Nitrate Therapy Research Articles

Hydrogel encapsulating gold nanoparticles for targeted delivery of nitroglycerin to reduce post-cardiac dysfunction inflammation by inhibiting the Wnt/β-catenin signaling pathway.

The discovery of nitric oxide's role in biological processes like platelet function, vasodilation, cell permeability, and inflammation has advanced our understanding of organic nitrate therapy's hemodynamic and nonhemodynamic effects. Short-term use of organic nitrates prevents left ventricular enlargement and infarct expansion. However, information on their long-term impact on LV remodeling in post-acute cardiac dysfunction patients is limited. In this study, we utilized an innovative active hydrogel with gelatin (Gel)/polyethylene glycol (PEG)/polylactic acid (PLA) encapsulating gold nanoparticles (AuNPs)-based drug delivery system for the sustained release of nitroglycerin (NTG). Gel/PEG/PLA/NTG/AuNPs hydrogel-based system is a non-transplant surgical method that can adhere to the surface of the heart and deliver the drug directly to the epicardium. Cardiac dysfunction was induced by ligating the left anterior descending coronary artery. Echocardiograms were used to study the pre- and post-operative hemodynamics. Hematoxylin and eosin (H&E) and Masson's trichrome stain (MTS) stainingrevealed that the acute myocardial infarction (AMI) rats' group had irregularly shaped fibers and a lack of transverse striations, whereas Gel/PEG/PLA/NTG/AuNPs hydrogel group showed significant improvement. Rats in the Gel/PEG/PLA hydrogel group demonstrated marked vasodilation, compared to the AMI group. Mechanistically, we determined that hydrogel disrupts the initiation of post-cardiac dysfunction via inhibiting Wnt/β-catenin transcriptional activation. Hence, the Gel/PEG/PLA/NTG/AuNPs hydrogel group effectively protected against ischemic injury and inflammation in AMI, demonstrating a novel method for treating acute cardiac dysfunction.

Facilitating Nitrite-Derived S-Nitrosothiol Formation in the Upper Gastrointestinal Tract in the Therapy of Cardiovascular Diseases.

Cardiovascular diseases (CVDs) are often associated with impaired nitric oxide (NO) bioavailability, a critical pathophysiological alteration in CVDs and an important target for therapeutic interventions. Recent studies have revealed the potential of inorganic nitrite and nitrate as sources of NO, offering promising alternatives for managing various cardiovascular conditions. It is now becoming clear that taking advantage of enzymatic pathways involved in nitrite reduction to NO is very relevant in new therapeutics. However, recent studies have shown that nitrite may be bioactivated in the acidic gastric environment, where nitrite generates NO and a variety of S-nitrosating compounds that result in increased circulating S-nitrosothiol concentrations and S-nitrosation of tissue pharmacological targets. Moreover, transnitrosation reactions may further nitrosate other targets, resulting in improved cardiovascular function in patients with CVDs. In this review, we comprehensively address the mechanisms and relevant effects of nitrate and nitrite-stimulated gastric S-nitrosothiol formation that may promote S-nitrosation of pharmacological targets in various CVDs. Recently identified interfering factors that may inhibit these mechanisms and prevent the beneficial responses to nitrate and nitrite therapy were also taken into consideration.

MYOCARDIAL INFARCTION DUE TO LEFT CIRCUMFLEX ARTERY OCCLUSION: A SUBTLE TROJAN HORSE

Abstract A 47–year–old man presented to the emergency department complaining of recurrent chest pain (CP) since the previous day. His medical history included active smoking and dyslipidemia. The ECG revealed sinus bradycardia (56 bpm) with widespread ST elevation, consistent with benign early repolarization, and hyperacute and broad–based T waves in V2–V3 (Fig. A). The echocardiography showed normal left and right ventricular systolic function and no valvular abnormalities. A low but abnormal initial high–sensitivity cardiac troponin I value (40 pg/mL, normal range: 1.7– 34,2 pg/mL) and a slightly and early increase after two hours (52 pg/ml) were seen. Therefore, the patient was admitted to our intensive cardiac care unit (ICCU) with a working diagnosis of non–ST–segment elevation myocardial infarction (NSTEMI). No sign or symptoms of heart failure on physical examination were recorded. GraceScore 2.0 was calculated as 68 points and coronary angiography was organized within 24h. Two hours after admission to the ICCU, the patient experienced a new episode of CP. Consequently, ECG and echo were repeated. Compared to the previous results, ECG showed dynamic changes in V2–V3, with the resolution of hyperacute T waves (Fig B); bedside echo remained unchanged. Considering the unresponsiveness to nitrate therapy, the cath lab was activated for a time–dependent coronary angiography. The exam showed an acute total thrombotic occlusion of the mid–segment of the circumflex branch (LCx) in the setting left–sided dominant circulation. A drug eluting stent was deployed into the culprit lesion (Fig. C), and the coronary flow was restored completely (TIMI Flow 3). The subsequent hospital stay proceeded without complications. The peak troponin level was 60’000 pg/ml. The patient was discharged on the fifth day, asymptomatic and hemodynamically stable, with instructions to continue dual antiplatelet therapy. The case report focuses on the electrocardiographic and angiographic expression of LCx total occlusion. Despite acute myocardial infarction (AMI) size was large, as confirmed by the abnormal troponin I values and the angiographic total occlusion, the first and the repeated ECGs showed only vague repolarization changes without clear ST–segment modifications. LCx occlusion is often characterized by the absence of significant ST–elevation, therefore categorized as NSTEMI. Greater awareness of the presentation of LCx–related AMI can be crucial to avoid delays in reperfusion.

Inflammation-induced sialin mediates nitrate efflux in dysfunctional endothelium affecting NO bioavailability

AimThe mechanism of NO bioavailability in endothelial dysfunction, the trigger for atherogenesis is still unclear as exogenous nitrate therapy fails to alleviate endothelial dysfunction. Recently, sialin, a nitrate transporter, has been linked to affect tissue nitrate/nitrite levels. Hence, we investigated the role of sialin in NO bioavailability in endothelial dysfunction. MethodsSerum-starved HUVECs were stimulated with either TNFα or AT-2 for 24 h either alone or in the presence of autophagy inducer or autophagy inhibitor alone. Nitric oxide, nitrite, and nitrate levels were measured in cell supernatant and cell lysate. Quantitative real-time PCR, Annexin V-PI, and monocyte adhesion assays were performed. Immunofluorescence staining for sialin, vWF, and LC3 was performed. STRING database was used to create protein interacting partners for sialin. ResultsSialin is strongly expressed in activated EC in vitro and atherosclerotic plaque as well as tumor neo-vessel ECs. Sialin mediates nitrate ion efflux and is negatively regulated by autophagy via mTOR pathway. Blocking sialin enhances NO bioavailability, autophagy, cell survival, and eNOS expression while decreasing monocyte adhesion. PPI shows LGALS8 to directly interact with sialin and regulate autophagy, cell-cell adhesion, and apoptosis. ConclusionSialin is a potential novel therapeutic target for treating endothelial dysfunction in atherosclerosis and cancer.

Revisiting nitrates use in pre-shock state of contemporary cardiogenic shock classification.

Patients at each shock stage may behave and present differently with a spectrum of shock severity and adverse outcomes. Shock severity, shock aetiology, and several factors should be integrated in management decision-making. Although the contemporary shock stages classification provided a standardized shock severity assessment, individual agents or management strategy has not yet been studied in the context of each shock stage. The pre-shock state may comprise a wide range of presentations. Nitrate therapy has potential benefit in myocardial infarction and acute heart failure. Herein, this review aims to discuss the potential use of nitrate therapy in the context of the pre-shock state or stage B of the contemporary shock classification given its various presentations.

Atomistic modelling and NMR studies reveal that gallium can target the ferric PQS uptake system in P. aeruginosa biofilms.

Intravenous gallium nitrate therapy is a novel therapeutic strategy deployed to combat chronic Pseudomonas aeruginosa biofilm infections in the lungs of cystic fibrosis (CF) patients by interfering with iron (Fe3+) uptake. The therapy is a source of Ga3+, which competes with Fe3+ for siderophore binding, subsequently disrupting iron metabolism and inhibiting biofilm proliferation in vivo. It was recently demonstrated that the Pseudomonas quinolone signal (PQS) can chelate Fe3+ to assist in bacterial iron uptake. However, it is unknown whether exogenous gallium also targets [Fe(PQS)3] uptake, which, in turn, would extend the mechanism of gallium therapy beyond siderophore competition, potentially supporting use of the therapy against P. aeruginosa mutants deficient in siderophore uptake proteins. To that end, the thermodynamic feasibility of iron-for-gallium cation exchange into [Fe(PQS)3] was evaluated using quantum chemical density functional theory (DFT) modelling and verified experimentally using 1H nuclear magnetic resonance (NMR). We demonstrate here that Ga3+ can strongly bind to three PQS molecules and, furthermore, displace and substitute Fe3+ from the native chelate pocket within PQS complexes, through a Trojan horse mechanism, retaining the key structural features present within the native ferric complex. As such, [Fe(PQS)3] complexes, in addition to ferric-siderophore complexes, represent another target for gallium therapy.

P231 CORONARY VASOSPASM REFRACTORY TO MEDICAL THERAPY AND COMPLICATED BY ASYSTOLE, HOW TO MANAGE IT?

Abstract Vasospastic angina is a form of angina caused by coronary artery spasm. This usually determines rest chest pain and electrocardiogram changes. In some patients severe ventricular tachyarrhythmias or bradyarrhythmias may develop during myocardial ischemia. Vasospastic angina attacks can be prevented by calcium antagonists and nitrates but artery spasm may be refractory to optimal medical therapy. A 66–year–old woman, affected by Hailey–Hailey disease was brought to the emergency department for hemorrhagic shock after anti–conservative purposes. She underwent emergency surgery for haemostasis of the neck lesion, reinsertion of the subhyoid muscles and right parotidectomy. After surgery an electrocardiogram (ECG) showed inferior and posterior ST–segment elevation, total atrioventricular block (AVB) and torsades de pointes (FIG 1), then evolved in asystole and cardiac arrest . ROSC occurred in 4 minutes. Temporary pacemaker (PM) was placed. Coronary angiography showed right coronary artery and left anteriori descending artery vasospasm, slightly reduced after nitroglycein infusion (FIG 2). Transdermal nitrates and calcium channel blocker were started. Hospitalization has been prolonged due to infectious/psychiatric problems, with necessity of percutaneous endoscopic gastrostomy and tracheostomy, A new episode of vasospastic angina developed during hospitalization with recurrence of total AVB and torsades de pointes. Temporary PM was placed but after 24 hours perforated the right ventricle free wall. Echocardiogram showed small circumferential pericardial effusion. The patient underwent transvenous removal of the right ventricular catheter and two lead DDD PM was implanted. She was discharged with nitrate and calcium channel blocker therapy. No recurrence of angina was documented at 6–months follow–up. The management of this clinical case was complex because it was a form of vasospastic angina complicated by 2 cardiac arrests, unresponsive to medical therapy and with temporary PM that perforated the right ventricle. We therefore opted for a definitive PM implant for protection. Few case report describes definitive PM implantation in fatal bradyarrhythmias during vasospastic angina. To date, the best treatment of coronary vasospasm refractory to medical therapy is debated, pecutaneous revascularization and sympathectomy are considered, treatment methods that we will consider at follow–up in case of (probable) anginal recurrences.

Phosphodiesterase Type 5 Inhibitors and Oral Nitrates in Male Patients with Ischemic Heart Disease.

This review sought to define the mechanism of the drug-drug interaction between phosphodiesterase-type-5 (PDE-5) inhibitors and organic nitrates as well as the clinical impact and recommended management across different clinical scenarios. This drug-drug interaction results in hemodynamically significant hypotension during episodic PDE-5 use and acute nitrate administration mainly during cardiovascular emergencies with multiple studies describing the expected impact. Chronic co-administration of long-acting nitrates and PDE-5 inhibitors has been observed in practice in a small percentage of patients despite the labeled contraindication without noted adverse effects. Acute nitrate therapy should be avoided in the context of episodic PDE-5 exposure, likely identified through systematic processes. Few data exist defining risk with lower-intensity daily PDE-5 administration. Chronic co-administration is not recommended but may be navigated with careful risk-benefit determination. Future directions also aim to identify potential areas where nitrate synergy may achieve clinical benefit.

Altered sialin mRNA gene expression in type 2 diabetic male Wistar rats: implications for nitric oxide deficiency

Nitrate therapy has been suggested to boost nitric oxide (NO) levels in type 2 diabetes (T2D); however, little is known about nitrate transport across the membranes. This study aimed to assess changes in the mRNA expression of sialin, as a nitrate transporter, in the main tissues of rats with T2D. Rats were divided into two groups (n = 6/group): Control and T2D. A high-fat diet combined with a low dose of streptozotocin (STZ, 30 mg/kg) was used to induce T2D. At month 6, samples from the main tissues of rats were used to measure the mRNA expression of sialin and levels of NO metabolites. Rats with T2D had lower nitrate levels in the soleus muscle (66%), lung (48%), kidney (43%), aorta (30%), adrenal gland (58%), epididymal adipose tissue (eAT) (61%), and heart (37%) and had lower nitrite levels in the pancreas (47%), kidney (42%), aorta (33%), liver (28%), eAT (34%), and heart (32%). The order of sialin gene expression in control rats was: soleus muscle > kidney > pancreas > lung > liver > adrenal gland > brain > eAT > intestine > stomach > aorta > heart. Compared to controls, rats with T2D had higher sialin mRNA expressions in the stomach (2.1), eAT (2.0), adrenal gland (1.7), liver (8.9), and soleus muscle (3.4), and lower sialin expression in the intestine (0.56), pancreas (0.42), and kidney (0.44), all P values < 0.05. These findings indicate altered sialin mRNA expression in the main tissues of male T2D rats and may have implications for future NO-based treatment of T2D.

Our treatment outcomes in bartholin cysts or abscesses

The purpose of this study was to examine the outcomes of Bartholin abscess or cyst surgery, silver nitrate therapy, and cyst or abscess excision in terms of recurrence, duration of the procedure, and healing times. The files of 100 patients treated in our hospital for Bartholin cysts or abscesses between March 2022 and December 2022 were reviewed retrospectively. The patients’ demographic characteristics were recorded. Demographic data, the location and size of Bartholin abscesses, complaints at presentation, and cases with recurrence were noted. The patients were divided into three groups according to the treatment applied and were compared with one another, especially in terms of recurrence, operative time, and recovery time. Group 1 consisted of those who underwent drainage due to Bartholin cyst or abscess, Group 2 of those treated with silver nitrate, and Group 3 of those who underwent cyst excision. Recurrence was detected in 12 (40%) of the cases in Group 1. Relapsed cases were treated with silver nitrate. Recurrence was observed in only one patient in the group treated with silver nitrate (Group 2). Bartholin cyst excision was performed on that patient. Mean operation times were 2.80 min in Group 1, 4.40 min in Group 2, and 23 min in Group 3 (p=0.0001). Mean recovery times were 3.37±0.49 days in Group 1, 6.13±0.73 days in Group 2, and 13.70±2.09 days in Group 3 (p=0.0001). A comparison of the patients in all three groups revealed that the recurrence rate was higher in the group receiving abscess drainage. While recurrence was observed in only one patient in the silver nitrate group, no recurrence occurred in the cyst excision group (p&lt;0.001). This study emphasizes that silver nitrate application is a simple practical method that can be performed using local anesthesia, and involving minimal scar tissue, a faster procedure time, and faster recovery.

Abstract 11380: Exercise Induced ST Segment Elevation Caused by Coronary Vasospasm

Case Presentation: A 52-year-old male with no known medical history was seen in the cardiology clinic for occasional pressure-like chest pain on exertion. Due to an intermediate pretest probability of CAD, ischemic workup with a nuclear perfusion exercise stress test was planned. Patient achieved maximum predicted heart rate after 12 minutes of exercising, with no anginal symptoms, ST segment changes or arrhythmias during the entire period. However, 3 minutes into the recovery phase, he developed chest pain and diaphoresis, with EKG now showing 7mm ST elevations in the inferior leads and BP falling to 77/56 mmHg. STEMI code was called, and patient was emergently taken to the cardiac cath lab for coronary angiogram and possible PCI. Angiogram found the coronary arteries to be non-obstructive but revealed vessels possibly having vasospasm. Intra coronary nitroglycerin was given with no further PCI. The patient’s symptoms subsided after the angiogram, and he remained asymptomatic thereupon and was eventually discharged on Verapamil and nitrate therapy. Discussion: Typically, vasospastic angina occurs at rest. Exercise induced and post-exercise recovery phase ST segment elevation on EKG is associated with severe atherosclerotic disease with significant coronary obstruction. However, exercise induced ST elevations in the post exercise recovery phase caused by non-obstructive, vasospastic coronary arteries, as seen in this patient, is a rare occurrence. The vasospasm is hypothesized to be due to coronary vascular smooth muscle hyperactivity and endothelial cell dysfunction. Treatment is usually with calcium channel blockers, nitrates and lifestyle modification such as smoking cessation and alcohol restriction. This case illustrates the importance of identifying the etiology of the angina, noting that post exercise ST segment elevations are not always associated with coronary vessel obstruction and vasospasm should be considered as a possible etiology.

Prognostic impact of nitrate therapy in patients with myocardial bridge and coexisting coronary artery spasm.

The aim of this study was to investigate the prognostic impact of nitrate therapy in patients with myocardial bridge (MB) and coexisting coronary artery spasm (CAS). MB often accompanies CAS. Nitrates have been widely used as anti-ischemic drugs in CAS patients, while it is not recommended in MB patients. Thus, we investigated the long-term impact of nitrate on clinical outcomes in patients with both CAS and MB. A retrospective observational study was performed using propensity score matching (PSM) in a total of 757 consecutive MB patients with positive acetylcholine (Ach) provocation test. Patients were divided into two groups according to the regular administration of nitrates (nitrate group: n = 504, No nitrate group; n = 253). The PSM was used to adjust for selection bias and potential confounding factors, and major clinical outcomes were compared between the two groups up to 5years. Baseline characteristics were well-matched between the two groups following PSM (n = 211 for both groups). There was no significant difference in the incidence of death, myocardial infarction, and major adverse cardiovascular events (MACEs) between the two groups. However, the nitrate group showed a significantly higher rate of recurrent angina which subsequently needed re-evaluation of coronary arteries by follow-up angiography (15.7 vs. 5.7%, Log-rank p = 0.012) compared to the non-nitrate group. Long-term nitrate administration in patients with MB and coexisting CAS did not show benefit in reducing MACE, rather it was associated with a higher incidence of recurrent angina requiring follow-up angiography.

Negative interaction between nitrates and remote ischemic preconditioning in patients undergoing cardiac surgery: the ERIC-GTN and ERICCA studies

Remote ischaemic preconditioning (RIPC) using transient limb ischaemia failed to improve clinical outcomes following cardiac surgery and the reasons for this remain unclear. In the ERIC-GTN study, we evaluated whether concomitant nitrate therapy abrogated RIPC cardioprotection. We also undertook a post-hoc analysis of the ERICCA study, to investigate a potential negative interaction between RIPC and nitrates on clinical outcomes following cardiac surgery. In ERIC-GTN, 185 patients undergoing cardiac surgery were randomized to: (1) Control (no RIPC or nitrates); (2) RIPC alone; (3); Nitrates alone; and (4) RIPC + Nitrates. An intravenous infusion of nitrates (glyceryl trinitrate 1 mg/mL solution) was commenced on arrival at the operating theatre at a rate of 2–5 mL/h to maintain a mean arterial pressure between 60 and 70 mmHg and was stopped when the patient was taken off cardiopulmonary bypass. The primary endpoint was peri-operative myocardial injury (PMI) quantified by a 48-h area-under-the-curve high-sensitivity Troponin-T (48 h-AUC-hs-cTnT). In ERICCA, we analysed data for 1502 patients undergoing cardiac surgery to investigate for a potential negative interaction between RIPC and nitrates on clinical outcomes at 12-months. In ERIC-GTN, RIPC alone reduced 48 h-AUC-hs-cTnT by 37.1%, when compared to control (ratio of AUC 0.629 [95% CI 0.413–0.957], p = 0.031), and this cardioprotective effect was abrogated in the presence of nitrates. Treatment with nitrates alone did not reduce 48 h-AUC-hs-cTnT, when compared to control. In ERICCA there was a negative interaction between nitrate use and RIPC for all-cause and cardiovascular mortality at 12-months, and for risk of peri-operative myocardial infarction. RIPC alone reduced the risk of peri-operative myocardial infarction, compared to control, but no significant effect of RIPC was demonstrated for the other outcomes. When RIPC and nitrates were used together they had an adverse impact in patients undergoing cardiac surgery with the presence of nitrates abrogating RIPC-induced cardioprotection and increasing the risk of mortality at 12-months post-cardiac surgery in patients receiving RIPC.

Nitrates as a Marker of Multiple Co-morbidities and Increased Mortality in Patients Undergoing Percutaneous Coronary Intervention (PCI).

BackgroundNotwithstanding the guideline endorsement of various anti-anginal medications, there is a paucity of data on whether one anti-anginal regimen or medication is superior to another. It is also unknown how anti-anginal medications affect outcomes of elective percutaneous coronary intervention (PCI). To fill this knowledge gap, we investigated an association between commonly used anti-anginal medications and elective PCI outcomes in stable ischemic heart disease (SIHD) patients. MethodsUsing the New York State's (NYS) PCI Reporting System, we reviewed data on 33,568 consecutive patients who underwent non-emergent PCI in 2015. The primary endpoint of this study was all-cause in-hospital mortality. ResultsRegardless of the combination therapy of nitrates with any other non-nitrate anti-anginal therapy, including beta-adrenergic blockers (BB) and/or calcium channel blockers (CCB), nitrate treatment continued to be associated with significantly increased post-elective PCI mortality.ConclusionsIn this large, all-inclusive state-wide contemporary cohort study of SIHD patients, treatment with nitrates, but not beta-blockers, calcium channel blockers, or ranolazine, was associated with increased post-PCI mortality. Utilization of nitrate therapy is likely reflective of advanced disease burden rather than directly related to the specific medication intolerance. Additional studies investigating optimal anti-anginal medical therapy on PCI outcomes are warranted.

Medical uses for silver nitrate in the urinary tract (Review)

Silver nitrate has been used for centuries for the treatment of a variety of diseases and in the prevention of infection. Silver nitrate exerts astringent, cauterizing and corrosive effects, as well as antimicrobial activities. Silver nitrate injection therapy has a long history of use in urology. It is reportedly effective for hemorrhagic cystitis, interstitial cystitis, renal hematuria and chyluria. The present review article summarizes the medical applications of silver nitrate in urology. The published studies available on the medical uses of silver nitrate are essentially older and retrospective, involving smaller numbers of patients. In the absence of comparative studies with other treatments, it is thus impossible to determine the relative benefits of silver nitrate. However, the outcomes of silver nitrate therapy have been fairly well established. Silver nitrate therapy may prove to be a treatment option for patients who are poor candidates for invasive treatment. Further studies on the uses of silver nitrate however, are required, and improvements also need to be made in the injection technique to reduce the rate of complications.

Evaluation of Quality of Care for US Veterans With Recent-Onset Heart Failure With Reduced Ejection Fraction

Multiple guideline-recommended therapies for heart failure with reduced ejection fraction (HFrEF) are available and promoted by performance measures. However, contemporary data on the use of these therapies are limited. To evaluate trends in guideline-directed medical therapy, implantable cardioverter-defibrillator (ICD) use, and risk-adjusted mortality among patients with recent-onset HFrEF. This cohort study analyzed claims and electronic health record data of patients with recent-onset HFrEF diagnosed at US Department of Veterans Affairs (VA) health care system facilities from July 1, 2013, through June 30, 2019. Veterans who had a history of heart transplant or used a ventricular assist device were among the patients who were excluded. Guideline-directed medical therapy (any β-blocker, guideline-recommended β-blocker [bisoprolol, carvedilol, or metoprolol succinate], angiotensin-converting enzyme inhibitor, angiotensin receptor blocker, angiotensin receptor-neprilysin inhibitor, mineralocorticoid receptor antagonist, and hydralazine plus nitrate) and ICD. Treatment rates for guideline-directed medical therapies and ICDs were calculated within 6 months of the index HFrEF date using medication fills, procedural codes for implantation and monitoring, and diagnosis codes. Risk-adjusted mortality was calculated after adjusting for baseline patient characteristics. For both treatment rates and risk-adjusted mortality, we evaluated the change over 3 periods (period 1: July 1, 2013, to June 30, 2015; period 2: July 1, 2015, to June 30, 2017; and period 3: July 1, 2017, to June 30, 2019) and variation across VA facilities. The final cohort comprised 144 074 eligible patients with incident HFrEF that was diagnosed between July 1, 2013, and June 30, 2019. The cohort had a mean (SD) age of 71.0 (11.4) years and was mostly composed of men (140 765 [97.7%]). Overall, changes in medical therapy rates were minimal over time, with the use of a guideline-recommended β-blocker increasing from 64.2% in 2013 to 72.0% in 2019. Rates for mineralocorticoid receptor antagonist therapy increased from 23.9% in 2013 to 26.9% in 2019, and rates for hydralazine plus nitrate therapy remained stable at 24.2% over the study period. Rates for angiotensin receptor-neprilysin inhibitor therapy increased since its introduction in 2015 but only to 22.6% in 2019. Among patients with an ICD indication, early use rates decreased over time. Substantial variation in medical therapy rates persisted across VA facilities. Risk-adjusted mortality decreased over the study period from 19.9% (95% CI, 19.6%-20.2%) in July 1, 2013, to June 30, 2015, to 18.4% (95% CI, 18.0%-18.7%) in July 1, 2017, to June 30, 2019 (OR, 0.96 per additional year; 95% CI, 0.96-0.97). This study found only marginal improvement between 2013 and 2019 in the guideline-recommended therapy and mortality rates among patients with recent-onset HFrEF. New approaches to increase the uptake of evidence-based HFrEF treatment are urgently needed and could lead to larger reductions in mortality.

Potential Role of Cardiopulmonary Exercise Testing as an Early Screening Tool for Patients With Suspected Pulmonary Hypertension Including Exercise-Induced Pulmonary Hypertension: Results From a Retrospective Analysis.

The primary goal of our retrospective case-control study was to evaluate the ability of cardiopulmonary exercise testing to screen for underlying exercise-induced pulmonary hypertension (EIPH) in symptomatic patients who had a negative stress test and elevated right ventricular systolic pressure on echocardiogram. We also evaluated long-acting nitrates and ranolazine as medication challenges. Performed at a single, tertiary-care medical center in the United States. Based on the inclusion and exclusion criteria, 81 patients were included in this study. The primary outcome of the study was to measure mean pulmonary arterial pressure at rest and exertion, as well as Wasserman curves. We also recorded patient demographics and risk factors, left ventricular ejection fraction, and mean oxygen consumption. Additionally, patients were monitored symptomatically after receiving long-acting nitrates and ranolazine. A total of 61 patients had resting pulmonary arterial hypertension, and 27 had EIPH. The EIPH group had a significantly higher mean age of 71.67 years. Wasserman curves calculated from the cardiopulmonary exercise testing data revealed 3 subgroups of EIPH patients: cardiac restriction, chronotropic incompetence, and combination of both patterns. The EIPH group showed significant improvement in symptoms after receiving long-acting nitrate therapy. Many patients with symptoms of angina, dyspnea, and/or fatigue on exertion with negative cardiac stress testing may have underlying pulmonary arterial hypertension, including EIPH. Therefore, these patients require adequate treatment and follow-up to prevent worsening of symptoms and pathology.

Treating Umbilical Granuloma with Topical Corticosteroid: A Systematic Review and Meta-analysis

Background: Umbilical granuloma so far can be treated with surgery or with silver nitrate. In limited facilities such as in remote areas where the surgeon is limited, pharmacological therapy with silver nitrate or topical steroid can be given. However, treatment with silver nitrate requires medical personnel and has unfavorable adverse effects if done by improper technique. This systematic review aimed to evaluate the effectiveness of topical steroid for treating an umbilical granuloma compared to silver nitrate therapy. Method: The literature search was done using search engines including PubMed, Embase, and Google Scholar. Literature selection was performed with limitations from 2000 to 2020 to get the novelty and written in the English language with a target population of infants less than 6 months were included. To retrieve the articles, topical corticosteroids, topical steroids, and umbilical granuloma were used as keywords. Results: The findings from the included studies show similar sample characteristics. The study conducted by Brodsgaard et al. had an older mean sample age than the study of Ogawa et al. (53.4 vs 31 days). The risk of topical steroid treatment failure on an individual study conducted by Brodsgaard et al. and Ogawa et al. was 3.0 (0.33–27.23, p = 0.33) and 0.94 (0.40–2.21; p = 0.33), respectively. Overall analysis, the risk of treatment failure was 1.09 (0.49–2.43, p = 0.82), there was no difference between the two interventions. Conclusions: One of the umbilical granuloma treatment options that can be considered is topical steroids, such as clobetasol proprionate 0.05% or betamethasone valerate 0.12%. When compared to silver nitrate, topical steroids have a longer therapeutic healing time but with a better safety profile. The non-inferiority study of topical steroids to silver nitrate has not been met yet.

Effect of an Emergency Department Care Bundle on 30-Day Hospital Discharge and Survival Among Elderly Patients With Acute Heart Failure

Clinical guidelines for the early management of acute heart failure in the emergency department (ED) setting are based on only moderate levels of evidence, with subsequent low adherence to these guidelines. To test the effect of an early guideline-recommended care bundle on short-term prognosis in older patients with acute heart failure in the ED. Stepped-wedge cluster randomized trial in 15 EDs in France of 503 patients 75 years and older with a diagnosis of acute heart failure in the ED from December 2018 to September 2019 and followed up for 30 days until October 2019. A care bundle that included early intravenous nitrate boluses; management of precipitating factors, such as acute coronary syndrome, infection, or atrial fibrillation; and moderate dose of intravenous diuretics (n = 200). In the control group, patient care was left to the discretion of the treating emergency physician (n = 303). Each center was randomized to the order in which they switched to the "intervention period." After the initial 4-week control period for all centers, 1 center entered in the intervention period every 2 weeks. The primary end point was the number of days alive and out of hospital at 30 days. Secondary outcomes included 30-day all-cause mortality, 30-day cardiovascular mortality, unscheduled readmission, length of hospital stay, and kidney impairment. Among 503 patients who were randomized (median age, 87 years; 298 [59%] women), 502 were analyzed. In the intervention group, patients received a median (interquartile range) of 27.0 (9-54) mg of intravenous nitrates in the first 4 hours vs 4.0 (2.0-6.0) mg in the control group (adjusted difference, 23.8 [95% CI, 13.5-34.1]). There was a significantly higher percentage of patients in the intervention group treated for their precipitating factors than in the control group (58.8% vs 31.9%; adjusted difference, 31.1% [95% CI, 14.3%-47.9%]). There was no statistically significant difference in the primary end point of the number of days alive and out of hospital at 30 days (median [interquartile range], 19 [0- 24] d in both groups; adjusted difference, -1.9 [95% CI, -6.6 to 2.8]; adjusted ratio, 0.88 [95% CI, 0.64-1.21]). At 30 days, there was no significant difference between the intervention and control groups in mortality (8.0% vs 9.7%; adjusted difference, 4.1% [95% CI, -17.2% to 25.3%]), cardiovascular mortality (5.0% vs 7.4%; adjusted difference, 2.1% [95% CI, -15.5% to 19.8%]), unscheduled readmission (14.3% vs 15.7%; adjusted difference, -1.3% [95% CI, -26.3% to 23.7%]), median length of hospital stay (8 d in both groups; adjusted difference, 2.5 [95% CI, -0.9 to 5.8]), and kidney impairment (1% in both groups). Among older patients with acute heart failure, use of a guideline-based comprehensive care bundle in the ED compared with usual care did not result in a statistically significant difference in the number of days alive and out of the hospital at 30 days. Further research is needed to identify effective treatments for acute heart failure in older patients. ClinicalTrials.gov Identifier: NCT03683212.

S-Nitrosylation of Akt by organic nitrate delays revascularization and the recovery of cardiac function in mice following myocardial infarction.

The effects of long‐term nitrate therapy are compromised due to protein S‐Nitrosylation, which is mediated by nitric oxide (NO). This study is to determine the role of Akt S‐Nitrosylation in the recovery of heart functions after ischaemia. In recombinant Akt protein and in HEK293 cells, NO donor decreased Akt activity and induced Akt S‐Nitrosylation, but was abolished if Akt protein was mutated by replacing cysteine 296/344 with alanine (Akt‐C296/344A). In endothelial cells, NO induced Akt S‐Nitrosylation, reduced Akt activity and damaged multiple cellular functions including proliferation, migration and tube formation. These alterations were ablated if cells expressed Akt‐C296/344A mutant. In Apoe−/− mice, nitroglycerine infusion increased both Akt S‐Nitrosylation and infarct size, reduced Akt activity and capillary density, and delayed the recovery of cardiac function in ischaemic hearts, compared with mice infused with vehicle. Importantly, these in vivo effects of nitroglycerine in Apoe−/− mice were remarkably prevented by adenovirus‐mediated enforced expression of Akt‐C296/344A mutant. In conclusion, long‐term usage of organic nitrate may inactivate Akt to delay ischaemia‐induced revascularization and the recovery of cardiac function through NO‐mediated S‐Nitrosylation.