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Novel sGC Stimulators and sGC Activators for the Treatment of Heart Failure

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Heart Failure

Part of the book series: Handbook of Experimental Pharmacology ((HEP,volume 243))

Abstract

The burden of heart failure (HF) increases worldwide with an aging population, and there is a high unmet medical need in both, heart failure with reduced ejection fraction (HFrEF) and with preserved ejection fraction (HFpEF). The nitric oxide (NO) pathway is a key regulator in the cardiovascular system and modulates vascular tone and myocardial performance. Disruption of the NO-cyclic guanosine monophosphate (cGMP) signaling axis and impaired cGMP formation by endothelial dysfunction could lead to vasotone dysregulation, vascular and ventricular stiffening, fibrosis, and hypertrophy resulting in a decline of heart as well as kidney function. Therefore, the NO-cGMP pathway is a treatment target in heart failure. Exogenous NO donors such as nitrates have long been used for treatment of cardiovascular diseases but turned out to be limited by increased oxidative stress and tolerance. More recently, novel classes of drugs were discovered which enhance cGMP production by targeting the NO receptor soluble guanylate cyclase (sGC). These compounds, the so-called sGC stimulators and sGC activators, are able to increase the enzymatic activity of sGC to generate cGMP independently of NO and have been developed to target this important signaling cascade in the cardiovascular system.

This review will focus on the role of sGC in cardiovascular (CV) physiology and disease and the pharmacological potential of sGC stimulators and sGC activators therein. Preclinical data will be reviewed and summarized, and available clinical data with riociguat and vericiguat, novel direct sGC stimulators, will be presented. Vericiguat is currently being studied in a Phase III clinical program for the treatment of heart failure with reduced ejection fraction (HFrEF).

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Abbreviations

ANP:

Atrial natriuretic peptide

BNP:

Brain natriuretic peptide

CAD:

Coronary artery disease

cGMP:

Cyclic guanosine monophosphate

CTEPH:

Chronic thromboembolic pulmonary hypertension

CV:

Cardiovascular

DILATE:

Acute Hemodynamic Effects of Riociguat in Patients With Pulmonary Hypertension Associated With Diastolic Heart Failure

eNOS:

Endothelial nitric oxide synthase

GC:

Guanylate cyclase

GTP:

Guanosine triphosphate

HF:

Heart failure

HFpEF:

HF with preserved ejection fraction

HFrEF:

HF with reduced ejection fraction

LEPHT:

Left Ventricular Systolic Dysfunction Associated With Pulmonary Hypertension Riociguat Trial

LOCF:

Last observation carried forward

LV:

Left ventricle

LVEDP:

Left ventricular end-diastolic pressure

LVEF:

Left ventricular ejection fraction

PAPmean:

Mean pulmonary arterial pressure

MI:

Myocardial infarction

NO:

Nitric oxide

NP:

Natriuretic peptide

PAH:

Pulmonary arterial hypertension

PDE:

Phosphodiesterase

PDEi:

Phosphodiesterase inhibitor

PDE5:

Phosphodiesterase type 5

pGC:

Particulate guanylate cyclase

PH:

Pulmonary hypertension

PH-sLVD:

Pulmonary hypertension associated with systolic left ventricular dysfunction

QoL:

Quality of life

ROS:

Reactive oxygen species

RV:

Right ventricle

sGC:

Soluble guanylate cyclase

SOCRATES:

Soluble guanylate cyclase stimulator in heart failure study

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All authors are employee of Bayer AG / Pharmaceutical Division.

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Authors and Affiliations

  1. Bayer AG, Wuppertal, 42069, Germany

    Stefanie Breitenstein, Lothar Roessig, Peter Sandner & Kelly S. Lewis

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  1. Stefanie Breitenstein
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  2. Lothar Roessig
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  3. Peter Sandner
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  4. Kelly S. Lewis
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Correspondence to Stefanie Breitenstein .

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Editors and Affiliations

  1. Klinik für Kardiologie und Angiologie, Medizinische Hochschule Hannover Klinik für Kardiologie und Angiologie, Hannover, Niedersachsen, Germany

    Johann Bauersachs

  2. Heart Institute, Stony Brook University , Stony Brook, New York, USA

    Javed Butler

  3. Heart and Lung Diseases, Bayer Pharma Aktiengesellschaft Heart and Lung Diseases, Wuppertal, Nordrhein-Westfalen, Germany

    Peter Sandner

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Breitenstein, S., Roessig, L., Sandner, P., Lewis, K.S. (2016). Novel sGC Stimulators and sGC Activators for the Treatment of Heart Failure. In: Bauersachs, J., Butler, J., Sandner, P. (eds) Heart Failure. Handbook of Experimental Pharmacology, vol 243. Springer, Cham. https://doi.org/10.1007/164_2016_100

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