University of Groningen Towards improved risk prediction of incident atrial fibrillation and progression of atrial fibrillation Marcos, Ernaldo Gonsalvis

University of Groningen

Towards improved risk prediction of incident atrial fibrillation and progression of atrial

fibrillation

Marcos, Ernaldo Gonsalvis

DOI:

10.33612/diss.136550017

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Publication date:

2020

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Marcos, E. G. (2020). Towards improved risk prediction of incident atrial fibrillation and progression of atrial

fibrillation. Rijksuniversiteit Groningen. https://doi.org/10.33612/diss.136550017

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Chapter 1

Introduction

InTRoduCTIon

Atrial fibrillation (AF) is one of the cardiovascular epidemics of the Western world.

Millions of Europeans suffer from AF and this number will continue to rise during the

next years, mainly due to ageing of the population and lifestyle.

_{Not only is AF the}

most frequent sustained cardiac arrhythmia, AF is not benign. AF is associated with

substantial morbidity and mortality, due to an increased risk of heart failure, stroke,

decreased quality of life, cognitive dysfunction, dementia, and death.

_{Therefore, AF}

has an enormous impact on public health.

The pathophysiologic processes that underlie AF are complex and poorly understood.

Atrial remodeling occurs as a consequence of multiple interacting mechanisms

trig-gered by underlying conditions such as hypertension, heart failure, valvular disease,

chronic kidney disease and/or diabetes, but also as a consequence of AF itself (AF begets

AF).

_{Due to progressive remodeling it is challenging to maintain sinus rhythm in the}

long term. Progression of AF to more sustained forms of the disease is deleterious, since

it is associated with significant cardiovascular morbidity, increased hospitalizations and

mortality, among others due to heart failure, stroke, or myocardial infarction.

Multiple interacting mechanisms, including electrical remodeling and continuous

structural remodeling of the atria are thought to play a key role in the pathophysiologic

processes that set the stage for AF and AF progression.

_{The process of remodeling}

is marked by activation of renin-angiotensin-aldosterone system, cellular calcium

overload, increased release of endothelin-1, heath shock proteins, natriuretic peptides,

adipokines, and inflammation and oxidative stress, leading to structural remodeling

as a consequence of fibrosis, cellular hypertrophy, dedifferentiation, fatty infiltration,

apoptosis and myolysis, and enlarged atria (Figure 1).

_{Structural remodeling results in}

electrical dissociation of the cardiac muscle bundles and local conduction

heterogene-ities, which helps to the initiation and perpetuation of AF.

_This

electro-anatom-ical substrate allows multiple small re-entry circuits to occur, leading to stabilization of

AF. The process of remodeling is initiated by underlying conditions long before the first

episode of AF occurs (Figure 2).

_{Once AF is present, the remodeling processes in the}

atria progress further to constitute a vicious circle.

Risk markers for incident atrial fibrillation

The amount of risk factors that are identified to be associated with an increased AF risk

is growing and varies over time.

_{It is important to distinguish between non-modifiable}

risk factors, such as advancing age, sex, and genetic and ethnic background, and

modifiable risk factors, because of the possibility to interfere in these modifiable risk

12

factors creating a window for new treatment strategies (

table 1).

_{Moreover, there}

are important diff erences between men and women as women with AF are in general

Figure 1. Hypothetical scheme of stretch induced by hypertension, heart failure and possibly extreme

endurance exercise leading to calcium overload, activation of the renin–angiotensin–aldosterone system (RAAS) and release of diff erent factors, resulting in structural remodeling and finally in AF. Reprinted with permission from de Jong et al.16

Figure 2. Time-dependent atrial remodeling and development of atrial fibrillation. Adapted from Cosio et

older, have a higher prevalence of hypertension, valvular heart disease and HF-PEF.

Modifiable risk factors include hypertension, heart failure with preserved and reduced

ejection fraction, diabetes mellitus, chronic kidney disease, obesity, lifestyle including

excessive alcohol consumption, smoking, caffeine consumption, drug use, psychosocial

factors, air pollution, (sub)clinical hyperthyroidism, (sub)clinical vascular disease,

valvular disease, cholesterol levels, length, a high normal blood pressure,

inflamma-tory diseases, and chronic kidney disease (table 1).

_{Of these associated diseases,}

among others hypertension, heart failure and obesity, cause atrial stretch, leading to

calcium overload, activation of RAAS, inflammation and oxidative stress and release of

several other factors, which cause structural remodeling setting the stage for AF (

Figure

1).

_{Once AF eventually occurs, AF itself also increases the risk for AF to occur (}

_Figure

2). A vicious circle is born.

Assessment of remodeling of the atrium

The severity of structural remodeling and subsequent substrate for initiation and

progression of AF is time dependent and is influenced by the normal aging process as

well as underlying conditions.

_{Assessing the severity of atrial remodeling is difficult}

and challenging, but it is necessary to improve personalized AF therapy and ideally

subsequently improve outcome. In addition, blood biomarkers may help to identify

the severity of atrial remodeling and the patients at risk for incident AF.

_{Yet, limited}

Table 1. Risk factors associated with development of atrial fibrillation. Adapted from Wyse et al.22

Established risk factors new and less validated risk factors

Advancing age Subclinical atherosclerosis

Male Borderline hypertension

Coronary heart disease Chronic kidney disease

Hypertension (above 140/90mmHg) Subclinical hyperthyroidism

Heart failure Inflammatory diseases

Valvular heart disease Widened pulse pressure

Diabetes Mellitus Excessive exercise/endurance training

Hyperthyroidism Excessive alcohol intake

Obstructive sleep apnea syndrome Length

Heart failure with preserved ejection fraction Increased birth weight

Chronic obstructive pulmonary disease Smoking

Left atrial function/dilatation Excessive caffeine intake

Obesity Ethnicity

Atrial conduction delay/ PR interval Psychological determinants

Left ventricular hypertrophy Genetic factors/ familial predisposition

14

data is available but AF progression has been associated with higher levels of fibrotic

and inflammatory markers, such as transforming growth factor β1.

_{Further, through}

measuring small-molecule metabolites in various biological systems, metabolomics

may offer the potential for including metabolic pathways responsible for the initiation

and progression of AF linking several exposures like dietary intake and the microbiota

with cardiometabolic traits.

_{Quantification of atrial fibrosis may be possible with}

late gadolinium enhancement magnetic resonance imaging. However, it is so far only

done by limited centers since this technique still is challenging.

_{Therefore, clinical}

and echocardiographic are predominantly used to evaluate the extent of the atrial

substrate in clinical practice. For years electrocardiographic (ECG) parameters have

been used to predict incident AF, with P-wave duration and PR-interval being the most

frequently studied parameters.

_{A longer P wave duration predicted incident AF in}

previously undiagnosed patients but unfortunately did not add predictive power over

clinical parameters associated with AF development.

_{The P wave duration is a}

sur-rogate parameter for the total atrial activation time. Prolongation of the P wave duration

and PR-interval indicate a global conduction slowing and can be assessed by measuring

the total atrial conduction time (TACT).

_{This may be an additional tool to assess the}

severity of atrial remodeling. TACT is measured by using 12-lead electrocardiogram and

Tissue Doppler Imaging (TDI) in the 4-chamber view and defined as the interval of time

from initiation of the ECG P-wave (lead II) until the peak of the local lateral left atrial

Tis-sue Doppler imaging (TDI). Recent development in the noninvasive surface

electrocar-diographic mapping and computers processing have made it possible to noninvasively

map atrial activation.

_{This technique may help to assess P-wave parameters looking}

at irregularities within the P-wave or at alternative lead positions, and may detect subtle

regional conduction disturbances further contributing to the quantification of the

sever-ity of atrial remodeling.

_{Another possibility to assess severity of atrial remodeling}

is measuring the left atrial function.

_{The contraction of the left atrium can be divided}

in three functional phases: reservoir, conduit and active atrial contraction function.

Those three phases of atrial contraction can be measured mechanically by strain. This

is a 2-dimensional speckle tracking echocardiography that measures the deformation

of the atrial myocardium

(Figure 3a).

_{Further, a volumetric assessment of the atrium}

can also be useful in providing information about the atrial function

(Figure 3b). The

atrial volumetric assessment can be obtained from atrial volume at his maximum (just

before mitral valve opens), at his minimum (when mitral valves close) and immediately

before atrial contraction (before electrocardiographic P-wave). This can be used for the

calculation of the atrial total, passive and active ejection.

Figure 3a. 2-dimensional speckle tracking echocardiography that measures the deformation of the atrial

myocardium.

16

Risk markers for progression of atrial fibrillation.

Risk markers associated with progression of AF are less well studied but likely include

comparable markers as for incident AF. The HATCH score, which stands for

hyperten-sion, age >75 years, stroke or transient ischemic attack (2 points), chronic obstructive

pulmonary disease and heart failure (2 points), is currently the only risk-score to predict

progression of AF.

_{For example, patients with a low HATCH score of 1 already had 10%}

progression rate a year (from paroxysmal to persistent AF). In validation cohorts, the

HATCH score has shown only to have modest predictive value of AF progression with a

C-statistic of 0.6 and 0.62, respectively.

_{This indicates that the current risk-stratification}

for AF progression is far from optimal. This low c-statistic may be attenuated by the

com-plex process of AF progression in which often subclinical cardiovascular diseases, such as

borderline hypertension and subclinical coronary or peripheral artery disease will have

an influence in the course of the disease.

_{Besides the clinical factors incorporated}

in the HATCH score, different blood biomarkers are associated with atrial remodeling

and could potential refine the risk scores. Inflammatory biomarkers (high-sensitivity

C-reactive protein, interleukin 6, tumor necrosis alpha, adiponectin, transforming growth

factor beta) and fibrotic biomarkers (procollagen, procollagen type I carboxy-terminal

propeptide, I collagen telopeptide, connective tissue growth factor, matrix

metallopro-teinase-9) have been associated with atrial remodeling.

_{For clinical practice, it is}

interesting to predict AF progression (as longer duration of AF is associated with failure

of rhythm control therapy) as this may affect the individual treatment strategy.

AIM oF ThIs ThEsIs

This thesis focuses on the risk markers for incident AF and progression of AF. In

chapter

2 we assess the relation of renal dysfunction with incident AF and the association with

cardiovascular morbidity and mortality by using the Prevention of Renal and Vascular

End-stage Disease (PREVEND) study. In

chapter 3 we evaluate metabolic profiling in the

relation to new-onset AF in the Framingham Heart Study. In

chapter 4 we continue to

search for a new technique assessing the severity of the atrial remodeling using body

surface mapping to assess p-wave complexity. In

chapter 5, 6 and 7 we focus on AF

progression. In

Chapter 5 we focus on the incidence and risk factors of AF progression

in a population with young onset AF.

Chapter 6 the incidence and clinical and

echo-cardiographic factors and blood biomarkers associated with AF progression in patients

with a short history of AF is investigated.

Chapter 7 focuses on sex differences in clinical

profile, AF progression incidence and risk factors. Finally, in

chapter 8 the thesis will be

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