Heart failure (HF) is a clinical manifestation induced by several cardiovascular pathologies. It can be characterized by the 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 in 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 that 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 an underlying process in all types of HF. HF commonly develops in patients with previous incidents of MI. MI is characterized by a reparative phase following the event, which leads to an increased deposition of collagen and other ECM proteins in the myocardium.  Cardiac fibrosis, characterized by a dynamic remodeling of extracellular matrix (ECM) proteins (figure 1), plays an important role in HFpEF pathogenesis. Understanding the balance of formation and degradation of ECM proteins in HFs is therefore of crucial importance.

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 manifestation 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 contribute to HFpEF pathogenesis.

How many suffer from heart failure with preserved ejection fraction?
It is estimated that HF affects around 26 million people worldwide and the number of HF patients are projected to increase. Approximately 915.000 new cases are reported annually in the United States, roughly affecting 10 out of 1000 in the population. In Europe, the incidence rate is calculated as approximately 4 out of 1000 being affected by HF. The incidence rate of HFpEF is steadily increasing, and roughly 50% of HF patients have HFpEF.

How is heart failure with preserved ejection fraction diagnosed?
The diagnosis of HFpEF is cumbersome. If HFpEF is suspected in a patient, EF and end-diastolic volume are assessed. If abnormalities are found, the patient is referred to haemodynamic measurements, tissue Doppler and biomarker analysis. Most commonly, HF is diagnosed using chest radiography, electrocardiogram (ECG), measurement of brain natriuretic peptide (BNP)- or N-terminal pro-brain natriuretic peptide (NT-proBNP), or heart catherization. Upon clinical examination, a combination of these diagnostic tools is usually implemented to accurately diagnose the patient. NT-proBNP is to date the best non-invasive biomarker for diagnosis and prognosis in HFpEF patients.

How is heart failure with preserved ejection fraction treated?
Despite numerous attempts and advancement in HFpEF research, no efficient treatment has shown to selectively reduce morbidity and mortality in HFpEF. The current treatment strategy is based on reducing the burden of comorbidities such as obesity, hypertension and diabetes. The most frequently used drugs to manage HFpEF include Angiotensin converting enzyme (ACE) inhibitors, Angiotensin II receptor blockers (ARBs), beta blockers and diuretics. Newer studies have explored the effect of mineralocorticoid receptor agonists, such as Spironolactone, but a consistent reduction in mortality or hospital readmission in HFpEF patients is yet to be demonstrated.

The first step in diagnosing HFpEF is the evaluation of 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 an accurate biomarker in obese 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 not 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 the ECM turnover in HFpEF patients can provide unique insight in structural and functional ECM changes relevant for 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. The Protein FingerprintTM Technology biomarkers may therefore provide an earlier detection of HFpEF.

Several collagens are upregulated in cardiac fibrosis, as the increased levels of biomarkers of collagen formation in patients with cardiac fibrosis show (figure 1).  A biomarker reflecting formation of type VI collagen (PRO-C6), has emerged as a promising biomarker for outcome in HFpEF. PRO-C6 also measures the deleterious signaling molecule endotrophin (released from type VI collagen), which may play a direct role in HFpEF pathogenesis.

In an analysis of a subset of the TOPCAT trial, PRO-C6 significantly predicted risk of mortality and rehospitalization due to heart failure, with greater statistical significance than NT-proBNP and the MAGGIC composite risk score (figure 2).

Higher degradation of titin (TIM) was shown to be significantly associated with a lowered functional capacity in HFpEF patients, and degradation markers of both titin and type I collagen (C1M) were significantly prognostic for risk of readmission in HFpEF patients.

Diagnostic Protein Fingerprint Technology biomarkers for cardiac fibrosis


C3M, C4M, C5M, C6M

Prognostic Protein Fingerprint Technology biomarkers for HFpEF


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