University of Groningen
Characterization of Different Patient Populations with Atrial Fibrillation
Kloosterman, Mariëlle
DOI:
10.33612/diss.143841478
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2020
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Kloosterman, M. (2020). Characterization of Different Patient Populations with Atrial Fibrillation. University
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7
General discussion and future
perspectives
Atrial fibrillation (AF) is a chronic, complex, highly prevalent disease with significant morbidity and no cure. More insight into the multifaceted aspects of this arrhythmia is needed. The general aim of this thesis was to better characterize patient populations with AF, focusing on underlying risk factors, sex differences, and concomitant heart failure. This was done by studying a variety of patient populations from several large (inter)national trials. In Chapter 2 we showed that almost all patients who present to the emergency department without traditionally-defined AF risk factors have less-established or borderline risk factors; these risk factor profiles differ across the world. In Chapter 3 we showed that women with permanent AF receiving rate control expe-rience more accumulation of risk factors than men. These risk factors are associated with a worse outcome and may (partially) drive the differences observed between the sexes, including the lower quality of life in women, especially in the physical domains. In Chapter 4 we showed that there were no major sex-differences in terms of efficacy and safety of first-time catheter ablation for AF under continuous anticoagulation. The gain in quality of life and cognitive function after ablation is similar between the sexes, although overall quality of life remains lower in women. In Chapter 5 we showed that an AF genetic risk score, based on the 97 currently known single nucleotide polymor-phisms (SNPs) associated with AF in patients from European ancestry, is associated with AF prevalence in patients with heart failure. Genetic variation accounted for 22.9% of overall AF SNP-heritability. Finally, in Chapter 6 we showed that in patients with heart failure with reduced ejection fraction (HFrEF), the presence of AF was associated with a homogeneously elevated blood biomarker profile, while in patients with heart failure with preserved ejection fraction (HFpEF) and AF a more scattered blood marker profile was observed. This may point towards differences in underlying pathophysiological pathways of AF in these heart failure phenotypes.
The heterogeneity of the clinical population of patients with AF, ranging from differ-ences in risk factors, treatment, and concomitant cardiovascular diseases like heart failure, make research challenging. It remains hard to distinguish if observed differences are an effect of the condition, associated treatment, inherent (sex-specific) patient char-acteristics or other factors. Nonetheless, our findings show that attempting to better characterize patient populations can provide valuable insights.
PART I - RIsK FACToRs AnD seX DIFFeRenCes
Risk factors
In all studied populations in this thesis, whether relatively young patients presenting to the emergency department with AF (average age 46 years), patients undergoing
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first-time AF catheter ablation (average age 64 years), patients with permanent AF (average age 68), or patients with AF and heart failure (average age 75), a multitude of different risk factors was present. In Chapter 2 we have shown that even in the absence of traditional AF risk factors, sub-clinical or less established risk factors are present in practically all patients, emphasizing that the term ‘’lone AF’’ should be avoided.1
Furthermore, we have shown that risk factor profiles may vary between geographic regions. Additionally, women accumulate more risk factors when they age than men (Chapter 3). Based on data from YOUNG-AF2 and RACE II3, no sex differences exist in
the number of risk factors in young patients (average age 46±9) included in YOUNG-AF. However, in the older RACE II population (average age 68±8) women had significantly more risk factors than men, including hypertension, HFpEF, kidney dysfunction, and mitral regurgitation (Figure 1) (Chapter 3). This higher prevalence of multimorbidity in older women is consistently observed in the literature,4-7 and worrisome since risk of
AF, hospitalization, and death in patients with AF is strongly associated with the level of multimorbidity.8-11 Timely identification of these modifiable risk factors and targeted
therapy may improve cardiovascular outcomes.12-15 Given the complexity of AF
man-agement and the heterogeneity of patients’ risk factor profiles, providing AF care by a multidisciplinary team in specialized AF clinics is recommended.10,16-19
sex differences in treatment and quality of life
Important sex-specific disparities exist in rate- and rhythm control strategies in women and men (Chapter 3, Chapter 4). There is a tendency to treat women more conserva-tively with a rate-control approach, despite their higher symptom burden and lower
Figure 1. Accumulation of risk factors in elderly women - data from YoUnG-AF and RACe II
Depicted is the prevalence (%, y-axis) of risk factors in young patients from the YOUNG-AF cohort2 (pink = women; light blue = men) and elderly patients from RACE II3 (red = women; blue = men). In the younger patients with AF, only familiar AF and obesity occur more frequently in women, while coronary artery dis-ease is more prevalent in men (*). The average number of risk factors does not differ between women and men. In the older RACE II population women have significantly more risk factors, including hypertension, heart failure, kidney dysfunction, and mitral regurgitation (**). Older men continue to have more coronary artery disease (**).
quality of life.20 This overall lower quality of life in women with AF, especially in the
physical domains21, is more strongly associated with the higher risk factor burden in
women than in men (Chapter 3).22 When they do receive antiarrhythmic drugs women
have an increased risk to suffer from brady- and tachyarrythmias, especially sick sinus syndrome and Torsades de Pointes. Catheter ablation for AF is also less often performed in women.23-26 When women do receive catheter ablation they are on average ~5 years
older, had a longer duration of the arrhythmia and accumulated more risk factors. These high risk features may partially explain the higher risk of peri-procedural complications and AF recurrences in women that are observed in some studies.27-30
In Chapter 4, we showed that women and men included in the AXAFA-AFNET 5 study experienced uniform benefit in terms of effectiveness in maintaining short-term sinus rhythm, increase in quality of life and cognitive function as assessed by the Montreal Cognitive Assessment (MoCA) test. Importantly, no major differences regarding safety were observed with the exception of slightly more nonfatal minor bleeding events. The fact that women can achieve similar results as men is an important reason to offer this therapy to women, especially since women, with their higher symptom burden and lower overall quality of life have potentially the most to gain from a successful ablation. Evolving ablation techniques with new tools and energy sources, magnetic resonance imaging-guided substrate modification, and intracardiac echocardiography and ultra-sound guidance may in the future further reduce complications, improve success, and completely eliminate any difference in complication rates between women and men.31
Attention for sex differences
Bias in medicine is a serious issue and while it is not the only factor in determining health outcomes, it can have a massive effect. Historically medicine has studied men’s bodies as a proxy for all. This has led to some women shaped blind spots in medicine. Sex differences deserve more attention, not in the least to describe and define their role so that our evaluation and treatment of patients incorporates sex differences if necessary.20
This requires ensuring adequate representation of women in future clinical trials and sex-specific analyses in the design of impending studies to study the similarities and differences between women and men. Understanding the biological and socio-cultural reasons for sex-specific differences may offer opportunities to help reduce the global burden of AF by allowing better clinical management of the whole patient population, women included.20
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PART II - ConCoMITAnT HeART FAIlURe
The overall life-time risk of heart failure is ~20%.32-35 As the burden of risk factors has
increased over the past decades, so has the combined presence of AF and heart failure. In patients with HFpEF up to two-thirds may develop AF at any time.36-39 A combination
that results in a substantial risk of hospitalization and mortality.40-42
In BIOSTAT-CHF 45% of patients with HFpEF had prevalent AF (Chapter 5 and 6). These individuals seem the most vulnerable to the deleterious effects of both condi-tions.43 Presence of both AF and HFpEF increases mortality risk with 80%, compared to
patients without either condition.44 Further, quality of life is most negatively affected
in patients with AF and HFpEF (Chapter 6), especially in women.35,45 But to date no
effective therapies for improving prognosis are available for patients with HFpEF.38,46,47
Patients with HFpEF have a heterogeneous underlying substrate35,48, which likely results
in unique pathophysiological interactions with AF. The scattered blood biomarker profile we described in Chapter 6 supports this hypothesis that AF and HFpEF may be the result of an array of underlying risk factors that trigger multiple pathophysiological pathways. This complex interplay of an underlying genetic AF pre-disposition (Chapter 5), advanced age, and multiple unique pathophysiological mechanisms and physiologi-cal processes driven by risk factors, masks temporal relationships and makes charac-terizing and successfully treating this diverse group of patients so extremely difficult. Our current understanding of the combined ‘’AF-HFpEF syndrome’’ is incomplete and more insights are needed to work towards potential therapeutic targets. Future efforts should be put in understanding the pathophysiology of the two diseases and the role of sex differences to gain insights into the relationships between AF and HFpEF.38 In the
future genetic profiling, together with more insights into the functional consequences of SNPs, may help increase our understanding on why some patients develop AF and others do not, as well as identify potential therapeutic targets for this major health burden (Chapter 5).
FUTURe PeRsPeCTIves
‘’An ounce of prevention is worth a pound of cure’’ - Benjamin Franklin
The constantly increasing number of AF patients, and the associated morbidity and mortality of the disease, requires wide-spread and dedicated research in the years to come. To improve outcome of AF we need to focus our attention on 1) health promotion
and cardiovascular disease prevention; 2) increased understanding of the pathophysiol-ogy of AF, combined with better prediction about which patients will experience AF progression, adverse events and cardiovascular diseases such as heart failure; 3) and better treatment with selected therapeutic targets for the individual patient (precision
medicine) (Figure 2).
Figure 2. Precision medicine for the AF patient
Improving AF management requires attention on 1) health promotion and cardiovascular disease preven-tion; 2) increased understanding of the pathophysiology of AF, combined with better predicting about which patients will experience AF progression, adverse events and cardiovascular diseases such as heart failure; 3) and better treatment response with in-depth characterization, remote monitoring and risk scores allowing selected therapeutic targets for the individual patient (precision medicine).
Lifestyle modifications and addressing AF risk factors have a great, largely untapped, potential for improving AF management and seem paramount in preventing or reduc-ing the burden of AF.49 This starts with primordial prevention, focusing on
154
risk factors.50 When risk factors do develop, primary prevention should be focused
on identifying and treating those (subclinical) AF risk factors, as this may prevent AF development.51,52 Secondary and tertiary prevention should be focused on preventing
AF recurrence and progression, as well as prevent the development of adverse events and cardiovascular diseases. Several studies have shown promising results in terms of reduced AF burden or arrhythmia-free survival, but maintaining a long-term healthy lifestyle remains difficult.53-58 It also seems that these therapies should be implemented
early, since intervention may be futile if patients are too old, risk factors have been present for a long time, and atrial remodeling is too severe.59,60
Knowledge on sex differences (Chapter 3-4), genetic analyses (Chapter 5), blood biomarkers (Chapter 6), imaging, and continuous rhythm monitoring may be helpful to improve assessment of AF risk (progression) and the development of adverse events or cardiovascular diseases. The Reappraisal of Atrial fibrillation: interaction between hy-perCoagulability, Electrical remodelling, and Vascular destabilization in the progression of atrial fibrillation (RACE V study) will hopefully provide more insight into this matter. In the future this may allow in-depth characterization, patient-specific risk scores, and to-gether with remote monitoring, may guide optimal individual patient care that is more effective, and more efficient (Figure 2). Artificial intelligence will help to incorporate and interpret these vast amounts of data with a greater depth than ever before.61
But better characterization can already start today. The risks associated with AF are predominately influenced by clinical risk factors and these risk factors, which are pres-ent in a unique combination in almost every patipres-ent (Chapter 2), will provide opportuni-ties for tailored therapy. Combined with a sex-sensitive approach, that acknowledges and recognizes that differences exist in risk factor profiles and treatment provided to women and men, may allow clinicians to improve the health of the individual patient, as well as the overall patient population (Chapter 3-4). Importantly, risk factor manage-ment should start early, and treatmanage-ments should not be withheld or delayed in women (Chapter 4). Genetic risk scores (Chapter 5), and blood biomarkers (Chapter 6) may provide the first step in understanding how, and in whom, AF develops.
When providing tailored care it is important to realize that therapy goals may differ across age-groups. The elderly patient, who will form a large part of the patient popula-tion in the years to come, will have different goals that include funcpopula-tioning indepen-dently, optimal quality of life, and preventing unnecessary hospitalizations. In the end the success of all treatments will depend on the effectiveness and appropriateness of the intervention at the individual-patient level.
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