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Is enhancing cGMP-PKG signalling a promising therapeutic target for heart failure with preserved ejection fraction?
1Department of Cardiovascular Physiology, Ruhr University Bochum, Bochum, Germany.
Insights
Heart failure with preserved ejection fraction (HFpEF) affects aging populations and lacks effective treatments. Targeting the cyclic guanosine monophosphate (cGMP)-protein kinase G (PKG) pathway shows promise for personalized HFpEF therapies.
Area of Science:
- Cardiology
- Pharmacology
- Molecular Biology
Background:
- Heart failure with preserved ejection fraction (HFpEF) is highly prevalent in aging populations, comprising over 50% of heart failure cases.
- HFpEF is associated with comorbidities like obesity, diabetes, and hypertension, yet large trials for HFpEF treatments have failed.
- Current treatment strategies may be inadequate, necessitating personalized approaches for specific HFpEF phenotypes.
Purpose of the Study:
- To review preclinical and early clinical evidence for therapies targeting the cyclic guanosine monophosphate (cGMP)-protein kinase G (PKG) pathway in HFpEF.
- To explore the role of cGMP-PKG pathway modulation in HFpEF, particularly concerning comorbidities and titin phosphorylation.
Main Methods:
- Literature review of preclinical studies.
- Analysis of early clinical trial data.
- Focus on cGMP-enhancing therapies and PKG activation.
Main Results:
- Growing evidence supports the cGMP-PKG pathway as a therapeutic target in HFpEF.
- Comorbidities contribute to systemic inflammation and oxidative stress, impacting cGMP levels and PKG activity.
- The pathway's role in titin phosphorylation is a key area of investigation.
Conclusions:
- Personalized therapeutic strategies are crucial for HFpEF due to its heterogeneity.
- Modulating the cGMP-PKG pathway represents a promising avenue for developing targeted HFpEF treatments.
- Further research into cGMP-enhancing therapies and PKG activation is warranted.
Abstract:
Heart failure with preserved ejection fraction, i.e. HFpEF, is highly prevalent in ageing populations, accounting for more than 50 % of all cases of heart failure in Western societies, and is closely associated with comorbidities such as obesity, diabetes and arterial hypertension. However, all large multicentre trials of potential HFpEF treatments conducted to date have failed to produce positive outcomes. These disappointing results suggest that a 'one size fits all' strategy may be ill-suited to HFpEF and support the use of tailored, personalised therapeutic approaches with specific treatments designed for specific comorbidity-related HFpEF phenotypes. The accumulation of a multitude of cardiovascular comorbidities over time leads to increased systemic inflammation, oxidative stress and coronary microvascular endothelial inflammation, eventually resulting in degradation of cyclic guanosine monophosphate (cGMP) via multiple pathways, thereby reducing protein kinase G (PKG) activity. The importance of cGMP-PKG pathway modulation is supported by growing evidence that suggests that this pathway may be a promising therapeutic target, evidence that is mainly based on its role in the phosphorylation of the giant cytoskeletal protein titin. This review will focus on the preclinical and early clinical evidence in the field of cGMP-enhancing therapies and PKG activation.
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