Antianginal Drugs Research Articles

Coronary sinus reducer device for the treatment of refractory angina: a single center experience

Abstract Introduction The coronary sinus Reducer emerged as a complementary therapy in patients with angina refractory to optimal medical therapy and not amenable to revascularization. Aim The aim of this study was to assess the safety and efficacy of the Reducer in a real-world cohort of patients presenting with refractory angina. Methods and population Twenty-six patients with refractory angina, objective evidence of myocardial ischemia attributable to the left coronary artery and deemed unsuitable for revascularization were treated with Reducer at a single center between April 2018 and January 2023. Safety endpoints were procedural success and complications. Efficacy endpoints, assessed at 6-month, were a reduction in Canadian Cardiovascular Society angina (CCS) class and a reduction in pharmacological antianginal therapy. Results Twenty-one (81%) patients had end-stage coronary artery disease without targets for further revascularization (13 had previous CABG ± PCI and 8 had only PCI) and 5 patients had microvascular disease without epicardial stenosis. All procedures were performed via right jugular vein. The mean procedure and fluoroscopy duration were 66±29 and 19±8 minutes. Procedural success was achieved in all patients, with no device related complications. There was one cardiac tamponade, promptly treated with pericardiocentesis. Regarding the efficacy endpoint, 21 patients (81%) had at least 1 grade reduction in CCS class, 13 patients (50%) had at least 2 class reductions, and 7 patients (28 %) became asymptomatic, with a mean reduction of CCS class of 1.4±0.9, from 2.6±0.5 to 1.2±0.9 (p=0.001) at 6-month follow-up. During this time frame, twelve patients (46%) withdrew or reduced the dose of at least one anti-anginal drug. The mean reduction of anti-anginal drugs was 0.54 ±0.86, from 3.5±1.02 to 2.9±1.07 (p=0.04). Conclusion In this real-world, single-center experience, implantation of Reducer was safe and associated with improvement of angina and reduction of anti-anginal drugs intake in patients with refractory angina unsuitable for revascularization.

Cardioprotective effects of nicorandil on mitochondrial apoptosis signaling in the failing heart of cardiac-specific Bcl-2-associated athanogene (BAG) 3 knockout mice

Abstract Background Bcl-2-associated athanogene (BAG) 3 is a known regulator of mitochondrial apoptotic cell death and autophagic protein degradation in the heart. Disruption of the BAG3 gene in a cardiac-specific manner can lead to cardiac failure in mice. However, therapeutic approaches for cardiac failure induced by BAG3 gene disruption remain poorly understood. Method and results We characterized mice with the ablated BAG3 gene using the Cre-recombinase-loxp site system in a cardiac-specific manner (BAG3f/f crossbred with cardiac specific Cre transgenic mice; BAG3 cKO) and examined the therapeutic effect of nicorandil, an antianginal drug, in BAG3 cKO mice. Cardiac BAG3 levels were markedly reduced in the cytoplasmic and mitochondrial fractions from the hearts of BAG3 cKO mice compared to BAG3f/f mice. BAG3cKO mice exhibited cardiac disease such as a reduction in fractional shortening detected by echocardiography, cardiac fibrosis at 6 months of age, and approximately 40% premature death by 6 months of age. Electron microscopy analysis confirmed cardiomyocyte loss and mitochondrial abnormalities in some areas of the heart section from BAG3cKO mice at 4.5 months of age. A marked decrease in the level of cytochrome C in the mitochondrial fraction and a slight increase in the cytoplasmic fraction, along with apoptotic cell death, were observed in hearts from BAG3 cKO mice at 4.5 months. Mitochondrial levels of anti-apoptotic factors, such as Bcl-2 and Bcl-xl, were reduced, while there was a marked increase in Bak1, an apoptotic inducible factor, in hearts from BAG3 cKO mice at 4.5 months of age. These results suggest that cardiac mitochondrial impairment and subsequent apoptotic cell death occurred in BAG3cKO mice. Nicorandil treatment (81 mg/L drinking water) initiated at 2 months of age prevented the reduction of fractional shortening, cardiac fibrosis, ultrastructural cardiac abnormalities, and premature death. Furthermore, nicorandil treatment prevented the decrease in mitochondrial cytochrome C and the increase in cytoplasmic cytochrome C in hearts from BAG3 cKO mice at 4.5 months of age. Nicorandil treatment also inhibited the elevation of mitochondrial Bak1 levels, reduction in Bcl-2 levels, and occurrence of apoptotic cell death in hearts from BAG3 cKO mice at 4.5 months of age. Conclusion Long-term treatment with nicorandil can inhibit cardiac disease induced by cardiac- specific BAG3 ablation through mitochondrial protection via the prevention of activation of mitochondrial apoptosis signaling.

Placebo-controlled efficacy of 17 anti-anginal drugs and percutaneous coronary intervention for first-line treatment of stable angina: systematic review & meta-analysis of 5153 patients from 53 trials

Abstract Background Percutaneous coronary intervention (PCI) for stable angina is currently recommended for patients with residual symptoms despite maximal anti-anginal medication. Placebo-controlled data demonstrating efficacy of PCI has recently become available. Purpose We evaluated the placebo-controlled efficacy of anti-anginal agents and PCI, as monotherapies for stable angina. Methods We performed a systematic review and meta-analysis of placebo-controlled randomised controlled trials (RCTs) of anti-anginal agents (17 medications across 7 drug classes [beta-blocker, dihydropyridine (DHP) calcium channel blocker (CCB), non-DHP CCB, ivabradine, nicorandil, nitrates and ranolazine]), and PCI, which reported the placebo-controlled treatment effect on standardised exercise duration in patients with stable angina, who were receiving no background anti-anginal medications. We searched MEDLINE, EMBASE, and Cochrane CENTRAL from database inception to 01 December 2023. Relevant systematic reviews and reference lists were inspected to identify publications which had not been identified in the primary searches. Two independent reviewers extracted the data and assessed the risk of bias of included studies. Intention-to-treat data were used. Meta-analyses were carried out using random-effects methods and reported using the PRISMA guidelines. The primary outcome was mean difference in total exercise time with treatment compared with placebo. A pairwise comparison of all anti-anginal medications and PCI was performed to evaluate their relative placebo-controlled efficacy on total exercise time. Results A total of 52 trials were eligible, evaluating 83 treatment arm comparisons of anti-anginal monotherapy (2408 patients) and placebo (2444 patients). The number of trials per medication class ranged from one (ivabradine) to 19 (non-DHP CCBs). All classes improved exercise time compared to placebo, with mean increment ranging from 22.4 seconds (95% confidence interval, 0.8 to 44.0, p=0.04) for ranolazine, to 76.5 seconds (63.2 to 89.8, p<0.0001) for DHP CCBs (Figure 1). There was substantial heterogeneity in exercise time increment between drug classes (I2 98%, p<0.0001). However, across all classes, there was a clear dose-response relationship (b-coefficient 24.8, 15.8 to 33.9, <0.0001). The only trial which compared PCI (151 patients) to placebo (150 patients) showed a placebo-controlled exercise duration increment of 59.5 seconds (16 to 103, P=0.001). This was comparable to the global mean effect across all anti-anginal medications (59, 39 to 79, P<0.0001). Conclusions Each anti-anginal drug class showed a clear increase in placebo-controlled exercise time, with varying effect sizes between classes. The DHP CCB class showed the largest effect size, and ivabradine and ranolazine showed the smallest. The effect of PCI monotherapy was similar to the mean anti-anginal medication monotherapy effect.Figure 1

Comparative effects of ranolazine and trimetazidine on cardiac structure and exercise capacity in a healthy rat model: a new doping agent?

Abstract Background/Introduction Anti-anginal drugs that have been shown to improve myocardial energy use include ranolazine and trimetazidine [1]. An inquiry is warranted into their ability to impact cardiac functions and exercise capacity. Purpose This study aims to evaluate the effects of ranolazine; and trimetazidine as a positive control group on cardiac structure and exercise capacity in a rodent model in comparison with the control group. Methods In a randomized, controlled trial, 24 Sprague-Dawley rats were divided into three groups: control, ranolazine, and trimetazidine. Rats were given daily doses of ranolazine (50 mg/kg/1 ml) [2], trimetazidine (10 mg/kg/1 ml) [3], or saline (control) via gastric gavage for 30 days. At the beginning of the trial, as well as on the 15th and 30th days, the rats were weighed, placed on rotarod, and assessed using transthoracic echocardiography (Figure 1). The rats underwent 21 days of forced swimming testing. According to the guidelines for rat exercise testing [4], signs of exhaustion, lack of coordinated movements, and failure to surface for three seconds following submersion in the water were designated as grounds for terminating the test. Weight, rotarod durations, M-mode and Doppler measurements, and forced swimming test durations were recorded on the 0th, 15th, and 30th days. Results No discernible differences were found between the groups in the initial evaluations. By using echocardiography, the left ventricular masses expanded in all three, indicating the emergence of an athlete's heart. In comparison to the control group, the ranolazine and trimetazidine groups showed considerable increases in their ability to exercise. In particular, the swimming times of the trimetazidine group and the ranolazine group improved to a mean of 1889 seconds by the 21st session, 1700 seconds in the trimetazidine group, and 1548 seconds in the control group (Figure 2), respectively, indicating enhanced cardiac performance. Conclusion(s) Ranolazine exhibits significant potential to enhance exercise capacity and cardiac efficiency in rats, surpassing the effects observed with trimetazidine. Trimetazidine is already registered as a doping agent in WADA [5]. These findings highlight the potential use of ranolazine as a performance enhancing agent in healthy subjects for a malicious purpose of creating unfair advantages in professional sports. Further studies in human subjects are needed.Figure 1Figure 2

Effect of trimetazidine dihydrochloride therapy on myocardial external efficiency in preclinical individuals with an HCM sarcomeric gene mutation

Abstract Background Hypertrophic cardiomyopathy (HCM) is frequently caused by pathogenic gene variants, i.e. mutations in genes encoding sarcomere proteins. Previous studies have shown that preclinical asymptomatic individuals with a heterozygous sarcomere mutation have decreased myocardial external efficiency (MEE), which is thought to be a key pathomechanism in the onset and progression of HCM. Purpose In the ENERGY trial, preclinical individuals with an HCM sarcomere gene mutation without hypertrophy were treated with the metabolic anti-anginal drug trimetazidine (TMZ) to determine whether the reduced MEE can be corrected at an early pre-hypertrophic disease stage. Methods 40 MYBPC3 and MYH7 asymptomatic mutation carriers without hypertrophy were treated for eight weeks with TMZ or placebo in a double-blind randomized study design. Directly before and after treatment, study participants underwent an [11C]-acetate PET/CT-scan and cardiac magnetic resonance imaging to measure MEE. A cardio-pulmonary exercise test was performed to measure the influence of TMZ on exercise parameters. Results Eight weeks of treatment with TMZ 20mg three times daily did not significantly alter MEE compared to placebo. The mean MEE changed from 30.3±3.8 percent to 29.8±4.3 percent in the placebo group and from 30.1±4 percent to 29.1±4 percent in the TMZ group. After adjustment for baseline, the TMZ group did not have a significantly different MEE (95% CI, -2.863 to 1.986, P=0.68) compared to placebo. Exercise parameters VO2max and respiratory exchange ratio were not significantly altered by treatment with TMZ. Conclusion The ENERGY trial is the first proof-of-concept randomized controlled trial with well-matched (age, sex, mutation) groups to test the hypothesis that TMZ improves MEE at a preclinical disease stage. We conclude that metabolic therapy does not correct reduced MEE in an early disease stage of HCM.methodsprimary outcome

Ranolazine therapy is associated with a reduced new diagnosis of diabetes mellitus in chronic coronary syndrome patients: the results of a real-world analysis of an Italian population

Abstract Background Ranolazine (Ran) is an anti-anginal drug acting as a late sodium current inhibitor at a cell membrane level. Some experimental and clinical studies showed an antihyperglycemic effect of the drug, possibly mediated by the increase of insulin secretion, the inhibition of glucagon release, and the protective action on beta-cell function. These effects, additive to the anti-anginal properties of Ran in patients with chronic coronary syndrome (CCS), could modulate and improve glucose metabolic balance. Indeed, data exploring at a population level the association of the drug with diabetes mellitus (DM) incidence are effectively lacking. Aims Aim of this study was to evaluate in CCS patients if the use of Ran, compared with other treatments (No-Ran), was associated with a lower incidence of DM in an Italian real-world clinical setting. Methods Patients included in the database of the National Health System were evaluated (N=6.1 million; about 10% of the Italian population); the recorded information concerned hospitalizations with the related diseases, clinical events, outpatient visits and drug therapy. Patients hospitalized for any cause and discharged with a diagnosis of angina between 2011 and 2020 (ICD-9-CM codes: 413-414) were included in the study after having proved the absence of DM in their medical history. Study population was divided into the Ran (at least one drug prescription) and in the No-Ran cohorts. The mean follow up was 4.3 years for the Ran and 5.0 years for the No-Ran cohorts, respectively. Results The study population included N=171,015 patients (mean age: 72 years, men: 66%). Among them, N=148,808 (No-Ran cohort) were treated with other therapies while N=22,207 (Ran cohort) received Ran. After propensity score matching, Ran (N=6,384) and No-Ran (N=25,536) cohorts did not differ for age, Charlson comorbidity index, use of aspirin and other antithrombotic agents, statins, beta-blockers, Ca-antagonists and nitrates. The incidence of a new diagnosis of DM during the follow-up period was 10.5 and 15.8% in the Ran and in the No-Ran cohorts, respectively (p<0.001). The Cox-regression analysis showed that Ran therapy was associated with a 30% risk reduction to present a new diagnosis of DM (HR=0.70, 95%CI: 0.64-0.76, p<0.001), independently of age, Charlson comorbidity index, heart failure, previous stroke, use of ivabradine, Ca-antagonists and nitrates. Conclusions This real-world study, performed in a whole subset of the Italian population, showed that, in the long-term, the incidence of a new DM diagnosis was lower in Ran users. This association could contribute to explain the benefits of the drug in patients with CCS.

Current Landscape of Gene Therapy for the Treatment of Cardiovascular Disorders.

Cardiovascular disorders (CVD) are the primary cause of death worldwide. Multiple factors have been accepted to cause cardiovascular diseases; among them, smoking, physical inactivity, unhealthy eating habits, age, and family history are flag-bearers. Individuals at risk of developing CVD are suggested to make drastic habitual changes as the primary intervention to prevent CVD; however, over time, the disease is bound to worsen. This is when secondary interventions come into play, including antihypertensive, anti-lipidemic, anti-anginal, and inotropic drugs. These drugs usually undergo surgical intervention in patients with a much higher risk of heart failure. These therapeutic agents increase the survival rate, decrease the severity of symptoms and the discomfort that comes with them, and increase the overall quality of life. However, most individuals succumb to this disease. None of these treatments address the molecular mechanism of the disease and hence are unable to halt the pathological worsening of the disease. Gene therapy offers a more efficient, potent, and important novel approach to counter the disease, as it has the potential to permanently eradicate the disease from the patients and even in the upcoming generations. However, this therapy is associated with significant risks and ethical considerations that pose noteworthy resistance. In this review, we discuss various methods of gene therapy for cardiovascular disorders and address the ethical conundrum surrounding it.

"Emerging clinical approaches in diabetic cardiomyopathy: insights from clinical trials and future directions".

We aim to explore the potential of diverse treatments, including perhexiline, calcium channel blockers, anti-hypertensives, PDE5 inhibitors, anti-anginal drugs, aldose reductase inhibitors, and SGLT-2 inhibitors, supported by clinical evidence. Additionally, this review seeks to identify novel therapeutic targets and future avenues for improving cardiovascular outcomes in diabetic populations. We performed a comprehensive literature review of English-language studies across multiple electronic databases, such as PubMed, ScienceDirect, Scopus, and Google Scholar, focusing on clinical trials. The search utilized keywords including 'Anti-hyperglycaemic drug,' 'Diabetic cardiomyopathy,' 'DPP-4 inhibitors,' 'GLP-1 receptor agonists,' 'Heart failure,' and 'SGLT-2 inhibitors.' We assessed clinical investigations in the treatment of cardiomyopathy and diabetes mellitus (DM) that are enhancing our understanding through trials evaluating the Polypill, Perhexiline, Eplerenone, IMB-1018972, AT-001, tadalafil, and dapagliflozin inhibitors. The development of new targeted interventions is of paramount importance due to the overlooked early symptoms, the complexity of the cellular and molecular pathways involved, and the absence of effective drug therapies. Pharmacological treatments like GLP-1 agonists, SGLT-2 inhibitors, NHE-1, NHE-3, and PPAR-γ agonists show promise for treating DCM. These treatments improve myocardial glucose absorption, address dysregulated glucose and lipid metabolism, and lower heart failure and cardiovascular events. Further research is needed to confirm effectiveness and safety.

FUNCTIONAL CHANGES IN THE HEPATOBILIARY SYSTEM IN PATIENTS WITH CHRONIC CORONARY SYNDROME DURING ANTIFUNGAL THERAPY

Modern medicine is faced with the global challenge of multimorbidity. It is a combination of various visceral diseases, which affect the development and manifestation of the underlying disease. In elderly patients, pathologies are often combined with cardiovascular diseases, such as coronary artery disease. Coronary artery disease is usually treated with several drugs or their combinations, such as antianginal, antithrombotic, lipid-lowering, and cardiac metabolic drugs. However, these drugs are metabolized in the liver and may have a direct effect on it. Besides, combined treatment of two pathologies has a pronounced negative effect on the liver. The purpose of the study was to examine functional changes in the liver while treating patients with onychomycosis and coronary artery disease. Materials and Methods. The study involved 68 people who consulted a dermatologist due to toenail changes. All patients were divided into 2 groups: patients with stable coronary artery disease (20 middle-aged and 14 elderly ones) and patients without coronary artery disease (24 middle-aged and 10 elderly ones). in both groups underwent systemic antifungal therapy (terbinafine, 250 mg once a day). Patients with stable coronary artery disease underwent the following therapy: antiplatelet agent (acetylsalicylic acid), HMG-CoA inhibitor (atorvastatin, 40 mg), beta-blocker (82 % of patients, bisoprolol) and ACE inhibitor (enalapril or lisinopril). The effectiveness of therapy was assessed according to the dynamics of clinical manifestations and the results of mycological nail tests. Control microscopic tests of the material from the nails were carried out three times after clinical recovery with a 3-month interval. Conclusion. When treated with antifungal drugs, patients demonstrated elevated liver enzymes. This is because the hepatobiliary system, which is already under high stress during the coronary artery disease treatment, also processes antifungal drugs. Therefore, it is necessary to take into account liver state when prescribing antifungal drugs. It is important to develop an algorithm for onychomycosis diagnosis and treatment in patients with coronary artery disease in order to prevent polypharmacy and impaired liver function.

Характеристика пацієнтів з ішемічною хворобою серця та стабільною стенокардією в Україні, оцінка підходів до їх лікування за даними багатоцентрового дослідження GO-OD

Treatment of coronary artery disease (CAD) and stable angina, includes lifestyle modification, pharmacological therapy and invasive interventions to achieve stabilization or regression of the disease. Knowledge of the current situation regarding the use of pharmacological therapy and evaluation of its effectiveness is necessary for further management optimization. Trimetazidine (TMZ) has previously been shown to reduce angina symptoms and increase exercise tolerance in patients with CAD and stable angina and may be among an option for optimizing antianginal treatment. However, the effectiveness of long-term treatment depends on patient adherence, so the use of TMZ once daily (OD) at a dose of 80 mg may improve satisfaction and adherence in patients with CAD and stable angina.Methods. The GO-OD study is a 3-month, non-interventional, observational, multicenter prospective study conducted in Ukraine in a real-world outpatient cardiology practice during February – August 2021. Physicians were instructed to continue monitoring and treating patients in accordance with usual practice and international guidelines. No additional diagnostic or monitoring procedures were performed. Clinical, instrumental and laboratory data, frequency of angina attacks, consumption of short-acting nitrates (SAN), adherence to antianginal drugs, as well as the overall efficacy, tolerability of TMZ OD 80 mg in real-world clinical practice were analyzed. The observation includes regular assessment of patients` clinical status, treatment optimization and its effectiveness at follow up visits.Results. The study included 1529 patients (mean age 62.5 years, 56 % men). In the absence of adequate control of risk factors, pharmacological control of symptoms, and limited use of interventional and surgical treatments, the frequency of angina episodes was high, most patients had a pronounced angina functional class according to the Canadian Society of Cardiology classification (10.5 % – CCS I, 60.1 % – CCS II, 29.5 % – CCS III). Thus, the average number of angina attacks per week in CCS I was 3.7, in CCS II – 5.2, and in CCS III – 7, 97 attacks. In addition to the severity of symptoms, the following pattern was observed: the higher the angina class, the more risk factors and comorbidities patients had. After 3 months of follow-up due to optimization of therapy, there was a significant (p<0.001) decrease in the frequency of angina attacks – from (5.8±4.7 to 1.6±2.0)/week, and the use of SAN – from (4.2±4.3 to 0.8±1.6)/week). At the same time, in 3 month the % of patients with CCS II and III significantly decreased, while the % of patients with CCS I increased (48.4 % – CCS I, 45.7 % – CCS II, 6 % – CCS III). Adherence to medication was improved: 49 % of patients reported high adherence (vs. 18 % at baseline) and 12 % – low adherence (vs. 52 % at baseline). After 3 months of follow-up most of doctors rated the overall tolerability and effectiveness of the therapy as «very satisfied». Patients’ satisfaction with TMZ OD 80 mg therapy after 3 months of follow-up was 9.5 points [on a scale of 1 to 10 (very satisfied)]. Patients’ assessment of daily physical activity increased significantly: 2.42 versus 5.89 points at baseline (on a scale of 1 to 10 (severe limitation)).Conclusions. In general, the management of outpatients with CAD and stable angina in the current cardiologists’ practice, which was complicated by the COVID-19 pandemic, was not effective enough, resulting in a high frequency of angina attacks – almost 6 per week, and a significant limitation of daily activity due to angina symptoms.Significant deficiency in the management of studied population was insufficient correction of such important risk factors as hypertension, heart rate, dyslipidemia, and lifestyle-related risk factors (overweight and obesity, low level of physical activity). The baseline therapy of patients in the study was in line with current guidelines, but with an insufficient frequency of statin prescription (78 %) and ACE inhibitors (54.5 %); antianginal treatment with an average of 2 or more antianginal drugs was not optimal for controlling angina symptoms, and the frequency of coronary revascularization procedures was also insufficient, mostly during acute MI (58.0 %).Optimization of drug therapy as the first step in correcting the condition of patients with CAD and stable angina in accordance with all current recommendations with the inclusion of the original trimetazidine OD 80 mg once daily among antianginal drugs, as well as active monitoring of patients for 3 months allowed to reduce the frequency of angina attacks regardless of its initial FC, increase patient adherence to treatment and their functional activity.

Trimetazidine: An Antianginal Drug and Not Only!

Trimetazidine, a piperazine derivative, has been in use for a long time as a safe drug in the long-term treatment of chronic ischemic disorders. The mechanism of action is basically that it partially inhibits mitochondrial fatty acid β-oxidation by blocking long-chain 3-ketoacyl-CoA thiolase and simultaneously enhances glucose oxidation, which means less oxygen consumption and increased mitochondrial efficiency by producing more adenosine triphosphate per mole of oxygen through glucose oxidation. However, as a metabolic modulator, the potency of trimetazidine has been studied to treat several diseases or disorders, which are considered to be caused by metabolic disorders. In this review, we highlight some of the studies that aimed to investigate the role of trimetazidine in treating some of these diseases, namely amyotrophic lateral sclerosis, statininduced skeletal muscle damage, and cardiomyopathy and peripheral arterial diseases, namely amyotrophic lateral sclerosis, statin-induced skeletal muscle damage, and cardiomyopathy and peripheral arterial disease associated with diabetes.

THE ADVANTAGES OF SYDNONIMINES COMPARED TO NITRATES IN THE TREATMENT OF PATIENTS WITH ISCHEMIC HEART DISEASE AND CORONARY INSUFFICIENCY

One of the primary challenges in treating patients with coronary artery disease and coronary insufficiency using nitrates is the development of tolerance. Nitrate tolerance is a condition in which the duration and intensity of anti-anginal and anti-ischemic effects decrease, despite maintaining a high concentration of the drug in the blood. In cases of developing tolerance, a continual increase in the nitrate dose is necessary to achieve the previous effect. To eliminate developed nitrate tolerance, discontinuing nitrates for 3-5 days is typically sufficient. Currently, molsidomine is employed as an alternative to nitrates, with sydnonimines emerging as a noteworthy substitute. Among sydnonimines, molsidomine (marketed as Sydnopharm, Dilasidom, Corvaton) stands out as the most effective. Despite its chemical distinction from nitrates, molsidomine operates through a similar mechanism. Functioning as a nitric oxide donor, this antianginal drug avoids the development of tolerance even with prolonged use. Molsidomine, akin to nitrates, acts as a vasodilator, exhibiting efficacy as an anti-ischemic and anti-anginal medication when administered in appropriate doses. Upon entering the human body, molsidomine undergoes hepatic metabolism, transforming into an active derivative compound known as SIN-1. This metabolite, upon entering the bloodstream, further converts into an active form (SIN-1A). From this active metabolite, the nitric oxide (NO) group is released, influencing the activation of guanylate cyclase. This activation prompts guanosine triphosphate to convert into cyclic guanosine triphosphate, ultimately contributing to the synthesis of proteins that bind calcium. This cascade of events results in the vasodilatory effect of molsidomine. Indications for molsidomine include stable angina pectoris, acute coronary syndrome, early post-infarction angina, congestive heart failure, portal hypertension, pulmonary hypertension, and Aerz's disease. Possible side effects following the therapy with molsidomine (dizziness, headache, and diplopia) occur much less frequently compared to nitrates. After using nitrates, such a side effect as methemoglobinемia may occur. Therapy with molsidomine does not lead to the development of this side effect.

(202) Comparative Study of the Efficacy of Avanafil and Atorvastatin Daily Dose in Management of Vasculogenic Erectile Dysfunction

Abstract Introduction Erectile dysfunction (ED) is defined as the “consistent inability to attain or maintain a penile erection, or both, sufficient for adequate sexual relations”. ED is not only a medical problem but affects the marital relations and patient's self-esteem and causes the quality of life to decrease. which in turn causes the patient to go into depression or develop anxiety. In the past, erectile dysfunction was considered, in most cases, to be a purely psychogenic disorder, but current evidence suggests that more than 80% of cases have an organic aetiology. Causes of organic erectile dysfunction can now be broadly divided into nonendocrine and endocrine. Of the nonendocrine aetiologies, vasculogenic (affecting blood supply) is the most common and can involve arterial inflow disorders and abnormalities of venous outflow (corporeal veno-occlusion). Avanafil is a second-generation phosphodiesterase type 5 inhibitor approved for erectile dysfunction by the FDA on 2012 and by EMA in 2013. With a high selectivity for phosphodiesterase type 5 isoform AND faster onset of action compared with other PDE5 inhibitors, it offers more tolerability and less adverse events. Atorvastatin is 3-hydroxy-methylglutaryl (HMG)-CoA reductase inhibitor act on the rate-limiting step in cholesterol biosynthesis (the conversion of HMG-CoA to mevalonate) and are effective in treating dyslipidemia. statins reverse endothelial dysfunction by decreasing the action of oxidized low-density lipoprotein (LDL) on endothelial cells, resulting in an increase of NO activity. Objective is to evaluate and compare the efficacy of avanafil and atorvastatin daily dose in management of patients with vasculogenic erectile dysfunction. Methods A 60 adult heterosexual males complaining of vasculogenic erectile dysfunction proven by penile duplex were collected from outpatient andrology clinics of Al-Azhar University Hospitals. The patients were divided into two treatment groups: (Group A): 30 patients received daily dose of 100 mg avanafil. (Group B): 30 patients received daily dose of 40 mg atorvastatin, The main outcome measures and the difference in penile duplex ultrasound results and IIEF-EF scores between the two groups are evaluated and compared at the end of the study, Age of patients between 20 and 50 years, established diagnoses of Vasculogenic erectile dysfunction, Normal lipid profile, Normal Total and Free testosterone levels and No contraindications to the study medications were included criteria. However patients who failed to fulfill any of the inclusion criteria, psychogenic or neurogenic erectile dysfunction, dyslipidemia Patients with Renal or Hepatic insufficiency and Patients with advanced cardiovascular diseases such as heart failure and coronary artery disease on antianginal drugs especially nitrates were excluded. Results Our study revealed statistically significant improvement in Penile Doppler ultrasonography parameters (PSV, EDV& RI) and IIEF-EF scores in avanafil group compared to atorvastatin group. Conclusions avanafil 100 mg daily dose leads to significant improvement in men with vasculogenic erectile, while atorvastatin 40 mg caused no significant differences, neither positively nor adversely. In summary, avanafil at dose of 100 mg can be a therapeutic appropriate choice in cases of vasculogenic ED. Disclosure No.

The efficacy of Chinese herbal drugs for adults with angina pectoris: Bayesian network meta-analysis of 331 RCTs involving 36,467 individuals

Ethnopharmacological relevanceHundreds of randomized controlled trials (RCT) on Chinese herbal drugs (CHDs) including Shexiang baoxin pill (BXP), compound Danshen dripping pill (DSP), compound Danshen tablet (DST), Suxiao jiuxin pill (JXP), Naoxintong capsule (NXT), Tongxinluo capsule (TXL), and Di'ao xinxuekang capsule (XXK) and conventional chemical drugs, such as isosorbide dinitrate (ISDN), for angina pectoris are available but have not been evaluated by a PRISMA-compliant network meta-analysis (NMA). Aim of the studyThis study aimed to compare the efficacy of nine anti-anginal drugs through NMA on RCTs. MethodsRCTs of drug treatment for adult patients with angina pectoris for improvements in symptoms and electrocardiography were retrieved. Odds ratios and 95% credible intervals were computed to measure effect sizes. RCT quality was evaluated with the Cochrane risk of bias tool. Evidence synthesis was performed with Bayesian NMA. Essential analyses including subgroup analysis, sensitivity analysis, meta-regression analysis, publication bias analysis, and ranking analysis were conducted to assess the robustness of efficacies. Evidence strength was assessed with the GRADE approach. ResultsA total of 331 RCTs with 36,467 participants were eligible. The overall quality of all included RCTs was low. Overall efficacy estimates from different approaches of evidential synthesis found that BXP, TXL, and DSP were more efficacious than DST and ISDN. Essential analyses indicated consistent efficacy estimates, insignificant publication bias, and corroborative ranking results. The overall GRADE evidence strength was low. ConclusionThis comprehensive Bayesian NMA found BXP, TXL, and DSP to be the top three candidates among the seven tested CHDs for treating adults suffering from angina pectoris. However, the quality and the evidence strength of eligible RCTs were low. Further high-quality RCTs with more outcome measures and their NMAs are warranted. RegistrationPROSPERO CRD42014007035.

Nose-to-Heart Approach: Unveiling an Alternative Route of Acute Treatment.

Intranasal (IN) administration has emerged as a novel approach for rapid systemic absorption, with potential applicability in the management of acute cardiovascular events. This review explores the evolution of IN cardiovascular pharmacotherapy, emphasizing its potential in achieving systemic effects and bypassing the first-pass metabolism associated with oral administration. The extensive vascularization of nasal mucosa and a porous endothelial basement membrane facilitate efficient drug absorption into the bloodstream. The IN route ensures a critical swift onset of action, which allows self-administration in at-home settings. For instance, etripamil nasal spray, a first-in-class formulation, exemplifies the therapeutic potential of this approach in the treatment of spontaneous supraventricular tachycardia. The review critically assesses studies on IN formulations for angina, acute myocardial infarction, hypertensive episodes, and cardiac arrhythmias. Preclinical evaluations of beta-blockers, calcium-channel blockers, and antianginal drugs demonstrate the feasibility of IN administration for acute cardiovascular events. A small number of clinical trials have revealed promising results, emphasizing the superiority of IN drug delivery over oral administration in terms of bioavailability and onset of action. Unambiguously, the limited clinical trials and patient enrollment pose challenges in generalizing experimental outcomes. However, the nose-to-heart approach has clinical potential.

Ethanol-induced atrial fibrillation results from late INa and can be prevented by ranolazine

Abstract Background Ethanol consumption is the most important self-triggered cause of atrial fibrillation (AF). As abstinence often fails, alternative therapies are needed. CaMKII-activation upon ethanol with consecutive Ca2+-leak from the sarcoplasmic reticulum (SR) appears to be an important pathomechanism for ethanol-induced AF, but is not a druggable target. CaMKII has previously been shown to induce late sodium current (late INa) which could be proarrhythmogenic. Purpose We hypothesized that late INa might be involved in the development of AF upon acute ethanol exposition and that thus, the antianginal drug ranolazine (an inhibitor of late INa) could be repurposed to prevent ethanol-induced AF. Methods Acute effects of ethanol were investigated in vivo and in vitro as compared to vehicle. The occurrence of AF in vivo was assessed by programmed electrical stimulation in mice. To test the role of late INa, we used ranolazine in vivo and in vitro, as well as tetrodotoxin in vitro. We measured late INa and cytosolic sodium concentration, recorded stimulated action potentials and spontaneous delayed afterdepolarizations (DAD), and assessed SR Ca2+-leak by recording Ca2+-sparks. Mechanistically, we inhibited CaMKII using AIP and used NaV1.5 S571A mice to specifically investigate the role of CaMKII-mediated late INa. Human biopsies were acquired during surgery and were used for cell isolation or chunk incubation. Results Ethanol acutely induced late INa, sodium overload, SR Ca2+-leak and delayed afterdepolarizations in isolated atrial cardiomyocytes, as well as atrial fibrillation in vivo (10 of 10 mice). All of these cellular ethanol effects were prevented by pharmacologic inhibition of late INa. Importantly, ranolazine prevented the development of AF upon ethanol exposure in vivo. Mechanistically, CaMKII-activation and, accordingly, CaMKII-dependent NaV1.5 phosphorylation (S571) were increased by ethanol exposure. Indeed, the phosphoresistant NaV1.5 S571A mutation prevented late INa, SR Ca2+-leak and in vivo AF upon ethanol, demonstrating a critical role of CaMKII-mediated NaV1.5 phosphorylation for acute ethanol effects. Conclusion We show that ethanol acutely induces late INa upstream of arrhythmogenic SR Ca2+-leak and delayed afterdepolarizations, dependent on NaV1.5 S571 phosphorylation, leading to atrial fibrillation in vivo. Importantly, these effects as well as AF in vivo can be prevented using the late INa inhibitor ranolazine. We suggest that this antianginal drug could be repurposed to prevent ethanol-induced AF.Late INa (Patch-Clamp)In vivo AF (programmed stimulation)

Combination of nicorandil and beta-adrenergic receptor blockers in patients with coronary heart disease: a real-world observational study

Abstract Background and objective Nicorandil and beta-adrenergic receptor blockers (BBs) are commonly used anti-anginal drugs. However, the effect of combined nicorandil and BBs compared with that of BBs alone on long-term clinical outcomes in patients with coronary heart disease (CHD) remains undetermined. Accordingly, a real-world observational study was performed to assess the long-term potential of nicorandil combined with BBs in Chinese patients with CHD. Methods A multicenter retrospective cohort study involving two tertiary healthcare institutions in our city was performed. Adult patients who had been hospitalized for CHD and treated for angina with a combination of nicorandil and BBs or BBs alone between August 2002 and March 2020 were included. The effect of different treatments on the cumulative incidence of major adverse cardiovascular events (MACE) and their components (myocardial infarction [MI], stroke, and all-cause mortality) within a follow-up duration of 2.5 years were analyzed using Kaplan–Meier survival curves. An inverse probability of treatment weighting (IPTW) method was used to adjust for the possible effect of confounding factors. The hazard ratio (HR) and corresponding 95% confidence interval (CI) were calculated using a Cox regression analysis. Sensitivity analyses based on IPTW with trimming or limited to patients admitted after January 1, 2012, were performed to evaluate the robustness of the findings. Results Overall, 4,669 patients receiving the combined treatment and 12,243 receiving BBs alone were included. After IPTW, the results demonstrated that the combined treatment was associated with a significantly reduced incidence of MACE (HR 0.80, 95% CI: 0.73–0.87, P < 0.0001)(Figure 1) and stroke (HR 0.48, 95% CI 0.42–0.54) but not of MI (HR 1.03, 95% CI 0.92–1.15) or all-cause mortality (HR 0.93, 95% CI 0.64–1.37). Interaction analyses were performed for the following subgroups: age (younger than 65 or is and older than 65 years), gender, acute coronary syndrome (ACS), smoking, drinking, revascularization, diabetes and hypertension, and showed a favorable consistency with the primary outcome (Figure 2). Conclusion A combined anti-angina treatment of nicorandil and BBs may be more effective than a treatment of BBs alone in reducing the long-term incidence of MACE in patients with CHD.The Kaplan-Meier curves of the outcomesThe forest plot of the subgroup analysis

Treatment of microvascular angina with the coronary sinus reducer: a first experience

Abstract The Coronary Sinus Reducer (CSR) is an hourglass-shaped device approved for the treatment of refractory angina. Its percutaneous implantation in the coronary sinus leads to a retrograde increase in venous pressure, which is thought to improve capillary recruitment and perfusion to the ischemic myocardium. No data is however available on the use of the CSR to treat microvascular angina, an increasingly recognized but still poorly understood condition. In this preliminary study, we evaluated the efficacy of the CSR in a small cohort of patients with non-obstructive disease. We screened consecutive patients from the prospective COMPLEX registry that received a CSR for refractory angina between June 2018 and November 2022. Inclusion criteria were the absence of obstructive coronary artery disease (<50% narrowing in all coronary arteries, or a negative intracoronary fractional flow reserve test) and no prior history of revascularization. Endpoints were angina and dyspnea symptoms, evaluated with the Canadian Cardiovascular Society (CCS) and the New York Hearth Association (NYHA) scores respectively, procedural success rate, and major adverse cardiovascular events (MACE), defined as a composite of all-cause mortality, cardiovascular death, acute coronary syndromes (ACS) and heart failure (HF) hospitalizations. We ultimately enrolled 8 patients; 6 (75%) were females and mean age was 67.8±9.9 years. Their baseline characteristics are further depicted in table 1. Microvascular dysfunction was invasively confirmed in 5 (62.5%) patients; mean index of microvascular resistance (IMR) was 32.8±15.7 and mean coronary flow reserve (CFR) was 1.7±0.7. In one patient, reduced global CFR (1.4) was evident on cardiac magnetic resonance examination. At baseline, mean CCS class was 2.9±0.6, NYHA class 2±0.9, and number of antianginal drugs 2.6±1.6. Procedural success was 100%, with only one patient experiencing a procedure-related complication (sternocleidomastoid muscle hematoma requiring no intervention). At a median follow-up of 647.5 days (IQR 132-732), mean CCS class was 1.5±0.8, NYHA class 1.9±0.9 and number of antianginal drugs 1.9±1.1. All patients improved by ≥1 CCS class and 3 (37.5%) by ≥2 CCS classes. No MACE was observed. To the best of our knowledge, we present the first report of CSR implantation for the treatment of microvascular angina. Our positive results are particularly promising given the paucity of treatment options currently available for the condition, but larger studies are needed to confirm these findings.table 1figure 1

Ranolazine is associated with a reduced incidence of atrial fibrillation in patients with chronic coronary syndrome: the results of a real-world analysis of an Italian population

Abstract Background Ranolazine (Ran) is an anti-anginal drug acting as a late sodium current inhibitor at a cell membrane level. This mechanism of action could be implicated in the control of arrhythmia development. Indeed, some evidence supports the efficacy of Ran as an anti-arrhythmic agent, with a synergistic effect with that of Class III agents, namely amiodarone and dronedarone. Aims Aim of this study was to evaluate if the use of Ran in patients with chronic coronary syndrome (CCS) in comparison with other treatments (No-Ran), was associated with a lower incidence of atrial fibrillation (AF) in a real-world clinical setting in Italy. Methods Patients included in the database of the National Health System were evaluated (N=6.1 million); the recorded information concerned hospitalizations with the related diseases, clinical events, visits and drug therapy. Patients hospitalized for any cause and discharged with a diagnosis of angina between 2011 and 2020 (ICD-9-CM codes: 413-414) were included in the study provided they had not experienced an AF episode in the 12 preceding months (characterization period). Study population was divided into the Ran (at least one drug prescription) and in the No-Ran cohorts. The mean follow up was 4.3 years for the Ran and 5.0 years for the No-Ran cohorts, respectively. Results The study population included N=171,015 patients (mean age: 72 years, men: 66%). Among them, N=148,808 (No-Ran cohort) were treated with other therapies while N=22,207 (Ran cohort) received Ran. After propensity score matching, Ran (N=6,384) and No-Ran (N=25,536) cohorts did not differ for age, Charlson comorbidity index, use of aspirin, beta-blockers, Ca-antagonists and nitrates. The incidence of a new episode of AF during the follow-up period was 5.3% and 9.6% in the Ran and in the No-Ran cohorts, respectively (p<0.001). The Cox-regression analysis showed that independently of age, male gender, heart and renal failure, COPD, use of beta-blockers, Ca-antagonists and nitrates, and of cardiovascular procedures, Ran therapy was associated with a 41% risk reduction to develop AF (HR=0.59, 95%CI: 0.53-0.67, p<0.001). Conclusions Our real-world study, performed in a whole subset of the Italian population, showed that Ran use in a long-term follow-up was associated with a lower incidence of AF in patients with CCS.

Incidence of restenosis after drug-coated balloon percutaneous coronary intervention in patients with diabetes mellitus - a single-centre experience

Abstract Background and aim Diabetes mellitus (DM) is related to higher rates of complications after coronary revascularization.1 The efficiency of drug-coated balloon (DCB) percutaneous coronary intervention (PCI) has been shown for in-stent restenosis (ISR) and native small-vessel disease, however data on outcomes in DM is scarce. 2 The aim is to compare the incidence of target lesion restenosis at follow-up (FUP) coronary angiography in patients with and without DM receiving DCB PCI. Material and methods The registry included patients undergoing a DCB PCI at our university hospital centre from February 2011 to January 2022 (n=645). Patient demographics, comorbidities, pharmacotherapy, as well as data on the initial and FUP coronary angiography/PCI was collected. An FUP angiography was performed in 50% of patients (n=317), with a median FUP of 6 (interquartile range 3-17) months. Results Data is shown in Table 1. The cohort was 75% male, mean age 65 ± 10 years. DM was present in 35% (n=223) of patients, equally in both sexes, and was associated with a history of myocardial infarction, PCI, coronary artery bypass grafting, stroke; as well as arterial hypertension, and renal insufficiency. No age difference was noted between groups. At initial PCI, more DM patients had multivessel coronary disease and ISR as the indication for DCB (DM vs non-DM: 41% vs 31%, p=0.023). After DCB, no group difference was noted in regards to the need for a bail-out PCI. FUP was performed in an equal percentage of patients in both groups (54% vs 48%, p=0.181), with no differences seen in the incidence of restenosis (17% vs. 18%, p=0.879), the need for target lesion PCI (14% vs. 13%, p=0.863), or the use of anti-anginal drugs. Conclusion The findings of our single-centre analysis show that although DM is related to more advanced comorbidities it does not increase the risk of target lesion restenosis after DCB PCI. DCB PCI should be considered as a therapeutic option in candidate patients regardless of DM status.Comparison between diabetic and non diab