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  • Review Article
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Novel therapeutic targets for the treatment of heart failure

Nature Reviews Drug Discovery volume 10, pages 536–555 (2011)Cite this article

Subjects

Key Points

  • Heart failure is a heterogeneous, multifactorial and progressive syndrome that presents as a wide spectrum of phenotypes and is often accompanied by other comorbidities. It represents a major health problem owing to its high morbidity and mortality and substantial health-care costs.

  • The goals of treatment are to reduce mortality and morbidity, prevent heart disease or its progression, and manage comorbidities that cause and/or contribute to the pathogenesis of heart failure.

  • Despite considerable therapeutic advances, treatment of acute decompensated heart failure has not changed much over the past 25 years, as new drugs have failed to reduce morbidity and mortality rates compared to placebo. Furthermore, no treatment strategy has improved clinical outcomes in patients with heart failure with preserved left ventricular ejection fraction.

  • There is an unmet need for the development of new drugs with a favourable safety profile that can improve cardiac performance and clinical outcomes in patients, and prevent the progression of heart failure.

  • In recent years, new potential therapeutic targets that are involved in the pathogenesis of heart failure have been identified and several promising new drugs are currently under investigation, both in experimental models and in clinical trials in patients with heart failure.

  • However, the positive results that are obtained in preclinical and Phase II studies are not always confirmed in large Phase III trials. In this Review, we provide a detailed analysis of the possible explanations for this discrepancy.

  • The development of new effective and safe drugs for the treatment of heart failure should be based on a better understanding of the pathophysiological mechanisms that are directly implicated in the onset and/or maintenance of heart failure, robust preclinical data and well-designed clinical trials.

Abstract

Despite considerable therapeutic advances, heart failure remains a medical and socioeconomic problem. Thus, there is a compelling need for new drugs that could improve clinical outcomes. In recent years, new potential therapeutic targets that are involved in the pathogenesis of heart failure have been identified, and new drugs are currently under investigation. A repeated finding is that the positive results that have been observed in preclinical studies and Phase II trials are not always confirmed in Phase III studies. This Review analyses the new therapeutic targets (for example, ventricular remodelling, renin–angiotensin–aldosterone system activation, defects in Ca2+ cycling, and so on), the mechanism of action, efficacy and future perspectives of new drugs that are currently under development for the treatment of heart failure, and the possible explanations for the discrepancy between Phase II and Phase III trials.

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Figure 1: Sites of action of drugs producing diuresis and natriuresis.
Figure 2: Schematic representation of the mechanisms of action of several vasodilators.
Figure 3: Sites of action of positive inotropic agents.
Figure 4: Scheme of the cardiac Ca2+-cycling defects in heart failure.

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Acknowledgements

This work was supported by grants from the Carlos III Health Institute (PI080665 and ISCIII-RETIC RD06/0009-FEDER) and the Spanish Society of Cardiology. We would like to thank E. Delpón for her critical reading and suggestions.

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Authors and Affiliations

  1. Department of Pharmacology, School of Medicine, Universidad Complutense, Madrid, 28040, Spain

    Juan Tamargo

  2. Department of Cardiology, Hospital Universitario La Paz (IDIPAZ), Paseo de la Castellana 261, Madrid, 28046, Spain

    José López-Sendón

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  1. Juan Tamargo
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Correspondence to Juan Tamargo.

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José Lopez-Sendón declares an association with the following pharmaceutical companies: Servier, Pfizer, Amgen and Novartis.

Supplementary information

Supplementary Information (Table S1)

Major large-scale randomized clinical trials comparing the effects of new developing drugs in patients with heart failure (PDF 457 kb)

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Glossary

Left ventricular ejection fraction

(LVEF). The percentage of blood that is pumped out from the left ventricles of the heart with each heart beat.

Inotropes

Drugs that increase (positive inotropes) or decrease (negative inotropes) myocardial contractility.

Heart failure with preserved ejection fraction

(HFPEF). Patients who have heart failure but with a normal left ventricular ejection fraction; that is, above 40–50% (there is no consensus for the cut-off).

Neurohumoral profile

A decrease in cardiac pump function that is associated with a neurohumoral response, which is characterized by the activation of the renin–angiotensin–aldosterone and sympathetic nervous systems and elevated circulating levels of natriuretic peptides, vasopressin, endothelin-1, urotensins, adrenomedullin and nitric oxide.

Loop diuretics

Diurectics that inhibit the Na+/K+/2Cl− co-transporter in the luminal membrane of the thick ascending limb of the loop of Henle. They are the most powerful diuretics available.

Ischaemic pre-conditioning

An increased tolerance to ischaemia and reperfusion that is induced by a previous sublethal period of ischaemia.

Left ventricular filling pressure

The pressure that builds up in the left ventricle as it is being filled with blood.

Myocardial oxygen demands

(MVO2). This relates to the amount of oxygen consumed per minute that is required to regenerate the ATP that is used by membrane transport mechanisms and in the excitation–contraction process. MVO2 is expressed as ml O2 per min per 100g of cardiac tissue.

Lusitropic effects

The effects of a drug on the properties of ventricular relaxation.

NT-proBNP

Amino terminal proBNP (NT-proBNP) is a cleavage product of the precursor brain natriuretic peptide (BNP).

Neprilysin

A zinc-dependent metalloproteinase that degrades several small secreted peptides such as natriuretic peptides, angiotensin II and endothelin-1.

Peripheral hypoperfusion

The decreased perfusion of organs (mainly skin, kidney and brain) as a result of a decrease in the pumping function of the heart, which results in cold, clammy skin, oliguria or lethargy.

Crossbridge cycle

The entire process by which the myosin heads interact with the actin filament.

dP/dtmax

The maximum rate of left ventricular systolic pressure development — an indirect index of cardiac contractility.

Left ventricular assist devices

Surgically implanted mechanical pumps that take blood from the left ventricle and pump it into the aorta.

Intestinal L cells

Cells that are found throughout the lining of the gastrointestinal tract and contain regulatory peptide hormones and/or biogenic amines.

Global and regional left ventricular performance

Changes in global left ventricular or regional (segmental) left ventricular contraction and function, respectively.

Functional class

A classification of the severity of heart failure that is based on the symptoms and exercise capacity of the patient (known as the New York Heart Association functional classification).

Preload reduction

The preload is the pressure and volume of blood that is present in the left ventricle at the end of diastole. The major drugs that reduce the preload in heart failure are loop diuretics and nitrates, which dilate the veins to reduce the amount of blood returning to the heart via the venous system.

Precipitant factors

Factors that may not be the underlying cause of the illness, but cause or contribute to the occurrence of heart failure or to hospitalization.

Titin springs

A large part of the titin molecule (a giant protein that is located in the sarcomere) that functions as a spring and develops passive stiffness when sarcomeres are stretched.

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Tamargo, J., López-Sendón, J. Novel therapeutic targets for the treatment of heart failure. Nat Rev Drug Discov 10, 536–555 (2011). https://doi.org/10.1038/nrd3431

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