Postural orthostatic tachycardia syndrome: pathophysiology, management, and experimental therapies.

INTRODUCTION: Postural orthostatic tachycardia syndrome (POTS) is an increasingly well-recognized condition encountered in clinical practice. Diagnosis and treatment remain extremely challenging. The limited success of currently available therapies has laid the foundation for a number of experimental therapies. AREAS COVERED: In this review, we will briefly outline the pathophysiology and clinical features of this syndrome, before moving on to its management, with a specific focus on experimental pharmacological therapies. Finally, we briefly discuss POTS related to the SARS CoV-2 (COVID-19) pandemic. EXPERT OPINION: Despite tremendous advances, the diagnosis and management of POTS remains extremely challenging. The multitude of contributory mechanisms, which predominate to varying degrees in different patients further complicates management. Improved characterization of pathophysiological phenotypes is essential to individualize management. Lifestyle measures form the first line of therapy, followed by beta-blockers, ivabradine, fludrocortisone, and midodrine. Supplemental therapies such as iron, vitamin D and α lipoic acid are quite safe and a trial of their use is reasonable. The use of erythropoietin, IVIG, desmopressin, etc., are more specialized and nuanced alternatives. In recent years, interest has grown in the use of cardiac neuromodulation. Though preliminary, some of these therapies are quite promising.

Exercise oscillatory ventilation during autonomic blockade in young athletes and healthy controls.

PURPOSE: Exercise oscillatory ventilation (EOV) is a form of periodic breathing that is associated with a poor prognosis in heart failure patients, but little is known about EOV in other populations. We sought to provide insights into the phenomenon of EOV after it was observed in young healthy subjects, including athletes, after the administration of dual autonomic blockade (DAB). METHODS: From 29 participants who completed cardiopulmonary exercise testing (CPET) with and without DAB (0.04 mg/kg atropine and 0.2 mg/kg metoprolol), 5 subjects developed EOV (age = 29 ± 5 years; 3/5 were athletes) according to American Heart Association criteria. For each case, we identified 2 non-EOV healthy controls (age = 34.2 ± 8.3; 7/10 were athletes) that were subsequently age- and sex-matched. RESULTS: No participants had EOV during exercise without DAB. The 5 participants (4 male, 1 female) who demonstrated EOV with DAB had lower mean tidal volume (1.7 ± 0.5 L/min vs. 1.8 ± 0.5 L/min; p = 0.04) compared to participants in the non-EOV group and a decrease in peak tidal volume (2.9 ± 0.6 L/min to 2.2 ± 0.7 L/min; p = 0.004) with DAB. There were few other differences in CPET measures between EOV and non-EOV participants, although the PETCO2 tended to be higher in the EOV group (p = 0.07). CONCLUSION: EOV can be elucidated in young healthy subjects, including athletes, during cardiopulmonary exercise testing, suggesting that it may not be an ominous sign in all populations.

Computational prediction of drug response in short QT syndrome type 1 based on measurements of compound effect in stem cell-derived cardiomyocytes.

Short QT (SQT) syndrome is a genetic cardiac disorder characterized by an abbreviated QT interval of the patient's electrocardiogram. The syndrome is associated with increased risk of arrhythmia and sudden cardiac death and can arise from a number of ion channel mutations. Cardiomyocytes derived from induced pluripotent stem cells generated from SQT patients (SQT hiPSC-CMs) provide promising platforms for testing pharmacological treatments directly in human cardiac cells exhibiting mutations specific for the syndrome. However, a difficulty is posed by the relative immaturity of hiPSC-CMs, with the possibility that drug effects observed in SQT hiPSC-CMs could be very different from the corresponding drug effect in vivo. In this paper, we apply a multistep computational procedure for translating measured drug effects from these cells to human QT response. This process first detects drug effects on individual ion channels based on measurements of SQT hiPSC-CMs and then uses these results to estimate the drug effects on ventricular action potentials and QT intervals of adult SQT patients. We find that the procedure is able to identify IC50 values in line with measured values for the four drugs quinidine, ivabradine, ajmaline and mexiletine. In addition, the predicted effect of quinidine on the adult QT interval is in good agreement with measured effects of quinidine for adult patients. Consequently, the computational procedure appears to be a useful tool for helping predicting adult drug responses from pure in vitro measurements of patient derived cell lines.

t-Butyl calixarene/Fe2O3@MWCNTs composite-based potentiometric sensor for determination of ivabradine hydrochloride in pharmaceutical formulations.

Ivabradine hydrochloride (IVB) has shown high medical importance as it is a medication for lowering the heart rate for the symptomatic chronic heart failure and symptomatic management of stable angina pectoralis. The high dose of IVB may cause severe and prolonged bradycardia, uncontrolled blood pressure, headache, and blurred vision. In this study, a highly sensitive carbon-paste electrode (CPEs) was constructed for the potentiometric determination of IVB in pharmaceutical formulations. t-Butyl calixarene (t-BCX) was used as an ionophore due to its ability to mask IVB in the cavity via multiple H-bonding at the lower rim, as estimated quantitatively by the sandwich membrane method (Log ßILn = 8.62). Besides, the use of multi-walled carbon nanotubes decorated with Fe2O3 nanoparticles (Fe2O3@MWCNTs) as an additive for the paste electrode significantly improved the detection limit of the sensor up to 36 nM, with Nernstian response of 58.9 mV decade-1 in the IVB linear dynamic range of 10-3-10-7 M in aqueous solutions. The constructed sensors showed high selectivity against interfering species that may exist in physiological fluids or pharmaceutical formulations (e.g. Na+, K+, NH4+, Ca2+, Mg2+, Ba2+, Fe3+, Co2+, Cr3+, Sr2+, glucose, lactose, maltose, glycine, dopamine, and ascorbic acid). The sensors were successfully employed for IVB determination in the pharmaceutical formulations (Savapran®).

Ivabradine, the hyperpolarization-activated cyclic nucleotide-gated channel blocker, elicits relaxation of the human corpus cavernosum: a potential option for erectile dysfunction treatment.

OBJECTIVE: To evaluate the effect of the If channel inhibitor, ivabradine on human corpus cavernosum (HCC) smooth muscle tone. METHODS: HCC samples were obtained from erectile dysfunction(ED) patients (n = 12) undergoing penile prosthesis surgery. Concentration-response curves for ivabradine were exposed to various inhibitory and stimulatory agents. The relaxant and contractile responses to electrical field stimulation (EFS, 10 Hz and 80 Hz) were examined in the presence or absence of ivabradine (10 µM). HCN3 and HCN4 channel expression and localization were determined by Western blot and immunohistochemical analyses of HCC tissues. RESULTS: Increasing ivabradine concentrations dependently reduced the maximal contractile responses of isolated HCC strips induced by KCl (59.5 ± 2.5%) and phenylephrine (84.0 ± 9.8%), which was not affected by nitric oxide synthase and soluble guanylyl cyclase inhibitors after phenylephrine-induced contraction. Nifedipine and tetraethylammonium inhibited the maximum relaxation to ivabradine by 75% and 39.3%, respectively. Fasudil and sildenafil increased the relaxation response to ivabradine without altering the maximum response. Pre-incubation with ivabradine significantly increased relaxant responses to EFS (p < 0.01) and reduced the contractile tension evoked by EFS (72.3%) (p < 0.001). Ivabradine incubation did not affect the expression and localization of HCN3 and HCN4 channels in the HCC smooth muscle cells. CONCLUSIONS: Ivabradine exhibits a relaxant effect on HCC tissues, which is likely to be attributed to the blocking of L-type Ca2+ channels and the opening of K+ channels, independent of changes in the activation of the nitric oxide/cyclic guanosine monophosphate system. Inhibition of HCN channels localized in cavernosal smooth muscle cells may offer pharmacological benefits for patients with cardiovascular risk factors.

Efficacy of ivabradine for heart failure: A protocol for a systematic review of randomized controlled trial.

BACKGROUND: Previous clinical trials have reported that ivabradine can effectively treat heart failure (HF). However, no systematic review has explored its efficacy and safety for HF. This systematic review will aim to evaluate the efficacy and safety of ivabradine for the treatment of patients with HF. METHODS: We will search the literature from the following electronic databases from inception to the January 31, 2019: Cochrane Central Register of Controlled Trials, EMBASE, MEDILINE, Web of Science, Cumulative Index to Nursing and Allied Health Literature, Allied and Complementary Medicine Database, Chinese Biomedical Literature Database, China National Knowledge Infrastructure, VIP Information, and Wanfang Data. All randomized controlled trials (RCTs) of ivabradine for HF will be fully considered for inclusion without any restrictions. Additionally, grey literature including clinical trial registries, dissertations, and reference lists of included studies, conference abstracts will also be searched. Two researchers will review these literatures, extract data, and assess risk of bias of included RCTs separately. Data will be pooled by either fixed-effects model or random-effects model, and meta-analysis will be conducted if it is appropriate. RESULTS: The primary outcome is all-cause mortality. The secondary outcomes comprise of change in body weight, urine output, change in serum sodium, and all adverse events. CONCLUSIONS: The results of this study will summary provide up-to-dated evidence for assessing the efficacy and safety of ivabradine for HF. ETHICS AND DISSEMINATION: It is not necessary to acquire ethical approval for this systematic review, because no individual patient data will be used in this study. The results of this systematic review will be published through peer-reviewed journals. SYSTEMATIC REVIEW REGISTRATION: PROSPERO CRD42019120814.

Heart Failure Update: Outpatient Management.

Outpatient management of heart failure (HF) is aimed at treating symptoms and preventing hospitalizations and readmissions. Management is initiated in a stepwise approach. Blockade of the renin-angiotensin system is a cornerstone of therapy and should be started, along with beta blockers, as soon as the diagnosis of HF is made. Other drugs, including diuretics, aldosterone antagonists, hydralazine, and nitrates, may be added based on symptoms and American College of Cardiology/American Heart Association stage. Despite a great interest in and theoretical benefit of naturoceutical products in the mitigation of oxidative stress and HF progression, none has been proven to be beneficial, and concerns exist regarding their interactions with standard HF drugs. Other nonpharmacologic interventions, including sodium restriction, regular exercise, and/or cardiac rehabilitation, should be initiated at diagnosis. HF often is progressive, and clinicians should be aware of late stage management options, including implantable devices, cardiac transplantation, and hospice care.

Effects of ivabradine on cardiac electrophysiology in dogs with age-related atrial fibrillation.

BACKGROUND: Ivabradine is an inhibitor of mixed Na+-K+ current that could combine with HCN channels to reduce the transmembrane velocity of funny current (If), heart rate, and cardiac efficiency, and thus be used for the treatment of cardiovascular diseases such as chronic heart failure. As an ion channel blocker, Ivabradine is also a potential antiarrhythmic agent. MATERIAL/METHODS: Twelve aging dogs (8-10 years old) underwent rapid atrial pacing for 2 months to induce age-related AF in this study. The dogs were randomly divided into the Ivabradine group and aging-AF group. The effects of Ivabradine on the electrophysiological parameters, including the effective refractory period (ERP) of the pulmonary veins and atrium, duration of AF, and inducing rate of AF, were investigated. RESULTS: As compared to the aging-AF group, the ERPs of the left superior pulmonary vein (139.00±4.18 ms vs. 129.00±4.08 ms, P=0.005) and left auricle (135.00±3.53 ms vs. 122.00±4.47 ms, P=0.001) were significantly increased, while the duration of AF (46.60±5.07 s vs. 205.40±1.14 s, P=0.001) and inducing rate of AF (25% vs. 60%, P=0.001) were significantly decreased. CONCLUSIONS: Ivabradine could effectively reduce the inducing rate of AF, and thus be used as an upstream drug for the prevention of age-related AF.

A case of atrial tachycardia treated with ivabradine as bridge to ablation.

Ivabradine is indicated in cardiac failure and ischemia to reduce sinus rate by inhibition of the pacemaker I(f) current in sinoatrial node. We report a case of an 18-year-old woman with left atrial tachyarrhythmia resistant to several antiarrhythmic drugs and to electric cardioversion who responded only to ivabradine, which significantly reduced heart rate without abolishing the arrhythmia itself. An ectopic focus in the ostium of left pulmonary veins was found and the patient was successfully ablated. We suggest that ivabradine might be therefore useful in the treatment of supraventricular tachyarrhythmias due to an enhanced automaticity.

Ivabradine in combination with metoprolol succinate in the treatment of inappropriate sinus tachycardia.

BACKGROUND: Inappropriate sinus tachycardia (IST) is a clinical syndrome characterized by excessive resting heart rate (HR) or a disproportional increase in HR during exercise. ß-blocker or calcium channel-blocker therapy is often noneffective or not well tolerated. The HR reduction on ivabradine is similar to ß-blockers but in some patients its efficacy to resolve all IST-related symptoms is limited. The aim of the study was to assess the efficacy and safety of combining ivabradine with metoprolol succinate in patients with refractory highly symptomatic IST. METHODS: Twenty patients (36 ± 10 years; 16 women) with IST were enrolled. All patients received metoprolol succinate 95 mg single dose during the first month of the study. After 4 weeks of treatment with metoprolol, ivabradine was administered as adjuvant therapy up to 7.5 mg twice daily. Holter monitoring and treadmill stress test were performed at baseline, after 4, and 8 weeks of the study, respectively. RESULTS: We observed significant and similar reduction in resting HR both for metoprolol and for combined therapy compared to the baseline. The mean HR during daily activity was significantly lower on ivabradine and metoprolol compared to monotherapy with ß-blocker. The combined treatment yielded a significant increase in exercise capacity as assessed by treadmill stress test. After 4 weeks of combined therapy a significant reduction in IST-related symptoms, measured by means of the European Heart Rhythm Association score, was observed. CONCLUSION: Combining ivabradine with metoprolol is an effective and well-tolerated treatment option for IST in patients with refractory to monotherapy.

[Alternative therapy with ivabradine in patients with functional class III chronic heart failure].

Aim of the study - to determine efficacy of therapy with the use of ivabradine in patients with functional class (FC) III chronic heart failure (CHF) on the basis of assessment of its action on regulatory adaptive status (RAS). We included into the study 100 patients with FC III CHF at the background of ischemic heart disease (IHD) and/or stage III hypertensive disease (HD) receiving complex therapy (quinapril, torasemide, spironolactone). After randomization group 1 comprised 56 patients (age 62.9+/-1.8 years) who were prescribed slow release metoprolol succinate (59.1+/-4.5 mg/day). Group 2 comprised 44 patients (age 59.4+/-1.3 years) who were prescribed If channel inhibitor ivabradine (12.1+/-2.3 mg/day) if beta-blocker use was not possible. Examination at baseline and in 6 months included treadmillometry with assessment of maximal oxygen consumption (VO2 max) at exercise, echocardiography, 24-hour blood pressure monitoring, measurement of N-terminal pro-brain natriuretic peptide (NT-proBNP) in blood plasma. For objective qualitative assessment of the state of RAS we used a test of cardio-respiratory synchronism. Therapy with the use of ivabradine improved structural and functional state of the myocardium, elevated tolerance to exercise, caused positive changes of NT-proBNP concentration in blood plasma and VO2 max at exercise. Thus ivabradine probably can serve as alternative to -adrenoblockers when their use is not possible patients with FC III CHF at the background of IHD and/or stage III HD.

Reversal of tachycardiomyopathy due to left atrial tachycardia by ivabradine.

Ivabradine has been shown to be effective in reducing sinus rate. Here we report of a case where ivabradine reduced the rate of a focal atrial tachycardia relieving patient's symptoms and reversing tachycardiomyopathy.

Successful use of ivabradine in a case of exaggerated autonomic dysfunction.

We present a 30-year-old male with complex and predominantly cardiovascular autonomic dysfunction. He had frequent syncopal attacks and paroxysmal atrial fibrillation (PAF). Physical, electrocardiographic, and echocardiographic findings were unremarkable. Syncopal attacks were precipitated by emotional stress, upright position, and micturition. Electrocardiograms obtained immediately after syncopal events revealed PAF with a low ventricular rate, which spontaneously returned to sinus rhythm without any medication. Syncopal events were suggestive of postural orthostatic tachycardia syndrome (POTS), were induced during upright position, and were associated with a sudden increase in heart rate to approximately 140 beats per minute and a sudden drop in blood pressure. Syncope was also induced during carotid sinus massage (CSM) in the upright position. It was thought that cardiac autonomic dysfunction, with POTS as the main component, was responsible for this clinical condition. Syncopal episodes increased in frequency during treatment with metoprolol. Treatment with ivabradine (5 mg twice a day) resulted in disappearance of syncopal episodes both during upright position and CSM. During six months of follow-up, the patient remained asymptomatic without syncope or atrial fibrillation.

Efficacy of ivabradine administration in patients affected by inappropriate sinus tachycardia.

BACKGROUND: Inappropriate sinus tachycardia (IST) is characterized by an elevated heart rate (HR) at rest and an exaggerated HR response to physical activity or emotional stress. Beta-blockers and calcium channel blockers are the first-line therapy but sometimes are poorly tolerated due to side effects. OBJECTIVE: The purpose of this study was to evaluate the efficacy and safety of ivabradine, a selective inhibitor of the I(f) current of the sinoatrial node, in patients affected by IST. METHODS: Eighteen consecutive symptomatic patients (2 men and 16 women; mean age 45 +/- 15 years) affected by IST were enrolled in the study. Every patient underwent resting ECG, 24-hour Holter ECG, and exercise ECG at baseline and at 3-month and 6-month follow-up. RESULTS: Sixteen patients (14 women; mean age 41 +/- 14 years) completed the study. Holter ECG assessment showed a significant reduction of medium HR (P <.001) and maximal HR (P <.001, basal vs 3-6 months; P = .02, 3 vs 6 months). Minimal HR slightly decreased at 3 months and then stabilized (P = .49, 3 vs 6 months) despite an increased drug dose. Stress test showed a significant decrease at rest (P <.001) and maximal HR (P <.05), suggesting an increased tolerance to physical stress, which was confirmed by a progressive increase of maximal load reached (>100 W) during stress test at 3 months (75%) and 6 months (85%). One patient was excluded because of phosphenes despite dose lowering, and another patient did not complete the protocol. CONCLUSION: Ivabradine could represent an effective and safe alternative to calcium channel blockers and beta-blockers for treatment of IST.

Review of the If selective channel inhibitor ivabradine in the treatment of chronic stable angina.

Coronary heart disease is the major cause of morbidity and mortality in industrialized countries, and its prevalence is predicted to grow as the population ages. Current drugs for chronic stable angina (such as beta-blockers, calcium-channel blockers, long- and short-acting nitrates, and potassium-channel activators) are often effective, either as monotherapy or in combination, but side effects and contraindications may limit their use. The "I(f)" (for "funny") channel, discovered in 1979, is expressed mainly in the membrane of pacemaker cells present in the sinus node, the atrioventricular node, the ventricular conduction pathways, and ventricular myocytes. By determining the slope of diastolic depolarization, which in turn controls action potential frequency, it is a key determinant of heart rate and so provides a new therapeutic target for controlling angina symptoms. A new antiangina drug, ivabradine, has been developed and licensed for clinical use. It exclusively reduces the heart rate by selectively blocking the I(f) channel of the sino-atrial node. As clinical trials have shown it to be remarkably well-tolerated, ivabradine offers an alternative for patients who cannot take, or are intolerant of, beta blockade. This review provides an insight into this new agent, its historical background, mechanism of action, and pathophysiologic basis, and provides up-to-date evidence-based information on its optimum use in stable angina.

Improvement of regional myocardial blood flow and function and reduction of infarct size with ivabradine: protection beyond heart rate reduction.

AIMS: Effects of the bradycardic agent ivabradine on regional blood flow, contractile function, and infarct size were studied in a pig model of myocardial ischaemia/reperfusion. Heart rate reduction by beta-blockade is associated with negative inotropism and unmasked alpha-adrenergic coronary vasoconstriction. Ivabradine is the only available bradycardic agent for clinical use. METHODS AND RESULTS: Anaesthetized pigs were subjected to 90 min controlled left anterior descending coronary artery hypoperfusion and 120 min reperfusion. Regional blood flow was measured with microspheres, regional function with sonomicrometry, and infarct size with triphenyl tetrazolium chloride staining. Pigs received placebo or ivabradine (0.6 mg/kg i.v.) before or during ischaemia or before reperfusion, respectively. Pre-treatment with ivabradine reduced infarct size from 35 +/- 4 (SEM) to 19 +/- 4% of area at risk (AAR). Ivabradine 15-20 min after the onset of ischaemia increased regional myocardial blood flow from 2.12 +/- 0.31 to 3.55 +/- 0.56 microL/beat/g and systolic wall thickening from 6.7 +/- 1.0 to 16.3 +/- 3.0%; infarct size was reduced from 12 +/- 4 to 2 +/- 1% of AAR. Ivabradine 5 min before reperfusion still reduced infarct size from 36 +/- 4 to 21 +/- 5% of AAR. The benefit of ivabradine on flow and function was eliminated by atrial pacing, but part of the reduction of infarct size by ivabradine was not. CONCLUSION: Ivabradine's protection goes beyond heart rate reduction.