Novel therapies in acute and chronic heart failure

Despite past advances in the pharmacological management of heart failure, the prognosis of these patients remains poor, and for many, treatment options remain unsatisfactory. Additionally, the treatments and clinical outcomes of patients with acute decompensated heart failure have not changed substantially over the past few decades. Consequently, there is a critical need for new drugs that can improve clinical outcomes. In the setting of acute heart failure, new inotrops such as cardiac myosin activators and new vasodilators such as relaxin have been developed. For chronic heart failure with reduced ejection fraction, there are several new approaches that target multiple pathophysiological mechanism including novel blockers of the renin-angiotensin-aldosterone system (direct renin inhibitors, dual-acting inhibitors of the angiotensin II receptor and neprilysin, aldosterone synthase inhibitors), ryanodine receptor stabilizers, and SERCA activators. Heart failure with preserved ejection fraction represents a substantial therapeutic problem as no therapy has been demonstrated to improve symptoms or outcomes in this condition. Newer treatment strategies target specific structural and functional abnormalities that lead to increased myocardial stiffness. Dicarbonyl-breaking compounds reverse advanced glycation-induced cross-linking of collagen and improve the compliance of aged and/or diabetic myocardium. Modulation of titin-dependent passive tension can be achieved via phosphorylation of a unique sequence on the extensible region of the protein. This review describes the pathophysiological basis, mechanism of action, and available clinical efficacy data of drugs that are currently under development. Finally, new therapies for the treatment of heart failure complications, such as pulmonary hypertension and anemia, are discussed.     

Learning from failure: congestive heart failure in the postgenomic age

The prognosis of heart failure is worse than that of most cancers, but new therapeutic interventions using stem and other cell-based therapies are succeeding in the fight against it, and old drugs, with new twists, are making a comeback. Genetically engineered animal models are driving insights into the molecular mechanisms that cause hearts to fail, accelerating drug discoveries, and inspiring cell-based therapeutic interventions for both acquired and inheritable cardiac diseases.     

Antiadrenergic therapy in the control of atrial fibrillation

Atrial fibrillation (AF) in heart failure develops commonly in older individuals and its prevalence increases as heart failure severity progresses. Because of deteriorating hemodynamics, patients with heart failure are at increased risk for developing AF and, conversely, AF in heart failure patients is associated with adverse hemodynamic changes. AF is believed to increase the mortality risk in heart failure, which may be minimized by treatment that includes the control of ventricular rate, prevention of thrombotic events, and conversion to normal sinus rhythm. Clinical guidelines recommend amiodarone or dofetilide in heart failure patients, but these drugs have certain drawbacks, such as an increased risk for bradyarrhythmias with amiodarone and proarrhythmic reaction with dofetilide. Some but not all clinical trials have suggested that rate control should be the primary therapeutic goal in high-risk heart failure patients with AF and, if unsuccessful, followed by rhythm control. The former is effectively achieved with rate-lowering beta-blockers alone or in combination with digoxin. Recent studies evaluating the effects of combination carvedilol/digoxin therapy demonstrate synergistic effects between the two drugs. This combination therapy decreased heart failure symptoms, effectively reduced ventricular rate, and improved ventricular function to a greater extent compared with that produced by either drug alone. Although digoxin alone is an effective heart failure treatment, its use as a single rate-control therapy is often ineffective in heart failure patients with AF associated with rapid ventricular response. Carvedilol is effective, alone or in combination, with digoxin in such heart failure patients with AF, and has been shown to reduce mortality risk in patients with chronic heart failure during prolonged therapy.     

A review of current therapies used in the treatment of congestive heart failure

Congestive heart failure is the leading cause of hospitalizations for patients older than 65 years. There are almost 700,000 new cases of heart failure annually and re-hospitalization rates are as high as 50% within the first few months of initial discharge. These statistics translate to healthcare costs that nearly reached US$40 billion in 2010. Understanding the therapeutic agents that can not only help decrease mortality and morbidity but also decrease the rate of re-hospitalizations is vital in the management of congestive heart failure. Here, the authors highlight the various classes of drugs used in the treatment of heart failure. They then provide a focused review examining the multiple clinical trials that have emphasized the evaluation of mortality, morbidity and hospitalization rates in heart failure patients who are receiving the different types of therapeutic agents.     

Ischemic vs nonischemic heart failure--does etiology matter?

In most large scale trials the prognosis of ischemic heart failure is worse than in patients with non-ischemic etiology. The therapeutic effect of essential drugs such as ACE-inhibitors, betablockers and diuretics is similar, but response to some other drugs (amiodarone, amlodipine, digoxin, growth hormone) is better in non-ischemic heart failure. Of great practical importance is the recognition of hibernating myocardium in coronary artery disease, since revascularisation may significantly improve left ventricular function. Specific therapeutic interventions are possible in hypertensive heart disease, alcoholic cardiomyopathy and LV-dysfunction to tachyarrhythmias. The etiology of heart failure should therefore be cleared in all patients.     

Developments in the management of Chagas cardiomyopathy

Over 100 years have elapsed since the discovery of Chagas disease and there is still much to learn regarding pathogenesis and treatment. Although there are antiparasitic drugs available, such as benznidazole and nifurtimox, they are not totally reliable and often toxic. A recently released negative clinical trial with benznidazole in patients with chronic Chagas cardiomyopathy further reinforces the concerns regarding its effectiveness. New drugs and new delivery systems, including those based on nanotechnology, are being sought. Although vaccine development is still in its infancy, the reality of a therapeutic vaccine remains a challenge. New ECG methods may help to recognize patients prone to developing malignant ventricular arrhythmias. The management of heart failure, stroke and arrhythmias also remains a challenge. Although animal experiments have suggested that stem cell based therapy may be therapeutic in the management of heart failure in Chagas cardiomyopathy, clinical trials have not been promising.     

Treatment of chronic heart failure with positive inotropic agents

Prognosis of heart failure patients remains poor and stimulates research of new active drugs and therapeutic improvements. Besides diuretic and vasodilating agents, the place of positive inotropic drugs remains to be defined. Long term benefit remains to be demonstrated for Milrinone, Enoximone and Digitalis. However, absence of benefit has been established with Amrinone and beta adrenoceptor agonists. Too many uncontrolled studies have complicated the accurate evaluation of efficacy of these positive inotropic drugs. Purpose of heart failure treatment remains to improve functional status without deterioration of myocardial fibers contractility. The respective roles of cAMP, gAMP and intracellular calcium concerning myocardial fiber longevity remains to be clarified.     

Guideline for the management of heart failure caused by systolic dysfunction: Part I. Guideline development, etiology and diagnosis

Over the past decade, the conceptual understanding of heart failure has changed significantly. Several large clinical trials have demonstrated that pharmacologic interventions can dramatically reduce the morbidity and mortality associated with heart failure. These trials have extended the therapeutic paradigm for treating heart failure beyond the goal of limiting congestive symptoms of volume overload. This two-part article presents an evidence-based guideline to assist primary care physicians in evaluating and treating patients with heart failure. Part I describes the new paradigm of heart failure and offers guidance for diagnostic testing. Part II presents a treatment guideline.     

Therapy for heart failure

The treatment of congestive heart failure focuses on three steps: 1. Elimination of the precipitating cause or mechanism, and/or treatment of the underlying disease respectively. 2. Treatment of the failing heart syndrome itself. We shall concern ourselves with pharmacotherapy, omitting technical and surgical aspects. 3. Prophylactic treatment of complications, such as thromboembolism and arrhythmias. Drugs for the treatment of heart failure can be classified as follows: 1. Diuretics 2. Vasodilators 3. Neurohumoral Inhibitors 4. Inotropic drugs. Diuretics improve symptoms and exercise capacity and probably survival. They are the drug of first choice in acute and chronic heart failure. Potassium supplementation is necessary. Renal function needs to be monitored. The aldosterone antagonist spironolactone has probably important effects upon the myocardium. It retards fibrous tissue development and improves prognosis. Vasodilators unload the heart and improve contractile geometry and hemodynamics, thereby lessening symptoms. Prognosis, however, is not affected. They are indispensable in acute heart failure. In longterm treatment only the combination of nitrates with hydralazin has been shown to be effective. Angiotensin converting enzyme inhibitors combine vasodilation with neurohumoral inhibition. They are most effective in improving symptoms, exercise capacity and surviving chronic heart failure. If side effects (cough, allergy) prevent their use, then angiotensin II receptor antagonists can be used with equal benefit. However, both groups of drugs impair renal function and cannot be given in advanced renal failure or renal artery stenosis. Beta-receptor antagonists, previously considered contraindicated in heart failure are today amongst the most important drugs in heart failure. They improve survival and retard the need for cardiac transplantation in advanced failure. Their use, however, is rather difficult requiring extremely slow dose titration beginning with very low doses. Inotropic drugs are today mainly used in acute failure and cardiogenic shock. In longterm treatment only the digitalisglycosides have been shown to be effective in improving symptoms, exercise capacity and the general clinical course. Often antiarrhythmic treatment is necessary. Here amiodarone is the drug of choice today if beta blockers do not suffice. Prophylactic anticoagulation is indicated in all cases NYHA III and IV, with large hearts already in II. Future developments may include new inotropes, the ANP-system, and cytokines, as well as gene therapy for correction of myocardial phenotype change.     

Relaxin: New Pathophysiological Aspects and Pharmacological Perspectives for an Old Protein

Human relaxin‐2 (hereafter simply defined as “relaxin”) is a 6‐kDa peptidic hormone best known for the physiological role played during pregnancy in the growth and differentiation of the reproductive tract and in the renal and systemic hemodynamic changes. This factor can also be involved in the pathophysiology of arterial hypertension and heart failure, in the molecular pathways of fibrosis and cancer, and in angiogenesis and bone remodeling. It belongs to the relaxin peptide family, whose members comprehensively exert numerous effects through interaction with different types of receptors, classified as relaxin family peptide (RXFP) receptors (RXFP1, RXFP2, RXFP3, RXFP4). Research looks toward the in‐depth examination and complete understanding of relaxin in its various pleiotropic actions. The intent is to evaluate the likelihood of employing this substance for therapeutic purposes, for instance in diseases where a deficit could be part of the underlying pathophysiological mechanisms, also avoiding any adverse effect. Relaxin is already being considered as a promising drug, especially in acute heart failure. A careful study of the different RXFPs and their receptors and the comprehension of all biological activities of these hormones will probably provide new drugs with a potential wide range of therapeutic applications in the near future.     

Advances in drug development for targeted therapies for glioblastoma

Glioblastoma is the most aggressive primary brain tumor in adults. The prognosis of patients with primary glioblastoma treated with the current standard of care, tumor resection followed by radiation therapy and auxiliary temozolomide, remains poor. Integrative genomic analyses have identified essential core signaling pathways and frequent genetic aberrations, which provide potential drug targets for glioblastoma treatment. Drugs against these therapeutic targets have been developed rapidly in recent years. Although some have shown promising effects on models in preclinical studies, many have shown only modest efficacy in clinical trials. New therapeutic strategies and potent drugs are urgently needed to improve the prognosis of patients with glioblastoma. The goal of this review is to summarize the current advances in drug development for targeted glioblastoma therapies and to reveal the major challenges encountered in clinical trials or treatment. This study will provide new perspectives for future studies of targeted therapeutic drug development and provide insights into the clinical treatment of glioblastoma.     

Seeking the best care for acute migraine

In recent years, we have seen exciting advances in the knowledge of mechanisms that underlie migraine. These have thus promoted investigations into new drugs for the management of acute migraine. The major goal in migraine research is to identify and study non-vascular targets for migraine therapy. The 5-HT_1F neuronal receptor is apparently not involved in the vascular effects of triptans. Clinical evaluation of LY33470, a potent agonist of 5-HT_1F receptors, has demonstrated that the drug is effective in ending of migraine attack. These results sugest that 5-HT_1F receptor agonists may represent new antimigraine drugs without cerebrovascular or cardiovascular effects. From the plasma extravasation model of migraine, potential therapeutic targets were identified, although in testing no effects were observed: endothelin and substance P antagonists and the specific serotonin agonist CP 122,288, potent inhibitors of neurogenic inflammation, were ineffective in the treatment of a migrain attack. Since a causative role of CGRP in migraine has been postulated, novel antimigraine drugs include CGRP antagonists. Molecules with highly selective antagonistic action of human CGRP receptors of cerebral circulation have been discovered. These CGRP antagonists are in preclinical and clinical trials and the results are awaited with great interest. In addition ,a small pilo study found civamide, a capsaicin derivative which causes CGRP depletion from trigeminal sensory fibers, to be effective in the migraine attack. Both NMDA and non-NMDA receptors for glutamate and related excitatory aminoacids are found on trigeminal neurons; therefore excitatory aminoacid receptor antagonists may provide therapeutic action in migraine. Recently, a glutamate receptor antagonists (LA293558) that had not shown vascular effects in animal models demonstrated an antimigraine effect. More specific compounds are also warranted in confirming nitric oxide inhibition as a therapeutic approach in migraine. Thus, it is likely that in the near future emerging therapies will increasingly meet patients' and physicians' goal.     

Sympathische Überaktivität und Niere

Hypertension is present in the majority of patients with chronic renal failure and constitutes a major risk factor for the very high cardiovascular morbidity and mortality in this patient population. Furthermore hypertension is known to be a substantial progression factor in renal disease. In the past, it had been presumed that hypertension in chronic renal failure is due to enhanced sodium retention, chronic hypervolemia and increased activity of the renin-angiotensin-aldosterone-system. Recent studies now provide evidence that sympathetic overactivity plays an additional important role and also promotes progression of renal failure. The treatment goal in renal patients is to delay or even prevent progression of renal failure and to reduce the cardiovascular risk. Recent studies have investigated the respective impact of sympatholytic drugs, e.g. inhibitors of the renin-angiotensin-aldosterone-system, beta-blockers or I1-Imidazolin-receptor-agonists in fulfilling these aims. The present report will review experimental and clinical studies on the role of sympathetic overactivity in hypertension and chronic renal failure and possible new therapeutic options.     

Crosstalk of the Heart and Periphery: Skeletal and Cardiac Muscle as Therapeutic Targets in Heart Failure

Heart failure syndrome is initiated as the body's metabolic needs temporarily exceed the pumping capacity of the heart. In most cases, this phenomenon tends to occur during physical exercise. Although not always subjectively recognized, limited exercise capacity remains the clinical hallmark of congestive heart failure. It can be measured objectively as reduced skeletal muscle performance and maximal whole-body oxygen uptake, which are not necessarily explained by central haemodynamic abnormalities. In fact, the initial cardiac condition sets forth a series of peripheral adaptations that are potentially life-saving during acute decompensation but become disadvantageous and symptom-generating in stable heart failure. Inodilator drugs were theoretically ideal to revert the adverse haemodynamic crosstalk between the heart and periphery. However, these drugs failed to improve prognosis in congestive heart failure, whereas drugs that did so showed typically unimpressive haemodynamic effects. Exercise therapy has recently emerged as a safe and effective way to enhance physical performance and subjective well-being in congestive heart failure. A dual therapeutic approach is suggested, consisting of exercise training to improve the periphery and the use of cardioprotective drugs to limit cardiac cellular damage from neurohormonal activation.     

Gene delivery approaches to heart failure treatment

Heart failure remains a leading cause of worldwide morbidity and mortality. Despite recent advances in treatment and our increasing knowledge of pathophysiology and the molecular derangements involved in the failing heart, our ability to affect the underlying cardiac disease processes is limited. In recent years, there has been considerable interest in myocardial gene transfer as both an investigational and potential therapeutic modality. Ultimately, the goal of any such strategy is to reprogramme failing cardiac myocytes and correct the aberrant molecular events causing heart failure. So far, viral vectors have been utilised with success more frequently than any other method of gene delivery in animal models. Studies in animal models and in failing human cardiomyocytes in culture targeting specific molecular pathways, including the beta-adrenergic receptor cascade and the myocyte intracellular calcium handling system, have shown encouraging results and offer hope that gene manipulation may provide novel adjunctive therapeutic modalities for human heart failure.     

Gene delivery approaches to heart failure treatment

Heart failure remains a leading cause of worldwide morbidity and mortality. Despite recent advances in treatment and our increasing knowledge of pathophysiology and the molecular derangements involved in the failing heart, our ability to affect the underlying cardiac disease processes is limited. In recent years, there has been considerable interest in myocardial gene transfer as both an investigational and potential therapeutic modality. Ultimately, the goal of any such strategy is to reprogramme failing cardiac myocytes and correct the aberrant molecular events causing heart failure. So far, viral vectors have been utilised with success more frequently than any other method of gene delivery in animal models. Studies in animal models and in failing human cardiomyocytes in culture targeting specific molecular pathways, including the β-adrenergic receptor cascade and the myocyte intracellular calcium handling system, have shown encouraging results and offer hope that gene manipulation may provide novel adjunctive therapeutic modalities for human heart failure.     

Calcium channel blocking drugs. Part II: Clinical applications

CCB are a diverse group of drugs that bind to specific glycoprotein receptors associated with the cell membrane that are most likely identical to the voltage-sensitive calcium channel. By inhibiting the influx of calcium into myocardial, pacemaker, and conducting tissues and vascular smooth muscle, these agents modify excitation-contraction coupling in muscle and electrical impulse transmission in the heart. The vasodilating and electrophysiologic actions of these drugs have been harnessed for the treatment of coronary vasospasm, angina pectoris, and supraventricular arrhythmias. They also have great potential for the treatment of hypertension, cerebrovascular disorders, and Raynaud's phenomenon. Their utility in hypertrophic cardiomyopathy, congestive heart failure, myocardial preservation, and primary pulmonary hypertension has not been convincingly established. Future second-generation CCB may offer greater selectivity, improved side effect profiles, and an even wider range of actions.     

Heart failure and neuroendocrine activation: diagnostic,prognostic and therapeutic perspectives

The important neuroendocrine systems involved in heart failure are reviewed with special emphasis on their possible role in pathophysiology and their relation to prognostic and diagnostic information. Plasma levels of noradrenaline (NA), renin, vasopressin, endothelin‐1, atrial natriuretic peptide (ANP), brain natriuretic peptide (BNP) and tumour necrosis factor‐α (TNF‐α) are all elevated in heart failure. Activity of the sympathetic nervous system as reflected by NA is correlated to mortality and seems to possess independent prognostic information. Several studies have now documented the beneficial effect of β‐blockade in chronic heart failure (CHF). Renin seems to be a poor prognostic marker in CHF possibly because of the interference with diuretic treatment, angiotensin converting enzyme (ACE)‐inhibitors and angiotensin II antagonist, and probably also because of the significance of tissue renin‐angiotensin system (RAS), poorly reflected by plasma renin. On the other hand, several large‐scale trials with ACE‐inhibitors and angiotensin II antagonists have demonstrated reduced mortality and morbidity in CHF. Plasma vasopressin does not seem to possess prognostic information but testing of non‐peptide antagonists is ongoing. Endothelin‐1 seems to have independent prognostic information and endothelin receptor antagonists may represent a therapeutic possibility. The natriuretic peptides ANP and BNP are correlated to prognosis and possess independent information. Brain natriuretic peptide and N‐terminal ANP seem to increase early, i.e. in asymptomatic heart failure. Plasma BNP being more stable than ANP is therefore a promising measure of left ventricular dysfunction. Increase in ANP and BNP, potentially beneficial, may be achieved by administration of neutral endopeptidase inhibitors, at present an unsettled therapeutic possibility. Several cytokines are increased in heart failure and especially TNF‐α has drawn attention. Experimental studies suggest that TNF‐α is important in the pathophysiology of heart failure and preliminary studies indicate that inhibition of TNF‐α seems to be a possible therapeutic approach. Thus, neuroendocrine markers seem to (i) have a role in diagnosis and classification of heart failure, (ii) be useful in providing a ‘neuroendocrine profile’ which enlightens different aspects of heart failure, and therefore (iii) in the future probably will be valuable in the choice of medical treatment of the individual patient. In addition to β‐blockers, ACE‐inhibitors and angiotensin II antagonists several new drugs based on neuroendocrine modification are on their way and might become important in the future.     

New treatment option for heart failure patients: eplerenone

Aldosterone plays an important role in the harmful cardiac remodeling process and pathophysiology of heart failure after a myocardial infarction. Until recently, spironolactone (Aldactone) was the only pharmacologic agent available to directly block the deleterious effects of aldosterone. The use of spironolactone is complicated by its antiprogesterone and antiandrogen side effects, such as gynecomastia and menstrual irregularities. Eplerenone (Inspra), a member of a new class of drugs called selective aldosterone receptor antagonists, was recently approved for the treatment of both hypertension and post-myocardial infarction heart failure and appears to be devoid of the antiprogesterone and antiandrogen effects. In a trial in patients with heart failure following a myocardial infarction, eplerenone treatment significantly reduced mortality and morbidity compared to placebo. Eplerenone may be considered as part of the therapeutic plan in patients who have suffered a myocardial infarction and demonstrate evidence of heart failure.     

Dopamine receptors--physiological understanding to therapeutic intervention potential

There are two families of dopamine (DA) receptors, called D1 and D2, respectively. The D1 family consists of D1- and D5-receptor subtypes and the D2 family consists of D2-, D3-, and D4-receptor subtypes. The amino acid sequences of these receptors show that they all belong to a large superfamily of receptors with seven transmembrane domains, which are coupled to their intracellular signal transduction systems by G-proteins. The implications of DA receptors in neuropsychiatry and cardiovascular and renal diseases are discussed. Neuropsychiatry indications include Parkinson's disease, schizophrenia, migraine, drug dependence, mania and depression, and Gilles de la Tourette syndrome. The underlying dysfunction of dopaminergic systems and the potential benefits of dopaminergic therapy in these different indications are critically examined. With respect to the pharmacological treatment of Parkinson's disease, a range of DA agonists are in various stages of preclinical and clinical development. D2-receptor agonist activity is predominant in most effective antiparkinsonian DA agonists. However, in practice, it is difficult to treat patients for several years with DA agonists alone; therapeutic benefit is not sustained. Rather, the use of a combination of DA agonists and levodopa is considered preferable. Reports of the efficacy of DA partial agonists await confirmation, and recent clinical investigations also suggest the potential of D1 receptor agonists as antiparkinson drugs. Regarding migraine pathogenesis, clinical and pharmacological evidence suggests that DA is involved in this disorder. Most prodromal and accompanying symptoms may be related to dopaminergic activation. Several drugs acting on DA receptors are effective in migraine treatment. Furthermore, migraine patients show a higher incidence of dopaminergic symptoms following acute DA agonist administration, when compared with normal controls. In cardiology, the therapeutic benefits of DA agonists are noted in the treatment of heart failure. Low doses of DA are widely used for its specific dopaminergic effects on renal function, which are suggested to be beneficial, and for its alpha- and beta-adrenergic-mediated responses that occur with higher doses. However, studies have been unable to demonstrate that DA can prevent acute renal failure or reduce mortality. It appears that the significant progress that is being made in the molecular understanding of DA receptors will continue to have a tremendous impact in the pharmacological treatment of neuropsychiatric, cardiovascular, and renal diseases.