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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1
General introduction and
outline of the thesis
Mariëlle Kloosterman
“When the pulse is irregular and tremulous and the beats occur at intervals, then the impulse of life fades.’’ - Huang Di Nei Jing Su Wen, Yellow emperor of China, third
RIsInG PRevAlenCe oF ATRIAl FIBRIllATIon
Atrial fibrillation (AF) is the most common sustained arrhythmia and its prevalence is rising.1-5 Due to improvements in medical treatments and interventions patients
experi-ence increased longevity. This causes the risk of age-related diseases, such as AF, to grow. Recent studies, including the European BiomarCaRE consortium and Framing-ham study, estimate that the lifetime risk of AF in individuals from European ancestry has increased from ~1 in 4 to ~1 in 3 by age 90 years.1-5 It is estimated that by 2060 there
will be almost 18 million patients with AF in the European Union, of which more than half a million in the Netherlands.6 This poses a tremendous burden on health care
provi-sion and expenditure, with AF costs totaling well over €550 million in the Netherlands alone.7,8
Especially the prevalence of elderly patients with AF will increase in the coming four decades (Figure 1A). This is problematic since AF is associated with increased risk of adverse diseases and events, including among others, heart failure, stroke, myocardial infarction, dementia, and death.7,9 These adverse events frequently occur in the older
AF patient (Figure 1B). AF diminishes the survival advantage typically observed in wom-en.10,11 The increased risk of death is even the most frequent observed adverse event in
newly diagnosed patients and linked to (worsening) risk factors.12 Early, comprehensive,
and aggressive treatment of these underlying risk factors might offer a solution.
RIsK FACToRs
The genesis and evolution of AF is complex and involves many, still incompletely under-stood, mechanisms. We know that several modifiable and non-modifiable risk factors promote the development and maintenance of AF. In almost all cases risk factors are present, making AF without underlying risk factors extremely rare.13 Advancing age is
the key non-modifiable risk factor for AF, others include male sex, length, and genetic factors with currently 97 genome-wide susceptibility loci for AF identified in individuals of European ancestry.14-17 Modifiable risk factors for AF include hypertension, coronary
artery disease, heart failure, obesity, diabetes, and valvular disease, just to name a few.18,19 Subclinical or less-established risk factors, such as borderline hypertension,
chronic kidney disease, and sleep apnea syndrome, are gaining more attention.14,20
Electrical and structural remodeling of the atria is central in the disease process and heavily influenced by the normal ageing process21, the abovementioned risk factors,
a role in inducing a unique atrial substrate that is characterized by atrial enlargement and conduction heterogeneity due to molecular and cellular changes, inflammation, fibrosis, fatty infiltration and atherosclerosis, making AF the manifestation of multiple pathophysiological pathways.22,23
Figure 1. Rising prevalence and adverse outcomes in elderly patients with AF
Panel A: Expected number (millions) of elderly patients with AF in the European Union in the coming four decades. Estimates are for the age categories >65 years (red), >75 years (grey), and >80 years (blue). Panel B: Cumulative incidence (%) of events in the 5-years after diagnosis of incident AF in elderly Medi-care patients (average age 79.5±7.3 years).7 Reprinted from Kloosterman et al.
Often patients have multiple risk factors, making multimorbidity a common occurrence in clinical practice.25 Prevalence of risk factors gradually increases when age rises and
lifetime risk of AF increases with this increased risk factor burden (Figure 2).20,26 In
pa-tients with an optimal risk factor profile, defined as never smoker, 14 or less units of alcohol per week for men and 7 or less for women, a body mass index (BMI) below 25, no hypertension, no diabetes, and no history of heart failure or myocardial infarction, the lifetime risk of AF is estimated to be around ~25%. Patients with the highest risk factor burden defined as current smokers with an alcohol consumption of >14 units of alcohol per week for men and >7 units for women, a BMI of ≥30, hypertension, diabetes, and a history of heart failure or myocardial infarction have a ~38% lifetime risk of AF.26
Figure 2. AF substrate
AF is a complex, multifactorial, progressive disease with a substrate that is influenced by the normal age-ing process (age-induced remodelage-ing, grey), the underlyage-ing cardiovascular (CV) risk factors (CV disease-induced remodeling, red), and the arrhythmia itself (AF-disease-induced remodeling, blue). The normal ageing process and lifetime accumulation of risk factors will decrease patients’ resilience against AF. In the case of an optimal risk factor profile*, the lifetime risk for AF is around ~25%, in case of a high risk factor bur-den* this increases to around ~38%.26
*For a definition of the risk factor profiles see paragraph ‘’risk factors’’. AF, atrial fibrillation; CV, cardiovascular.
All in all AF is a complex, multifactorial, progressive disease, with an individually unique atrial substrate that may differ depending on the genetics, risk factors, sex, and other elements.16,17,27,28
seX DIFFeRenCes
AF plagues both women and men, but not in the same manner. Women are generally underrepresented in trials, but data on sex-specific differences in AF is accumulating, and in the recent years it has come to light that sex differences exist in all facets of
the disease: from incidence, risk factors, and clinical presentation, to treatment and outcomes (Figure 3).29
Figure 3. Women experience differences in all facets of AF
Sex differences exists in all facets of AF, from epidemiology, clinical presentation and risk factors, to treat-ment and outcomes. AF, atrial fibrillation.
Women and men have a similar cumulative lifetime risk of AF but are generally older when AF is diagnosed, resulting in a lower age-adjusted incidence and prevalence.30
Women frequently have more AF risk factors (including hypertension, valvular disease, and heart failure with preserved ejection fraction), experience a higher symptom burden than men, and have a lower quality of life.31 Women are often treated with
a more conservative approach based on rate control, and there is a tendency that women receive more calcium channel blockers and digoxin than men.30,32 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.33,34 Part of this
increased susceptibility can be explained by electrophysiology differences in corrected QT intervals.35,36 But sex differences in pharmacodynamics and pharmacokinetics likely
also play an important role and contribute to differences in optimal doses of cardiovas-cular medications for women and men.37
Sex hormones also play a role, but the exact mechanisms and extent of their influ-ence, remain incompletely understood.38 Women are also less likely to be referred for
catheter ablation and are older when they do receive the procedure.39-41 Results of the
ablation tend to be less favorable, and procedure-related complications are more often observed in women, possibly associated with the older age at the time of ablation.41-43
Crude stroke rates are higher in women than in men. But whether this is because female sex has considerable interactions with age and other risk factors, or whether female sex is truly an independent risk factor remains topic of debate, especially in younger age
groups or in the absence of risk factors.29,44 Furthermore, AF-related mortality in women
is higher.11
ConCoMITAnT HeART FAIlURe
Heart failure has a high prevalence in patients with AF, with reported rates ranging from ~20% to ~70%; prevalence increases as the arrhythmia becomes more permanent.45,46
Vice versa all types of heart failure: reduced- (HFrEF), mid-range- (HFmrEF), and preserved ejection fraction (HFpEF), experience an increased risk of AF and reported prevalence is increasing. In the CHARM study (Candesartan in Heart failure-Assessment of Reduction in Mortality and morbidity) prevalence of AF was 19% in HFpEF and 17% in HFrEF.47 The Framingham Heart Study reported slightly over 20% in both HFpEF
and HFrEF.48 Medicare claim analyses report 48% AF in HFpEF and 44% in HFrEF.49 Two
recent studies highlight the extremely high burden of AF, especially in HFpEF and older patients with prevalence rates of 39-65% in HFpEF, 29-60% in HFmrEF, and 27-53% in HFrEF.50,51
When viewed as separate entities AF and heart failure are already complex clinical syndromes, but when occurring together, especially AF and HFpEF, they pose one of the most challenging conditions to date. Both conditions share risk factors and can pre-dispose to each other, but exact pathophysiological mechanisms remain unclear and
Figure 4. AF and heart failure
AF and heart failure are inextricably linked. They share many risk factors and can predispose to each other. Depicted are some mechanistic hypotheses (dotted lines) but exact pathophysiological mechanisms are unclear and untangling cause and effect remains difficult.
a direct cause and effect paradigm is too simplistic (Figure 4).52 The epidemiological,
clinical and mechanistic parallelisms between AF and HFpEF support the hypothesis that both conditions may be the manifestation of similar underlying myocardial dis-ease; an atrial and ventricular cardiomyopathy triggering a systemic manifestation of inflammation, metabolic disarray, and microvascular dysfunction and fibrosis with an important role for epicardial adipose tissue.53
In clinical practice affected patients are often the elderly with a significant risk factor burden.54 Regardless of which condition occurs first, the combination of AF and heart
failure heralds a worse prognosis than when either condition occurs alone.55,56 Generally
patients with AF have an almost 5-fold increased risk of heart failure9, and while stroke is
historically the most feared complication of AF, heart failure causes two to three times as many deaths in patients with AF.55 In patients with congestive heart failure who develop
AF mortality rates double, while in patients with AF the development of congestive heart failure triples mortality.56 In the last few years there have been several conflicting
studies and meta-analyses on mortality rates in HFrEF versus HFpEF patients with AF, but overall mortality risk seems at least as high, if not higher in patients with HFpEF and AF compared to patients with HFrEF and AF.50,51,57-60
Potential role for genetics and biomarkers
While the prevalence of combined heart failure and AF is high, some patients with AF will never develop heart failure, and some patients with heart failure will never develop AF. Gene polymorphisms, genetic risk scores, and blood biomarkers may improve our understanding of how, and in whom, AF develops.61 Genetics may point towards
devel-opmental factors and molecular mechanisms of the arrhythmia, and blood biomarkers, although often not specific to just atrial myocardial disease, may provide insight into the pathophysiological mechanisms and specific pathways involved in disease develop-ment and progression.62 Assessing a combination of these alterations could
character-ize different AF populations, which ultimately could help to personalcharacter-ize management.
AIMs oF THe THesIs
AF encompasses so much more than just an irregular heart rhythm and is one of the major chronic conditions and challenges in modern cardiology. More insight into some key factors may provide the first steps in improving AF care for the individual patient. This requires stepping away from a single-disease framework and creating more awareness of: the multimorbidity that plagues AF patients, including subclinical and less-established risk factors; knowledge of sex differences in risk factor profiles,
treat-ment (utilization) and outcome; and elucidation of genetic risk and biomarker profiles of AF patients with concomitant HFrEF or HFpEF as a first step towards risk stratification and potentially novel therapeutic targets by gaining more insights into the underlying pathophysiological mechanisms.
This thesis aims to better characterize these multifaceted aspects of AF and consists of sub-analyses from several large (inter)national studies. In Chapter 2 we studied prevalence, patient characteristics, and outcomes of AF patients without traditional risk factors in the RE-LY AF registry, a study that included 15400 patients with AF from emergency departments in 47 countries worldwide. In Chapter 3 we assessed sex dif-ferences in risk factors, outcome and quality of life in elderly patients with permanent AF enrolled in the Rate Control Efficacy in Permanent AF: A Comparison between Lenient versus Strict Rate Control II (RACE II) study. RACE II recruited patients from 33 centers in the Netherlands. In Chapter 4 we assessed sex differences in patients undergoing first-time catheter ablation under continuous anticoagulation in The Anticoagulation using the direct factor Xa inhibitor apixaban during Atrial Fibrillation catheter Abla-tion: comparison to vitamin K antagonist therapy (AXAFA-AFNET 5) study. The trial was conducted in 48 sites in Europe and North America. In Chapter 5 we studied the association between a genetic risk score based on 97 single nucleotide polymorphism with prevalent AF and all-cause mortality. For this we used a large sample of patients with heart failure included in The BIOlogy Study to Tailored Treatment in Chronic Heart Failure (BIOSTAT-CHF) study, consisting of an index cohort that enrolled patients from 11 European countries, as well as a validation cohort from Scotland. In Chapter 6 we studied blood biomarker profiles, consisting of 92 cardiovascular risk markers, compar-ing sinus rhythm and AF in heart failure patients from BIOSTAT-CHF with reduced and preserved ejection fraction.
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