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Drug discovery for heart failure: a new era or the end of the pipeline?

Key Points

  • Heart failure is a progressive disorder initiated by myocardial injury (typically myocardial infarction), which is subsequently perpetuated by the deleterious effects of a wide range of secondary myocardial, neurohormonal and vascular changes.

  • Heart failure affects 6–10% of those aged over 65 years, and on average is associated with a 4-year survival rate of 50%.

  • An extensive body of evidence based on clinical research demonstrated that β-adrenoceptor blockade and renin–angiotensin system inhibition improved survival, and slowed progression of heart failure.

  • Despite extensive cellular, molecular biological and biochemical studies in heart failure there have recently been a number of disappointing clinical trial failures in the attempt to find new targets for therapy in heart failure.

  • As a consequence of these failures, the rate of development of new compounds for heart failure treatment seems to have significantly slowed. Instead, a greater emphasis has been put on the development of devices, including pacemakers and implantable defibrillators.

  • In this review, we provide an insight into current and emerging targets for drug development. We also highlight the emerging role of pharmacogenomics in optimizing the utilization of current drug therapy.

  • As heart failure is typically a disease of older individuals, other disease processes, such as diabetes, anaemia and renal failure, might co-exist. Tailoring of current and new therapies to address these issues could also be of importance.

Abstract

Although there have been significant advances in the therapy of heart failure in recent decades, such as the introduction of beta-blockers and antagonists of the renin–angiotensin system, there is still a major unmet need for better therapies for many patients with heart failure. However, disappointment related to late-stage clinical failures of a number of novel agents, including endothelin antagonists and tumour-necrosis factor blockers, has reduced the impetus of drug development in this field. Here, we review possible targets for heart failure therapy that have emerged from recent progress in our understanding of the underlying disease mechanisms, and highlight key issues that need to be addressed to improve the chances of success of novel therapies directed against these targets.

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Figure 1: Pathophysiology of heart failure.
Figure 2: Potential drug targets in the myocardium in heart failure.
Figure 3: Chemical structures of selected compounds under investigation for use in heart failure.

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Acknowledgements

The authors receive support from the National Health and Medical Research Council of Australia. D.K. receives support from the Atherosclerosis Trust (UK).

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Correspondence to David M. Kaye.

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DATABASES

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FURTHER INFORMATION

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American Heart Association

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Glossary

Hypertrophy

An increase in ventricular mass, which is typically characterized by an increased cardiac myocyte size in conjunction with cardiac fibrosis.

Altered load

Altered load causes elevated ventricular wall stress, which increases ventricular work, thereby increasing metabolic demand and activates a hypertrophic gene programme.

Advanced glycation end-products

Proteins and lipids that undergo non-enzymatic glycation in the context of diabetes, which results in their altered structure and function.

Ejection fraction

A widely used measure of ventricular performance.

Sinus node

The principal biological pacemaker of the heart.

Aquaresis

Renal excretion of water.

Euvolaemic range

The normal range of circulatory volume.

Hyponatraemia

Low serum sodium concentration.

Natriuretic peptides

These include the cardiac secreted peptides atrial natriuretic peptide and brain natriuretic peptide, which both promote the renal excretion of sodium and water.

Erythropoietin

A protein secreted by the kidneys that is responsible for stimulating red blood cell production.

Cachexia

Weight loss (typically muscle) in the context of chronic illness, including heart failure and cancer.

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Kaye, D., Krum, H. Drug discovery for heart failure: a new era or the end of the pipeline?. Nat Rev Drug Discov 6, 127–139 (2007). https://doi.org/10.1038/nrd2219

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