ReviewThe war against heart failure: the Lancet lecture
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
References (159)
- et al.
Global and regional mortality from 235 causes of death for 20 age groups in 1990 and 2010: a systematic analysis for the Global Burden of Disease Study 2010
Lancet
(2012) - et al.
The global health and economic burden of hospitalizations for heart failure: lessons learned from hospitalized heart failure registries
J Am Coll Cardiol
(2014) - et al.
2013 ACCF/AHA guideline for the management of heart failure: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines
J Am Coll Cardiol
(2013) - et al.
Calcium movements inside the sarcoplasmic reticulum of cardiac myocytes
J Mol Cell Cardiol
(2013) - et al.
Subclinical abnormalities in sarcoplasmic reticulum Ca(2+) release promote eccentric myocardial remodeling and pump failure death in response to pressure overload
J Am Coll Cardiol
(2014) - et al.
Dysfunctional ryanodine receptors in the heart: new insights into complex cardiovascular diseases
J Mol Cell Cardiol
(2013) - et al.
The effects of the cardiac myosin activator, omecamtiv mecarbil, on cardiac function in systolic heart failure: a double-blind, placebo-controlled, crossover, dose-ranging phase 2 trial
Lancet
(2011) - et al.
Reversal of cardiac dysfunction after long-term expression of SERCA2a by gene transfer in a pre-clinical model of heart failure
J Am Coll Cardiol
(2008) - et al.
Calcium upregulation by percutaneous administration of gene therapy in cardiac disease (CUPID Trial), a first-in-human phase 1/2 clinical trial
J Card Fail
(2009) - et al.
Design of a phase 2b trial of intracoronary administration of AAV1/SERCA2a in patients with advanced heart failure: the CUPID 2 trial (calcium up-regulation by percutaneous administration of gene therapy in cardiac disease phase 2b)
JACC Heart Fail
(2014)
Percutaneous cardiac recirculation-mediated gene transfer of an inhibitory phospholamban peptide reverses advanced heart failure in large animals
J Am Coll Cardiol
S100A1 genetically targeted therapy reverses dysfunction of human failing cardiomyocytes
J Am Coll Cardiol
Genetic manipulation of myocardial beta-adrenergic receptor activation and desensitization
J Mol Cell Cardiol
The C. elegans heterochronic gene lin-4 encodes small RNAs with antisense complementarity to lin-14.
Cell
Posttranscriptional regulation of the heterochronic gene lin-14 by lin-4 mediates temporal pattern formation in C. elegans
Cell
microRNAs in cardiovascular diseases: current knowledge and the road ahead
J Am Coll Cardiol
Cell therapy, 3D culture systems and tissue engineering for cardiac regeneration
Adv Drug Deliv Rev
Embryonic stem cell trials for macular degeneration: a preliminary report
Lancet
Target populations for first-in-human embryonic stem cell research in spinal cord injury
Cell Stem Cell
Induction of pluripotent stem cells from mouse embryonic and adult fibroblast cultures by defined factors
Cell
Determinants of the decline in mortality from acute myocardial infarction in England between 2002 and 2010: linked national database study
BMJ
Heart disease and stroke statistics—2014 update: a report from the American Heart Association
Circulation
Heart failure: epidemiology and prevention in India
Natl Med J India
Trends in age-specific coronary heart disease mortality in the European Union over three decades: 1980–2009
Eur Heart J
Epidemiology of heart failure
Circ Res
The global burden of ischemic heart disease in 1990 and 2010: the Global Burden of Disease 2010 study
Circulation
Heart disease and stroke statistics—2014 update: a report from the American Heart Association
Circulation
Aging of the United States population: impact on heart failure
Curr Heart Fail Rep
Developed in collaboration with the Heart Failure Association (HFA) of the ESC
Eur Heart J
Evidence of improving prognosis in heart failure: trends in case fatality in 66 547 patients hospitalized between 1986 and 1995
Circulation
Angiotensin-neprilysin inhibition versus enalapril in heart failure
N Engl J Med
Acute heart failure syndromes: current state and framework for future research
Circulation
Factors identified as precipitating hospital admissions for heart failure and clinical outcomes: findings from OPTIMIZE-HF
Arch Intern Med
The national heart failure audit for England and Wales 2008–2009
Heart
Heart failure epidemiology: European perspective
Curr Cardiol Rev
National and regional trends in heart failure hospitalization and mortality rates for Medicare beneficiaries, 1998–2008
JAMA
Cardiovascular risk and events in 17 low-, middle-, and high-income countries
N Engl J Med
Mechanisms of cardiac contraction and relaxation
Calcium cycling proteins and heart failure: mechanisms and therapeutics
J Clin Invest
The relationship between arrhythmogenesis and impaired contractility in heart failure: role of altered ryanodine receptor function
Cardiovasc Res
Cardiac calcium handling on trial: targeting the failing cardiomyocyte signalosome
Circ Res
Alterations of sarcoplasmic reticulum proteins in failing human dilated cardiomyopathy
Circulation
Mechanisms of altered Ca2+ handling in heart failure
Circ Res
Outcome in phospholamban R14del carriers: results of a large multicentre cohort study
Circ Cardiovasc Genet
S100A1 in human heart failure: lack of recovery following left ventricular assist device support
Circ Heart Fail
Ca2+/calmodulin-dependent protein kinase modulates cardiac ryanodine receptor phosphorylation and sarcoplasmic reticulum Ca2+ leak in heart failure
Circ Res
The deltaC isoform of CaMKII is activated in cardiac hypertrophy and induces dilated cardiomyopathy and heart failure
Circ Res
Role of RyR2 phosphorylation at S2814 during heart failure progression
Circ Res
Cardiac myosin activation: a potential therapeutic approach for systolic heart failure
Science
Glybera and the future of gene therapy in the European Union
Nat Rev Drug Discov
Cited by (642)
Remodelers of the vascular microenvironment: The effect of biopolymeric hydrogels on vascular diseases
2024, International Journal of Biological MacromoleculesCardiac regeneration: Pre-existing cardiomyocyte as the hub of novel signaling pathway
2024, Genes and DiseasesClinical Heart fAilure Management Program: Changing the practice by partnering primary care and specialists (CHAMP-HF)
2024, IJC Heart and VasculatureRemote management in patients with heart failure (from new onset to advanced): A practical guide
2024, Archives of Cardiovascular Diseases