The first step in diagnosing heart failure with preserved ejection fraction (HFpEF) is the evaluation of ejection fraction (EF) combined with the measurement of NT-proBNP. However, patients may not present a clear reduction in EF; additionally, NT-proBNP is reported to fluctuate in HFpEF patients depending on obesity, a common condition in HFpEF patients.

This means that NT-proBNP is not a suitable biomarker in a subgroup of patients. There is a need for non-invasive biomarkers accurately reflecting the risk of developing HFpEF as well as being able to diagnose HFpEF patients irrespective of comorbidities. A strategy of "one biomarker fits all" is unlikely to be applicable in HFpEF patients, and the future of diagnosis and risk assessment in HFpEF may be a combination of biomarkers.

Cardiac fibrosis is one of the underlying causes of HFpEF. Quantifying extracellular matrix (ECM) turnover in HFpEF patients can provide a unique insight into structural and functional ECM changes relevant to HFpEF pathogenesis.

Furthermore, it is possible that an increase in deposition of ECM proteins may precede functional changes, detected by the currently available diagnostic procedures. Our biomarkers may therefore provide earlier detection of HFpEF onset.

Browse our list of heart failure biomarkers

Several extracellular matrix components in circulation have previously shown a potential association with cardiac fibrosis. nordicPRO-C6™ is a biomarker reflecting formation of type VI collagen. Most importantly is able to measure endotrophin, a peptide deriving from collagen type VI that mediates metabolic dysregulation, inflammation, and fibrosis.

NordicPRO-C6™ has shown outstanding performance in the context of HFpEF and has even received a letter of support (LoS) from the FDA as a prognostic enrichment tool in HFpEF clinical trials.

Recent data published in NEJM Evidence, include a subset analysis of the TOPCAT trial, where endotrophin, measured by nordicPRO-C6™,  significantly predicts risk of mortality and rehospitalization due to heart failure, with greater prognostic power than NT-proBNP and the MAGGIC composite risk score (Figure 1).

These findings were validated in six independent cohorts where endotrophin levels were measured with nordicPRO-C6™.

Endotrophin levels were associated with all-cause death (Figure 2A) and to death or heart failure-related hospitalization in all HFpEF cohorts (Figure 2C).

This association remained unaffected after adjustment for MAGGIC risk score for all-cause death (Figure 2B) and for death or heart failure-related hospitalization (Figure  2D).

Figure 1.
 Multivariable Cox Proportional-Hazards Models in the TOPCAT trial. The included endotrophin, NT-proBNP, and MAGGIC risk score as predictors.

Figure 2. 
Forest plot of participant-level meta-analysis assessing the relationship between (Panels A and B) endotrophin and death and (Panels C and D) death or heart failure-related hospital admission in six HFpEF cohort studies unadjusted analyses (Panel A and C) and models adjusted for MAGGIC risk score (Panels B and D)

Heart failure (HF) is a clinical manifestation induced by several cardiovascular pathologies. It can be characterized by inefficiency of the heart to pump enough oxygenated blood to the body. HF is associated with an overall decrease in quality of life and high rates of admission to the hospital and mortality. HF severity is categorized according to the New York Heart Association (NYHA) classification groups:

  • NYHA Class I: No symptoms and no limitation in physical activity
  • NYHA Class II: Mild symptoms, mild shortness of breath and/or angina, mild limitation to physical activity
  • NYHA Class III: Marked limitation in physical activity caused by symptoms, decreased physical capacity, only comfortable at rest
  • NYHA Class IV: Severe limitation to physical activity, experiences symptoms while at rest, mainly hospitalized patients

HF can be further divided into sub-categories based on the patient’s ejection fraction (EF). Three sub-categories have been accepted to date: Heart Failure with Reduced Ejection Fraction (HFrEF), Heart Failure with Mid-Range Ejection Fraction (HFmrEF), and Heart Failure with Preserved Ejection Fraction (HFpEF). HFrEF, and partially HFmrEF, have well-established treatment strategies which are effective in reducing morbidity and outcome. Conversely, specific biomarkers and treatments for HFpEF patients are urgently needed.

Common causes of HF regardless of subtype include coronary heart disease, previous myocardial infarction(s), high blood pressure, arrhythmias, and cardiomyopathy.

Cardiac fibrosis is a pathological process characterized by the accumulation of extracellular matrix proteins, such as collagens, within the cardiac muscle. It is a common feature of all types of heart failure and is associated with impaired cardiac function. The degree of cardiac fibrosis in HFpEF is associated with the severity of diastolic dysfunction and is a predictor of adverse clinical outcomes. Therefore, understanding the balance of the formation and degradation of ECM proteins in HFpEF patients is of crucial importance.

Biomarkers for other cardiovascular indications

HFpEF is a subtype of HF in which the patients have an EF above 50%, and it is projected to become the dominant type of HF in the coming years. Clinical manifestations of HFpEF are similar to other types of HF. HFpEF is a complex pathology influenced by the severity of comorbidities such as diabetes, obesity, and hypertension. HFpEF is greatly affected by cardiac fibrosis induced by extrinsic factors such as diabetes and hypertension. Cardiac fibrosis, in combination with other processes significantly contributes to HFpEF pathogenesis.

How many suffer from heart failure and heart failure with preserved ejection fraction?

According to recent reports, 26 million people live with heart failure worldwide. In the United States, heart failure affects approximately 6.2 million adults and is the leading cause of hospitalization among people over the age of 65. Similarly, in Europe, an estimated 15 million people are affected by heart failure, with heart failure being the leading cause of hospitalization in people over the age of 65 in the European Union. In both US and Europe, approximately 50% of HF patients have heart failure with preserved ejection fraction (HFpEF).

How is heart failure with preserved ejection fraction diagnosed?

Heart failure with preserved ejection fraction (HFpEF) is diagnosed through a thorough evaluation that involves a medical history, physical examination, and various tests, such as electrocardiogram, echocardiogram, and cardiopulmonary exercise testing. EF and end-diastolic volume are assessed. In addition to these diagnostic tools, circulating biomarkers that indicate the presence and severity of heart failure may also be used. Common biomarkers for HFpEF include brain natriuretic peptide (BNP) and N-terminal pro-brain natriuretic peptide (NT-proBNP). In case of uncertainty and to establish etiology, the patient is referred to further testing such as echocardiographic testing (diastolic stress test), hemodynamic measurements, cardiac MRI, and genetic testing.

How is heart failure with preserved ejection fraction treated?

Treatment for HFpEF typically involves managing the underlying conditions that contribute to the development of heart failure, such as hypertension, diabetes, and obesity, through lifestyle changes and medications. For symptom management, various medications may be prescribed, such as diuretics, beta-blockers, ACE inhibitors, or angiotensin receptor blockers (ARBs). According to the American College of Cardiology, several studies have explored the benefit of mineralocorticoid receptor agonists, such as spironolactone, the benefit of angiotensin receptor neprilysin inhibitors (ARNi), such as sacubitril-valsartan and more recently, the benefit of sodium-glucose cotransport-2 inhibitors (SGLT2i) such as empagliflozin and dapagliflozin, showing promising results in the reduction of risk of HF hospitalization or composite CV death. Current treatments focus on improving symptoms and quality of life, reducing the risk of complications, and addressing the underlying conditions that contribute to the development of heart failure. Still, no anti-fibrotic treatment has yet been approved for the treatment of HF.

The applications presented here are for research use only.

Please don't hesitate to contact us if you have any questions or other inquiries.

Are you interested in learning more about Nordic Bioscience?
Enter your information in the form and a representative will contact you shortly.

By submitting this form you agree to our terms and conditions.