Elsevier

The Lancet

Volume 385, Issue 9970, 28 February–6 March 2015, Pages 812-824
The Lancet

Review
The war against heart failure: the Lancet lecture

https://doi.org/10.1016/S0140-6736(14)61889-4Get rights and content

Summary

Heart failure is a global problem with an estimated prevalence of 38 million patients worldwide, a number that is increasing with the ageing of the population. It is the most common diagnosis in patients aged 65 years or older admitted to hospital and in high-income nations. Despite some progress, the prognosis of heart failure is worse than that of most cancers. Because of the seriousness of the condition, a declaration of war on five fronts has been proposed for heart failure. Efforts are underway to treat heart failure by enhancing myofilament sensitivity to Ca2+; transfer of the gene for SERCA2a, the protein that pumps calcium into the sarcoplasmic reticulum of the cardiomyocyte, seems promising in a phase 2 trial. Several other abnormal calcium-handling proteins in the failing heart are candidates for gene therapy; many short, non-coding RNAs—ie, microRNAs (miRNAs)—block gene expression and protein translation. These molecules are crucial to calcium cycling and ventricular hypertrophy. The actions of miRNAs can be blocked by a new class of drugs, antagomirs, some of which have been shown to improve cardiac function in animal models of heart failure; cell therapy, with autologous bone marrow derived mononuclear cells, or autogenous mesenchymal cells, which can be administered as cryopreserved off the shelf products, seem to be promising in both preclinical and early clinical heart failure trials; and long-term ventricular assistance devices are now used increasingly as a destination therapy in patients with advanced heart failure. In selected patients, left ventricular assistance can lead to myocardial recovery and explantation of the device. The approaches to the treatment of heart failure described, when used alone or in combination, could become important weapons in the war against heart failure.

Introduction

Spectacular advances have occurred in the past three decades in cardiovascular medicine and surgery. In high-income countries, early mortality rates associated with acute coronary syndromes (figure 1), valvular and congenital heart disease, hypertension, and many arrhythmias have decreased substantially. However, in many patients with these disorders some myocardial damage has occurred, and although their lives have been prolonged, their heart disease has not been cured; an increasing number become at risk of subsequently developing heart failure, which might be regarded as the price of success, and for many patients this price is steep.

Heart failure is a global problem,1, 2, 3, 4, 5, 6, 7 with an estimated 38 million patients with this diagnosis worldwide. The Global Burden of Disease 2010 study3, 8 reported that from 1990 to 2010, ischaemic heart disease was the most common cause of death worldwide. Although the age-standardised incidence of acute myocardial infarction has decreased worldwide, the prevalence of ischaemic heart failure, the most common type of heart failure, has increased.8 Heart failure is now becoming more common in low-income and medium-income countries, where an increasing proportion of the population have a high-income-country lifestyle that leads to obesity, hypertension, and diabetes,4, 5 all risk factors for the development of heart failure.

Heart failure is the most common diagnosis for hospital admission in patients aged 65 years and older in high-income countries. Since heart failure occurs most commonly in elderly people, the demographic imperative is immense. Every year, about 1 million hospital admissions occur for heart failure in the USA (figure 1) and a similar number occur in Europe. With the surge in the elderly population that is expected in both industrially developed and developing nations, a 50% increase in the number of new patients with heart failure every year is estimated in 15 years, unless there is real progress in prevention or treatment, or both.9, 10

The results of the management of heart failure, as described in practice guidelines, are mixed.11, 12 In patients with chronic heart failure with reduced ejection fraction, both the survival13 and quality of life have improved with the use of β-adrenoreceptor blockers, with drugs that block the renin-angiotensin-aldosterone system,11 and, according to a recent report,14 with an angiotensin receptor-neprilysin inhibitor and with devices, including pacemakers, which enhance cardiac synchronisation and implanted cardiac defibrillators.12

However, we are unable to do much more than reduce congestion with diuretics in patients with chronic heart failure with preserved ejection fraction, which occurs in almost half of the population with heart failure.7, 9, 11, 12 The outlook for patients with acute decompensated heart failure, irrespective of ejection fraction, is also grave.15 In patients older than 65 years in the USA, the 30-day hospital mortality rate for patients admitted to the hospital with heart failure is fairly constant at about 11%, and the 30-day hospital readmission rate is around 30%.16 Similar outcomes have been reported in England and Wales17 and in Europe.18 The 5-year survival rate for heart failure is worse than it is for most cancers and the annual cost of care for heart failure in the USA has been estimated to exceed US$30 billion, most of it spent on hospital care.7 Although the increased application of clinical practice guidelines in high-income countries,11, 12, 13 especially in patients with heart failure with reduced ejection fraction, has resulted in some improvement in outcome,19 many patients now experience a more prolonged course, resulting in increases in the prevalence of the disorder,8 and in the economic burden on the health-care system. Heart failure is a particular threat in middle-income and low-income countries, where the adjusted hazard ratios for case fatality were 2·61 and 3·72, with high-income countries as the referent.20

Increased efforts to enhance the understanding of the pathobiology of heart failure and to develop new approaches for prevention or improvement of the care of patients with this condition is important. Research about heart failure is now quite active worldwide and many areas are being explored.

Section snippets

Calcium cycling

Calcium cycling in the cardiomyocyte is crucial to both cardiac contraction and relaxation. Normally, depolarisation of the cell membrane and of its invaginations, the transverse tubules, triggers the entry of small quantities of calcium into the cardiomyocyte, through L-type ion-specific channels located in the cardiomyocyte sarcoplasmic reticulum membrane.21 This influx of calcium opens the nearby calcium release channels, also known as the type 2 ryanodine receptors (RyR2), large tetrameric

Gene therapy

The idea of replacing a faulty gene with a normal one has been a dream of biologists and clinical investigators for decades. The goal is to correct molecular defects using the affected cells' own genetic machinery. After a slow start followed by several technical and safety concerns, notable progress in this area has been made. In 2012, the European Medical Agency approved the first gene-based treatment.37 The general approach is shown in figure 3. The gene to be transferred is attached to a

MicroRNAs (miRNAs)

In 1993, two papers published back to back in Cell64, 65 described short, non-coding RNAs (miRNAs), which are present in almost all higher eukaryocytes. miRNAs are gene products processed first in the nucleus and then in the cytoplasm; they silence mRNA by pairing with its messenger sites, thereby preventing protein translation and gene expression. The association between these two forms of RNA is complex; each miRNA might attach to several mRNAs, while each of the mRNAs can bind several

Early studies

The potential value of cell therapy was suggested almost a century ago, when Jacobson and colleagues88 showed the importance of cells in the spleen and bone marrow in protecting mice from otherwise lethal irradiation. In the 1970s, autologous bone marrow transplantation was introduced and this treatment has become routine in the treatment of haematological malignancies. The implantation of stem or progenitor cells into the failing or damaged heart with the hope that they will cause regeneration

Left ventricular assistance devices (LVADs)

Since the development of the cardiopulmonary bypass in the 1950s, the treatment of advanced heart failure by replacing a failing heart with an implanted artificial heart has been an important goal for the treatment of heart failure. After many setbacks in animal experiments, and some widely publicised failures in a few patients, this goal was adjusted to develop devices that would provide left ventricular assistance (LVA) instead of total heart replacement. At first, the assistance was

Conclusion

As stated, the pandemic of heart failure represents a major global health problem, and one that is likely to grow, especially in the low-income and medium-income countries. A concerted series of actions are needed to deal with this problem, hence the war against heart failure. A combination of two broad approaches will be needed. The first is the prevention of heart failure,158 which in turn will need prevention of the development of heart disease.159 This is a great goal, but some progress has

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