sildenafil-citrate and Arrhythmias--Cardiac

The phosphodiesterese-5 (PDE5) inhibitors, including sildenafil (Viagra™), vardenafil (Levitra™), tadalafil (Cialis™) and avanafil (Stendra™) have been developed for the treatment of erectile dysfunction. Moreover, sildenafil and tadalafil have been approved for the management of pulmonary arterial hypertension. A number of preclinical studies have shown that PDE5 inhibitors have powerful protective effect against several clinical scenarios including myocardial ischemia/reperfusion injury, doxorubicin and post-MI, heart failure, cardiac hypertrophy, heart transplantation, Duchenne muscular dystrophy and preconditioning of stem cells. Based on these studies, it appears that sildenafil and other PDE5 inhibitors hold promise for further development as novel drug therapies in cardioprotection.

Topics: Animals; Arrhythmias, Cardiac; Cardiotonic Agents; Doxorubicin; Heart; Heart Transplantation; Muscular Dystrophy, Duchenne; Phosphodiesterase 5 Inhibitors; Piperazines; Purines; Rabbits; Reperfusion Injury; Sildenafil Citrate; Sulfones

Sildenafil citrate is a drug commonly used to manage erectile dysfunction. It is designated chemically as 1-[[3-(6,7-dihydro-1-methyl-7-oxo-3-propyl-1H -pyrazolo[4,3-d]pyrimidin-5-yl)-4 ethoxyphenyl] sulfonyl]-4-methylpiperazine citrate (C22H30N6(O4)S). It is a highly selective inhibitor of cyclic guanine monophosphate-specific phosphodiesterase type 5. In late March through mid-November 1998, the US Food and Drug Administration (FDA) published a report on 130 confirmed deaths among men (mean age, 64 years) who received prescriptions for sildenafil citrate, a period during which >6 million outpatient prescriptions (representing about 50 million tablets) were dispensed. The US FDA recently reported that significant cardiovascular events, including sudden cardiac death, have occurred in men with erectile dysfunction who were taking sildenafil citrate. These reports have raised concerns that sildenafil citrate may increase the risk of cardiovascular events, particularly fatal arrhythmias, in patients with cardiovascular disease. In the past few years, the cardiac electrophysiological effects of sildenafil citrate have been investigated extensively in both animal and clinical studies. According to extensive data available to date, sildenafil citrate has been shown to pose minimal cardiovascular risks to healthy people taking this drug. Some precautions are needed for patients with cardiovascular diseases. However, the only absolute contraindication for sildenafil citrate is the concurrent use of nitrates. This article is intended to review sildenafil citrate's cardiovascular effects, as well as current debates about its arrhythmogenic effects.

Topics: Adult; Aged; Arrhythmias, Cardiac; Blood Pressure; Cardiovascular Diseases; Death, Sudden, Cardiac; Electrophysiology; Erectile Dysfunction; Heart Rate; Humans; Male; Middle Aged; Myocardial Contraction; Phosphodiesterase Inhibitors; Piperazines; Purines; Risk Factors; Sildenafil Citrate; Sulfones; Vasodilator Agents

Sildenafil has been registered for the treatment of erectile dysfunction since 1998. World wide a large number of patients were reported, dying of acute heart disease after using sildenafil. Therefore the patient instruction text was adapted. Simultaneous use of sildenafil and nitrates is contraindicated because of serious decrease of the blood pressure. The use of sildenafil can lead to physical stress in patients with a history of heart disease and a treadmill test assessment is advisable. In two years 38 adverse reactions were seen in 25 Dutch patients. The Dutch reports (three cardiovascular deaths since the introduction) also show the dilemmas in the assessment of the safety of sildenafil: is it the underlying disease or is it the drug that causes death? Further research into the adverse reactions has to be done, therefore reporting suspected side effects of sildenafil is important.

Topics: Adverse Drug Reaction Reporting Systems; Arrhythmias, Cardiac; Cardiovascular Diseases; Erectile Dysfunction; Humans; Male; Myocardial Infarction; Netherlands; Phosphodiesterase Inhibitors; Physical Exertion; Piperazines; Purines; Retinal Hemorrhage; Sildenafil Citrate; Sulfones

Myocardial relaxation and stiffness are influenced by fibrillar collagen content. Cyclic nucleotide signaling regulators have been investigated targeting more effective modulation of collagen deposition during myocardial healing process. To assess the effects of phosphodiesterase type 3 and phosphodiesterase type 5 inhibitors on cardiac function and left ventricular myocardial fibrosis in catecholamine-induced myocardial injury, sildenafil and pimobendan were administered to male Wistar rats 24 hours after isoproterenol injection. Echocardiography and electrocardiogram were performed to assess kinetic and rhythm changes during 45 days of drug administration. At the end of study, type I and type III collagen were measured through immunohistochemistry analysis, and left ventricular pressure was assessed through invasive method. Echocardiography assessment showed increased relative wall thickness at 45 days in pimobendan group with significant diastolic dysfunction and increased collagen I deposition compared with nontreated positive group (3.03 ± 0.31 vs. 2.73 ± 0.28%, P < 0.05). Diastolic pressure correlated positively with type I collagen (r = 0.54, P < 0.05). Type III collagen analysis did not demonstrate difference among the groups. Sildenafil administration attenuated type I collagen deposition (2.15 ± 0.51 vs. positive group, P < 0.05) and suggested to be related to arrhythmic events. Arrhythmic events were not related to the quantity of fibrillar collagen deposition. Although negative modulation of collagen synthesis through cyclic nucleotides signaling have shown promising results, in this study, pimobendan postconditioning resulted in increased collagen type I formation and severe diastolic dysfunction while sildenafil postconditioning reduced collagen type I deposition and attenuated diastolic dysfunction.

Topics: Animals; Arrhythmias, Cardiac; Collagen Type I; Collagen Type III; Disease Models, Animal; Fibrosis; Isoproterenol; Male; Myocardium; Phosphodiesterase 3 Inhibitors; Phosphodiesterase 5 Inhibitors; Pyridazines; Rats, Wistar; Risk Assessment; Sildenafil Citrate; Ventricular Dysfunction, Left; Ventricular Function, Left; Ventricular Remodeling

Cardiac arrhythmia is a common cause of mortality, and its progression may be due to abnormal sympathetic nerve activity and catecholamine release. Besides, lactate dehydrogenase (LDH) and creatine kinase (CK) downregulation and adiponectin expression play important roles in promoting coronary artery disease. The study aimed to examine the possible cardioprotective effect of members of phosphodiesterase type 5 (PDE-5) inhibitors in epinephrine-induced arrhythmia in rats. Arrhythmia was induced by cumulative boluses of epinephrine (4, 8, 16, 32, 64, and 128 mg/kg) given at 10-min intervals. Rats were randomly allocated into five groups. Group I: Normal control group received only saline. Group II: Rats injected with epinephrine and served as arrhythmia group. Groups III, IV, and V: Rats received daily oral sildenafil (0.5 mg/kg), vardenafil (3 mg/kg), and tadalafil (10 mg/kg), respectively, for 30 days prior to epinephrine injections. Injection of epinephrine to rats decreased heart rate and QTc interval but increased RR interval and duration of arrhythmia. Epinephrine group had lower serum reduced glutathione (GSH) and adiponectin levels and higher serum malondialdehyde (MDA), nitric oxide (NO), heart LDH, and CK contents. Histopathological investigations of epinephrine group provoked necrotic changes with strong positive immunoreactivity for caspases-3. While pretreatment of rats with PDE-5 inhibitors improved GSH and adiponectin contents, ameliorated serum MDA and NO levels and heart LDH and CK contents and corrected epinephrine-induced histopathological changes. PDE-5 inhibitors may delay epinephrine-induced arrhythmia through expression of adiponectin and downregulation of heart LDH and CK.

Topics: Adiponectin; Animals; Anti-Arrhythmia Agents; Apoptosis; Arrhythmias, Cardiac; Caspase 3; Creatine Kinase; Disease Models, Animal; Electrocardiography; Epinephrine; Glutathione; Heart Rate; L-Lactate Dehydrogenase; Male; Malondialdehyde; Myocardium; Necrosis; Nitric Oxide; Phosphodiesterase 5 Inhibitors; Rats, Wistar; Sildenafil Citrate; Tadalafil; Vardenafil Dihydrochloride

A retrospective analysis of the records of all the patients of pulmonary arterial hypertension with pregnancy at AIIMS, New Delhi, India, to study maternal and perinatal outcome and to compare outcome between severe and mild pulmonary arterial hypertension.. A retrospective analysis was carried out of 30 pregnancies in women with pulmonary arterial hypertension (PAH) who delivered at ≥ 28 weeks of gestation from July 2006 through July 2012 at a tertiary care center in India. Pulmonary artery blood pressure (PABP) during the first trimester of pregnancy or before pregnancy was considered to define PABP as severe or mild, with severe cases having systolic PABP >50 mmHg on echocardiography.. Out of 30 patients, 14 patients had severe PAH and 16 patients had mild PAH. Women with severe PAH had a significantly higher incidence of preterm delivery (11 vs. 3, P < 0.05), small for gestational age infants (10 vs. 2, P < 0.05) and cardiac complications (6 vs. 1, P < 0.05) compared to women with mild PAH. There was maternal mortality in a patient with Eisenmenger syndrome. In women with severe PAH and mild PAH, PABP increased in later pregnancy from 63.14 ± 7.6 to 71.57 ± 7.9 mmHg (P < 0.05) and from 40.37 ± 3.6 to 41.69 ± 4.1 mmHg (P < 0.05), respectively.. Pregnancy in women with severe PAH is associated with higher maternal morbidity and adverse fetal outcome compared to pregnancy in women with mild PAH.

Topics: Adult; Arrhythmias, Cardiac; Arterial Pressure; Birth Weight; Cesarean Section; Echocardiography; Eisenmenger Complex; Familial Primary Pulmonary Hypertension; Female; Gestational Age; Heart Failure; Humans; Hypertension, Pulmonary; India; Infant, Newborn; Infant, Small for Gestational Age; Piperazines; Pregnancy; Pregnancy Complications, Cardiovascular; Pregnancy Outcome; Pregnancy Trimester, First; Pregnancy Trimester, Third; Premature Birth; Purines; Retrospective Studies; Severity of Illness Index; Sildenafil Citrate; Sulfones; Vasodilator Agents; Young Adult

Pre-clinical studies in swine have demonstrated that a supratherapeutic concentration of sildenafil citrate decreased defibrillation efficacy and facilitated cardiac arrhythmia. We therefore, decided to investigate the effects of Kaempferia parviflora (KP) extract on these parameters in the swine heart. The underlying assumption was that in the heart, KP might be producing effects similar to sildanafil citrate as KP has long been used in southeast Asian traditional medicine to correct erectile dysfunction.. The study was conducted as the defibrillation study, and ventricular fibrillation (VF) induction study. In both studies, the defibrillation threshold (DFT), the upper limit of vulnerability (ULV) and VF threshold were determined before and after KP extract administration.. In both studies KP extract at high concentrations (100 and 50 mg/kg) significantly increased the DFT and ULV, without altering the VF threshold. At these concentrations, systolic and diastolic blood pressures were also attenuated.. High concentrations of KP extract attenuated defibrillation efficacy and increased cardiac vulnerability to arrhythmia in a normal swine heart. When used in appropriate concentrations, its blood pressure lowering effect may be useful in hypertensive states. Further studies need to be done to elucidate its mechanism of action.

Topics: Animals; Arrhythmias, Cardiac; Blood Pressure; Electric Countershock; Electrophysiological Phenomena; Heart; Heart Conduction System; Piperazines; Plant Extracts; Purines; Sildenafil Citrate; Sulfones; Swine; Ventricular Fibrillation; Zingiberaceae

Right ventricular (RV) dysfunction, caused by severe pulmonary hypertension (PH), is associated with high mortality because of RV failure. However, some patients can suffer from sudden cardiac death (SCD). We hypothesized that severe PH can cause RV arrhythmogenesis, leading to SCD. We sought to investigate arrhythmogenesis in PH. Optical mapping analysis (OMP) with an electrophysiological study (EPS) and pathological examination were performed in a monocrotaline (MCT)-induced rat PH model. Rats were injected with MCT (60 mg/kg), and OMP was performed in isolated Langendorff-perfused hearts. OMP revealed abnormal RV conduction delays and abnormal patterns, along with elevated RV pressure. In addition, impaired action potential duration dispersion (APDd), an index of myocardial repolarization instability, was observed only in the RVs with severe PH. The EPS demonstrated that lethal arrhythmias were induced by burst pacing to the RV when deteriorated APDd became evident. This arrhythmogenesis was inhibited by combination treatment with sildenafil and beraprost (SIL + BERA). RT-PCR showed an mRNA up-regulation of Type I collagen and down-regulation of connexin-43 in the RV at 5 weeks after MCT injection. Pathological examination revealed pulmonary vascular remodeling and RV hypertrophy with interstitial fibrosis, which was substantially reduced by SIL + BERA. Immunohistochemistry also revealed connexin-43 degradation in the RVs with severe PH. In contrast, connexin-43 was well preserved, and no lethal arrhythmias were induced by burst pacing to the RV in the absence of PH after SIL + BERA. In conclusion, RV electrical remodeling, including impaired APDd, causes arrhythmogenesis in severe PH, potentially associated with SCD attributable to PH.

Topics: Animals; Arrhythmias, Cardiac; Cardiotonic Agents; Collagen Type I; Connexin 43; Death, Sudden, Cardiac; Drug Therapy, Combination; Epoprostenol; Gene Expression Regulation; Heart; Humans; Hypertension, Pulmonary; Male; Monocrotaline; Organ Culture Techniques; Piperazines; Purines; Rats; Rats, Sprague-Dawley; Sildenafil Citrate; Sulfones; Ventricular Dysfunction, Right; Ventricular Remodeling; Voltage-Sensitive Dye Imaging

We have demonstrated that activation of ATP-sensitive potassium (K(ATP)) channels can attenuate sympathetic hyperinnervation. Sildenafil, a phosphodiesterase-5 inhibitor, has been shown to provide a preconditioning-like cardioprotective effect via opening of K(ATP) channels. The aim of this study was to investigate whether chronic administration of sildenafil attenuates cardiac sympathetic hyperinnervation after myocardial infarction through activation of K(ATP) channels and to compare it with the nitric oxide donor isosorbide dinitrate. Male Wistar infarcted rats induced by ligation of the anterior descending artery were randomized to either vehicle, nicorandil, sildenafil, isosorbide dinitrate, glibenclamide, or a combination of nicorandil and glibenclamide, or sildenafil and glibenclamide. Myocardial norepinephrine levels revealed a significant elevation in vehicle-treated rats compared with sham-operated rats, consistent with sympathetic hyperinnervation after infarction assessed by immunohistochemical analysis for tyrosine hydroxylase, growth associated factor 43 and neurofilament and by protein expression and mRNA of nerve growth factor. Sympathetic hyperinnervation was reduced after administering either nicorandil or sildenafil. Arrhythmic scores during programmed stimulation in the sildenafil-treated rats were significantly lower than those treated with the vehicle. Furthermore, the beneficial effects of sildenafil-induced were reversed by the addition of either glibenclamide or 5-hydroxydecanoate, implicating mitochondrial K(ATP) channels as the relevant target. Isosorbide dinitrate failed to confer similar antiarrhythmia. 1H-[1,2,4]oxadiazolo[4,3-α]quinoxalin-1-one, a soluble guanylyl cyclase inhibitor, did not influence the effect of sildenafil on the nerve growth factor. These data indicate that sildenafil after infarction attenuated sympathetic hyperinnervation and arrhythmias by activation of mitochondrial K(ATP) channels through a guanylyl cyclase-cGMP-independent pathway.

Topics: Animals; Arrhythmias, Cardiac; Electric Stimulation; Enzyme Inhibitors; Heart Ventricles; KATP Channels; Male; Myocardial Infarction; Nerve Growth Factor; Nitric Oxide; Norepinephrine; Piperazines; Purines; Rats; Rats, Wistar; Sildenafil Citrate; Sulfones

Sildenafil (Viagra) prolongs repolarisation in cardiac muscle, an effect that could lead to ventricular fibrillation (VF). Sildenafil (2 mg kg(-1)) was given by mouth to 12 mongrel dogs and, 24 h later, these dogs were anaesthetised, thoracotomised and subjected to a 25 min occlusion of the anterior descending coronary artery. Haemodynamic parameters were similar in this and the control group, but there were fewer and less serious ventricular arrhythmias during occlusion in the sildenafil group (VF 17 vs 60%; ventricular premature beats 140+/-52 vs 437+/-127% and episodes of ventricular tachycardia 4.0+/-3.2 vs 19.3+/-7.7%, all P<0.05). However, reperfusion VF and indices of ischaemia severity (epicardial ST-segment mapping, inhomogeneity) were not modified by the drug. Sildenafil increased the QT interval, especially during ischaemia. Our conclusion is that ischaemia-induced ventricular arrhythmias are reduced by sildenafil, but this protection is less pronounced than that following cardiac pacing or exercise.

Topics: Animals; Anti-Arrhythmia Agents; Arrhythmias, Cardiac; Coronary Vessels; Dogs; Electrocardiography; Hemodynamics; Myocardial Reperfusion Injury; Phosphodiesterase Inhibitors; Piperazines; Purines; Sildenafil Citrate; Stroke Volume; Sulfones; Tachycardia, Ventricular; Ventricular Dysfunction, Left; Ventricular Fibrillation; Ventricular Premature Complexes

Erectile dysfunction (ED) is frequently observed in male cardiovascular disease (CVD) patients, creating concern about cardiac risk of their sexual activity, and their therapeutic use of sildenafil. Relatively little information exists about sildenafil effects on exercise testing, hemodynamic parameters or on occurrence of ventricular arrhythmias during normal activities in CVD patients.. Single, oral doses of sildenafil do not significantly affect exercise-induced changes in hemodynamic parameters or occurrence of arrhythmias in ED/CVD patients.. ED patients, with or without CVD, were enrolled in one of two studies. In the first, patients underwent standard (Bruce Protocol) treadmill tests; an initial control test was followed 1 hour later by administration of 100mg oral sildenafil. After another hour, they underwent a second treadmill test. Systolic and diastolic blood pressure (SBP and DBP), heart rate, and double product were determined for each evaluation at pretest, maximum stress, and recovery. In the second, Holter ambulatory ECGs were recorded 5 hours before and 6 hours after 100mg oral sildenafil administration.. Sildenafil had no clinically significant effects on exercise-induced changes in hemodynamic parameters in cardiac patients and only slight, clinically insignificant effects in noncardiac patients. ECG showed sildenafil did not affect incidence of ventricular arrhythmias.. Sildenafil does not alter hemodynamic response to exercise or change incidence of ventricular arrhythmias in men with CVD and ED. These results suggest that, when used in accordance with prescribing information and current treatment guidelines, sildenafil should be safe for most patients with both these conditions.

Topics: Adult; Aged; Arrhythmias, Cardiac; Blood Pressure; Cardiovascular Diseases; Echocardiography; Electrocardiography; Electrocardiography, Ambulatory; Erectile Dysfunction; Exercise Test; Heart; Heart Rate; Humans; Male; Middle Aged; Piperazines; Purines; Sildenafil Citrate; Sulfones; Vasodilator Agents

Sildenafil (Viagra) has been proved effective in the therapy for erectile dysfunction. Cardiovascular adverse effects are a matter of continuous debate. The aim of the study was to investigate effects of sildenafil on isolated human cardiovascular tissue directly. Isometric force of contraction was determined in isolated, electrically stimulated (1 Hz, 37 degrees C) human right atrial and left ventricular muscle strips. Vascular tension was determined in rings of human internal mammaria arteries and saphenous veins. Sildenafil (0.0001-10 microM) neither in human atrium (n = 12) nor in failing (n = 8) or nonfailing (n = 5) ventricle exerted a significant inotropic response. Furthermore, no effect on isoprenaline-elicited arrhythmias was observed. Neither addition of isoprenaline (0.1 microM) nor addition of the nitric oxide donor S-nitroso-N-acetylpenicillamine (SNAP) (100 microM) affected myocardial contractility in the presence of sildenafil (10 microM). In precontracted arteries and veins, addition of sildenafil (0.1-10 microM) led to pronounced vasorelaxation (maximal 35.5 +/- 2.2% and 45.6 +/- 6.3%, respectively, in the presence of 10 microM sildenafil). In the presence of SNAP (0.03 microM), this effect was markedly increased in arteries (72.4 +/- 10.1%, n = 4, P < 0.02) as well as in veins (73.5 +/- 6.3%, n = 6, P < 0.02). Sildenafil exerts potent vasodilatory actions but has no direct influence on human myocardial contractility or proarrhythmic effects in vitro.

Topics: 3',5'-Cyclic-GMP Phosphodiesterases; Arrhythmias, Cardiac; Cyclic Nucleotide Phosphodiesterases, Type 5; Electric Stimulation; Heart Atria; Heart Ventricles; Humans; In Vitro Techniques; Isometric Contraction; Isoproterenol; Mammary Arteries; Milrinone; Muscle, Smooth, Vascular; Myocardial Contraction; Nitric Oxide Donors; Phosphodiesterase Inhibitors; Phosphoric Diester Hydrolases; Piperazines; Purines; S-Nitroso-N-Acetylpenicillamine; Saphenous Vein; Sildenafil Citrate; Sulfones; Vasodilation; Vasodilator Agents

There has been considerable media attention surrounding the commercialisation of Sildenafil. The advice of cardiologists is often solicited before its prescription because of its potential side effects; the cardiovascular stress due to sexual activity is generally modest, both in normal subjects and coronary patients with, however, important individual variations, the "legitimate" nature of the intercourse seeming to be one of the principal factors. Recent coronary events, poorly controlled hypertension and uncompensated cardiac failure are the main contra-indications; the prescription should be based on the results of maximal exercise stress testing in patients at risk.

Topics: Adolescent; Adult; Arrhythmias, Cardiac; Coronary Disease; Erectile Dysfunction; Female; Humans; Male; Middle Aged; Myocardial Ischemia; Phosphodiesterase Inhibitors; Piperazines; Purines; Risk Factors; Sexuality; Sildenafil Citrate; Stress, Physiological; Sulfones