4.4. Is atrial fibrillation a mechanism or a bystander in heart failure?

AF and HFpEF are vicious twins. Both AF and HFpEF are increasing in prevalence. Patients with AF and HFpEF are heterogeneous and share clinical risk factors, like hypertension, diabetes and obesity. These factors are linked, both to each other and to adverse cardiovascular outcomes. AF is an independent prognostic factor in patients with HFpEF. It is questioned whether it is AF itself that contributes to worse prognosis, or, instead, whether AF is just a bystander being a marker of more severe atrial and ventricular diseases.

There are many unanswered questions about the pathophysiology, risk factors, symptomatology, diagnosis, and prognosis of AF and HFpEF. The diagnosis of HFpEF in AF, however, is challenging because risk factors, symptoms, and natriuretic peptides overlap, and diastolic dysfunction, a hallmark of HFpEF, is difficult to determine in AF. Additionally, treatment is cumbersome. Although it is generally assumed that eliminating AF is associated with improved outcome, so far, however, the trials did not show any benefit of attempts to abolish AF. Recent data, though, demonstrated that in patients with AF and HFpEF a strategy focusing on risk factor management, i.e. optimal therapy of HFpEF, hypertension, diabetes and obesity, instead of antiarrhythmic therapies, was associated with a favourable effect on sinus rhythm maintenance, in addition to risk factor reduction. Therefore, more systematic research is needed to answer these issues and to provide treatments that improve quality of life and reduce adverse outcomes. For that, extensive phenotyping to assess the presence of risk factors using (new) imaging techniques, measures of atrial myopathy, and of diastolic dysfunction, are essential. The central hypothesis of our proposal links AF (progression) with HFpEF (progression), and risk factors. It is our hypothesis that

1. the pathophysiology and prognostic significance of AF depends on severity of risk factors;
2. atrial myopathy develops in association with and as marker of ventricular myopathy;
3. diabetes, hypertension and obesity play a pivotal role as risk factors for atrial and ventricular myopathy; and finally
4. personalized risk factor reduction reduces AF progression, atrial myopathy and severity of HFpEF. AF, thus, is just a bystander being a marker of severity of disease.

1. To link AF (progression) with HFpEF (progression), and (borderline) risk factors including hypertension, diabetes and obesity
2. To show that the pathophysiology and prognostic significance of AF differs depending on severity risk factors.
3. To show that atrial myopathy develops in association with a ventricular myopathy, due to shared mechanisms.
4. To assess the role of personalized risk factor reduction on AF progression, atrial myopathy and severity of HFpEF

A total of 200 patients will be included: 50 patients with early AF and early HFpEF; 50 with early AF and more progressive HFpEF; 50 patients without (a history of) AF and early HFpEF; and 50 patients without (a history of) AF and more progressive HFpEF. An implantable loop recorder is implanted to monitor AF burden and extensive phenotyping at baseline is performed as depicted in the Table.

Blood samples for analysis of biomarkers will be collected at inclusion and at 2.5 years of follow-up. During the course of the study, additional biomarkers of interest can be added to the list of biomarkers including now haemodynamic parameters, inflammation, fibrosis, adipose tissue, hypercoagulability, ischemia, metabolic stress. Echocardiographic image acquisition will be performed to assess atrial and ventricular sizes and function in accordance to the recommendations of the American Society of Echocardiography and European Association of Cardiovascular Imaging. Cardiac catheterization will be done to asses pulmonary wedge pressure as a surrogate measure of the left ventricular end diastolic pressure (LVEDP). Left heart catheterization will be performed to assess the presence of significant coronary artery disease or left-sided valve disease, and LVEDP will be assessed.

1. Personalised risk factor management in AF - review
2. Shared underlying mechanisms of AF (progression), HFpEF (progression), due to shared associated risk factors
3. Pathophysiology and prognostic significance of AF differs depending on severity risk factors.
4. Atrial myopathy develops in association with a ventricular myopathy, due to shared mechanisms.
5. Personalised risk factor reduction has a benefical outcome on AF progression, atrial myopathy and severity of HFpEF
6. Discussion and future perspectives

Extensive phenotyping of patients with AF and HFpEF will more than before reveal which risk factors need attention and therapy. These will differ among patients and contribute to precision medicine In this way, medical decisions and therapies are tailored to the individual patient. We use diagnostic testing to select appropriate and optimal therapies based on the context of a patient’s phenotype including risk factors, blood biomarkers and imaging. In this way interventions are concentrated on those who will benefit, sparing expense and side effects for those who will not.

Disease mechanisms

• Bootsma – immunology
• Bisschof - biomarkers
• Slart - vascular imaging
• Navis – lifestye