Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0018801 (heart failure)
 72,216 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Ranolazine (Ranexa), a piperazine derivative, is a new antianginal agent approved for the treatment of chronic stable angina pectoris for use as combination therapy when angina is not adequately controlled with other antianginal agents. While the exact mechanism of action of ranolazine is not known, its antianginal and anti-ischemic effects do not appear to depend upon changes in BP or heart rate. An extended-release (ER) oral formulation of ranolazine has been developed to facilitate twice-daily administration whilst maintaining therapeutically effective plasma concentrations. In patients with chronic stable angina, ranolazine ER monotherapy was shown to improve exercise duration at trough plasma drug concentration in a dose-dependent manner compared with placebo. The drug was effective as adjunctive therapy in patients with chronic stable angina whose condition was not controlled adequately with conventional antianginal therapy. In randomized clinical trials, ranolazine ER was well tolerated, with no overt effects on cardiovascular hemodynamics or conduction, apart from a modest increase in corrected QT interval (but no torsades de pointes). Importantly, the efficacy and tolerability of ranolazine ER were not affected by old age and co-morbid conditions (heart failure or diabetes mellitus). Comparative trials of ranolazine ER with other antianginal agents and trials examining its effects on long-term morbidity and mortality in patients with ischemic heart disease are required to determine with greater certainty the place of the drug in current antianginal therapy. Nevertheless, ranolazine ER may well prove to be a useful alternative and adjunct to conventional hemodynamic antianginal therapy in the treatment of chronic stable angina.
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PMID:Spotlight on ranolazine in chronic stable angina pectoris. 1708 71

Angina pectoris is usually the first clinical sign of underlying myocardial ischemia, which results from an imbalance between oxygen supply and oxygen demand in the heart. This report describes the pharmacology of beta-adrenoceptor antagonists as it relates to the treatment of angina. The beta-adrenoceptor antagonists are widely used in long-term maintenance therapy to prevent acute ischemic episodes in patients with chronic stable angina. Beta-adrenoceptor antagonists competitively inhibit the binding of endogenous catecholamines to beta1-adrenoceptors in the heart. Their anti-ischemic effects are due primarily to a reduction in myocardial oxygen demand. By decreasing heart rate, myocardial contractility and afterload, beta-adrenoceptor antagonists reduce myocardial workload and oxygen consumption at rest as well as during periods of exertion or stress. Predictable adverse effects include bradycardia and cardiac depression, both of which are a direct result of the blockade of cardiac beta1-adrenoceptors, but adverse effects related to the central nervous system (eg, lethargy, sleep disturbances, and depression) may also be bothersome to some patients. Beta-adrenoceptor antagonists must be used cautiously in patients with diabetes mellitus, peripheral vascular disease, heart failure, and asthma or other obstructive airway diseases. Beta-adrenoceptor antagonists may be used in combination with nitrates or calcium channel blockers, which takes advantage of the diverse mechanisms of action of drugs from each pharmacologic category. Moreover, concurrent use of beta-adrenoceptor antagonists may alleviate the reflex tachycardia that sometimes occurs with other antianginal agents.
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PMID:Antianginal actions of beta-adrenoceptor antagonists. 1799 92

The 'funny' (pacemaker, I(f)) current, first described almost 30 years ago in sinoatrial node (SAN) myocytes, is a mixed sodium/potassium inward current, activated on hyperpolarisation in the diastolic range of voltages. 'Funny' (f) channels are activated by intracellular cyclic adenosine monophosphate (cAMP) concentrations according to a mechanism mediating regulation of heart rate by the autonomic nervous system, as well as by voltage hyperpolarisation. Structural subunits of native f-channels are the hyperpolarisation-activated cyclic nucleotide-gated (HCN) channels; of the four HCN isoforms known, HCN4 is the most highly expressed in SAN tissue. The I(f) current is a natural target in the search for drugs aimed specifically at affecting heart rate, given its function in pacemaking. Increased heart rate has a negative influence on clinical outcome in patients with cardiovascular disease, and indeed is also an established risk factor for cardiovascular and all-cause mortality in the general population. Clearly, therefore, independent reduction of heart rate, through inhibition of the I(f) current, appears to be a suitable therapeutic option for patients with ischaemic heart disease.beta-Adrenoceptor antagonists (beta-blockers) reduce intracellular cAMP levels, and a substantial part of their negative chronotropic effect is therefore attributable to a reduction of the I(f) current. However, neither beta-blockers nor Ca(2+) channel antagonists, both of which have traditionally been used to reduce myocardial ischaemia, are 'pure' heart rate-lowering drugs. These agents may, in fact, have adverse cardiovascular and noncardiovascular effects.Conversely, the novel heart rate-reducing agent ivabradine is a specific blocker of f-channels, hence a selective inhibitor of the pacemaker I(f) current in the SAN. Ivabradine slows heart rate by reducing the I(f) current-regulated steepness of the diastolic depolarisation in SAN myocytes, thereby increasing diastolic duration, without altering action potential duration or causing negative inotropy. As such, ivabradine is particularly useful in patients with chronic stable angina pectoris. Further clinical studies are ongoing to evaluate the efficacy of ivabradine in patients with coronary heart disease, left ventricular dysfunction and heart failure. This short article reviews the current state of knowledge of the properties of the 'funny' current in relation to exploitation of the I(f) function in pacemaking generation and modulation for the pharmacological control of heart rate.
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PMID:The funny current: cellular basis for the control of heart rate. 1799 60

The clinical syndrome of chronic stable angina is an age-related condition that is one common manifestation of coronary artery disease (CAD). The presence of angina significantly affects quality of life when patients must limit their activities of daily living in an effort to prevent the occurrence of anginal attacks. In addition, patients are at risk for significant complications of CAD such as myocardial infarction, heart failure, stroke, and death. Therefore, treatment should focus not only on relief of symptoms and improvements in quality of life, but also on preventing disease progression and reducing the risk of complications from CAD. All patients should be instructed on the appropriate use of sublingual nitroglycerin for the immediate treatment of anginal episodes. Beta-blockers, calcium channel blockers, long-acting nitrate therapy, and ranolazine can prevent anginal symptoms. In addition, aggressive risk factor management, healthy lifestyle changes, antiplatelet agents such as aspirin, and angiotensin-converting enzyme inhibitors all should be used to prevent disease progression and occurrence of myocardial infarction or death. Many patients will be candidates for revascularization of the myocardium with either percutaneous coronary intervention or coronary artery bypass grafting for relief of symptoms as well as improvement in prognosis. Even after revascularization, patients may still require antianginal drug therapy. All patients undergoing revascularization should be guided to make appropriate lifestyle changes and to make concerted efforts to manage risk factors for CAD.
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PMID:Traditional management of chronic stable angina. 1804 88

A greater understanding of the molecular basis of hibernating myocardium may assist in identifying those patients who would most benefit from revascularization. Paired heart biopsies were taken from hypocontractile and normally-contracting myocardium (identified by cardiovascular magnetic resonance) from 6 patients with chronic stable angina scheduled for bypass grafting. Gene expression profiles of hypocontractile and normally-contracting samples were compared using Affymetrix microarrays. The data for patients with confirmed hibernating myocardium were analysed separately and a different, though overlapping, set (up to 380) of genes was identified which may constitute a molecular fingerprint for hibernating myocardium. The expression of B-type natriuretic peptide (BNP) was increased in hypocontractile relative to normally-contracting myocardium. The expression of BNP correlated most closely with the expression of proenkephalin and follistatin 3, which may constitute additional heart failure markers. Our data illustrate differential gene expression in hypocontractile and/hibernating myocardium relative to normally-contracting myocardium within individual human hearts. Changes in expression of these genes, including increased relative expression of natriuretic and other factors, may constitute a molecular signature for hypocontractile and/or hibernating myocardium.
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PMID:Gene expression profiling of human hibernating myocardium: increased expression of B-type natriuretic peptide and proenkephalin in hypocontractile vs normally-contracting regions of the heart. 1897 21

Up to 1 in 25 people in Europe and the USA have stable angina, with symptoms that may limit function and quality of life. Beta-blockers are usually used in initial symptomatic treatment, but may cause unwanted effects. They are also contraindicated in some patients (e.g. those with uncontrolled heart failure, severe peripheral vascular disease) and should be avoided in patients with asthma or a history of reversible obstructive airways disease or bronchospasm. Ivabradine (Procoralan-Servier) is the first in a new class of specific heart rate-reducing drugs and is licensed for the "symptomatic treatment of chronic stable angina pectoris in patients with normal sinus rhythm, who have a contra-indication or intolerance for beta-blockers". Here we consider the place of ivabradine in the management of patients with stable angina.
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PMID:Ivabradine for stable angina? 1898 82

Inhibition of the persistent or late Na current (INa) using ranolazine (Ranexa) represents a novel mechanism of action that was approved in the United States in 2006 and only recently in the European Union for use in patients with stable angina pectoris. In general, myocardial ischemia is associated with reduced adenosine triphosphate fluxes and decreased energy supply, resulting in severe disturbances of intracellular ion homeostasis in cardiac myocytes. In the recent years, increased late INa was suggested to contribute to this phenomenon by elevating intracellular Na concentration with subsequent rise in diastolic Ca levels by means of the sarcolemmal Na-Ca exchange system. Ranolazine, a specific inhibitor of late INa, reduces Na influx and hence ameliorates disturbed Na and Ca homeostasis. This is associated with a symptomatic improvement of angina in patients unlike other antianginal drugs without affecting heart rate or systemic blood pressure as shown in placebo-controlled studies. Therefore, ranolazine is a useful new option for patients with chronic stable angina not only as an add-on therapy. New clinical and experimental studies even point to potential antiarrhythmic effects, beneficial effects in diastolic heart failure, and under hyperglycemic conditions. In the present article, the relevant pathophysiological concepts for the role of late INa inhibition are reviewed and the most recent data from basic studies and clinical trials are summarized.
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PMID:A novel mechanism for the treatment of angina, arrhythmias, and diastolic dysfunction: inhibition of late I(Na) using ranolazine. 1933 33

Beta-blockers were documented to reduce reinfarction rate more than 3 decades ago and subsequently touted as being cardioprotective for a broad spectrum of cardiovascular indications such as hypertension, diabetes, angina, atrial fibrillation as well as perioperatively in patients undergoing surgery. However, despite lowering blood pressure, beta-blockers have never shown to reduce morbidity and mortality in uncomplicated hypertension. Also, beta-blockers do not prevent heart failure in hypertension any better than any other antihypertensive drug class. Beta-blockers have been shown to increase the risk on new onset diabetes. When compared with nondiuretic antihypertensive drugs, beta-blockers increase all-cause mortality by 8% and stroke by 30% in patients with new onset diabetes. Beta-blockers are useful for rate control in patients with chronic atrial fibrillation but do not help restore sinus rhythm or have antifibrillatory effects in the atria. Beta-blockers provide symptomatic relief in patients with chronic stable angina but do not reduce the risk of myocardial infarction. Adverse effects of beta-blockers are common including fatigue, dizziness, depression and sexual dysfunction. However, beta-blockers remain a cornerstone in the management of patients having suffered a myocardial infarction and for patients with heart failure. Thus, recent evidence argues against universal cardioprotective properties of beta-blockers but attest to their usefulness for specific cardiovascular indications.
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PMID:Cardioprotection with beta-blockers: myths, facts and Pascal's wager. 1970 92

Ivabradine, an I(f) inhibitor, acts primarily on the sinoatrial node and is used to reduce the heart rate with minimal effect on myocardial contractility, blood pressure, and intracardiac conduction. Heart rate reduction is an important aspect of care in patients with chronic stable angina and heart failure. Many patients with coronary artery disease have coexisting asthma or chronic obstructive airway disease, and most of them are unable to tolerate beta blockers. Ivabradine may thus be a useful medicine in therapeutic heart rate management especially in patients who are intolerant of beta-blockers.
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PMID:Heart rate and cardiovascular disease: an alternative to Beta blockers. 1993 14

Our objective was to determine the gender differences in the relation between the echocardiographic parameters of cardiac remodeling and clinical outcomes in patients with chronic stable angina. The baseline ejection fraction (EF), end-diastolic volume, and end-systolic volume were assessed in 7,016 patients in the study "A Coronary disease Trial Investigating Outcomes with Nifedipine gastrointestinal therapeutic system" (ACTION). All-cause and cardiac mortality and incident heart failure were determined after a median of 5.0 years. Cox proportional hazard models were fit to determine the effect of gender on the relation between the echocardiographic parameters and clinical outcomes (interaction p <0.10). The association between the EF and mortality differed significantly between men and women, with women demonstrating a marked increase in risk as the EF decreased, compared to men (interaction p = 0.03, adjusted p = 0.07). Also, a significant interaction by gender was seen for the association between the end-systolic volume and the risk of heart failure (interaction p = 0.01, adjusted p = 0.05). In conclusion, the relation between EF and mortality differed according to gender in patients with chronic coronary disease, with women having a greater risk of adverse outcomes as the EF decreased. Similar findings were observed with the end-systolic and end-diastolic volumes and the risk of heart failure. These findings may reflect inherent gender-based differences in ischemic heart disease and cardiac remodeling and might help to identify women at high risk.
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PMID:Gender differences in cardiac remodeling and clinical outcomes in chronic stable angina pectoris (from the ACTION Trial). 2034 10


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