Apelin improves cardiac function mainly through peripheral vasodilation in a mouse model of dilated cardiomyopathy.

There is growing evidence that apelin plays a role in the regulation of the cardiovascular system by increasing myocardial contractility and acting as a vasodilator. However, it remains unclear whether apelin improves cardiac contractility in a load-dependent or independent manner in pathological conditions. For this purpose we investigated the cardiovascular effects of apelin in α-actin transgenic mice (mActin-Tg mice), a model of cardiomyopathy. [Pyr1]apelin-13 was administered by continuous infusion at 2 mg/kg/d for 3 weeks. Effects on cardiac function were determined by echocardiography and a Pressure-Volume (PV) analysis. mActin-Tg mice showed a dilated cardiomyopathy (DCM) phenotype similar to that encountered in patients expressing the same mutation. Compared to WT animals, mActin-Tg mice displayed cardiac systolic impairment [significant decrease in ejection fraction (EF), cardiac output (CO), and stroke volume (SV)] associated with cardiac ventricular dilation and diastolic dysfunction, characterized by an impairment in mitral flow velocity (E/A) and in deceleration time (DT). Load-independent myocardial contractility was strongly decreased in mActin-Tg mice while total peripheral vascular resistance (TPR) was significantly increased. As compared to vehicle-treated animals, a 3-week treatment with [Pyr1]apelin-13 significantly improved EF%, SV, E/A, DT and corrected TPR, with no significant effect on load-independent indices of myocardial contractility, blood pressure and heart rate. In conclusion [Pyr1]apelin-13 displayed no intrinsic contractile effect but improved cardiac function in dilated cardiomyopathy mainly by reducing peripheral vascular resistance, with no change in blood pressure.

Ablation of lysozyme M-positive cells prevents aircraft noise-induced vascular damage without improving cerebral side effects.

Aircraft noise induces vascular and cerebral inflammation and oxidative stress causing hypertension and cardiovascular/cerebral dysfunction. With the present studies, we sought to determine the role of myeloid cells in the vascular vs. cerebral consequences of exposure to aircraft noise. Toxin-mediated ablation of lysozyme M+ (LysM+) myeloid cells was performed in LysMCreiDTR mice carrying a cre-inducible diphtheria toxin receptor. In the last 4d of toxin treatment, the animals were exposed to noise at maximum and mean sound pressure levels of 85 and 72 dB(A), respectively. Flow cytometry analysis revealed accumulation of CD45+, CD11b+, F4/80+, and Ly6G-Ly6C+ cells in the aortas of noise-exposed mice, which was prevented by LysM+ cell ablation in the periphery, whereas brain infiltrates were even exacerbated upon ablation. Aircraft noise-induced increases in blood pressure and endothelial dysfunction of the aorta and retinal/mesenteric arterioles were almost completely normalized by ablation. Correspondingly, reactive oxygen species in the aorta, heart, and retinal/mesenteric vessels were attenuated in ablated noise-exposed mice, while microglial activation and abundance in the brain was greatly increased. Expression of phagocytic NADPH oxidase (NOX-2) and vascular cell adhesion molecule-1 (VCAM-1) mRNA in the aorta was reduced, while NFκB signaling appeared to be activated in the brain upon ablation. In sum, we show dissociation of cerebral and peripheral inflammatory reactions in response to aircraft noise after LysM+ cell ablation, wherein peripheral myeloid inflammatory cells represent a dominant part of the pathomechanism for noise stress-induced cardiovascular effects and their central nervous counterparts, microglia, as key mediators in stress responses.

Rationale and design of ApoA-I Event Reducing in Ischemic Syndromes II (AEGIS-II): A phase 3, multicenter, double-blind, randomized, placebo-controlled, parallel-group study to investigate the efficacy and safety of CSL112 in subjects after acute myocardial infarction.

Acute myocardial infarction (MI) patients remain at high risk for recurrent events. Cholesterol efflux, mediated by apolipoprotein A-I, removes excess cholesterol from atherosclerotic plaque and transports it to the liver for excretion. Impaired cholesterol efflux is associated with higher cardiovascular (CV) event rates among both patients with stable coronary artery disease and recent MI. CSL112, a novel intravenous formulation of apolipoprotein A-I (human) derived from human plasma, increases cholesterol efflux capacity. AEGIS-II is a phase 3, multicenter, double-blind, randomized, placebo-controlled, parallel-group trial investigating the efficacy and safety of CSL112 compared to placebo among high-risk acute MI participants. Eligibility criteria include age ≥ 18 years with type 1 (spontaneous) MI, evidence of multivessel stable coronary artery disease, and presence of diabetes requiring pharmacotherapy, or ≥2 of the following: age ≥ 65 years, prior MI, or peripheral artery disease. A target sample of 17,400 participants will be randomized 1:1 to receive 4 weekly infusions of CSL112 6 g or placebo, initiated prior to or on the day of discharge and within 5 days of first medical contact. The primary outcome is the time to first occurrence of the composite of CV death, MI, or stroke through 90 days. Key secondary outcomes include the total number of hospitalizations for coronary, cerebral, or peripheral ischemia through 90 days and time to first occurrence of the composite primary outcome through 180 and 365 days. AEGIS-II will be the first trial to formally test whether enhancing cholesterol efflux can reduce the rate of recurrent major adverse CV events.

Hydroxyurea Dose Escalation for Sickle Cell Anemia in Sub-Saharan Africa.

BACKGROUND: Hydroxyurea has proven safety, feasibility, and efficacy in children with sickle cell anemia in sub-Saharan Africa, with studies showing a reduced incidence of vaso-occlusive events and reduced mortality. Dosing standards remain undetermined, however, and whether escalation to the maximum tolerated dose confers clinical benefits that outweigh treatment-related toxic effects is unknown. METHODS: In a randomized, double-blind trial, we compared hydroxyurea at a fixed dose (approximately 20 mg per kilogram of body weight per day) with dose escalation (approximately 30 mg per kilogram per day). The primary outcome was a hemoglobin level of 9.0 g or more per deciliter or a fetal hemoglobin level of 20% or more after 24 months. Secondary outcomes included the incidences of malaria, vaso-occlusive crises, and serious adverse events. RESULTS: Children received hydroxyurea at a fixed dose (94 children; mean [±SD] age, 4.6±1.0 years) or with dose escalation (93 children; mean age, 4.8±0.9 years); the mean doses were 19.2±1.8 mg per kilogram per day and 29.5±3.6 mg per kilogram per day, respectively. The data and safety monitoring board halted the trial when the numbers of clinical events were significantly lower among children receiving escalated dosing than among those receiving a fixed dose. At trial closure, 86% of the children in the dose-escalation group had reached the primary-outcome thresholds, as compared with 37% of the children in the fixed-dose group (P<0.001). Children in the dose-escalation group had fewer sickle cell-related adverse events (incidence rate ratio, 0.43; 95% confidence interval [CI], 0.34 to 0.54), vaso-occlusive pain crises (incidence rate ratio, 0.43; 95% CI, 0.34 to 0.56), cases of acute chest syndrome or pneumonia (incidence rate ratio, 0.27; 95% CI, 0.11 to 0.56), transfusions (incidence rate ratio, 0.30; 95% CI, 0.20 to 0.43), and hospitalizations (incidence rate ratio, 0.21; 95% CI, 0.13 to 0.34). Laboratory-confirmed dose-limiting toxic effects were similar in the two groups, and there were no cases of severe neutropenia or thrombocytopenia. CONCLUSIONS: Among children with sickle cell anemia in sub-Saharan Africa, hydroxyurea with dose escalation had superior clinical efficacy to that of fixed-dose hydroxyurea, with equivalent safety. (Funded by the Doris Duke Charitable Foundation and the Cincinnati Children's Research Foundation; NOHARM MTD ClinicalTrials.gov number, NCT03128515.).

Novel treatment of severe radial artery spasm using "homemade sheathless technique": A case report.

RATIONALE: Transradial access (TRA) is common for cardiac catheterization, but radial artery spasm (RAS) is suggested to be highlighted. Severe radical artery spasm could be solved by a relative novel approach called "sheathless technique," using a Tiger diagnostic catheter. PATIENT CONCERNS: A 73-year-old woman presented to our institution with a recurrent feeling of discomfort in her chest. Her electrocardiogram showed ST segment depression. Her medical history indicated arterial hypertension, diabetes, and chronic renal failure. She was on hemodialysis for 5 years for the management of renal problems. Five stents were implanted from femoral access in another hospital via 2 percutaneous coronary interventions. The patient agreed to angiography this time and wanted a more comfortable solution. DIAGNOSIS: Recurrent exertional angina was confirmed based on the chief complaint, electrocardiogram, and history. INTERVENTIONS: After a successful radial artery puncture, a 6F arterial sheath pipe and a 5F Tiger diagnostic ductus could only advance slightly because of the RAS. Glonoin and verapamil functioned with the help of the radial sheath, and systemic nitroglycerin was applied later but had a negative outcome. Warm covers were positioned on the antebrachium, but no relief was reported.The "homemade sheathless technique" was applied. The 5F tube was held, and the 6F sheath was withdrawn. A blade was used to damage the sheath in reverse, and the excess sheath tube was removed. OUTCOMES: The diagnostic catheter was successfully advanced to the ascending aorta, enabling left main and right coronary engagement and angiography. No significant coronary lesion was observed. The patient was discharged 3 days after angiography. Moreover, no complications were observed. A follow-up for 1 month after discharge also showed no complications. LESSONS: Severe RAS causing failure of TRA is frequent in the transradial catheterization procedure. The sheathless technique may be useful in relieving spasm when other measures fail.

Estimating State-Level Health Burden of Diabetes: Diabetes-Attributable Fractions for Diabetes Complications.

INTRODUCTION: Limited information is available on the health burden of diabetes at the state level. This study estimated state-specific attributable fractions and the number of cases attributable to diabetes for diabetes-related complications. METHODS: For each state, diabetes-attributable fractions for nine diabetes complications were estimated: three self-reported complications from the 2013 Behavioral Risk Factor Surveillance System, hospitalizations with three complications from 2011 to 2014 State Inpatient Databases, and three complications from 2013 Medicare data. Attributable fractions were calculated using RR and diabetes prevalence and the total number of cases using attributable fractions and total number of complications. Adjusted RR of each complication for people with and without diabetes by age and sex was estimated using a generalized linear model. Analyses were conducted in 2015-2016. RESULTS: Median state-level diabetes-attributable fractions for self-reported complications were 0.14 (range, 0.10-0.19) for mobility limitations; 0.13 (range, 0.04-0.21) for limitations in instrumental activities of daily living; and 0.12 (range, 0.06-0.20) for severe visual impairment or blindness. Median state-level diabetes-attributable fractions for diabetes-associated hospitalizations were 0.19 (range, 0.08-0.24) for congestive heart failure; 0.08 (range, 0.02-0.16) for myocardial infarction; and 0.62 (range, 0.46-0.73) for lower extremity amputations. Median state-level diabetes-attributable fractions for complications among Medicare beneficiaries were 0.17 (range, 0.14-0.23) for coronary heart disease; 0.28 (range, 0.24-0.33) for chronic kidney disease; and 0.22 (range, 0.08-0.32) for peripheral vascular disease. CONCLUSIONS: Diabetes carries a significant health burden, and results vary across states. Efforts to prevent or delay diabetes or to improve diabetes management could reduce the health burden because of diabetes.

Identifying the Risk Factor and Prevention of Limb Ischemia in Extracorporeal Membrane Oxygenation with Femoral Artery Cannulation.

OBJECTIVE: Application of extracorporeal membrane oxygenation (ECMO) for life support has been widely used in various fields of resuscitation. When the common femoral artery (CFA) is used during cannulation for ECMO support in adults, it is often complicated by limb ischemia. Placement of distal perfusion catheter (DPC) can reduce the incidence of limb ischemia and increases the likelihood of limb preservation, but selection criteria is uncertain. METHODS: This is a retrospective study. Data was reviewed for patients in one medical center who were supported by venoarterial extracorporeal membrane oxygenation (VA-ECMO) via CFA cannulation percutaneously between January 2008 and June 2014. Two groups were divided into no-ischemia and ischemic limb. Age, sex, height, weight, body surface area (BSA), cannula size, femoral artery diameter, comorbidity, acute physiology and chronic health evaluation (APACHE) II score, vasoactive-inotropic score (VIS) and mortality rate were analyzed. Doppler was used by measuring the distal pulsation in the dorsalis pedis and posterior tibial artery to select the patients. A DPC was prophylactically inserted percutaneously into the superficial femoral artery for antegrade flow to the extremity in the patients who met selection criteria. RESULTS: 139 (43.6%) patients were included in the study and limb ischemia occurred in 46 (33%) of 139. There was a significant difference between the no-ischemia group and the ischemia group in age (55.5 ± 14.2 versus 63.2 ± 13.2; P < .001), common femoral artery diameter (0.82 ± 0.14 versus 0.63 ± 0.17; P < .001 ), known peripheral artery occlusive disease (9% versus 24%; P < .001) and VIS (12.1 ± 8.1 versus 15.8 ± 10.1; P < .001). Mortality rate was higher in the ischemia group (46% versus 26% ; P < .001). 11 patients who met the selection criteria had a DPC prophylactically inserted and no ischemia limb occurred. CONCLUSION: Smaller common femoral artery diameter (≤6.3 cm); known peripheral arterial occlusive disease; higher VIS (≥15.8); absence of distal pulsation pre-cannulation or immediately after post-cannulation or 4 hrs later have higher risk of limb ischemia when CFA cannulation is used for VA-ECMO. Due to this, the mortality and morbidity rate increases when limb ischemia occurs. A DPC should be prophylactically inserted in high-risk patients who meet selection criteria.

Aortocaval Compression Syndrome: Time to Revisit Certain Dogmas.

More than 70 years ago, the phenomenon of "postural shock" in the supine position was described in healthy women in late pregnancy. Since then, avoidance of the supine position has become a key component of clinical practice. Indeed, performing pelvic tilt in mothers at term to avoid aortocaval compression is a universally adopted measure, particularly during cesarean delivery. The studies on which this practice is based are largely nonrandomized, utilized a mix of anesthetic techniques, and were conducted decades ago in the setting of avoidance of vasopressors. Recent evidence is beginning to refine our understanding of the physiologic consequences of aortocaval compression in the context of contemporary clinical practice. For example, magnetic resonance imaging of women at term in the supine and tilted positions has challenged the dogma that 15° of left tilt is sufficient to relieve inferior vena cava compression. A clinical investigation of healthy term women undergoing elective cesarean delivery with spinal anesthesia found no difference in neonatal acid-base status between women randomized to be either tilted to the left by 15° or to be in the supine position, if maternal systolic blood pressure is maintained at baseline with a crystalloid coload and prophylactic phenylephrine infusion. This review presents a fresh look at the decades of evidence surrounding this topic and proposes a reevaluation and appraisal of current guidelines regarding entrenched practices.

Anti-oxidative treatment with vitamin E improves peripheral vascular function in patients with diabetes mellitus and Haptoglobin 2-2 genotype: A double-blinded cross-over study.

Vascular dysfunction in both conduit arteries and small vessels is a major contributor to the development of cardiovascular disease (CVD) in diabetes mellitus (DM). In diabetes there is a process of systemic chronic inflammation accompanied by high oxidative stress causing a subsequent decrease in vascular reactivity and negatively affect the metabolic processes responsible for functioning of the microvasculature. Vitamin E is classified as an antioxidant due to its ability to scavenge lipid radicals and terminate oxidative chain reactions. We conducted a double-blinded cross-over study with vitamin E versus placebo in individuals with type 2DM and the Hp2-2 genotype and assessed different aspects of peripheral vascular function in these patients. Twenty patients completed the study with 10 individuals in each study cohort. We were able to show significant improvement of indirect indices of vascular function following 8weeks of treatment with vitamin E. This improvement was consistent for weeks even after stopping the vitamin E treatment. We concluded that a pharmacogenomic rationale utilizing the Hp genotype might potentially provide cardiovascular benefit with vitamin E.

Angiosomas 2.0: mito o realidad / Angiosomes 2.0: Myth or reality

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Should catheter-directed thrombolysis be monitored?

Catheter-directed thrombolysis for deep venous thrombosis is considered the basic treatment modality for intrathrombus removal. This method is preferably used in patients with iliofemoral deep venous thrombosis due to poor spontaneous recanalization in this segment, especially on the left side. The method was published almost 25 years ago and has gained ground in the treatment because of poor results from systemic thrombolysis and because of the possibility of stenting any underlying iliac obstruction during the procedure. However, the publications of catheter-directed thrombolysis reveal a great heterogeneity concerning catheter-directed thrombolysis technique and the lack of high quality evidence about monitoring as a tool to minimize the risk of bleeding and pulmonary embolism. Strict inclusion and exclusion criteria, correct composition and infusion of thrombolysis agent, imaging thrombus clearance during catheter-directed thrombolysis, ensuring flow enhancement during the bedridden situation, careful evaluation of indication for stenting based on imaging, and sufficient conversion to anticoagulation treatment following catheter-directed thrombolysis are essential. The aim of this paper is to discuss different treatment aspects of catheter-directed thrombolysis for iliofemoral thrombosis and to suggest a monitoring model for future treatment.

A Multinational Trial of Prasugrel for Sickle Cell Vaso-Occlusive Events.

BACKGROUND: Sickle cell anemia is an inherited blood disorder that is characterized by painful vaso-occlusive crises, for which there are few treatment options. Platelets mediate intercellular adhesion and thrombosis during vaso-occlusion in sickle cell anemia, which suggests a role for antiplatelet agents in modifying disease events. METHODS: Children and adolescents 2 through 17 years of age with sickle cell anemia were randomly assigned to receive oral prasugrel or placebo for 9 to 24 months. The primary end point was the rate of vaso-occlusive crisis, a composite of painful crisis or acute chest syndrome. The secondary end points were the rate of sickle cell-related pain and the intensity of pain, which were assessed daily with the use of pain diaries. RESULTS: A total of 341 patients underwent randomization at 51 sites in 13 countries across the Americas, Europe, Asia, and Africa. The rate of vaso-occlusive crisis events per person-year was 2.30 in the prasugrel group and 2.77 in the placebo group (rate ratio, 0.83; 95% confidence interval, 0.66 to 1.05; P=0.12). There were no significant differences between the groups in the secondary end points of diary-reported events. The safety end points, including the frequency of bleeding events requiring medical intervention, of hemorrhagic and nonhemorrhagic adverse events that occurred while patients were taking prasugrel or placebo, and of discontinuations due to prasugrel or placebo, did not differ significantly between the groups. CONCLUSIONS: Among children and adolescents with sickle cell anemia, the rate of vaso-occlusive crisis was not significantly lower among those who received prasugrel than among those who received placebo. There were no significant between-group differences in the safety findings. (Funded by Daiichi Sankyo and Eli Lilly; ClinicalTrials.gov number, NCT01794000.).

Assessment of the clinical effects of cholesteryl ester transfer protein inhibition with evacetrapib in patients at high-risk for vascular outcomes: Rationale and design of the ACCELERATE trial.

BACKGROUND: Potent pharmacologic inhibition of cholesteryl ester transferase protein by the investigational agent evacetrapib increases high-density lipoprotein cholesterol by 54% to 129%, reduces low-density lipoprotein cholesterol by 14% to 36%, and enhances cellular cholesterol efflux capacity. The ACCELERATE trial examines whether the addition of evacetrapib to standard medical therapy reduces the risk of cardiovascular (CV) morbidity and mortality in patients with high-risk vascular disease. STUDY DESIGN: ACCELERATE is a phase 3, multicenter, randomized, double-blind, placebo-controlled trial. Patients qualified for enrollment if they have experienced an acute coronary syndrome within the prior 30 to 365 days, cerebrovascular accident, or transient ischemic attack; if they have peripheral vascular disease; or they have diabetes with coronary artery disease. A total of 12,092 patients were randomized to evacetrapib 130 mg or placebo daily in addition to standard medical therapy. The primary efficacy end point is time to first event of CV death, myocardial infarction, stroke, hospitalization for unstable angina, or coronary revascularization. Treatment will continue until 1,670 patients reached the primary end point; at least 700 patients reach the key secondary efficacy end point of CV death, myocardial infarction, and stroke, and the last patient randomized has been followed up for at least 1.5 years. CONCLUSIONS: ACCELERATE will establish whether the cholesteryl ester transfer protein inhibition by evacetrapib improves CV outcomes in patients with high-risk vascular disease.

Fingolimod-Associated Peripheral Vascular Adverse Effects.

Fingolimod is the first oral disease-modifying drug approved for the treatment of multiple sclerosis. The drug is usually well tolerated, and common adverse effects include bradycardia, headache, influenza, diarrhea, back pain, increased liver enzyme levels, and cough. Fingolimod is thought to provide therapeutic benefit by preventing normal lymphocyte egress from lymphoid tissues, thus reducing the infiltration of autoaggressive lymphocytes into the central nervous system. However, because the drug acts on different sphingosine-1-phosphate receptors, it may induce several biological effects by influencing endothelial cell-cell adhesion, angiogenesis, vascular development, and cardiovascular function. We describe a patient with multiple sclerosis who, after 3 weeks of fingolimod administration, developed purplish blotches over the dorsal surface of the distal phalanges of the second and fifth digits and the middle phalanx of the fourth ray, itching, and edema on his left hand, without other evident clinical manifestations. When fingolimod therapy was discontinued, the clinical picture regressed within a few days but reappeared after a rechallenge test. Physicians should be aware of unexpected peripheral vascular adverse effects due to fingolimod use, and patients with vascular-based acropathies should be carefully screened and monitored when taking this drug.

Diabetes mellitus and the increased risk of foot injuries.

With one person dying from diabetes-related preventable complications, including foot complications, every 7 seconds across the world, it is clear this is a major health challenge. Foot ulceration in diabetes remains the commonest reason for hospital admission in Western countries. From neuropathy to peripheral vascular disease, the challenges are significant and can result in premature death, but early diagnosis by aware health-care professionals, combined with supporting people in self-care, can help reduce the problems of diabetes to manageable proportions.

The imperative to prevent diabetes complications: a broadening spectrum and an increasing burden despite improved outcomes.

Diabetes mellitus and its complications are common; the complications are, of themselves, a major reason to manage diabetes. Recent data from Australia and similar developed health care systems overseas indicate that morbidity and mortality outcomes relating to diabetes complications are improving. However, these benefits are offset by increasing numbers of people diagnosed with diabetes, resulting in an increased disease burden with significant health care implications. Thus the imperative to prevent diabetes and diabetes complications has never been greater. Furthermore, the recognised spectrum of diabetes complications is broadening, especially complications relating to lipid levels, insulin resistance and the metabolic syndrome. Clinicians now need to be aware of both traditional complications (eg, nephropathy and cardiovascular disease) and non-traditional complications (eg, polycystic ovary syndrome, non-alcoholic fatty liver disease, some cancers and eating disorders). Complications outcomes could be further improved by decreasing the evidence-treatment gap - for example, by increasing personalisation of care in managing diabetes complications.

Text messaging to motivate exercise among Latino adults at risk for vascular disease: a pilot study, 2013.

In 2013, we administered a 15-item survey to determine the extent of text message usage among Latino adults in Kansas; for a subset of the survey participants, we also conducted a 6-week pilot trial to determine the effect of text messaging on exercise behaviors. Among the 82 survey participants, 78% had unlimited text messaging. At baseline, all trial participants were at the stage of contemplation; at 6 weeks, one (9%) trial participant remained at the contemplation stage and the other 10 (91%) participants progressed to the action/maintenance/termination stage. Use of text messaging to motivate exercise is feasible and potentially efficacious among Latinos.