Ticagrelor Treatment is Associated With Increased Coronary Flow Reserve in Survivors of Myocardial Infarction.

BACKGROUND: The pleiotropic action of ticagrelor, with effects in addition to platelet inhibition, has been shown to improve endothelial function in patients with coronary artery disease. These positive effects are possibly adenosine mediated. This study investigated the association of ticagrelor therapy and coronary artery flow reserve in survivors of myocardial infarction (MI). METHODS: This was an exploratory, cross-sectional, open substudy of PROFLOW. High-risk individuals with a history of MI were identified. Coronary flow reserve (CFR) was measured non-invasively in the left anterior descending artery using transthoracic Doppler echocardiography. Coronary flow velocity was measured at rest and at maximal flow after induction of hyperaemia by intravenous infusion of adenosine at 140 µg/kg/min. Patients receiving ticagrelor (n=75) were compared with those not receiving ticagrelor (n=506), using simple and multiple linear regression models. Most patients in both groups were treated with aspirin (97% in the ticagrelor and 94% in the non-ticagrelor group). Adjustment for traditional risk factors was conducted. RESULTS: The mean age at study inclusion was 68.5±6.8 years, and most patients were male (81.8%). The simple linear regression analysis showed ticagrelor treatment to be significantly associated with increased CFR: ticagrelor 2.95±0.76 (mean±SD), non-ticagrelor 2.70±0.77, (coefficient 0.25; 95% CI 0.063-0.438; p=0.009). This association was significant in two of the three multiple linear regression models with increasing numbers of variables: Model 1 (0.28; 0.06-0.50; p=0.014), Model 2 (0.26; 0.03-0.48; p=0.025), and borderline significant in Model 3 (0.21; -0.01 to 0.43; p=0.058). CONCLUSIONS: Ticagrelor treatment was associated with increased CFR in this high-risk population. Increased CFR may be a clinically important therapeutic effect of ticagrelor in addition to platelet inhibition.

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

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

Microvesicles in plasma reflect coronary flow reserve in patients with cardiovascular disease.

High levels of microvesicles (MVs), a type of extracellular vesicles, are detected in several pathological conditions. We investigated the connection between coronary flow reserve (CFR), a prognostic clinical parameter that reflects blood flow in the heart, with levels of MVs and their cargo, from plasma of patients with cardiovascular disease. The PROFLOW study consists of 220 patients with prior myocardial infarction and measured CFR with transthoracic echocardiography. The patients were divided into high and low CFR groups. Plasma MVs were captured with acoustic trapping. Platelet- and endothelial-derived MVs were measured with flow cytometry, and vesicle lysates were analyzed with proteomic panels against cardiovascular biomarkers. Flow cytometry was further applied to identify cellular origin of biomarkers. Our data show a negative correlation between MV concentration and CFR values. Platelet and endothelial MV levels were significantly increased in plasma from the low CFR group. CFR negatively correlates with the levels of several proteomic biomarkers, and the low CFR group exhibited higher concentrations of these proteins in MVs. Focused analysis of one of the MV proteins, B cell activating factor (BAFF), revealed platelet and not leukocyte origin and release upon proinflammatory stimulus. Higher levels of MVs carrying an elevated concentration of proatherogenic proteins circulate in plasma in patients with low CFR, a marker of vascular dysfunction, reduced blood flow, and poor prognosis. Our findings demonstrate a potential clinical value of MVs as biomarkers and possible therapeutic targets against endothelial deterioration.NEW & NOTEWORTHY We investigated how microvesicles (MVs) from patients with cardiovascular diseases are related to coronary flow reserve (CFR), a clinical parameter reflecting blood flow in the heart. Our results show a negative relationship between CFR and levels of platelet and endothelial MVs. The pattern of MV-enriched cardiovascular biomarkers differs between patients with high and low CFR. Our findings suggest a potential clinical value of MVs as biomarkers of reduced blood flow and proatherogenic status, additional to CFR.

Misdiagnosis of ruptured abdominal aortic aneurysms is common and is associated with increased mortality.

OBJECTIVE: To investigate the rate of misdiagnosis in the emergency department in patients with ruptured abdominal aortic aneurysms (rAAAs), and to investigate how misdiagnosis affects rAAA mortality. METHODS: Data were extracted from the Swedish Cause of Death Registry and the Swedish National Registry for Vascular Surgery from 2010 to 2015. All rAAA patients registered in the health care system in the west of Sweden were identified. Medical charts for rAAA patients were reviewed, and patients who were correctly diagnosed at the first assessment in the emergency department were compared with patients who were misdiagnosed. RESULTS: Altogether, 455 patients with rAAA were identified, including both patients who underwent surgery and those who did not. One hundred seventy-seven (38.9%) were initially misdiagnosed. The mortality rate was 74.6% in patients who were misdiagnosed, as compared with 62.9% in correctly diagnosed patients (P = .01). The adjusted odds ratio for mortality in misdiagnosed patients relative to correctly diagnosed patients was 1.83 (95% confidence interval, 1.13-2.96) (P = .01). When excluding patients offered palliative care (n = 134) after detection of the rAAA, the mortality in initially misdiagnosed patients was 65.1% as compared with 46.4% in correctly diagnosed patients (P = .001). In patients reaching surgical intervention, 37 (45.1%) of the primarily misdiagnosed patients died (30-day or in-hospital mortality) as compared with 63 (38.0%) of the correctly diagnosed (P = .34). CONCLUSIONS: Misdiagnosis is common in patients with rAAA, and it is associated with a substantially higher risk of dying from the ruptured aneurysm.

Ticagrelor improves peripheral arterial function in patients with a previous acute coronary syndrome.

OBJECTIVE: The novel P2Y12 antagonist ticagrelor inhibits adenosine diphosphate (ADP)-induced platelet aggregation more potently than clopidogrel and reduces the incidence of myocardial infarction and total death in patients with an acute coronary syndrome (ACS). Furthermore, ticagrelor inhibits adenosine reuptake and increases coronary flow reserve during adenosine infusion in man. We wanted to determine whether ticagrelor improves peripheral arterial function in patients with a previous ACS compared to patients treated with aspirin, clopidogrel, or prasugrel. METHODS: 127 patients with a previous ACS (>3 months to <3 years ago) on maintenance dose of (1) no ADP blocker (n = 35); (2) clopidogrel 75 mg (n = 35); (3) prasugrel 10 mg (n = 32), or (4) ticagrelor 90 mg twice daily (n = 25) were evaluated with peripheral arterial tonometry after forearm ischemia. RESULTS: Ticagrelor improves peripheral arterial function compared to the other groups [(1) controls 1.78 ± 0.53; (2) clopidogrel 1.78 ± 0.45; (3) prasugrel 1.64 ± 0.33, and (4) ticagrelor 2.25 ± 0.54 (means ± SD)] with a significance of p < 0.01 for ticagrelor versus no ADP blocker, p < 0.01 for ticagrelor versus clopidogrel, and p < 0.001 for ticagrelor versus prasugrel. There were fewer patients with endothelial dysfunction (<1.67 reactive hyperemia index) in the ticagrelor group (12%) compared to aspirin (51%), clopidogrel (46%), and prasugrel (53%) (p < 0.01). CONCLUSION: Treatment with ticagrelor improves peripheral endothelial function compared to no ADP blocker, clopidogrel, or prasugrel treatment.

A Reperfusion BOLD-MRI Tissue Perfusion Protocol Reliably Differentiate Patients with Peripheral Arterial Occlusive Disease from Healthy Controls.

There is no established technique that directly quantifies lower limb tissue perfusion. Blood oxygenation level-dependent magnetic resonance imaging (BOLD-MRI) is an MRI technique that can determine skeletal muscle perfusion. BOLD-MRI relies on magnetic differences of oxygenated and deoxygenated hemoglobin, and regional changes in oxy/deoxyhemoglobin ratio can be recorded by T2* weighted MRI sequences. We aimed to test whether BOLD-MRI can differentiate lower limb tissue perfusion in peripheral arterial occlusive disease (PAOD) patients and healthy controls. Twenty-two PAOD patients and ten healthy elderly volunteers underwent lower limb BOLD-MRI. Reactive hyperemia was provoked by transient cuff compression and images of the gastrocnemius and soleus muscles were continuously acquired at rest, during ischemia and reperfusion. Key BOLD parameters were baseline T2* absolute value and time to T2* peak value after cuff deflation (TTP). Correlations between imaging parameters and ankle-brachial index (ABI) was investigated. The mean TTP was considerably prolonged in PAOD patients compared to healthy controls (m. gastrocnemius: 111 ± 46 versus 48 ± 22 s, p = 0.000253; m. soleus: 100 ± 42 versus 41 ± 30 s, p = 0.000216). Both gastrocnemius and soleus TTP values correlated strongly with ABI (-0.82 and -0.78, p < 0.01). BOLD-MRI during reactive hyperemia differentiated most PAOD patients from healthy controls. TTP was the most decisive parameter and strongly correlated with the ABI.

Association of coronary calcium score with endothelial dysfunction and arterial stiffness.

BACKGROUND AND AIMS: The aim of the study was to determine potential associations between endothelial dysfunction and arterial stiffness, measured by peripheral arterial tonometry, and coronary artery calcium score (CACS) assessed by computed tomography (CT). METHODS AND RESULTS: The BIG3 study is a prospective longitudinal, non-interventional, pulmonary-cardiovascular cohort study exploring the three major smoking-induced diseases: cardiovascular disease, chronic obstructive pulmonary disease, and lung cancer, in a 45-75 aged cohort (mean 62 years), enriched in smokers. Computed tomography of the chest with assessment of CACS was performed in a selected subset of the participants (n = 2080). Peripheral arterial tonometry (EndoPAT) was used to assess endothelial function and arterial stiffness measured as reactive hyperaemia index (RHI) and augmentation index (AI), respectively. We observed significant associations of CACS, endothelial dysfunction, and arterial stiffness with several risk factors for coronary heart disease including age, sex, BMI, diabetes mellitus, and blood pressure. There was significant association of CACS, classified into three levels of severity, with RHI and AI (p = 0.0005 and p = 0.0009, respectively). For groups of increasing CACS (0, 1-400 and > 400 Agatston score), RHI decreased from median 1.89 (1.58-2.39), and 1.93 (1.62-2.41) to 1.77 (1.51-2.10). AI increased from median 14.3 (5.7-25.2), and 16.4 (8.1-27.6) to 18.0 (9.1-29.2). RHI, but not AI, remained significantly associated with CACS after risk factors adjustment. CONCLUSIONS: In this large study of coronary artery calcium and vascular function, we found an association between CACS and both endothelial dysfunction and arterial stiffness, indicating that they may reflect similar mechanisms for development of cardiovascular disease.

Deep Femoral Vein Reconstruction of the Abdominal Aorta and Adaptation of the Neo-Aortoiliac System Bypass Technique in an Endovascular Era.

BACKGROUND:: Primary infection of the abdominal aorta is a rare pathology that may threaten the integrity of the aortic wall, while secondary aortic prosthesis infection represents a devastating complication to open surgical and endovascular aortic surgery. Curative treatment is achievable by removal of all infected prosthetic material followed by a vascular reconstruction. DESIGN AND METHODS:: Twelve consecutive patients treated with the neo-aortoiliac system bypass (NAIS) procedure were reviewed. Nine were treated for a secondary aortic prosthesis infection (tube graft n = 3, bifurcated graft n = 4, endovascular aortic repair (EVAR) stent graft n = 1, and fenestrated EVAR [FEVAR] stent graft n = 1), while 3 patients underwent NAIS repair due to an emergent primary mycotic aortoiliac aneurysm. PRIMARY RESULTS:: Ten of 12 patients survived 30 days. Three patients were operated on acutely, and 9 patients had elective or subacute NAIS surgery. Two of 3 patients operated acutely died within 30 days, whereas no 30-day or 1-year mortality was observed in patients undergoing elective or subacute surgery. The median time from primary reconstruction to the NAIS procedure was 11 months (range: 0-201 months). Stent grafts (n = 5 of 12) were in 4 cases explanted using endovascular balloon clamping. Of the explanted endografts, 2 patients presented with a secondary graft infection after EVAR/FEVAR, while 3 patients had been emergently treated with endovascular cuffs as a "bridge-to-surgery" procedure due to aortoenteric fistula (AEF). Patients who received a "bridge-to-surgery" regimen were treated with the NAIS procedure within 8 weeks (median 27 days, range: 27-60) after receiving emergency stent grafting. PRINCIPAL CONCLUSIONS:: Aortic balloon-clamping during explantation of infected aortic prosthetic endografts is feasible and facilitates complete endograft removal. Endovascular bridging procedures could be beneficiary in the treatment of AEF or anastomotic dehiscence due to graft infection, offering a possibility to convert the acute setting to an elective definitive reconstructive procedure with a higher overall success rate.

PROspective evaluation of coronary FLOW reserve and molecular biomarkers in patients with established coronary artery disease the PROFLOW-trial: cross-sectional evaluation of coronary flow reserve.

BACKGROUND: Survivors of myocardial infarction (MI) are at high risk of new major adverse cardiovascular events (MACE). Coronary flow reserve (CFR) is a strong and independent predictor of MACE. Understanding the prevalence of impaired CFR in this patient group and identifying risk markers for impaired CFR are important steps in the development of personalized and targeted treatment for high-risk individuals with prior MI. METHODS: PROFLOW is a prospective, exploratory, cross-sectional open study. We used information from the SCAAR (Swedish Coronary Angiography and Angioplasty Registry) to identify high-risk patients with a history of type-1 MI. We measured CFR non-invasively in a left anterior descending artery (LAD) using transthoracic Doppler echocardiography. Coronary flow velocity was measured at rest and at maximal flow after induction of hyperemia by intravenous infusion of adenosine (140 µg/kg/min). Independent predictors of CFR were assessed with multiple linear regression. RESULTS: We included 619 patients. The median age was 69 (IQR 65-73), and 114 (18.4%) were women. Almost one-half of the patients, 285 (46.0%) had the multi-vessel disease, and 147 (23.7%) were incompletely revascularized. The majority were on optimal standard treatment eg ASA (93.1%), statins (90.0%), ACEI/ARB (82.6%) and beta-blockers (80.8%). The majority, 547 (88.4%) had no angina pectoris, and 572 (92.2%) were in NYHA class I. Evaluation of CFR was possible in 611 (98.7%) patients. Mean CFR was 2.74 (±0.79 (mean ± SD)). A substantial number of patients (39.7%) had CFR ≤2.5. In a multiple linear regression model age, dyslipidemia, smoking, hypertension, body mass index, incomplete revascularization, and treatment with angiotensin receptor blockers were independent predictors of CFR. CONCLUSION: In this high-risk group of patients with prior MI, the prevalence of impaired CFR was high. Further risk stratification with CFR in addition to traditional cardiovascular risk factors may improve predictive accuracy for future MACE in this patient population.