determining the number and type of DRPs, nephrologist acceptance of pharmacist interventions and time investment. METHODS: From September 2017 until December 2018, pharmacist-led medication reviews were performed on pre-dialysis and dialysis patients. DRPs (medication discrepancies, prescribing issues related to drug and dose selection, drug use problems) were identified using the pharmacists' expert opinion and the STOPP/START criteria. Number and type of accepted pharmacist interventions, sustainability of interventions after at least 1 month and time investment were determined. Practical barriers in the process were appraised. RESULTS: One-hundred twenty five patients were reviewed: 37 pre-dialysis and 88 dialysis patients. In 100 (80%) patients 277 medication discrepancies were identified of which 224 (81%) were accepted by the nephrologist. Pharmacists suggested 422 interventions concerning drug or dose selection for 115 patients; 106 interventions were accepted by the nephrologist, which resulted in 60 patients having medication changed. Ninety percent of those changes remained implemented on follow-up after at least 1 month. In 46 (37%) patients, the clinical pharmacist detected DRPs concerning the drug use process and performed patient counseling. The average time investment was 85 min per patient for the clinical pharmacist and 15 min for the nephrologist. Besides time investment, unclear responsibility for medication management due to multiple prescribers was an important barrier in the process and the main reason for nephrologists to reject pharmacist interventions. CONCLUSION: Pharmacist-led medication reviews in pre-dialysis and dialysis patients led to medication changes in half of the patients. However, efficiency should be improved before adopting pharmacist-led medication reviews into clinical practice.

Effects of chronic beta-blocker treatment on admission haemodynamics in STEMI patients treated with primary angioplasty.

BACKGROUND: The association between chronic beta-blocker treatment and haemodynamics at admission in patients with ST-segment elevation myocardial infarction treated by primary percutaneous coronary intervention is not well studied. We investigated the impact of chronic beta-blocker treatment on the risk of cardiogenic shock and pre-shock at admission in patients with ST-segment elevation myocardial infarction treated by primary percutaneous coronary intervention. METHODS AND RESULTS: A total of 4907 patients with ST-segment elevation myocardial infarction treated with primary percutaneous coronary intervention were included in the study. A total of 1148 patients (23.3%) were on chronic beta-blocker treatment. Cardiogenic shock was observed in 264 patients (5.3%). Pre-shock was defined as a shock index (the ratio of heart rate and systolic blood pressure) of 0.7 or greater, and was observed in 1022 patients (20.8%). The risk of cardiogenic shock in patients with chronic beta-blocker treatment was not increased (adjusted hazard ratio (HR) 0.97, 95% confidence interval (CI) 0.65-1.46, P=0.90). Chronic beta-blocker treatment was also not associated with an increased risk of pre-shock (adjusted HR 0.86, 95% CI 0.68-1.07, P=0.19). Also after propensity score matched analysis, there was no increased risk of cardiogenic shock or pre-shock in patients with chronic beta-blocker treatment (respectively HR 0.97, 95% CI 0.61-1.51, P=0.88 and HR 0.82, 95% CI 0.65-1.06, P=0.12). CONCLUSION: In ST-segment elevation myocardial infarction, chronic beta-blocker treatment is not associated with an increased risk of cardiogenic shock or pre-shock.

Archival, paleopathological and aDNA-based techniques in leprosy research and the case of Father Petrus Donders at the Leprosarium 'Batavia', Suriname.

OBJECTIVE: We assessed whether Petrus Donders (died 1887), a Dutch priest who for 27 years cared for people with leprosy in the leprosarium Batavia, Suriname, had evidence of Mycobacterium (M.) leprae infection. A positive finding of M. leprae ancient (a)DNA would contribute to the origin of leprosy in Suriname. MATERIALS: Skeletal remains of Father Petrus Donders; two additional skeletons excavated from the Batavia cemetery were used as controls. METHODS: Archival research, paleopathological evaluation and aDNA-based testing of skeletal remains. RESULTS: Neither archives nor inspection of Donders skeletal remains revealed evidence of leprosy, and aDNA-based testing for M. leprae was negative. We detected M. leprae aDNA by RLEP PCR in one control skeleton, which also displayed pathological lesions compatible with leprosy. The M. leprae aDNA was genotyped by Sanger sequencing as SNP type 4; the skeleton displayed mitochondrial haplogroup L3. CONCLUSION: We found no evidence that Donders contracted leprosy despite years of intense leprosy contact, but we successfully isolated an archaeological M. leprae aDNA sample from a control skeleton from South America. SIGNIFICANCE: We successfully genotyped recovered aDNA to a M. leprae strain that likely originated in West Africa. The detected human mitochondrial haplogroup L3 is also associated with this geographical region. This suggests that slave trade contributed to leprosy in Suriname. LIMITATIONS: A limited number of skeletons was examined. SUGGESTIONS FOR FURTHER RESEARCH: Broader review of skeletal collections is advised to expand on diversity of the M. leprae aDNA database.

Who owns responsibility? An administrator's take on implementing time-variable medical training in teaching hospitals.

Introduction: Developments in outcome-based medical education led to the introduction of time-variable medical training (TVMT). Although this idea of training may be a consequence of competency-based training that calls for individualized learning, its implementation has posed significant challenges. As a new paradigm it is likely to have repercussions on the organization of teaching hospitals. The purpose of this study is therefore to explore how hospital administrators cope with this implementation process. Methods: We conducted an exploratory qualitative study for which we interviewed administrators of hospitals who were actively implementing TVMT in their postgraduate programs. Results: Several problems of implementation were identified: existing governance structures proved unfit to cope with the financial and organizational implications of TVMT. Administrators responded to these problems by delegating responsibilities to departments, reallocating tasks, learning from other hospitals and scaling up their teaching facilities. Conclusions: Hospital administrators perceived the implementation of TVMT as challenging. TVMT affects the existing equilibrium between education and clinical service. Administrators' initial attempts to regain control, using steering strategies that were based on known concepts and general outcomes, including cutting departmental budgets did not work, nor did their subsequent wait-and-see approach of leaving the implementation to the individual departments.

Influence of coronary calcification on hyperemic response during fractional flow reserve measurements.

AIM: During invasive fractional flow reserve (FFR) adenosine and nitrates are used to obtain maximal hyperemia. Severe coronary artery calcification (CAC) is associated with impaired vasodilation. We investigated the hyperemic response during FFR in vessels with severe versus mild CAC. METHODS AND RESULTS: We retrospectively selected 236 patients who underwent both CAC scoring and invasive FFR. FFR was performed in 304 vessels with intermediate stenoses. Delta (Δ) FFR, the pressure gradient before the administration of adenosine minus FFR after the administration of adenosine, was used to investigate the hyperemic response. Mean age of the total population was 65 ±â€¯10 years, 65% was male. Median CAC score was 510 (range 0 to 6141). Mean pressure gradient before the administration of adenosine was comparable in vessels with severe versus mild CAC. FFR was more often ≤0.80 in vessels with severe CAC (p = 0.045). Patients with a large Δ FFR were younger (p = 0.05). There was no association between Δ FFR and severity of calcifications. Regression analysis did not demonstrate an association between CAC score and the hyperemic response (p = 0.49). CONCLUSION: We did not find an association between the severity of CAC and the hyperemic response during invasive FFR.

Trends in cardiovascular and bleeding outcomes in acute coronary syndrome patients treated with or without proton-pump inhibitors during the introduction of novel P2Y12 inhibitors: a five-year experience from a single-centre observational registry.

AIMS: Proton-pump inhibitors (PPIs) are commonly prescribed in acute coronary syndrome (ACS) patients on antiplatelet therapy. We studied PPI prescription in ACS patients in the era of novel P2Y12 inhibitors and assessed the association between PPI use and clinical outcomes. METHODS AND RESULTS: Between 2010 and 2014, we included all consecutive ACS patients admitted to a Dutch tertiary hospital. The main outcome was PPI prescription at discharge. Additionally, we present 1-year mortality and 30-day cardiovascular and bleeding outcomes. Of 4595 ACS patients with known discharge medication, 63.9% received a PPI. PPI-treated patients were older (67.1 ± 12.5 vs. 63.0 ± 13.3, P < 0.001). PPI treatment at discharge increased from 34.7% in 2010 to 88.7% in 2014 (P < 0.001). Concurrently, ticagrelor prescription at discharge increased from 0.0% to 48.6% in 2014 (P < 0.001), while clopidogrel prescription decreased from 78.6% in 2010 to 28.7% in 2014 (P < 0.001). PPI treatment was associated with reductions in death or myocardial infarction (MI) [adjusted hazard ratio (HR) 0.27, 95% confidence interval (CI) 0.10-0.76] and death, MI or stroke (adjusted HR 0.33, 95% CI 0.14-0.81) at 30-days post-discharge. However, this association was not present in subgroup analyses of patients treated with clopidogrel or ticagrelor. CONCLUSION: In this single-centre registry, PPI prescription in ACS patients doubled between 2010 and 2014. PPI treatment at discharge was associated with a reduction in death, MI, or stroke at 30-days post-discharge, mainly driven by a reduction in MI. There were no differences gastrointestinal bleeding between patients treated with or without a PPI. PPI treatment may serve as a marker of improved therapies and outcome, rather than causing a reduction in cardiovascular events.

Alternative Approaches to the Assessment of the Systemic Circulation and Left Ventricular Performance: A Proof-of-Concept Study.

BACKGROUND: The purpose of this article is to examine the systemic circulation and left ventricular (LV) performance by alternative, nonconventional approaches: systemic vascular conductance (G SV ) and the head-capacity relation (ie, the relation between LV pressure and cardiac output), respectively; in so doing, we aspired to present a novel and improved interpretation of integrated cardiovascular function. METHODS: In 16 open-chest, anaesthetized pigs, we measured LV pressure (P LV ), central aortic pressure (P Ao ), and central venous pressure (P CV ) and aortic flow (Q Ao ). We calculated heart rate (HR), stroke volume, cardiac index (CI = cardiac output/body weight), mean PLV ( P ¯ LV ) , and the average arteriovenous pressure difference ( Δ P = P ¯ Ao - P ¯ CV ); G SV  = CI/( P ¯ Ao - P ¯ CV ). We studied the effects of changing loading conditions with the administration of phenylephrine (Δ P ¯ Ao ≥ +25 mm Hg), isoproterenol (ΔHR ∼+25%), sodium nitroprusside (Δ P ¯ Ao ≥ -25 mm Hg), and proximal aortic constriction (to maximize developed P LV and minimize Q Ao ). RESULTS: Sodium nitroprusside and isoproterenol increased G SV compared with phenylephrine and constriction. A maximum head-capacity curve was derived from pooled data using nonlinear regression on the maximum P ¯ LV values in Q Ao bins 12.5 mL/min/kg wide. The head-capacity relation and the plots of conductance were combined using CI as a common axis, which illustrated that CI is the output of the heart and the input of the circulation. CONCLUSIONS: Thus, at a given CI, G SV determines the driving pressure and, thereby, P Ao . We also demonstrated how decreases in G SV compensate for arterial hypotension by restoring the arteriovenous pressure difference and arterial pressure.

CONTEXTE: Le présent article examine l'efficacité de la circulation générale et la fonction ventriculaire gauche à l'aide de paramètres de rechange non conventionnels, soit la conductance vasculaire systémique (G VS ) pour l'une et la relation pression-volume (c.-à-d. la relation entre la pression ventriculaire gauche et le débit cardiaque) pour l'autre, dans le but de présenter une interprétation nouvelle et améliorée de la fonction cardiovasculaire intégrée. MÉTHODOLOGIE: Chez 16 porcs anesthésiés, nous avons mesuré à thorax ouvert la pression ventriculaire gauche (P VG ), la pression aortique centrale (P AC ), la pression veineuse centrale (P VC ) et le flux aortique (Q A ). Nous avons établi la fréquence cardiaque (FC), le volume d'éjection systolique, l'index cardiaque (IC; rapport entre le débit cardiaque et le poids corporel), la P VG moyenne ( P ¯ VG ) et la différence de pression artérioveineuse moyenne ( Δ P = P ¯ A C − P ¯ V C ); G VS  = IC/( P ¯ AC − P ¯ VC ). Nous avons aussi étudié les effets d'une modification des conditions de charge cardiaque provoquée par l'administration de phényléphrine (Δ P ¯ AC ≥ + 25 mmHg), d'isoprotérénol (ΔFC d'environ + 25 %) ou de nitroprussiate de sodium (Δ P ¯ AC ≥ − 25 mmHg) et par la constriction de l'aorte proximale (pour maximiser la P VG développée et réduire le plus possible le Q A ). RÉSULTATS: Le nitroprussiate de sodium et l'isoprotérénol ont augmenté la G VS comparativement à la phényléphrine et à la constriction. Une courbe de la relation pression-volume maximale a été dérivée à partir des données groupées, au moyen d'une régression non linéaire sur les valeurs maximales de la P ¯ VG réparties dans des classes de Q A de 12,5 ml/min/kg d'amplitude. La courbe de la relation pression-volume et le tracé de la conductance ont été superposés en utilisant l'IC comme axe commun, ce qui a permis de constater que l'IC correspond au débit cardiaque et au volume entrant dans la circulation. CONCLUSIONS: Pour un IC donné, la G VS détermine la pression motrice et donc, la P AC . Nous avons aussi démontré comment une diminution de la G VS compense l'hypotension artérielle en rétablissant la différence de pression artérioveineuse et la pression artérielle.

Partial Deletion of Tie2 Affects Microvascular Endothelial Responses to Critical Illness in A Vascular Bed and Organ-Specific Way.

Tyrosine kinase receptor (Tie2) is mainly expressed by endothelial cells. In animal models mimicking critical illness, Tie2 levels in organs are temporarily reduced. Functional consequences of these reduced Tie2 levels on microvascular endothelial behavior are unknown. We investigated the effect of partial deletion of Tie2 on the inflammatory status of endothelial cells in different organs. Newly generated heterozygous Tie2 knockout mice (exon 9 deletion, ΔE9/Tie2) exhibiting 50% reduction in Tie2 mRNA and protein, and wild-type littermate controls (Tie2), were subjected to hemorrhagic shock and resuscitation (HS + R), or challenged with i.p. lipopolysaccharide (LPS). Kidney, liver, lung, heart, brain, and intestine were analyzed for mRNA levels of adhesion molecules E-selectin, vascular cell adhesion molecule 1 (VCAM-1), and intercellular cell adhesion molecule 1 (ICAM-1), and CD45. Exposure to HS + R did not result in different expression responses of these molecules between organs from Tie2 or Tie2 mice and sham-operated mice. In contrast, the LPS-induced mRNA expression levels of E-selectin, VCAM-1, and ICAM-1, and CD45 in organs were attenuated in Tie2 mice when compared with Tie2 mice in kidney and liver, but not in the other organs studied. Furthermore, reduced expression of E-selectin and VCAM-1 protein, and reduced influx of CD45 cells upon LPS exposure, was visible in a microvascular bed-specific pattern in kidney and liver of Tie2 mice compared with controls. In contrast to the hypothesis that a disbalance in the Ang/Tie2 system leads to increased microvascular inflammation, heterozygous deletion of Tie2 is associated with an organ-restricted, microvascular bed-specific attenuation of endothelial inflammatory response to LPS.

Comparison of Outcomes and Intervention Among Patients With Non-ST-Segment Elevation Acute Myocardial Infarction of Those With a Left Circumflex Versus Those With a Non-Left Circumflex-Related Coronary Artery (From the ELISA-3 Trial).

Previous studies found that patients with an acute coronary syndrome (ACS) due to occlusion of the left circumflex (LC) coronary artery often present without ST-elevation, leading to a delay in diagnosis and revascularization, a larger infarct size, and a worse prognosis. In this subgroup analysis of the ELISA-3 study (early or late intervention in high-risk non-ST-segment elevation acute coronary syndromes [NSTE-ACS]) incidence, characteristics and prognosis of LC-related NSTE-ACS was investigated, and the outcome of early versus late invasive strategy was compared. In 383 of 542 patients the culprit vessel could be identified, with the LC artery in 112 (29%) of them. Patients with LC-related ACS had more often single vessel disease and underwent percutaneous coronary intervention more and CABG less frequently. The primary end point of the combined incidences of death, myocardial infarction, and recurrent ischemia at 30-day follow-up occurred in 9.0% of LC versus 16.5% of non-LC-related ACS (p = 0.057). Enzymatic infarct size and incidence of bleeding were comparable. Of patients with LC-related ACS, 62 were assigned to an early and 50 to a late invasive treatment with a median time from admission to angiography of 5.5 and 65.7 hours, respectively. The primary end point occurred in 9.7% and 8.0%, respectively (p = 1.00) with comparable enzymatic infarct size and bleeding. In conclusion, no significant differences in outcome were found between patients with an LC- and a non-LC-related NSTE-ACS. In LC-related NSTE-ACS, angiography within 12 hours of admission is feasible but not superior to angiography after more than 48 hours.

Dynamic and Irregular Distribution of RyR2 Clusters in the Periphery of Live Ventricular Myocytes.

Cardiac ryanodine receptors (RyR2s) are Ca2+ release channels clustering in the sarcoplasmic reticulum membrane. These clusters are believed to be the elementary units of Ca2+ release. The distribution of these Ca2+ release units plays a critical role in determining the spatio-temporal profile and stability of sarcoplasmic reticulum Ca2+ release. RyR2 clusters located in the interior of cardiomyocytes are arranged in highly ordered arrays. However, little is known about the distribution and function of RyR2 clusters in the periphery of cardiomyocytes. Here, we used a knock-in mouse model expressing a green fluorescence protein (GFP)-tagged RyR2 to localize RyR2 clusters in live ventricular myocytes by virtue of their GFP fluorescence. Confocal imaging and total internal reflection fluorescence microscopy was employed to determine and compare the distribution of GFP-RyR2 in the interior and periphery of isolated live ventricular myocytes and in intact hearts. We found tightly ordered arrays of GFP-RyR2 clusters in the interior, as previously described. In contrast, irregular distribution of GFP-RyR2 clusters was observed in the periphery. Time-lapse total internal reflection fluorescence imaging revealed dynamic movements of GFP-RyR2 clusters in the periphery, which were affected by external Ca2+ and RyR2 activator (caffeine) and inhibitor (tetracaine), but little detectable movement of GFP-RyR2 clusters in the interior. Furthermore, simultaneous Ca2+- and GFP-imaging demonstrated that peripheral RyR2 clusters with an irregular distribution pattern are functional with a Ca2+ release profile similar to that in the interior. These results indicate that the distribution of RyR2 clusters in the periphery of live ventricular myocytes is irregular and dynamic, which is different from that of RyR2 clusters in the interior.