Improved heart failure care organization including studies of diagnosis, risk prediction and biomarkers in heart failure with preserved ejection fraction

Background: Heart failure (HF) is a prevalent condition with low quality of life, high morbidity and mortality, and high societal costs. HF can be divided according to left ventricular ejection fraction (EF) into HF with reduced (HFrEF) or preserved EF (HFpEF). Diagnosis of HFpEF is more complex than for HFrEF. Evidence-based treatment is well defined for HFrEF, but not proven for HFpEF. Therapy implementation in HF is poor and better organization of HF care could impact therapy and outcome. Biomarkers may fill knowledge gaps in the pathogenesis of HFpEF, and potentially be used to discriminate between HFpEF and HFrEF.

Aims: To study 1) prevalence and prognostic importance of diagnostic echocardiographic variables in patients with suspected HFpEF, 2) effects of introducing a comprehensive HF care program in a large urban region, 3) circulating extracellular vesicles (EVs) as biomarkers in HF. 4) if biomarkers for myocardial fibrosis and inflammation differ between HFpEF and HFrEF.

Methods and results: Paper I. HFpEF patients (n=356) were included after a presentation with acute HF, clinical signs of HF, elevated natriuretic peptides and LVEF ≥45%, and studied for long term outcome. Diagnosis of HFpEF was assessed according to the 2016 ESC (European Society of Cardiology) Guidelines and confirmed in 76-94% of patients. We identified two independent predictors of prognosis: moderate or severe diastolic dysfunction, or ≥4 abnormal diastolic echocardiographic variables (both p <.01).

Paper II. A standardized program (4D HF) for optimization of HF management was implemented in Stockholm County 2012-2017. Yearly visits to the HF clinics increased 3.4 times from 3,372 to 11,527, and dispensed evidence-based HF medications increased (p<.0001). These effects were associated with lower numbers of admitted HF patients (n=35,880; decrease by 13-20%/106 inhabitants; p <.0001) and lower adjusted 1-year all-cause mortality or HF readmissions (HR 0.98 per year, CI 0.97-0.99, p <.0001).

Paper III. Patients undergoing elective coronary artery bypass graft surgery (n=81) were included and divided in three groups: HFpEF, HFrEF and Normal LV function. Blood samples from coronary sinus, radial artery, and right atrium were analysed for extracellular vesicles (EVs) in plasma. EVs coexposing Connexin-43 and Caveolin-3, or Connexin-43 and Troponin T showed significant transcoronary concentration gradients, with the highest levels in HFrEF patients. EV levels correlated with various HF related variables. Further studies should be performed to assess EVs as biomarkers in HF.

Paper IV. Patients with new-onset HF (n=247) were divided into HFpEF and HFrEF. Blood samples were analysed for biomarkers of fibrosis and inflammation. In HFpEF, collagen degradation (CITP), and inflammation (VCAM-1) were increased, and collagen cross-linking (CITP:MMP-1 ratio) reduced compared to HFrEF (p <.05). CITP was an independent discriminator of HFpEF vs HFrEF (OR 1.15 CI 1.03 - 1.28).

Conclusions: The use of 2016 ESC HF guidelines for diagnosis and risk prediction in HFpEF is strongly supported. Implementation of a Guideline-based HF management program is associated with improved health care quality and patient outcome. New biomarkers such as EVs originating from the myocardium, and markers of fibrosis and collagen degradation revealed differences between HFpEF and HFrEF which should be further explored

List of scientific papers

I. Persson H, Donal E, Lund LH, Matan D, Oger E, Hage C, Daubert JC, Linde C; KaRen Investigators. Importance of structural heart disease and diastolic dysfunction in heart failure with preserved ejection fraction assessed according to the ESC guidelines - a sub study in the Ka (Karolinska) Ren (Rennes) study. Int J Cardiol. 2019 Jan 1; 274:202-207.
https://doi.org/10.1016/j.ijcard.2018.06.078

II. Matan D, Löfström U, Corovic Cabrera C, Eriksson B.L, Ekström M, Hage C, Ljunggren G, Lyngå P, Wallén H, Malmqvist K, Linde C, Persson H. Reorganization of heart failure management and improved outcome – the 4D HF Project. Scand Cardiovasc J. 2020 Sep 24:1-8.
https://doi.org/10.1080/14017431.2020.1820075

III. Matan D, Mobarrez F, Corbascio M, Ekström M, Hage C., Lyngå P, Eriksson M. J, Persson B, Linde C, Persson H, Wallén H. Extracellular vesicles as biomarkers in heart failure - a study in patients with HFpEF or HFrEF characteristics undergoing coronary artery bypass grafting. [Manuscript]

IV. Matan D, Löfsjögård J, Ekström M, López B, Diez J, Kahan T, Linde C, Wallén H, Persson H. Circulating biomarkers for myocardial fibrosis in new onset heart failure in relation to preserved or reduced ejection fraction: Results from a pre-specified interim analysis of the PREFERS study. [Manuscript]