Outcomes of Alprostadil As an Adjuvant Therapy with Indirect Angiosomal Revascularization in Patients with Critical Limb Ischemia after Failure of Direct Revascularization.

BACKGROUND: This study was carried out to assess the effectiveness of alprostadil (prostaglandin E1) when used as an adjuvant therapy with indirect revascularization in patients with critical limb ischemia (CLI) after the failure of direct revascularization (DR). METHODS: At our centers, 120 patients suffering from infrainguinal peripheral arterial disease with CLI underwent a failed trial of DR procedure, all revascularization procedures were endovascular. Median follow-up was 2 years and 2.5 years for patients with and without diabetes mellitus (DM). In the alprostadil group, the mean age was 63.41 ± 12.52; 36 (60%) for males and 24 (40%) for females. Post-endovascular intervention alprostadil was administrated immediately postoperatively by intravenous infusion of 40 µg alprostadil diluted in 100 ml of normal saline, over 2 hr every 12 hr for 6 days. RESULTS: In the alprostadil group, the mean ± standard deviation (SD) of the baseline ankle-brachial index (ABI) was 0.45 ± 0.175, while the mean ± SD of ABI at the end of our study was 0.65 ± 0.216 with a difference from the baseline of 0.2 ± 0.041 (P value = 0.08, <0.05 meaning that it is significant). Our 1-month primary patency rate was 93.3%, while our 3- and 6-month patency rate was 92.9%. In the control group, the mean ± SD of the baseline ABI was 0.68 ± 0.22, while the mean ± SD of ABI at the end of our study was 0.69 ± 0.23 with a difference from the baseline of 0.01 ± 0.01 (P value >0.05 meaning that it is nonsignificant) 1-month patency rate was 89%, while 3- and 6-month patency rate was 75%. When we compared the patient's leg vessels before and after our intervention, we found that the percentage of the no-runoff-vessels group decreased from 10 (16.7%) to 4 (6.67%). One-runoff-vessel group percentage dropped from 40 (66.7%) to 36 (60%), whereas, in the two-runoff-vessel group, the percentage increased from 10 (16.7%) to 20 (33.3%). We evaluate leg arteries; we do no pedal arch intervention in the alpostradil group. Out of the total of 60 patients, limb salvage occurred in 58 (96.7%) patients, and 2 (3.3%) patients underwent below-the-knee amputation before the study ended. CONCLUSIONS: Our results show the efficacy and safety of alprostadil as an adjuvant therapy with indirect angiosomal revascularization in patients with tissue loss due to CLI.

Role of the clinical radiopharmacist in patient safety during myocardial perfusion imaging with vasodilator stress agents.

AIM: To assess the radiopharmacist's role in a multidisciplinary team focused on the contraindications of regadenoson in order to ensure the safe use of pharmacologic vasodilator stress agents in patients undergoing SPECT-MPI. METHODS: We ambispectively studied its safe use in 1905 patients (54.1% female, mean age: 66.6±11.7 years, range: 20-95 years). Sex, age, medical history, medications, drug allergies, and contraindications for stress testing were registered together with recommendations for the nuclear physician in charge. RESULTS: Detected contraindications and corresponding recommendations were as follows: risk factors for QTc interval prolongation 7.5% - measurement of QTc interval previously to test and monitor ECG; prior stroke or TIA 4.2% - consider carotid stenosis assessment; salicylates/sulfonamides allergy 3.1% - use 99mTc-sestamibi; epilepsy or risk factors for seizures 2.4% - use of adenosine or reconsider test indication; systemic corticosteroid therapy for severe COPD 1.3% - reassessment of patient's condition; acute exacerbation of COPD 0.8% - defer test until acute episode is over; severe asthma 0.4% - do not perform test; methylxanthine ingestion 0.3% - avoid consumption previously; other 6.1% - evaluation of other contraindications. No contraindications were detected in 73.6% of patients. The test was canceled due to absolute contraindications in 2.9% of the requests. CONCLUSIONS: Working in a systematic way, the radiopharmacist was able to detect a high number of issues related to regadenoson, with one out of four patients presenting some clinical contraindication. The recommendations given by the radiopharmacist were well accepted by the nuclear physicians who changed their approach contributing to increase the safety of patients referred for MPI.

Safety of dobutamine or adenosine stress cardiac magnetic resonance imaging in patients with left ventricular thrombus.

BACKGROUND: Left ventricular (LV) thrombus formation is a common but potentially serious complication, typically occurring after myocardial infarction. Due to perceived high thromboembolic risk and lack of safety data, stress cardiac magnetic resonance (CMR) imaging especially with dobutamine is usually avoided despite its high diagnostic yield. This study aimed to investigate the characteristics, safety and outcome of patients with LV thrombus undergoing dobutamine or vasodilator stress CMR. METHODS: Patients undergoing stress CMR with concomitant LV thrombus were retrospectively included. Risk factors, comorbidities, and previous embolic events were recorded. Periprocedural safety was assessed for up to 48 h following the examination. Major adverse cardiac events (MACE) 12 months before the diagnosis were compared to 12 months after the exam and between patients and a matched control group. Additionally, patients were followed up for all-cause mortality. RESULTS: 95 patients (78 male, 65 ± 10.7 years) were included. Among them, 43 patients underwent dobutamine (36 high-dose, 7 low-dose) and 52 vasodilator stress CMR. Periprocedural safety was excellent with no adverse events. During a period of 24 months, 27 MACE (14.7%) occurred in patients and controls with no statistical difference between groups. During a median follow-up of 33.7 months (IQR 37.6 months), 6 deaths (6.3%) occurred. Type of stress agent, thrombus mobility, or protrusion were not correlated to embolic events or death. CONCLUSION: The addition of a stress test to a CMR exam is safe and does increase the generally high cardioembolic event rate in LV thrombus patients. Therefore, it is useful to support reperfusion decision-making.

Cardioprotective and Antianginal Efficacy of Nicorandil: A Comprehensive Review.

ABSTRACT: Angina pectoris remains a significant burden despite advances in medical therapy and coronary revascularization. Many patients (up to 30%) with angina have normal coronary arteries, with coronary microvascular disease and/or coronary artery vasospasm being major drivers of the myocardial demand-supply mismatch. Even among patients revascularized for symptomatic epicardial coronary stenosis, recurrent angina remains highly prevalent. Medical therapy for angina currently centers around 2 disparate goals, viz secondary prevention of hard clinical outcomes and symptom control. Vasodilators, such as nitrates, have been first-line antianginal agents for decades, along with beta-blockers and calcium channel blockers. However, efficacy in symptoms control is heterogenous, depending on underlying mechanism(s) of angina in an individual patient, often necessitating multiple agents. Nicorandil (NCO) is an antianginal agent first discovered in the late 1970s with a uniquely dual mechanism of action. Like a typical nitrate, it mediates medium-large vessel vasodilation through nitric oxide. In addition, NCO has adenosine triphosphate (ATP)-dependent potassium channel agonist activity (K ATP ), mediating microvascular dilatation. Hence, it has proven effective in both coronary artery vasospasm and coronary microvascular disease, typically challenging patient populations. Moreover, emerging evidence suggests that cardiomyocyte protection against ischemia through ischemic preconditioning may be mediated through K ATP agonism. Finally, there is now fairly firm evidence in favor of NCO in terms of hard event reduction among patients with stable coronary artery disease, following myocardial infarction, and perhaps even among patients with congestive heart failure. This review aims to summarize the mechanism of action of NCO, its efficacy as an antianginal, and current evidence behind its impact on hard outcomes. Finally, we review other cardiac and emerging noncardiac indications for NCO use.

Adenosine triphosphate (ATP): a safe and effective vasodilator for stress perfusion cardiac magnetic resonance imaging.

AIM: To evaluate the efficiency and safety of adenosine triphosphate (ATP) as a stress agent in a cohort of patients undergoing stress perfusion cardiac magnetic resonance imaging (CMRI). MATERIALS AND METHODS: This retrospective study was conducted between December 2019 and October 2021. The study recruited patients who underwent stress perfusion CMRI using ATP as a vasodilator. Adverse events, such as chest pain, flushing, dyspnoea, headache, and splenic switch-off (SSO) phenomenon, were evaluated in the patients who underwent stress perfusion CMRI. RESULTS: The study included 107 patients (age range: 53 ± 11 years; male:female, 62%:38%). The haemodynamic response (heart rate increased by ≥ 10 beats/min) was quick and observed within 2 minutes of ATP infusion. Scanning was stopped in three patients because of atrioventricular block. CMRI images of seven out of 104 patients were excluded from the final analysis because of inferior quality. During ATP infusion, 37/107 patients (35%) experienced mild adverse events, such as chest pain, flushing, dyspnoea, headache, and atrioventricular block. Myocardial infarction and bronchospasms were not observed during ATP infusion. SSO, a marker of adequate stress, was observed in 91% (94/103) of the patients who underwent stress perfusion CMRI. CONCLUSIONS: As a coronary vasodilator, ATP was safe for stress perfusion CMRI. In addition, the adverse events during ATP infusion were mild, which were relieved within 2 minutes of ATP injection cessation. SSO could serve as an indicator of stress success in ATP stress perfusion CMRI.

Adenosine as adjunctive therapy in acute coronary syndrome: a meta-analysis of randomized controlled trials.

AIMS: Adenosine has been tested in several randomized controlled trials (RCTs) to minimize the incidence of coronary microvascular obstruction (CMVO). The aim of this study was to pool all the RCTs comparing intracoronary or intravenous adenosine versus placebo in patients with acute coronary syndrome (ACS) undergoing myocardial revascularization. METHODS AND RESULTS: PubMed and Scopus electronic databases were scanned for eligible studies up to 5th June 2022. A total of 26 RCTs with 5843 patients were included. Efficacy endpoints were major adverse cardiac events (MACE), all-cause death, non-fatal myocardial infarction, and heart failure. Atrioventricular blocks and ventricular fibrillation/sustained ventricular tachycardia (VF/SVT) were the safety endpoints. Myocardial blush grade, thrombolysis in myocardial infarction (TIMI) flow grade, left ventricular ejection fraction (LVEF), infarct size, and ST-segment resolution were also assessed. Adenosine administration was not associated with any clinical benefit in terms of MACE, all-cause death, non-fatal myocardial infarction, and heart failure. However, adenosine was associated with an increased rate of advanced atrioventricular blocks and of VF/SVT in studies with total mean ischaemic time >3 h, compared to placebo. Remarkably, among patients undergoing percutaneous coronary intervention, adenosine was associated with reduced myocardial blush grade 0-1 and TIMI flow grade 0-2, compared to placebo. Furthermore, adenosine did not show favourable effects on LVEF and infarct size. CONCLUSION: Adenosine infusion, as adjunctive therapy in ACS, was associated with an increased risk of advanced atrioventricular blocks and increased rates of adenosine-triggered ventricular arrhythmias in patients with long ischaemic time, without providing any clinical benefit compared to placebo.

The Impact of Trimetazidine on Cardiac Fibrosis, Inflammation, and Function in Ischemic Cardiomyopathy Patients.

BACKGROUND: Previous studies have shown that Trimetazidine (TMZ) improves vascular endothelial function and reduces the inflammatory process progression. However, limited data have been available regarding its effects on myocardial fibrosis following ischemia and causing left ventricular dysfunction. PURPOSE: To investigate the impact of TMZ adjuvant therapy for ischemic cardiomyopathy (ICM) on cardiac fibrosis, vascular endothelial function, inflammation, and myocardial functions. METHODS: This randomized, double-blind controlled clinical trial included 48 patients (aged 59.4 ± 9 years) with ICM who were randomly assigned to two groups: TMZ 35 mg twice daily and placebo in addition to conventional ICM medications. All patients received the tablets for 3 months. Both groups were then compared in terms of connective tissue growth factor (CTGF), endothelin-1 (ET-1), tumor necrosis factor-alpha (TNF-α), and some echocardiographic indices, weekly angina attacks and nitrate consumption before and after treatment. RESULTS: No significant differences between CTGF, ET-1, and TNF-α levels, in addition to some echocardiographic indices, were observed between both groups before treatment. After treatment, the TMZ group had significantly lower ET-1 than the placebo group, with both groups exhibiting a substantial decrease in TNF-α and CTGF. The TMZ group had lower mean ± SD levels for TNF-α and CTGF and showed significant improvement in echocardiographic indices and weekly angina attacks after treatment. CONCLUSION: Adjunctive TMZ therapy for ICM effectively improved vascular endothelial function and reduced inflammation. Furthermore, our exploratory findings may be used to provide new information on the potential effects of TMZ on myocardial fibrosis by downregulating CTGF.

Milrinone Versus Sildenafil in Treatment of Neonatal Persistent Pulmonary Hypertension: A Randomized Control Trial.

ABSTRACT: Persistent pulmonary hypertension of the newborn (PPHN) is a condition caused by failure of pulmonary vascular adaptation at birth, resulting in severe hypoxia. Several therapeutic modalities are being tried in developing countries where established therapies (inhaled nitric oxide and extracorporeal membrane oxygenation) are widely unavailable. This study aimed to assess the efficacy of milrinone versus sildenafil as available alternative therapeutics in treating PPHN. Forty neonates (>34 weeks) admitted to neonatal intensive care units with evidence of PPHN were randomly allocated to receive either oral sildenafil (0.5-2 mg/kg/6 hours) or intravenous milrinone (0.25-0.75 mic/kg/min). Primary outcomes included improvements in systolic pulmonary artery pressure and oxygen saturation index (OSI) at 24 and 48 hours after treatment. Secondary outcomes included the duration of hospitalization and mechanical ventilation. The ClinicalTrials identifier is NCT04391478. Both groups showed significant improvement in the post-treatment hemodynamic variables compared with pretreatment levels ( P < 0.05 for all parameters). Systolic pulmonary artery pressure and OSI values significantly improved in both study groups compared with baseline ( P < 0.001). The 24-hour and 48-hour post-treatment OSI values were much lower in the milrinone group than those in the sildenafil group ( P < 0.05). The length of hospital stay was significantly shorter in the milrinone group than that in the sildenafil group ( P < 0.05). There were no significant differences in the duration of mechanical ventilation, incidence of intracranial hemorrhage and pulmonary hemorrhage, or mortality between the 2 groups ( P > 0.05). In conclusion, milrinone and sildenafil are effective and well-tolerated in neonates with PPHN, particularly when inhaled nitric oxide and extracorporeal membrane oxygenation are not available. Milrinone is superior to sildenafil in improving oxygenation without lowering blood pressure parameters.

Nitric Oxide Is the Cause of Nitroglycerin Tolerance: Providing an Old Dog New Tricks for Acute Heart Failure.

Our paper highlights the past 50 years of research focusing solely on tolerance involving nitroglycerin (glyceryl trinitrate, GTN). It also identifies and discusses inconsistencies in previous mechanistic explanations that have failed to provide a way to administer GTN continuously, free of limitations from tolerance and without the requirement of a nitrate-free interval. We illustrate, for the first time in 135 years, a mechanism whereby nitric oxide, the mediator of vasodilation by GTN, may also be the cause of tolerance. Based on targeting superoxide from mitochondrial complex I, uncoupled by glutathione depletion in response to nitric oxide from GTN, a novel unit dose GTN formulation in glutathione for use as a continuous i.v. infusion has been proposed. We hypothesize that this will reduce or eliminate tolerance seen currently with i.v. GTN. Finally, to evaluate the new formulation we suggest future studies of this new formulation for the treatment of acute decompensated heart failure.

Safety and tolerability of regadenoson in comparison with adenosine stress cardiovascular magnetic resonance: Data from a multicentre prospective registry.

To assess the feasibility and incidence of immediate complications of stress cardiovascular magnetic resonance (CMR) with regadenoson in comparison with adenosine in a large referral population. This is a large, multicenter, prospective registry of vasodilator stress-CMR in a referral population. We recorded the clinical and demographic data, quality of test, CMR findings, hemodynamic data, and complications. Between January 2016 and July 2019, 2908 patients underwent stress-CMR, 2253 with regadenoson and 655 with adenosine. 25.1% of patients had previously known coronary artery disease (CAD). In 305 patients regadenoson was used due to presence of chronic obstructive pulmonary disease (COPD) or asthma, while in 1948 subjects regadenoson was used as first-line vasodilator. Quality was optimal in 90.0%, suboptimal in 9.5%, and poor in 0.5%. Images were diagnostic in 98.9%. After stress with regadenoson, aminophylline 200 mg was administered intravenously in all patients. No patient died or had severe immediate complications with regadenoson as opposed to 2 severe bronchospasm with adenosine (p = 0.05). 11 patients (0.5%) had non-severe complications with regadenoson and five patients (0.8%) with adenosine (p = n.s.). Only two patients (0.088%) had non-severe bronchospasm after regadenoson administration. All complications were solved in the CMR unit, with no need for further specific care. Factors significantly associated with presence of complications were history of COPD or asthma and detection of inducible ischaemia. Patients had significantly more minor symptoms when adenosine was used (66.0% vs. 18.4%, p < 0.0001). Stress-CMR with regadenoson is feasible, providing diagnostic information in a referral population. Regadenoson had an excellent safety profile and better tolerability than adenosine, with no serious immediate complications and low incidence of non-severe complications. Only inducible ischaemia and previous history of COPD or asthma were associated with complications after regadenoson-CMR. The incidence of minor symptoms was low.

Global endothelial function assessment using pulse wave analysis in hypercholesterolemia

To compare global endothelial function assessed by pulse wave analysis (PWA) using the ratio of endothelium dependent vasodilatation (EDV) to endothelium independent vasodilatation (EIV) in patients with hypercholesterolemia and controls. 92 subjects [46 hypercholesterolemics, 46 controls] were studied at standardized conditions. Baseline augmentation index (AIx) was assessed followed by the administration of 0.5 mg sublingual nitroglycerine, an endothelium independent vasodilator. AIx was assessed and the maximum change in AIx after nitroglycerine was recorded as EIV. After a washout period of 30 minutes, 400 µg of inhaled salbutamol, an endothelium dependent vasodilator was administered. AIx was assessed again and the maximum change in AIx after salbutamol was recorded as EDV. Global endothelial function was calculated as EDV:EIV ratio. EDV and EIV in patients with hypercholesterolemia compared to controls were 2.97 ± 3.95 and 6.65 ± 3.80 (p<0.001); and 13.41 ± 4.57 and 15.88 ± 4.78 (p=0.01) respectively. EDV:EIV ratio was significantly reduced in patients with hypercholesterolemia compared to controls; 0.21 ± 0.38 and 0.44 ± 0.24 (p<0.001) respectively. EDV:EIV ratio was significantly reduced in patients with hypercholesterolemia compared to controls. PWA is a potential clinical tool to assess global endothelial function in patients with hypercholesterole

Drug-induced orthostatic hypotension: A systematic review and meta-analysis of randomised controlled trials.

BACKGROUND: Drug-induced orthostatic hypotension (OH) is common, and its resulting cerebral hypoperfusion is linked to adverse outcomes including falls, strokes, cognitive impairment, and increased mortality. The extent to which specific medications are associated with OH remains unclear. METHODS AND FINDINGS: We conducted a systematic review and meta-analysis to evaluate the extent to which specific drug groups are associated with OH. EMBASE, MEDLINE, and Web of Science databases were searched from inception through 23 November 2020. Placebo-controlled randomised controlled trials (RCTs) on any drug reporting on OH as an adverse effect in adults (≥18 years) were eligible. Three authors extracted data on the drug, OH, dose, participant characteristics, and study setting. The revised Cochrane risk-of-bias tool for randomised trials (RoB 2) was used to appraise evidence. Summary odds ratios (ORs) were estimated for OH using fixed effects Mantel-Haenszel statistics. We conducted subgroup analysis on validity of OH measurement, drug dose, risk of bias, age, and comorbidity. The Grading of Recommendations Assessment, Development, and Evaluation (GRADE) tool was used to summarise the certainty of evidence. Of 36,940 citations, 69 eligible RCTs were included in the meta-analysis comprising 27,079 participants. Compared with placebo, beta-blockers and tricyclic antidepressants were associated with increased odds of OH (OR 7.76 [95% CI 2.51, 24.03]; OR 6.30 [95% CI 2.86, 13.91]). Alpha-blockers, antipsychotics, and SGLT-2 inhibitors were associated with up to 2-fold increased odds of OH, compared to placebo. There was no statistically significant difference in odds of OH with vasodilators (CCBs, ACE inhibitors/ARBs, SSRIs), compared to placebo. Limitations of this study are as follows: data limited to placebo-controlled studies, (excluding head-to-head trials), many RCTs excluded older participants; therefore results may be amplified in older patients in the clinical setting. The study protocol is publicly available on PROSPERO (CRD42020168697). CONCLUSIONS: Medications prescribed for common conditions (including depression, diabetes, and lower urinary tract symptoms) were associated with significantly increased odds of OH. Drugs causing sympathetic inhibition were associated with significantly increased odds of OH, while most vasodilators were associated with small nonsignificant differences in odds of OH, compared to placebo. Drugs targeting multiple parts of the orthostatic blood pressure (BP) reflex pathway (e.g. sympathetic inhibition, vasodilation, cardio-inhibitory effects) may carry cumulative risk, suggesting that individuals with polypharmacy could benefit from postural BP monitoring.

Trimetazidine offers myocardial protection in elderly coronary artery disease patients undergoing non-cardiac surgery: a randomized, double-blind, placebo-controlled trial.

BACKGROUND: Trimetazidine (TMZ) pretreatment protects cardiomyocytes during cardiac surgery. TMZ may protect elderly patients with ischaemic heart disease (IHD) undergoing non-cardiac surgery. METHODS: This was a randomized, double-blind, placebo-controlled trial (registration #ChiCTR1900025018) of patients with IHD scheduled to undergo non-cardiac surgery at Shenzhen People's Hospital (Shenzhen, Guangdong Province, China) between June 2014 and September 2015, randomized to 60 mg TMZ or placebo 12 h before surgery. The primary endpoint was the occurrence of in-hospital cardiovascular events. The secondary endpoints were myocardial ischaemia on five-lead electrocardiogram (cECG), cardiac troponin I (cTnI) elevation, cardiac death, acute coronary events, heart failure, and arrhythmia requiring treatments. RESULTS: Compared with the placebo group, the TMZ group showed a lower occurrence of in-hospital cardiovascular events (primary endpoint, 20.0% vs. 37.5%, P = 0.02), myocardial ischaemia (15.0% vs. 32.5%, P < 0.01), cTnI elevation (2.5% vs. 10%, P < 0.01), acute coronary events (10.0% vs. 20.0%, P < 0.05), heart failure (0% vs. 2.5%, P < 0.05), and arrhythmia requiring treatment (17.5% vs. 35.0%, P < 0.05). There was no acute myocardial infarction during the 30-day postoperative period. CONCLUSIONS: In elderly patients with IHD undergoing non-cardiac surgery, TMZ pretreatment was associated with myocardial protective effects. Trial registration The trial was prospectively registered at http://www.chictr.org.cn/showproj.aspx?proj=41909 with registration number [ChiCTR1900025018] (7/8/2019).

Cutaneous microvascular vasodilatory consequences of acute consumption of a caffeinated soft drink sweetened with high-fructose corn syrup.

This study tested the hypotheses that compared to drinking water, consumption of a caffeinated soft drink sweetened with high-fructose corn syrup (HFCS) attenuates the cutaneous vasodilatory response to local skin heating without (Protocol 1) and following ischemia-reperfusion injury (Protocol 2). In a randomized, counterbalanced crossover design, 14 healthy adults (25 ± 3 year, 6 women) consumed 500 ml of water (water) or a caffeinated soft drink sweetened with HFCS (Mtn. Dew, DEW). Thirty minutes following beverage consumption local skin heating commenced on the right forearm (Protocol 1), while on the left forearm ischemia-reperfusion commenced with 20 min of ischemia followed by 20 min of reperfusion and then local skin heating (Protocol 2). Local skin heating involved 40 min of heating to 39℃ followed by 20 min of heating to 44℃. Skin blood flow (SkBf, laser Doppler) data were normalized to mean arterial pressure and are presented as a cutaneous vascular conductance (CVC) and as percentage of the CVC response during heating to 44℃ (%CVCmax ). Protocol 1: During local heating at 39℃, no differences were observed in CVC (water: 2.0 ± 0.6 PU/mmHg; DEW: 2.0 ± 0.8 PU/mmHg, p = 0.83) or %CVCmax (water: 59 ± 14%; DEW 60 ± 15%, p = 0.84) between trials. Protocol 2: During local skin heating at 39℃, no differences were observed in CVC (water: 1.7 ± 0.5 PU/mmHg; DEW: 1.5 ± 0.5 PU/mmHg, p = 0.33) or %CVCmax (water: 64 ± 15%; DEW 61 ± 15% p = 0.62) between trials. The cutaneous microvascular vasodilator response to local heating with or without prior ischemia-reperfusion injury is not affected by acute consumption of a caffeinated soft drink sweetened with HFCS.

Evidence and Current Use of Levosimendan in the Treatment of Heart Failure: Filling the Gap.

Levosimendan is a distinctive inodilator combing calcium sensitization, phosphodiesterase inhibition and vasodilating properties through the opening of adenosine triphosphate-dependent potassium channels. It was first approved in Sweden in 2000 for the short-term treatment of acutely decompensated severe chronic heart failure when conventional therapy is not sufficient, and in cases where inotropic support is considered appropriate. After more than 20 years, clinical applications have considerably expanded across critical care and emergency medicine, and levosimendan is now under investigation in different cardiac settings (eg, septic shock, pulmonary hypertension) and for non-cardiac applications (eg, amyotrophic lateral sclerosis). This narrative review outlines key milestones in levosimendan history, by addressing regulatory issues, pharmacological peculiarities and clinical aspects (efficacy and safety) of a drug that did not receive great attention in the heart failure guidelines. A brief outlook to the ongoing clinical trials is also offered.

Effect of Vasoactive Intestinal Polypeptide on Development of Migraine Headaches: A Randomized Clinical Trial.

Importance: Vasoactive intestinal polypeptide (VIP) and pituitary adenylate cyclase-activating polypeptides (PACAPs) are structurally and functionally related, yet different in their migraine-inducing properties. It remains unclear whether the lack of migraine induction can be attributed to the only transient vasodilatory response after a 20-minute infusion of VIP. Objective: To determine whether a 2-hour infusion of VIP would provoke migraine attacks. Design, Setting, and Participants: A randomized, double-blind, placebo-controlled, crossover study was conducted between May and September 2020 at the Danish Headache Center in Copenhagen, Denmark. Patients were eligible for inclusion if they were ages 18 to 40 years, weighed between 50 and 90 kg, had a diagnosis of migraine without aura as defined by the International Classification of Headache Disorders, and had a migraine frequency of 1 to 6 attacks per month. Interventions: Patients were randomly allocated to receive a 2-hour infusion of VIP or placebo on 2 different days. Main Outcomes and Measures: The primary end point was the difference in incidence of experimentally induced migraine attacks during the observational period (0-12 hours) between VIP and placebo. Results: Twenty-one patients (17 [81%] women and 4 [19%] men; mean [range] age, 25.9 [19-40] years) were recruited in the study. Fifteen patients (71%; 95% CI, 48%-89%) developed migraine attacks after VIP compared with 1 patient (5%; 95% CI, 0%-24%) who developed a migraine attack after placebo (P < .001). The VIP-induced migraine attacks mimicked patients' spontaneous attacks. The area under the curve (AUC) of headache intensity scores (0-12 hours), as well as the AUC of the superficial temporal artery diameter (0-180 minute) were significantly greater after VIP compared with placebo (AUC0-12h, P = .003; AUC0-180min, P < .001). Conclusions and Relevance: A 2-hour infusion of VIP caused migraine attacks, suggesting an important role of VIP in migraine pathophysiology. VIP and its receptors could be potential targets for novel migraine drugs. Trial Registration: ClinicalTrials.gov Identifier: NCT04260035.

Characteristics of Heart Failure Patients With or Without Hypotension When Transitioning From Nitroprusside to Sacubitril-Valsartan.

BACKGROUND: Sacubitril-valsartan is an angiotensin receptor-neprilysin inhibitor indicated for the treatment of patients with symptomatic heart failure with reduced ejection fraction (HFrEF). Little is known about outcomes of HFrEF patients transitioned from sodium nitroprusside (SNP) to sacubitril-valsartan during an admission for acute decompensated heart failure. We sought to describe characteristics of patients initiated on sacubitril-valsartan while receiving SNP and, in particular, those patients who did and did not experience hypotension requiring interruption or discontinuation of sacubitril-valsartan. METHODS: We performed a retrospective case series of adult patients (>18 years) with HFrEF (left ventricular ejection fraction ≤40%) admitted to the University of Michigan cardiac intensive care unit between July 2018 to September 2020 who received sacubitril-valsartan while on SNP. RESULTS: A total of 15 patients with acute decompensated heart failure were initiated on sacubitril-valsartan while on SNP. The mean age was 57 ± 15.9 years. Seven (46.7%) patients experienced hypotension. The patients in the cohort who experienced hypotension were numerically older (60 ± 17 vs. 55 ± 15.5), and the majority were white (86%). Patients with hypotension had a numerically lower left ventricular ejection fraction (13 ± 4.2 vs. 18 ± 8.2) and higher serum creatinine (1.4 ± 0.54 vs. 0.88 ± 0.25). Seven (100%) patients received a diuretic on the day of sacubitril-valsartan initiation in those who experienced hypotension compared with 2 (25%) in those who did not experience hypotension. CONCLUSIONS: In almost half of patients admitted to the cardiac intensive care unit with acutely decompensated HFrEF, significant hypotension was seen when initiating sacubitril-valsartan while on SNP. Future studies should evaluate appropriate patients for this transition and delineate appropriate titration parameters.