Heart Failure

HF

Heart failure (HF) is a major emerging public health problem associated with increasing prevalence in the ageing population, high morbidity and mortality rates, and the challenges involved with patient management and healthcare costs.1

The number of patients with heart failure worldwide increased from 33.5 million in 1990 to 64.3 million in 2017 and this number is projected to increase in the next decade.2 Common risk factors that predispose individuals to heart failure include age (>65 years), coronary artery disease, a history of myocardial infarction, hypertension, obesity, smoking and diabetes.

Heart failure is a clinical syndrome characterized by typical symptoms and signs caused by a structural and/or functional cardiac abnormality that results in reduced cardiac output and/or elevated intracardiac pressures.3 There are two distinct subpopulations of HF classified based on the pumping function measured by echocardiography called HF with reduced ejection fraction (HFrEF) and HF with preserved ejection fraction (HFpEF), respectively. HFrEF and HFpEF are distinguished further by different disease mechanisms, co-morbidities and responses to treatment.3,4 The prevalence estimates for HFpEF lies in the range from 1 to 3 %, and is anticipated to increase.5,6HFpEF is associated with high mortality rates of 20-29 % annually, and 53-74 % in a 5-year period.5,7 Due to the increase in prevalence and limited options for therapy, there is an urgent need for novel and improved treatment strategies for HFpEF patients.

Inflammation, tissue damage and/or adverse tissue remodeling are the biological processes that lead to the development of chronic heart failure.8 In HF, extracellular matrix degrading enzymes present in myocardial tissues such as ADAMTS-4 cause adverse tissue remodelling; as well as inflammation and vascular endothelial cell activation which affect cardiac function.9,10

Heart Failure

hf

Heart failure (HF) is a major emerging public health problem associated with increasing prevalence in the ageing population, high morbidity and mortality rates, and the challenges involved with patient management and healthcare costs.1

The number of patients with heart failure worldwide increased from 33.5 million in 1990 to 64.3 million in 2017 and this number is projected to increase in the next decade.2 Common risk factors that predispose individuals to heart failure include age (>65 years), coronary artery disease, a history of myocardial infarction, hypertension, obesity, smoking and diabetes.

Heart failure is a clinical syndrome characterized by typical symptoms and signs caused by a structural and/or functional cardiac abnormality that results in reduced cardiac output and/or elevated intracardiac pressures.3 There are two distinct subpopulations of HF classified based on the pumping function measured by echocardiography called HF with reduced ejection fraction (HFrEF) and HF with preserved ejection fraction (HFpEF), respectively. HFrEF and HFpEF are distinguished further by different disease mechanisms, co-morbidities and responses to treatment.3,4 The prevalence estimates for HFpEF lies in the range from 1 to 3 %, and is anticipated to increase.5,6HFpEF is associated with high mortality rates of 20-29 % annually, and 53-74 % in a 5-year period.5,7 Due to the increase in prevalence and limited options for therapy, there is an urgent need for novel and improved treatment strategies for HFpEF patients.

Inflammation, tissue damage and/or adverse tissue remodeling are the biological processes that lead to the development of chronic heart failure.8 In HF, extracellular matrix degrading enzymes present in myocardial tissues such as ADAMTS-4 cause adverse tissue remodelling; as well as inflammation and vascular endothelial cell activation which affect cardiac function.9,10

Key HF Figures

Estimated global prevalence11
≥32M+
Lifetime risk of developing HFpEF at age 4013
10%
Rehospitalisation rate within 60–90 days of discharge14
29%

Key HF Figures

Estimated global prevalence11
32M+
Lifetime risk of developing HFpEF at age 4013
10%
Rehosp. rate within 60–90 days of discharge14
29%

Drug in development

Drug in development

Pentosan
Polysulfate
Sodium

Pentosan
Polysulfate
Sodium

Potential

Pentosan Polysulfate Sodium (PPS) has been investigated as a therapeutic agent targeting tissue remodelling in HFrEF in preclinical animal models (aortic banding and myocardial infarction animal models). In these models, PPS was shown to target ADAMTS-4, a key enzyme that degrades the extracellular matrix (ECM) component called versican, in myocardial tissue.9 Additionally, PPS therapy may complement standard of care (SOC) treatments in both HFpEF and HFrEF patients due to its anti-inflammatory actions resulting in improved vascular perfusion. There is currently an unmet medical need for the treatment of adverse cardiac remodelling for HF.

The mechanisms of action of PPS that are potentially relevant to the treatment of heart failure include:

- Reduction in the synthesis of ADAMTS-4 mRNA and protein9
- Inhibition of adverse cardiac tissue remodeling evidenced by reduction in versican degradation9
- Improved cardiac function9
- Reduction in pro-inflammatory cytokines and inhibition of transcription factor activity such as NF-κB15

Remodelling
Inflammation

Development milestones

A translational animal model of HFpEF using the ZSF-1 obese rats to confirm pilot data on the therapeutic effects of PPS is being performed in collaboration with the Center for Heart Failure Research & Institute for Experimental Research, at Oslo University.  

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