Future therapies for heart failure

The treatment of heart failure has changed as the understanding of the disease evolves. Heart failure remains the only cardiovascular disease that continues to rise in both incidence and prevalence, despite recent advances in treating symptoms and thwarting disease progression. Many opportunities exist for improving patient outcomes with pharmaceutical agents and technologies available now or in the near future. This article discusses recently approved drugs and devices and clinical trials that may affect the management of this challenging disease.     

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.     

Sex differences in response to chronic heart failure therapies

Sex-related differences in clinical and laboratory characteristics, course and prognosis are well documented in patients with heart failure. However, most information regarding heart failure therapies has been obtained from studies conducted primarily in men. Reviewing the existing literature indicates that the recommendations regarding pharmacological and device therapies should apply similarly to men and women. One possible exception, however, is the possibility of more benefit derived from angiotensin receptor blockers in women, and from angiotensin converting enzyme inhibitors in men. Future clinical trials should be conducted either exclusively in women or have a larger representation of women to insure the adequate assessment of the potential benefit versus risk in women.     

Sex differences in response to chronic heart failure therapies

Sex-related differences in clinical and laboratory characteristics, course and prognosis are well documented in patients with heart failure. However, most information regarding heart failure therapies has been obtained from studies conducted primarily in men. Reviewing the existing literature indicates that the recommendations regarding pharmacological and device therapies should apply similarly to men and women. One possible exception, however, is the possibility of more benefit derived from angiotensin receptor blockers in women, and from angiotensin converting enzyme inhibitors in men. Future clinical trials should be conducted either exclusively in women or have a larger representation of women to insure the adequate assessment of the potential benefit versus risk in women.     

Congestive heart failure: a review of nonpharmacologic therapies

Although pharmacologic therapy is the mainstay of treatment for patients with congestive heart failure (CHF), several nonpharmacologic interventions are useful adjuncts in the overall management of this clinical syndrome. Comprehensive treatment plans include sodium and fluid restriction, as well as a balance of rest and physical activity. Hemofiltration and peritoneal dialysis may be effective in patients who have become resistant to diuretic therapy. Mechanical support from intraaortic balloon counterpulsation and ventricular assist devices has improved survival in certain high-risk patients. For patients refractory to conventional therapies, cardiac transplantation offers new hope. These interventions and the nursing care of patients with CHF are discussed in this article.     

Acutely decompensated congestive heart failure: new therapies for an old problem

Acutely decompensated heart failure is a common presentation to US emergency departments, and represents a major and increasing proportion of health burden. In contrast to chronic heart failure, where there have been numerous advances in care and corresponding decreases in morbidity and mortality, outcomes of patients with acutely decompensated heart failure have remained relatively unchanged with an approximate 10% 30-day mortality and almost 40% 1-year rehospitalization rate. This is reflected in the relative paucity of guidelines for this condition.     

Acutely decompensated congestive heart failure: new therapies for an old problem

Acutely decompensated heart failure is a common presentation to US emergency departments, and represents a major and increasing proportion of health burden. In contrast to chronic heart failure, where there have been numerous advances in care and corresponding decreases in morbidity and mortality, outcomes of patients with acutely decompensated heart failure have remained relatively unchanged with an approximate 10% 30-day mortality and almost 40% 1-year rehospitalization rate. This is reflected in the relative paucity of guidelines for this condition.     

Cellular therapies for kidney failure

Dialysis and transplantation of human kidneys represent effective therapies to replace kidney function, but each has limitations. Xenotransplantation of whole kidneys from non-primate donors is complicated by humoral and severe cellular rejection. The use of individual cells or groups of cells to regenerate or repair damaged tissue (cellular therapies) offers an alternative for renal replacement. Cellular strategies include: incorporation of new nephrons into the kidney; growing new kidneys in situ/renal organogenesis; use of embryonic or adult stem cells; and nuclear transplantation/therapeutic cloning. These approaches circumvent humoral rejection of xenogeneic tissue. Cellular rejection is ameliorated if embryonic cells are transplanted. It is likely that replacement of renal function via one or more cellular approach will constitute a part of future mainstream medical practice.     

Cellular therapies for kidney failure

Dialysis and transplantation of human kidneys represent effective therapies to replace kidney function, but each has limitations. Xenotransplantation of whole kidneys from non-primate donors is complicated by humoral and severe cellular rejection. The use of individual cells or groups of cells to regenerate or repair damaged tissue (cellular therapies) offers an alternative for renal replacement. Cellular strategies include: incorporation of new nephrons into the kidney; growing new kidneys in situ/renal organogenesis; use of embryonic or adult stem cells; and nuclear transplantation/therapeutic cloning. These approaches circumvent humoral rejection of xenogeneic tissue. Cellular rejection is ameliorated if embryonic cells are transplanted. It is likely that replacement of renal function via one or more cellular approach will constitute a part of future mainstream medical practice.     

Alternative therapies: Part II. Congestive heart failure and hypercholesterolemia

Natural supplements are widely used by the American public but, while claims of their therapeutic effects abound, medical research does not always support their effectiveness. Clinical trials using Q10 for the management of congestive heart failure have had conflicting results; hawthorn is prescribed in Germany for the treatment of this condition, but no trials have been conducted in the United States. Although initial research about the use of garlic in the management of hypercholesterolemia was encouraging, follow-up studies have failed to verify these results. Substituting soy protein for high-fat animal protein diets, however, does have a beneficial effect on serum lipid levels. So far, cholestin (a natural product containing several statins) has proved to be a cost-saving lipid-lowering medication, and fenugreek may offer modest improvement as well. Gugulipid is also promising but requires further research.     

慢性射血分数保留心力衰竭的发病机制与诊治

左心室射血分数保留的心力衰竭(HF-p EF)在临床中较常见,处理此类心力衰竭对临床医生是一个挑战。HF-p EF的发病率和死亡率与左心室射血分数降低的心力衰竭(HF-r EF)相同,且发病机制更加复杂,既有心脏本身也有其他脏器的异常,同时还存在多种并发症间的相互作用影响。现有治疗心力衰竭的多数药物对于HFp EF无效,因此这类患者应该受到更多的关注。本文基于临床实践和基础研究,总结了HFp EF的流行病学特点、发病机制、诊断标准、医学上曾经尝试过的治疗方法,并对未来治疗本病的新手段进行讨论。     

Aquatic therapies in patients with compromised left ventricular function and heart failure

With water immersion, gravity is partly eliminated, and the water exerts a pressure on the body surface. Consequently there is a blood volume shift from the periphery to the central circulation, resulting in marked volume loading of the thorax and heart. This paper presents a selection of published literature on water immersion, balneotherapy, aqua exercises, and swimming, in patients with left ventricular dysfunction (LVD) and/or stable chronic heart failure (CHF). Based on exploratory studies, central hemodynamic and neurohumoral responses of aquatic therapies will be illustrated. Major findings are: 1. In LVD and CHF, a positive effect of therapeutic warm-water tub bathing has been observed, which is assumed to be from afterload reduction due to peripheral vasodilatation caused by the warm water. 2. In coronary patients with LVD, at low-level water cycling the heart is working more efficiently than at lowlevel cycling outside of water. 3. In patients with previous extensive myocardial infarction, upright immersion to the neck resulted in temporary pathological increases in mean pulmonary artery pressure (mPAP) and mean pulmonary capillary pressures (mPCP). 4. Additionally, during slow swimming (20-25m/min) the mPAP and/or PCP were higher than during supine cycling outside water at a 100W load. 5. In CHF patients, neck- deep immersion resulted in a decrease or no change in stroke volume. 6. Although patients are hemodynamically compromised, they usually maintain a feeling of well-being during aquatic therapy. Based on these findings, clinical indications for aquatic therapies are proposed and ideas are presented to provoke further research.     

Evolving targeted therapies for right ventricular failure

Introduction: Although right and left ventricular embryological origins, morphology and cardiodynamics differ, the notion of selectively targeted right ventricular therapies remains controversial.

Areas covered: This review focuses on both the currently evolving pharmacologic agents targeting right ventricular failure (metabolic modulators, phosphodiesterase type V inhibitors) and future therapeutic approaches including epigenetic modulation by miRNAs, chromatin binding complexes, long non-coding RNAs, genomic editing, adoptive gene transfer and gene therapy, cell regeneration via cell transplantation and cell reprogramming and cardiac tissue engineering.

Expert opinion: Strategies for adult right ventricular regeneration will require a more holistic approach than strategies for adult left ventricular failure. Instances of right ventricular failure requiring global reconstitution of right ventricular myocardium, attractive approaches include: i) myocardial patches seeded with cardiac fibroblasts reprogrammed into cardiomyocytes in vivo by small molecules, miRNAs or other epigenetic modifiers; and ii) administration of miRNAs, lncRNAs or small molecules by non-viral vector delivery systems targeted to fibroblasts (e.g., episomes) to stimulate in vivo reprogramming of fibroblasts into cardiomyocytes. For selected heritable genetic myocardial diseases, genomic editing affords exciting opportunities for allele-specific silencing by site-specific directed silencing, mutagenesis or gene excision. Genomic editing by adoptive gene transfer affords similarly exciting opportunities for restoration of myocardial gene expression.     

Severe congestive heart failure. How successful are drug and transplant therapies?

Severe congestive heart failure is a fatal illness. Aggressive use of proven medical regimens, including vasodilators and angiotensin-converting enzyme inhibitors, may prolong survival time for some patients. Those with refractory symptoms and seriously reduced left ventricular function, impaired exercise capacity, and complex or frequent ventricular arrhythmias should be considered for cardiac transplantation. Candidacy for transplantation is based on the absence of other illnesses that would limit survival or diminish the likelihood of success of the transplant. With the introduction of potent immunosuppressive agents, particularly cyclosporine (Sandimmune), survival rates after transplantation have improved to 90% at 1 year. Major problems include organ rejection, serious infection, development of coronary artery disease in the transplanted heart, and the limited donor organ supply.     

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.     

Stem cell therapies for congenital heart disease

Congenital heart disease (CHD) is the most prevalent congenital anomaly in newborn babies. Cardiac malformations have been induced in different animal model experiments, by perturbing some molecules that take part in the developmental pathways associated with myocyte differentiation, specification, or cardiac morphogenesis. The exact epigenetic, environmental, or genetic, basis for these molecules perturbations is yet to be understood. But, scientist have bridged this gap by introducing autologous stem cell into the defective hearts to treat CHD. The choice of stem cells to use has also raised an issue. In this review, we explore different stem cells that have been recently used, as an update into the pool of this knowledge and we suggested the future perspective into the choice of stem cells to control this disease. We propose that isolating mesenchymal stem cells from neonate will give a robust heart regeneration as compared to adults. This source are easily isolated. To unveil stem cell therapy beyond its possibility and safety, further study is required, including largescale randomized, and clinical trials to certify the efficacy of stem cell therapy.     

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.