Administration Of Nitroglycerin Research Articles

The first study to evaluate non-invasive haemodynamic profile changes in reaction to nitroglycerin in patients with HFmrEF in comparison to HFpEF and HFrEF

Abstract Introduction According to 2021 guidelines for management of heart failure (HF) there are 3 types of HF – with reduced (HFrEF; ≤40%), mildly reduced (HFmrEF; 41–49%) and preserved (HFpEF; ≥50%) left ventricle ejection fraction (LVEF). The middle group – HFmrEF – is the least known and requires further research. The aim of the study was to assess clinical and hemodynamic profile of patients with HFmrEF at rest and after sublingual administration of 0.4 mg of nitroglycerin (NTG). Material and methods The hemodynamic profile was assessed on the last day of hospitalization due to acute decompensated heart failure. The control groups for patients with HFmrEF were groups of HFpEF and HFrEF, while there was no control group on healthy subjects. The clinical profile of patients was assessed by data from medical interview, results of laboratory tests and measured echocardiographic parameters, while the hemodynamic profile – at rest and after administration of 0.4mg of NTG – was assessed by electrical cardiometry (EC) using the ICON® device. Results Overall, 15 consecutive patients from each type of HF were included into the study and most of them were men (N=32; 71%). Diabetes was significantly more frequent in the HFpEF group. The HFrEF group had significantly higher left ventricle end-diastolic dimension (LVDD; p=0.0003) and lower right ventricle systolic function (TAPSE; p=0.0026). The analysis of the hemodynamic profile at rest showed significant differences between HFmrEF and HFrEF in systolic time ratio (STR; p=0.0202) and pre-ejection period (PEP; p=0.0487). In comparison to HFrEF group, patients with HFmrEF were significantly different in the change of stroke volume and stroke volume index (SV/SI; p=0.0134/0.0223), cardiac output and cardiac index (CO/CI; p=0.005/0.0079), systemic vascular resistance and its' indexed values (SVR/SVRI; p=0.0339/0.0294), the cardiac power index (CPI; p=0.0489) and corrected flow time (FTC; p=0.0369). The change in the following parameters: SV, SI, CO, CI, FTC, SVR, SVRI and CPI after NTG administration, in the HFmrEF group had and an opposite direction in comparison to patients with HFpEF (p=NS) and HFrEF (p<0.05) (Fig. 1). The principal component analysis showed that the HFmrEF group is less heterogenetic and located within the two others (Fig. 2). Conclusions Clinical profile of patients with HFmrEF based on medical interview, laboratory and echographic findings showed that they are a mid-filed group. Patients with HFmrEF significantly differs from HFrEF in the changes of hemodynamic profile after sublingual NTG administration, considering EC parameters of the blood flow (SV, SI, CO, CI, SVR, SVRI) and heart muscle contractility (CPI, FTC). The reaction to NTG showed that HFmrEF is the intermediate and more homogeneous group that is comprised in the other two groups. The median reaction to NTG in the HFmrEF group was opposite to the reaction in HFpEF and HFrEF patients. Funding Acknowledgement Type of funding sources: None.

Air pollution and coronary vasomotor disorders in patients with myocardial ischemia and non-obstructive coronary arteries

Abstract Background Coronary vasomotor abnormalities are an important cause of myocardial ischemia in patients with non-obstructive coronary artery disease (NOCAD). However, the role of air pollution in determining vasomotor disorders has never been investigated. Purpose In this study, we evaluated the association between long-term exposure to particulate matter (PM) PM2.5 and PM10 and coronary vasomotor disorders in NOCAD patients. Methods Patients with myocardial ischemia and NOCAD undergoing intracoronary provocative test with acetylcholine (ACh) were prospectively enrolled. The test was considered positive for epicardial coronary spasm in the presence of focal or diffuse epicardial coronary diameter reduction ≥90% in comparison with the relaxed state following intracoronary nitroglycerin administration given to relieve the spasm, associated with the reproduction of the patient's symptoms and ischaemic ECG shifts. Both patients with chronic myocardial ischemia (INOCA) and myocardial infarction with non-obstructive coronary arteries (MINOCA) were enrolled. Based on each case's home address, exposure to PM2.5 and PM10 was assessed. Only patients with >2 years of available data on air pollution exposure prior to coronary angiography were included. Results We enrolled 287 patients (median age 62.0 years [52.0–70.0], 149 [51.9%] males): 161 (56.1%) INOCA and 126 (43.9%) MINOCA. One hundred seventy-six patients (61.3%) had positive provocative test. Exposure to PM2.5 (Figure 1) and PM10 was higher in patients with a positive provocative test (p<0.001). PM2.5 and PM10 were independent predictors of a positive coronary provocative test after adjustment for confounders. Interestingly, among patients with a positive provocative test, PM2.5 and PM10 were both independent predictors of MINOCA (p<0.001 and p=0.001, respectively; Figure 2) as clinical presentation, while only PM2.5 was independently associated with the occurrence of epicardial spasm as opposed to microvascular spasm (p<0.001). Conclusions We provide novel insights into the missing link between air pollution and ischemic heart disease. In particular, higher exposure to air pollution in patients with myocardial ischemia and NOCAD is associated with coronary vasomotor abnormalities, and PM2.5 is an independent risk factor for the occurrence of epicardial spasm and for MINOCA as clinical presentation. Funding Acknowledgement Type of funding sources: None.

A c-Fos activation map in nitroglycerin/levcromakalim-induced models of migraine

BackgroundChronic migraine is a common and highly disabling disorder. Functional MRI has indicated that abnormal brain region activation is linked with chronic migraine. Drugs targeting the calcitonin gene-related peptide (CGRP) or its receptor have been reported to be efficient for treating chronic migraine. The CGRP signaling was also shared in two types of chronic migraine models (CMMs). However, it remains unclear whether the activation of specific brain regions could contribute to persistent behavioral sensitization, and CGRP receptor antagonists relieve migraine-like pain in CMMs by altering specific brain region activation. Therefore, it’s of great interest to investigate brain activation pattern and the effect of olcegepant (a CGRP receptor-specific antagonist) treatment on alleviating hyperalgesia by altering brain activation in two CMMs, and provide a reference for future research on neural circuits.MethodsRepeated administration of nitroglycerin (NTG) or levcromakalim (LEV) was conducted to stimulate human migraine-like pain and establish two types of CMMs in mice. Mechanical hypersensitivity was evaluated by using the von Frey filament test. Then, we evaluated the activation of different brain regions with c-Fos and NeuN staining. Olcegepant was administered to explore its effect on mechanical hyperalgesia and brain region activation.ResultsIn two CMMs, acute and basal mechanical hyperalgesia was observed, and olcegepant alleviated mechanical hyperalgesia. In the NTG-induced CMM, the medial prefrontal cortex (mPFC), anterior cingulate cortex (ACC), and the caudal part of the spinal trigeminal nucleus (Sp5c) showed a significant increase of c-Fos expression in the NTG group (p < 0.05), while pre-treatment with olcegepant reduced c-Fos expression compared with NTG group (p < 0.05). No significant difference of c-Fos expression was found in the paraventricular thalamic nucleus (PVT) and ventrolateral periaqueductal gray (vlPAG) between the vehicle control and NTG group (p > 0.05). In the LEV-induced CMM, mPFC, PVT, and Sp5c showed a significant increase of c-Fos expression between vehicle control and LEV group, and olcegepant reduced c-Fos expression (p < 0.05). No significant difference in c-Fos expression was found in vlPAG and ACC (p > 0.05).ConclusionsOur study demonstrated the activation of mPFC and Sp5c in two CMMs. Olcegepant may alleviate hyperalgesia of the hind paw and periorbital area by attenuating brain activation in CMMs.

Intracoronary injection of nitroglycerine can prevent unnecessary percutaneous coronary intervention

BackgroundDespite the recommendation of the current guidelines, intracoronary administration of nitroglycerine during coronary angiography is often neglected. We investigated the effect of intra-coronary nitroglycerin on the relief of coronary artery stenosis in the candidates for percutaneous coronary intervention (PCI).MethodsWe included patients with angina pectoris or myocardial infarction who were candidates for PCI. In the coronary angiography, the culprit vessel involved was evaluated, and bolus nitroglycerin at a dose of 25–200 mcg was injected into the affected coronary artery. A significant change in the percentage of coronary artery stenosis was considered a positive response, and these patients were then compared with patients who did not have a substantial change in the percentage of stenosis at the same time. Univariate analysis and then multivariate logistic regression analysis was performed to determine the predictors of response to intracoronary nitroglycerin.ResultsAmong 360 patients, 27 (7.5%) responded to nitroglycerine, and 333 (92.5%) were non-responsive. The mean age of patients was 60.2 ± 11.6 years, ranging from 23 to 93 years, and 265 (73.6%) were men. The study groups were not significantly different in the baseline demographic characteristics. The presence of multivessel disease (Odds ratio (OR) = 16.26, 95% confidence interval (CI):2.07–127.6; P = 0.008) and stenosis in the left circumflex artery (OR = 3.62, 95% CI: 1.03–12.70; P = 0.044) were the independent predictors for nonresponse to nitroglycerine, leading to PCI.ConclusionIn some cases, especially those without multivessel diseases, intracoronary nitroglycerine administration can efficiently relieve coronary stenosis and prevent unnecessary PCI.

Modelling migraine-related features in the nitroglycerin animal model: Trigeminal hyperalgesia is associated with affective status and motor behavior

Migraine is a complex neurovascular disorder characterized by recurrent attacks of pain and other associated symptoms. Emotional-affective aspects are important components of pain, but so far they have been little explored in animal models of migraine. In this study, we aimed to explore the correlation between trigeminal hyperalgesia and affective status or behavioral components in a migraine-specific animal model. Male Sprague-Dawley rats were treated with nitroglycerin (10 mg/kg, i.p.) or its vehicle. Four hours later, anxiety, motor/exploratory behavior and grooming (a nociception index) were evaluated with the open field test. Rats were then exposed to formalin in the orofacial region to evaluate trigeminal hyperalgesia. The data analysis shows an inverse correlation between trigeminal hyperalgesia and motor or exploratory behavior, and a positive association with anxiety-like behavior or self-grooming. These findings further expand on the translational value of the migraine-specific model based on nitroglycerin administration and prompt additional parameters that can be investigated to explore migraine disease in its complexity.

Primary erythromelalgia mainly manifested by hypertensive crisis: A case report and literature review.

BackgroundPrimary erythrocytic (PEM) is a rare autosomal dominant single gene disease. Most of the changes of gene loci can be found by whole exon gene sequencing, and the clinical symptoms and patient survival can be improved by specific site-to-site drug treatment. The other manifestations of this patient population are not remarkable. After the application of common drugs, the toxicity and side effects can be limiting. In addition to other common clinical manifestations, we found that the only unique manifestation of this patient was hypertensive crisis. Following multidisciplinary diagnosis and treatment (MDT), we decided to first control hypertension to alleviate the acute and critical patients. However, after controlling the hypertensive crisis, we unexpectedly found that the clinical symptoms of the patients had been significantly improved. Therefore, we concluded that the use of antihypertensive drugs can treat erythematous limb pain with the clinical manifestation of hypertensive crisis. Here, we describe a typical PEM disease, primary clinical features, diagnosis and treatment.MethodsMedical records of an 8-year-old boy with PEM were analyzed retrospectively, which included clinical characteristics, follow-up information, and SCN9A (Sodium Voltage-Gated Channel Alpha Subunit 9) gene analysis.ResultsThe 8-year-old boy had complained of abnormal paresthesia in his feet and ankles with burning sensation and pain for 2 years. The skin of both lower legs was red and underwent ichthyosis and lichenification. Genetic analysis confirmed the existence of a SCN9A gene mutation. The symptoms were gradually improved by treating with intravenous drip and oral administration of nitroglycerin to slow his heart rhythm.ConclusionPrimary erythrocytic is characterized by skin ulceration, redness, elevated temperature, and severe burning pain primarily in both lower extremities. PEM can be diagnosed by genetic analysis. As this case demonstrates, treating with nitroglycerin as the drug of choice to control the hypertensive crisis significantly improved the symptoms of PEM and hypertension in this patient.

Potentiation of endocannabinoids and other lipid amides prevents hyperalgesia and inflammation in a pre-clinical model of migraine

Targeting fatty acid amide hydrolase (FAAH) is a promising therapeutic strategy to combat certain forms of pain, including migraine headache. FAAH inhibitors, such as the O-biphenyl-3-yl carbamate URB597, have been shown to produce anti-hyperalgesic effects in animal models of migraine. The objective of this study was to investigate the behavioral and biochemical effects of compounds ARN14633 and ARN14280, two URB597 analogs with improved solubility and bioavailability, in a migraine-specific rat model in which trigeminal hyperalgesia is induced by nitroglycerin (NTG) administration. ARN14633 (1 mg/kg, i.p.) and ARN14280 (3 mg/kg, i.p.) were administered to adult male Sprague-Dawley rats 3 hours after NTG injection. One hour after the administration of either compound, rats were subjected to the orofacial formalin test. ARN14633 and ARN14280 attenuated NTG-induced nocifensive behavior and reduced transcription of genes encoding neuronal nitric oxide synthase, pain mediators peptides (calcitonin gene-related peptide, substance P) and pro-inflammatory cytokines (tumor necrosis factor-alpha, interleukin-1beta and 6) in the trigeminal ganglion, cervical spinal cord and medulla. Finally, both compounds strongly elevated levels of endocannabinoids and/or other FAAH substrates in cervical spinal cord and medulla, and, to a lesser extent, in the trigeminal ganglia. The results indicate that the novel global FAAH inhibitors ARN14633 and ARN14280 elicit significant anti-hyperalgesic effects in a migraine-specific animal model and inhibit the associated peptidergic-inflammatory response. Although the precise mechanism underlying these effects remains to be elucidated, our results support further investigational studies of FAAH blockade as a potential therapeutic strategy to treat migraine conditions.

Low-dose interleukin-2 reverses chronic migraine-related sensitizations through peripheral interleukin-10 and transforming growth factor beta-1 signaling

Low-dose interleukin-2 (LD-IL-2) treatment has been shown to effectively reverse chronic migraine-related behaviors and the sensitization of trigeminal ganglion (TG) neurons through expansion and activation of peripheral regulatory T cells (Tregs) in mice. In this study, we investigated the molecular mechanisms underlying the effects of LD-IL-2 and Treg cells. LD-IL-2 treatment increases the production of cytokines interleukin-10 (IL-10) and transforming growth factor beta-1 (TGFβ1) in T cells, especially Treg cells, suggesting that they may mediate the therapeutic effect of LD-IL-2. Indeed, neutralizing antibodies against either IL-10 or TGFβ completely blocked the effects of LD-IL-2 on the facial mechanical hypersensitivity as well as the sensitization of TG neurons resulting from repeated nitroglycerin (NTG, a reliable trigger of migraine in patients) administration in mice, indicating that LD-IL-2 and Treg cells engage both peripheral IL-10 and TGFβ signaling pathways to reverse chronic-migraine related sensitizations. In an in vitro assay, incubation of TG culture with exogenous IL-10 or TGFβ1 fully reversed NTG-induced sensitization of TG neurons, suggesting that the IL-10 and TGFβ1 signaling in TG neurons contribute to LD-IL-2′s therapeutic effects. Collectively, these results not only elucidate the molecular mechanisms through which LD-IL-2 and Treg cells reverse chronic-migraine related sensitizations, but also suggest that the IL-10 and TGFβ1 signaling pathways in TG neurons are potential targets for chronic migraine therapy.

Chronic snus use in healthy males alters endothelial function and increases arterial stiffness.

BackgroundSnus usage is commonly touted as a safer alternative to cigarette smoking. However, recent studies have demonstrated possible adverse cardiovascular effects in chronic snus users. The present study evaluates the effects of chronic snus use on vascular function by assessing central arterial stiffness and endothelial vasodilatory function in healthy chronic snus users as compared to matched non-users.Methods and resultsFifty healthy males (24 snus users, 26 age-matched controls) with a mean age of 44 years were included in the study. Arterial stiffness was assessed employing both pulse wave velocity and pulse wave analysis. Endothelial vasodilatory function was measured by venous occlusion plethysmography, utilizing intra-arterial administration of acetylcholine, glyceryl trinitrate and bradykinin to further gauge endothelium-dependent and -independent vasodilatory function. Arterial stiffness was significantly higher in chronic snus users as compared to controls: pulse wave velocity [m/s]: 6.6±0.8 vs 7.1±0.9 resp. (p = 0.026), augmentation index corrected for heart rate [%]: 0.1±13.2 vs 7.3±7.8 resp. (p = 0.023). Endothelial independent vasodilation, i.e. the reaction to glyceryl trinitrate, was significantly lower in snus users as measured by venous occlusion plethysmography.ConclusionsThe results of this study show an increased arterial stiffness and an underlying endothelial dysfunction in daily snus users as compared to matched non-tobacco controls. These findings indicate that long-term use of snus may alter the function of the endothelium and therefore reinforces the assertion that chronic snus use is correlated to an increased risk of development of cardiovascular disease.

RADIAL-DIGITAL PULSE WAVE VELOCITY: RESPONSE OF SMALL ARTERIES TO A MODIFICATION OF ARTERIAL STIFFNESS GRADIENT INDUCED BY NITROGLYCERIN

Objective: We previously demonstrated that it is possible to modulate the arterial stiffness gradient with the administration of nitroglycerin (NTG). This alteration of the physiological stiffness gradient would increase the transmission of greater pulsatility to the microcirculation, thus explaining the damage to the pressure-sensitive organs. We aimed to describe small conducting arteries response following the pharmacological alteration of the stiffness gradient using regional stiffness of the hand (radial-digital PWV, rd-PWV). Design and method: The simultaneous application of piezoelectric sensors (Complior) at the level of the carotid ®, the radial artery ®, and the tip of the index finger (d) was used to calculate the rd-PWV by the following formula (rd-PWV = cd-cr distances/cd-cr transit time). Rd-PWV was obtained before and 4 minutes after a sublingual administration of 0.4 mg of NTG, in healthy adults (controls, n = 23) and patients with moderate chronic kidney disease (CKD, n = 18). Changes in arterial stiffness pre-post NTG and comparisons between the two groups were analyzed using generalized estimating equations. Results: Pre NTG, despite similar cr-PWV, rd-PWV in CKD seemed lower than controls (3.7 ± 1.6 m/s vs. 4.6 ± 1.5 m/s, p = 0.067). This difference between the two groups faded (p = 0.865) after adjusting for age, where the standardized coefficient B of age = -0.407 (p = 0.037). Post NTG, cr-PWV decreased in both groups (p &lt; 0.001) while rd-PWV increased similarly (no interaction, p = 0.111)), between controls (from 4.62 ± 1.49 m/s to 5.94 ± 2.29m /s, p &lt; 0.001) and CKD (from 3.71 ± 1.60 m/s to 5.18 ± 2.12m/s, p &lt; 0.001). There was no difference in changes of brachial pressures between the two groups. Conclusions: Again, we observed opposite changes in arterial stiffness in two different arterial territories following the administration of NTG. In contrast with cr-PWV, regional stiffness of the hand increase after NTG administration. Rd-PWV is a new approach for the measurement of the regional stiffness of small arteries that could open the way to a better hemodynamic understanding of the consequences of the inversion of the stiffness gradient.

Hyperhomocysteinemia Increases Cortical Excitability and Aggravates Mechanical Hyperalgesia and Anxiety in a Nitroglycerine-Induced Migraine Model in Rats.

Homocysteine is a sulfur-containing endogenous amino acid leading to neurotoxic effects at high concentrations. Population studies suggest an association between plasma homocysteine levels and the risk of migraine headaches. The aim of this study was to analyze the sensitivity of rats with prenatal hyperhomocysteinemia (hHCY) in respect of the development of behavioral correlates of headache and spreading cortical depolarization (CSD) in a migraine model induced by the administration of the nitric oxide (NO) donor nitroglycerin. Animals with hHCY were characterized by migraine-related symptoms such as mechanical hyperalgesia, high-level anxiety, photophobia, as well as an enhanced level of neuronal activity in the somatosensory cortex along with a lower threshold of CSD generation. Likewise, acute or chronic intermittent administration of nitroglycerin also induced the development of mechanical allodynia, photophobia and anxiety in control groups. However, these symptoms were more pronounced in rats with hHCY. Unlike hHCY, nitroglycerin administration did not affect the threshold of CSD generation, but like hHCY, increased the background neuronal activity in layers 2/3 and 4 of the cerebral cortex. The latter was more pronounced in animals with hHCY. Thus, the migraine profile associated with hHCY can be further exaggerated in conditions with enhanced levels of migraine triggering the gaseous transmitter NO. Our data are consistent with the view that high levels of plasma homocysteine can act as a risk factor for the development of migraine.

Severe Coronary Artery Vasospasm after Mitral Valve Replacement in a Diabetic Patient with Previous Stent Implantation: A Case Report.

Postoperative coronary vasospasm is a well-known cause of angina that may lead to myocardial infarction if not treated promptly. We report a case of a 70-year-old female with severe mitral regurgitation submitted to mitral valve replacement, and a history of diabetes mellitus type II, stroke, idiopathic thrombocytopenic purpura on steroid therapy, and previous percutaneous coronary intervention (PCI) for severe obstruction of the circumflex coronary artery, 4 months prior to surgery. Immediately after intensive care unit admission, the patient developed pulseless electrical activity which required extracorporeal membrane oxygenation for hemodynamic support. The coronary angiography showed diffuse occlusive coronary artery vasospasm, ameliorated after intra-coronary administration of nitroglycerin. The following postoperative evolution was marked by cardiogenic shock and multiple organ dysfunction syndrome. Subsequent echocardiographic findings showed an increase in left ventricular function with an EF of 40%, and extracorporeal membrane oxygenation (ECMO) support was weaned after seven days. However, after a few hours, the patient progressively deteriorated, with cardiac arrest and no response to resuscitation maneuvers. Hemodynamic instability following the surgical procedure in a patient with previous PCI associated with an autoimmune disease and diabetes mellitus should raise the suspicion of a coronary artery vasospasm.

Randomized Clinical Trial on Prevention of Radial Occlusion After Transradial Access Using Nitroglycerin: PATENS Trial.

The aim of this study was to evaluate whether administration of nitroglycerin at the beginning or end of a transradial approach (TRA) procedure would preserve radial patency. The TRA is becoming the preferred vascular access route in coronary interventions. Radial artery occlusion (RAO) is the most frequent complication. Routine vasodilator treatment aims to reduce spasm and possibly prevent RAO. The authors designed a prospective, multicenter, randomized, double-blind, 2-by-2 factorial, placebo-controlled trial encompassing patients undergoing the TRA. Patients were randomized to either 500μg nitroglycerin or placebo; each arm was also subrandomized to early (upon sheath insertion) or late (right before sheath removal) nitroglycerin administration to evaluate the superiority of nitroglycerin in the prevention of RAO with 24 hours on Doppler ultrasound. A total of 2,040 patients were enrolled. RAO occurred in 49 patients (2.4%). Fifteen of these patients (30.6%) showed re-establishment of flow at 30days. Nitroglycerin, compared with placebo, did not reduce the risk for RAO at either of the 2 time points (early, 2.5% vs 2.3% [P=0.66]; late, 2.3% vs 2.5% [P=0.66]). By multivariable analysis, the presence of spasm (OR: 3.53; 95%CI: 1.87-6.65; P< 0.001) and access achieved with more than 1 puncture attempt (OR: 2.58; 95%CI: 1.43-4.66; P=0.002) were independent predictors of RAO. The routine use of nitroglycerin was not associated with a reduction in the rate of RAO, regardless ofthe time of administration (at the beginning or end of the TRA procedure).

Acetylcholine Re-Challenge After Intracoronary Nitroglycerine Administration.

Coronary artery spasm (CAS) can be diagnosed in a large proportion of patients with recurrent angina with non-obstructive coronary artery disease (ANOCA) using acetylcholine (ACh) spasm provocation testing. CAS can further be divided into different subtypes (e.g., focal, diffuse epicardial, or microvascular spasm), each with different pathophysiological mechanisms that may require tailored drug treatment. The evidence behind the role of nitrates in the setting of each CAS subtype is lacking, and the effectivity can vary on a per-patient basis. In order to assess on a per-patient level whether nitroglycerine (NTG) can prevent inducible spasm, the vasospastic ACh dose can be readministered after NTG administration as part of the spasm provocation test. The preventive effect of NTG is assessed by evaluating improvements in the severity of induced symptoms, ischemic ECG changes, and by reassessing the site and mode of spasm on angiography. This technique can therefore be used to assess the nitrate responsiveness on a per-patient level and unmask co-existing microvascular spasm in patients with epicardial spasm that is prevented with NTG. The NTG rechallenge, therefore, allows to further guide targeted therapy for CAS and provide new insights into the pathophysiological mechanism behind vasospastic disorders.

Prognostic Power of Pulmonary Arterial Compliance Is Boosted by a Hemodynamic Unloading Test With Glyceryl Trinitrate in Heart Failure Patients With Post-capillary Pulmonary Hypertension.

BackgroundPulmonary hypertension (PH) is an established risk factor in patients with heart failure (HF). However, right heart catheterisation (RHC) and vasoreactivity testing (VRT) are not routinely recommended in these patients.MethodsThe primary objective of the present study was to explore the impact of VRT using sublingual glyceryl trinitrate (GTN) on transplant/ventricular assist device-free survival in HF patients with post-capillary PH. RHC parameters were correlated retrospectively with the primary outcome.ResultsThe cohort comprised 154 HF patients with post-capillary PH undergoing RHC with GTN-VRT at a tertiary heart failure centre. Multiple parameters were associated with survival. After adjustment for established prognosis-relevant clinical variables from the MAGGIC Score, variables with the most relevant odds ratios (OR) obtained after GTN-VRT were: calculated effective pulmonary arterial (PA) elastance (adjusted OR 2.26, 95%CI 1.30–3.92; p = 0.004), PA compliance (PAC-GTN; adjusted OR 0.45, 95%CI 0.25–0.80; p = 0.006), and total pulmonary resistance (adjusted OR 2.29, 95%CI 1.34–3.93; p = 0.003). Forest plot analysis including these three variables as well as PAC at baseline, delta PAC, and the presence of combined post- and pre-capillary PH revealed prognostic superiority of PAC-GTN, which was confirmed by Kaplan-Meier analysis.ConclusionsIn our cohort of symptomatic HF patients with post-capillary PH, improved PAC after administration of GTN was associated with survival independent of established hemodynamic and clinical risk factors. VRT using GTN may be better described as unloading test due to GTN's complex effects on the circulation. This could be used for advanced prognostication and should be investigated in further studies.

WHAT DRUGS YOU CAN PREFER IN CARDIOGENIC SHOCK?

Abstract: Relevance. The use of nitroglycerin (NG) in cardiogenic shock (СS) helps to normalize blood pressure, reduce the risk of death and improve prognosis. Aim. To study the effect of vasopressors, inotropic drugs and nitroglycerin on hemodynamics and reducing the risk of death in patients with cardiogenic shock. Material and methods. A comparative assessment of the effectiveness of treatment of СS in myocardial infarction with nitroglycerin and traditional approaches to therapy was carried out. In the control group of patients with СS (17 people), dopamine or norepinephrine was administered in the traditional way. In the main group of patients with СS (22 people), large doses of nitroglycerin were administered. After the stabilization of the state of health, the drip injection of NG continued in the usual doses. Results. In 20 of 22 patients of the main group, immediately after the jet injection of nitroglycerin, blood pressure began to be determined or significantly increased, 14 of them survived (63.6%). In 9 cases, blood pressure did not decrease anymore, vasopressors were not administered, nitroglycerin was administered by drop for another 2-3 days, the treatment ended with discharge in a satisfactory state. In another 2 cases, it was necessary to administer vasopressors in parallel with the drip administration of nitroglycerin, after its jet administration. In the control group, the only patient survived (5.9%). Conclusions. Analysis of literature data indicates that in conditions of maximum depletion of reserves and a decrease in myocardial contractility in patients with cardiogenic shock, the use of vasopressors and inotropic drugs accelerates the decompensation of insufficient blood supply and increases the risk of death. The main way to combat СS is still urgent myocardial revascularization, however, the restoration of the functional activity of hibernated cardiomyocytes will be more successful and safer with their gradual activation. This problem can be successfully solved using the methods of mechanical support of blood circulation or with the help of nitroglycerin. It will be possible to verify the validity of this assumption only on the basis of the results of randomized clinical trials.

Calcitonin gene-related peptide receptor antagonist BIBN4096BS regulates synaptic transmission in the vestibular nucleus and improves vestibular function via PKC/ERK/CREB pathway in an experimental chronic migraine rat model

BackgroundVestibular symptoms are frequently reported in patients with chronic migraine (CM). However, whether vestibular symptoms arise through overlapping neurobiology of migraine remains to be elucidated. The neuropeptide calcitonin gene-related peptide (CGRP) and CGRP1 receptor play important pathological roles in facilitating central sensitization in CM. Therefore, we aimed to investigate whether CGRP1 receptor contributes to vestibular dysfunction after CM by improving synaptic transmission in the vestibular nucleus (VN).MethodsA CM rat model was established by recurrent intermittent administration of nitroglycerin (NTG). Migraine- and vestibular-related behaviors were assessed. CGRP1 receptor specific antagonist, BIBN4096BS, and protein kinase C (PKC) inhibitor chelerythrine chloride (CHE) were administered intracerebroventricularly. The expressions of CGRP and CGRP1 receptor components, calcitonin receptor-like receptor (CLR) and receptor activity modifying protein 1 (RAMP1) were evaluated by western blot, immunofluorescent staining and quantitative real-time polymerase chain reaction in the vestibular nucleus (VN). Synaptic associated proteins and synaptic morphological characteristics were explored by western blot, transmission electron microscope, and Golgi-cox staining. The expressions of PKC, phosphorylated extracellular signal regulated kinase (p-ERK), phosphorylated cAMP response element-binding protein at serine 133 site (p-CREB-S133) and c-Fos were detected using western blot or immunofluorescent staining.ResultsThe expressions of CGRP, CLR and RAMP1 were significantly upregulated in CM rats. CLR and RAMP1 were expressed mainly in neurons. BIBN4096BS treatment and PKC inhibition alleviated mechanical allodynia, thermal hyperalgesia and vestibular dysfunction in CM rats. Additionally, BIBN4096BS treatment and PKC inhibition markedly inhibited the overexpression of synaptic associated proteins and restored the abnormal synaptic structure in VN after CM. Furthermore, BIBN4096BS treatment dysregulated the expression levels of PKC, p-ERK and p-CREB-S133, and attenuated neuronal activation in VN after CM. ConclusionsThe present study demonstrated that CGRP1 receptor inhibition improved vestibular function after CM by reversing the aberrant synaptic transmission via downregulating PKC/ERK/CREB signaling pathway. Therapeutic interventions by inhibiting CGRP/CGRP1 signaling may be a new target for the treatment of vestibular symptoms in CM.

Comparative study of photoplethysmographic waveforms with application of antihypertensive medication in hypertensive patients.

BackgroundMultiple studies have been published using a pulse oximeter's photoplethysmographic (PPG) capability to detect tissue perfusion. However, the origin of the PPG signal is still debatable.AimA comparative study was performed of PPG waveforms in hypertensive patients before and after treatment with antihypertensive medication. The aim of this study was to observe the changes of PPG waveforms before and after lowering blood pressure in hypertensive patients and then to detect the relationship between blood pressure and PPG waveforms.MethodsThe PPG waveforms of 60 patients with hypertension were collected. After administration of the antihypertensive medication nitroglycerin, PPG waveforms were collected again. The changes of the T3 (time3): This phase occurred between Marker 3 and Marker 4 (this phase occurs mid‐diastolic) angle, before and after the antihypertensive medication treatment, were compared. The statistical analyses of two related groups were performed using the Paired t‐test.ResultsThe blood perfusion waveforms of hypertensive patients before and after antihypertensive medication administration were differently indicated with the tilt angle T3. The slope angle of the T3 phase waveform increased significantly when the blood pressure dropped to normal (−41.9 ± 16.2° vs. −25.6 ± 21.9°, p < .0001), and the tilt angle of some patients was similar to that of adults with normal blood pressure.ConclusionIn patients with hypertension, the tilt angle of the PPG waveform in the T3 phase increased significantly after administration of the antihypertensive medication nitroglycerin. It is worth to conduct deeper research about the relationship between hypertension and the blood perfusion of microcirculation in the diastolic period.

Sphincter of Oddi dysfunction.

Sphincter of Oddi dysfunction (SOD) is a benign non-tumoral disorder of the major papilla. It occurs mainly after cholecystectomy but can also occur before surgery. Biliary pain and biliary colic are the most frequent symptoms although recurrent pancreatic pain or pancreatitis can also be presenting symptoms. In about half of the cases, there is a fibrotic stricture of the sphincter of Oddi, probably secondary to the passage of biliary stones, while in the remaining half, the syndrome is due to ampullary motility disorders. The diagnosis of SOD first requires exclusion of choledocholithiasis or ampullary tumor, by means of ERCP, endoscopic ultrasound or magnetic resonance imaging. Findings on biliary manometry will establish the diagnosis, but this technique is performed less and less often because its high risk of inducing pancreatitis discourages its use as a diagnostic procedure. Biliary scintigraphy offers a risk-free alternative albeit with lower sensitivity. Medical treatment relies on the administration of trimebutine and nitroglycerine when pain occurs. Their efficacy is moderate. Sometimes patients are referred for endoscopic sphincterotomy. Endoscopic treatment should be performed only for patients with biliary pain associated with hepatic function disorders and/or bile duct dilatation. Practicians and patients should be aware that endoscopic sphincterotomy in this clinical setting is associated with a high risk of pancreatitis and its efficacy is limited in patients with pain but without laboratory anomalies or dilatation of the biliary duct (type III Milwaukee classification). Patients with Milwaukee classification type III disorders have mostly functional complaints or psychosocial disabilities and require only medical management.

Nitroglycerin Plus Whole Intracranial Radiation Therapy for Brain Metastases in Patients With Non-Small Cell Lung Cancer: A Randomized, Open-Label, Phase 2 Clinical Trial

Hypoxia has been associated with chemoradioresistance secondary to vascular endothelial growth factor receptor induced by hypoxia-induced factor (HIF). Nitroglycerin (NTG) can reduce HIF-1 in tissues, and this may have antiangiogenic, proapoptotic, and antiefflux effects. Particularly, epidermal growth factor-mutated (EGFRm) tumor cell lines have been shown to overexpress both vascular endothelial growth factor and HIF. In this phase 2 study, we evaluated the effect of transdermal NTG plus whole brain radiation therapy (WBRT) in patients with non-small cell lung cancer (NSCLC) with brain metastases (BM). This was an open-label, phase 2 clinical trial with 96 patients with NSCLC and BM. Patients were randomized 1:1 to receive NTG plus WBRT (30 Gy in 10 fractions) or WBRT alone. The primary endpoint was intracranial objective response rate (iORR) evaluated 3 months posttreatment. NTG was administered using a transdermal 36-mg patch from Monday through Friday throughout WBRT administration (10 days). The protocol was retrospectively registered at ClinicalTrials.gov (NCT04338867). Fifty patients were allocated to the control group, and 46 were allocated to the experimental group (NTG); among these, 26 (52%) had EGFRm in the control group and 21 (45.7%) had EGFRm in the NTG arm. In terms of the iORR, patients in the NTG group had a significantly higher response compared with controls (56.5% [n = 26/46 evaluable patients] vs 32.7% [n = 16/49 evaluable patients]; relative risk, 1.73; 95% confidence interval [CI], 1.08-2.78; P = .024). Additionally, patients who received NTG + WBRT had an independently prolonged intracranial progression-free survival (ICPFS) compared with those who received WBRT alone (27.7 vs 9.6; hazard ratio [HR], 0.5; 95% CI, 0.2-0.9; P = .020); this positively affected overall progression-free survival among patients who received systemic therapy (n = 88; HR, 0.5; 95% CI, 0.2-0.9; P = .043). The benefit of ICPFS (HR, 0.4; 95% CI, 0.2-0.9; P = .030) was significant in the EGFRm patient subgroup. No differences were observed in overall survival. A significantly higher rate of vomiting presented in the NTG arm of the study (P = .016). The concurrent administration of NTG and radiation therapy improves iORR and ICPFS among patients with NSCLC with BM. The benefit in ICPFS is significant in the EGFRm patient subgroup.