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Cardiology 2018Ischaemic heart disease is a major cause of death and disability worldwide, while angina represents its most common symptom. It is estimated that approximately 9 million... (Review)
Review
Ischaemic heart disease is a major cause of death and disability worldwide, while angina represents its most common symptom. It is estimated that approximately 9 million patients in the USA suffer from angina and its treatment is challenging, thus the strategy to improve the management of chronic stable angina is a priority. Angina might be the result of different pathologies, ranging from the "classical" obstruction of a large coronary artery to alteration of the microcirculation or coronary artery spasm. Current clinical guidelines recommend antianginal therapy to control symptoms, before considering coronary artery revascularization. In the current guidelines, drugs are classified as being first-choice (beta-blockers, calcium channel blockers, and short-acting nitrates) or second-choice (ivabradine, nicorandil, ranolazine, trimetazidine) treatment, with the recommendation to reserve second-line modifications for patients who have contraindications to first-choice agents, do not tolerate them, or remain symptomatic. However, such a categorical approach is currently questioned. In addition, current guidelines provide few suggestions to guide the choice of drugs more suitable according to the underlying pathology or the patient comorbidities. Several other questions have recently emerged, such as: is there evidence-based data between first- and second-line treatments in terms of prognosis or symptom relief? Actually, it seems that newer antianginal drugs, which are classified as second choice, have more evidence-based clinical data that are more contemporary to support their use than what is available for the first-choice drugs. It follows that actual guidelines are based more on tradition than on evidence and there is a need for new algorithms that are more individualized to patients, their comorbidities, and pathophysiological mechanism of chronic stable angina.
Topics: Adrenergic beta-Antagonists; Angina, Stable; Calcium Channel Blockers; Cardiovascular Agents; Chest Pain; Humans; Ivabradine; Nicorandil; Patient Selection; Practice Guidelines as Topic; Ranolazine; Treatment Outcome; Trimetazidine
PubMed: 29874661
DOI: 10.1159/000487936 -
Cell Death Discovery Sep 2021Skeletal muscle atrophy is one of the major side effects of high dose or sustained usage of glucocorticoids. Pyroptosis is a novel form of pro-inflammatory programmed...
Skeletal muscle atrophy is one of the major side effects of high dose or sustained usage of glucocorticoids. Pyroptosis is a novel form of pro-inflammatory programmed cell death that may contribute to skeletal muscle injury. Trimetazidine, a well-known anti-anginal agent, can improve skeletal muscle performance both in humans and mice. We here showed that dexamethasone-induced atrophy, as evidenced by the increase of muscle atrophy F-box (Atrogin-1) and muscle ring finger 1 (MuRF1) expression, and the decrease of myotube diameter in C2C12 myotubes. Dexamethasone also induced pyroptosis, indicated by upregulated pyroptosis-related protein NLR family pyrin domain containing 3 (NLRP3), Caspase-1, and gasdermin-D (GSDMD). Knockdown of NLRP3 or GSDMD attenuated dexamethasone-induced myotube pyroptosis and atrophy. Trimetazidine treatment ameliorated dexamethasone-induced muscle pyroptosis and atrophy both in vivo and in vitro. Activation of NLRP3 using LPS and ATP not only increased the cleavage and activation of Caspase-1 and GSDMD, but also increased the expression levels of atrophy markers MuRF1 and Atrogin-1 in trimetazidine-treated C2C12 myotubes. Mechanically, dexamethasone inhibited the phosphorylation of PI3K/AKT/FoxO3a, which could be attenuated by trimetazidine. Conversely, co-treatment with a PI3K/AKT inhibitor, picropodophyllin, remarkably increased the expression of NLRP3 and reversed the protective effects of trimetazidine against dexamethasone-induced C2C12 myotube pyroptosis and atrophy. Taken together, our study suggests that NLRP3/GSDMD-mediated pyroptosis might be a novel mechanism for dexamethasone-induced skeletal muscle atrophy. Trimetazidine might be developed as a potential therapeutic agent for the treatment of dexamethasone-induced muscle atrophy.
PubMed: 34537816
DOI: 10.1038/s41420-021-00648-0 -
Nature Reviews. Cardiology Feb 2018In clinical guidelines, drugs for symptomatic angina are classified as being first choice (β-blockers, calcium-channel blockers, short-acting nitrates) or second choice... (Review)
Review
In clinical guidelines, drugs for symptomatic angina are classified as being first choice (β-blockers, calcium-channel blockers, short-acting nitrates) or second choice (ivabradine, nicorandil, ranolazine, trimetazidine), with the recommendation to reserve second-choice medications for patients who have contraindications to first-choice agents, do not tolerate them, or remain symptomatic. No direct comparisons between first-choice and second-choice treatments have demonstrated the superiority of one group of drugs over the other. Meta-analyses show that all antianginal drugs have similar efficacy in reducing symptoms, but provide no evidence for improvement in survival. The newer, second-choice drugs have more evidence-based clinical data that are more contemporary than is available for traditional first-choice drugs. Considering some drugs, but not others, to be first choice is, therefore, difficult. Moreover, double or triple therapy is often needed to control angina. Patients with angina can have several comorbidities, and symptoms can result from various underlying pathophysiologies. Some agents, in addition to having antianginal effects, have properties that could be useful depending on the comorbidities present and the mechanisms of angina, but the guidelines do not provide recommendations on the optimal combinations of drugs. In this Consensus Statement, we propose an individualized approach to angina treatment, which takes into consideration the patient, their comorbidities, and the underlying mechanism of disease.
Topics: Angina Pectoris; Cardiology; Cardiovascular Agents; Clinical Decision-Making; Comorbidity; Consensus; Humans; Patient Selection; Patient-Centered Care; Risk Assessment; Risk Factors; Treatment Outcome
PubMed: 28880025
DOI: 10.1038/nrcardio.2017.131 -
Frontiers in Pharmacology 2020Heart failure is a systemic syndrome caused by multiple pathological factors. Current treatments do not have satisfactory outcomes. Several basic studies have revealed... (Review)
Review
Heart failure is a systemic syndrome caused by multiple pathological factors. Current treatments do not have satisfactory outcomes. Several basic studies have revealed the protective effect of trimetazidine on the heart, not only by metabolism modulation but also by relieving myocardial apoptosis, fibrosis, autophagy, and inflammation. Clinical studies have consistently indicated that trimetazidine acts as an adjunct to conventional treatments and improves the symptoms of heart failure. This review summarizes the basic pathological changes in the myocardium, with an emphasis on the alteration of cardiac metabolism in the development of heart failure. The clinical application of trimetazidine in heart failure and the mechanism of its protective effects on the myocardium are carefully discussed, as well as its main adverse effects. The intention of this review is to highlight this treatment as an effective alternative against heart failure and provide additional perspectives for future studies.
PubMed: 33597865
DOI: 10.3389/fphar.2020.569132 -
Arquivos Brasileiros de Cardiologia Aug 2021
Topics: Baroreflex; Flavanones; Humans; Reperfusion Injury; Trimetazidine
PubMed: 34495222
DOI: 10.36660/abc.20210453 -
European Cardiology Dec 2018Treatment goals for people with chronic angina should focus on the relief of symptoms and improving mortality rates so the patient can feel better and live longer. The... (Review)
Review
Treatment goals for people with chronic angina should focus on the relief of symptoms and improving mortality rates so the patient can feel better and live longer. The traditional haemodynamic approach to ischaemic heart disease was based on the assumption that increasing oxygen supply and decreasing oxygen demand would improve symptoms. However, data from clinical trials, show that about one third of people continue to have angina despite a successful percutaneous coronary intervention and medical therapy. Moreover, several trials on chronic stable angina therapy and revascularisation have failed to show benefits in terms of primary outcome (survival, cardiovascular death, all-cause mortality), symptom relief or echocardiographic parameters. Failure to significantly improve quality of life and prognosis may be attributed in part to a limited understanding of ischaemic heart disease, by neglecting the fact that ischaemia is a metabolic disorder. Shifting cardiac metabolism from free fatty acids towards glucose is a promising approach for the treatment of patients with stable angina, independent of the underlying disease (macrovascular and/or microvascular disease). Cardiac metabolic modulators open the way to a greater understanding of ischaemic heart disease and its common clinical manifestations as an energetic disorder rather than an imbalance between the demand and supply of oxygen and metabolites.
PubMed: 30697354
DOI: 10.15420/ecr.2018.15.2 -
The Cochrane Database of Systematic... Mar 2017Patients with stable angina not controlled by monotherapy with nitrates, beta blockers, or calcium channel blockers are often treated with combinations of these drugs.... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
Patients with stable angina not controlled by monotherapy with nitrates, beta blockers, or calcium channel blockers are often treated with combinations of these drugs. There may be adverse effects from, or contraindications to, the use of combinations. In low risk groups, medical treatment appears to be as good an option as percutaneous transluminal coronary angioplasty in terms of averting myocardial infarction, death, or subsequent revascularization. Revascularization procedures are too costly or inaccessible for many patients in developing countries therefore effective and safe medical treatment is needed. Trimetazidine is a less well known anti-anginal drug that controls myocardial ischaemia through intracellular metabolic changes. Trimetazidine has been reported, in some studies, to be better tolerated than combined anti-anginal therapy; however it is not considered in published guidelines.
OBJECTIVES
To determine the efficacy and tolerability of trimetazidine in patients with stable angina.
SEARCH METHODS
We searched The Cochrane Central Register of Controlled Trials, MEDLINE, EMBASE, LILACS and SCISEARCH, without language restriction, from inception to October 2003. Experts in the field were contacted to locate unpublished studies.
SELECTION CRITERIA
Randomised studies comparing trimetazidine with placebo, or other anti-angina drug in adults with stable angina.
DATA COLLECTION AND ANALYSIS
Two reviewers independently applied the inclusion criteria, assessed trial quality and extracted data.
MAIN RESULTS
Twenty-three studies (1378 patients) met the inclusion criteria. There was a paucity of information about mortality, cardiovascular events and quality of life. Trimetazidine, compared with placebo, reduced the number of weekly angina attacks ( mean difference -1.44, 95% CI -2.10 to -0.79; P < 0.0001), reduced weekly nitroglycerin tablet consumption (95% CI -1.47 to -2.20, -0.73; P < 0.0001) and improved exercise time to 1 mm segment depression (P = 0.0002). Four small trials (263 patients) compared trimetazidine against other anti-anginal agents. One favoured trimetazidine over nitrates. Three tended to favour alternative regimens but with confidence intervals consistent with both major increases and decreases in frequency of angina episodes. In this subgroup, adverse events were considered in 5 trials (448 patients) and totals of 2 versus 12 drop outs due to adverse events were observed in the trimetazidine and alternative regimens respectively, but this was mostly driven by a single trial.
AUTHORS' CONCLUSIONS
Trimetazidine is effective in the treatment of stable angina compared with placebo, alone or combined with conventional anti-anginal agents. Trimetazidine may result in fewer dropouts due to adverse events. Large, long term trials comparing trimetazidine with other anti-anginal drugs assessing clinically relevant important outcomes are required to establish its role in clinical management.
Topics: Adult; Angina Pectoris; Humans; Randomized Controlled Trials as Topic; Trimetazidine; Vasodilator Agents
PubMed: 28319269
DOI: 10.1002/14651858.CD003614.pub3 -
British Journal of Pharmacology Apr 2022Amyotrophic lateral sclerosis (ALS), a neurodegenerative disease characterized by the degeneration of upper and lower motor neurons, progressive wasting and paralysis of...
BACKGROUND AND PURPOSE
Amyotrophic lateral sclerosis (ALS), a neurodegenerative disease characterized by the degeneration of upper and lower motor neurons, progressive wasting and paralysis of voluntary muscles and is currently incurable. Although considered to be a pure motor neuron disease, increasing evidence indicates that the sole protection of motor neurons by a single targeted drug is not sufficient to improve the pathological phenotype. We therefore evaluated the therapeutic potential of the multi-target drug used to treatment of coronary artery disease, trimetazidine, in SOD1 mice.
EXPERIMENTAL APPROACH
As a metabolic modulator, trimetazidine improves glucose metabolism. Furthermore, trimetazidine enhances mitochondrial metabolism and promotes nerve regeneration, exerting an anti-inflammatory and antioxidant effect. We orally treated SOD1 mice with trimetazidine, solubilized in drinking water at a dose of 20 mg kg , from disease onset. We assessed the impact of trimetazidine on disease progression by studying metabolic parameters, grip strength and histological alterations in skeletal muscle, peripheral nerves and the spinal cord.
KEY RESULTS
Trimetazidine administration delays motor function decline, improves muscle performance and metabolism, and significantly extends overall survival of SOD1 mice (increased median survival of 16 days and 12.5 days for male and female respectively). Moreover, trimetazidine prevents the degeneration of neuromuscular junctions, attenuates motor neuron loss and reduces neuroinflammation in the spinal cord and in peripheral nerves.
CONCLUSION AND IMPLICATIONS
In SOD1 mice, therapeutic effect of trimetazidine is underpinned by its action on mitochondrial function in skeletal muscle and spinal cord.
Topics: Amyotrophic Lateral Sclerosis; Animals; Disease Models, Animal; Drug Repositioning; Female; Male; Mice; Mice, Transgenic; Neurodegenerative Diseases; Superoxide Dismutase; Superoxide Dismutase-1; Trimetazidine
PubMed: 34783031
DOI: 10.1111/bph.15738 -
Evidence-based Complementary and... 2021Myocardial infarction (MI) is one of the leading causes of death worldwide. However, there is no effective treatment for MI. In this study, trimetazidine (TMZ) and...
Myocardial infarction (MI) is one of the leading causes of death worldwide. However, there is no effective treatment for MI. In this study, trimetazidine (TMZ) and Danhong injection (DHI), representing western medicine and traditional Chinese medicine for MI, were used as tools to identify vital processes in alleviating MI injury. Administration of DHI and TMZ obviously decreased myocardial infarct size, improved ultrasonic heart function, and reduced creatine kinase (CK), lactate dehydrogenase (LDH), and glutamic oxaloacetic transaminase (AST) levels after MI. RNA-seq results indicated calcium ion handling and negative regulation of apoptotic process were vital processes and DHI and TMZ obviously reduced the expression of CaMK II and inhibited cleaved caspase-3 and Bax. Furthermore, DHI and TMZ increased p-S16-PLB, p-S16T17-PLB, CACNA1C, p-RyR2, and p-PKA expression but did not affect SERCA2a expression. In addition to the enhancement of cardiac myocyte shortening amplitude, maximum shortening velocity, and calcium transients, DHI and TMZ increased sarcoplasmic reticulum calcium content and enhanced SERCA2a calcium uptake capability by upregulating the phosphorylation of PLB but did not affect calcium exclusion by NCX. In conclusion, DHI and TMZ protect against MI through inhibiting apoptosis by downregulating CaMKII pathway and enhancing cardiac myocyte contractile functions possibly through the PKA signaling pathway.
PubMed: 33510801
DOI: 10.1155/2021/2480465 -
Arquivos Brasileiros de Cardiologia Aug 2021Nucleus tractus solitarius (NTS) is a brain area that plays a key role in kidney and cardiovascular regulation via baroreceptors impulses.
BACKGROUND
Nucleus tractus solitarius (NTS) is a brain area that plays a key role in kidney and cardiovascular regulation via baroreceptors impulses.
OBJECTIVES
The aim of this study was to evaluate the effect of naringin (NAR) and trimetazidine (TMZ) alone and their combination on NTS electrical activity and baroreceptor sensitivity (BRS) in renal ischemia- reperfusion (I/R) injury.
METHODS
Forty male Sprague-Dawley rats (200- 250 g) were allocated into 5 groups with 8 in each. 1) Sham; 2) I/R; 3) TMZ 5 mg/kg; 4) NAR 100 mg/kg; and 5) TMZ5+ NAR100. The left femoral vein was cannulated to infuse saline solution or drug and the BRS was evaluated. I/R was induced by occlusion of renal pedicles for 45 min, followed by 4 hours of reperfusion. The NTS local electroencephalogram (EEG) was recorded before, during ischemia and throughout the reperfusion. Phenylephrine was injected intravenously to evaluate BRS at the end of reperfusion time. The data were analyzed by two-way repeated measurement ANOVA followed by Tukey's post hoc test. A p-value <0.05 was considered significant.
RESULTS
NTS electrical waves did not change during ischemia time, while they significantly decreased during the entire reperfusion time. NTS electrical activity and BRS dramatically reduced in rats with I/R injury; however, administration of NAR, TMZ alone or their combination significantly improved these changes in rats with I/R injury.
CONCLUSIONS
The results showed that I/R injury leads to reduced BRS and NTS electrical activity and there may be an association between I/R and decreased BRS. In addition, NAR and TMZ are promising agents to treat I/R complications.
Topics: Animals; Baroreflex; Flavanones; Kidney; Male; Rats; Rats, Sprague-Dawley; Reperfusion Injury; Solitary Nucleus; Trimetazidine
PubMed: 34495221
DOI: 10.36660/abc.20200121