Early detection of left ventricular remodeling
Hendriks, Tom
DOI:
10.33612/diss.144600179
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Publication date: 2020
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Hendriks, T. (2020). Early detection of left ventricular remodeling. University of Groningen. https://doi.org/10.33612/diss.144600179
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Chapter 1.
Introduction
Cardiovascular disease
Cardiovascular disease remains the leading cause of death in developed countries, accounting for roughly 45% of all deaths1. Although treatment for cardiovascular disease steadily improves,
population growth and aging contribute to high mortality rates that have not decreased over the last decade. Of all cardiovascular deaths, ischemic heart disease accounts for 44% and (non-ischemic) heart failure accounts for 9%. To minimize the relentlessly high societal burden of cardiovascular disease in an aging population, the focus in the cardiovascular field should shift towards primary prevention2. An approach to identify individuals at high risk of developing major cardiovascular
disease is to assess cardiac remodeling using imaging modalities such as cardiovascular magnetic resonance imaging (CMR) or transthoracic echocardiography (TTE).
Cardiac structure and function, concepts and terminology
This thesis will study changes in left atrial volume, right ventricular structure and function, with a focus on the left ventricle (LV), arguably the most important chamber of the heart. Although LV structure is complex, consisting of various layers of muscle bands with different orientations3,
structural characteristics of the LV are measured and described in a simple way, using LV end-diastolic volume (LVEDV), LV end-systolic volume (LVESV), and LV mass. To account for interindividual differences due to body size, structural cardiac measurements are generally indexed to body surface area (BSA) using simple division4,5. Indexed values still show great
variation between sexes, ages, and ethnicities, meaning current indexation methods are clearly suboptimal. LV function is twofold; the LV has to allow sufficient blood to enter during the relaxation phase (diastolic function) and has to eject sufficient blood during the contraction phase (systolic function). The most widely used measurement of LV function in clinical practice is LV ejection fraction (LVEF). Indications for pharmacologic therapy for heart failure and treatment with implantable cardioverter defibrillators, as well as discriminations between subtypes of heart failure, are based on thresholds of LVEF6,7. However, the measurement of LVEF has considerable
limitations. Suboptimal axis orientation during imaging assessment affects measurements, high heart rates often results in underestimation of LVEF, and intra- and interobserver variability in measurements is high8. Recently, myocardial strain, defined as the fractional change in the
length of a myocardial segment, emerged as a more sensitive marker of early-stage LV systolic dysfunction8. Myocardial strain can be measured in three dimensions; longitudinally – measuring
longitudinal shortening from the base to the apex of the left ventricle, radially – measuring radial thickening of the myocardium, and circumferentially – measuring circumferential shortening (“twisting”) of the myocardium. These three dimensions correspond with the orientation of muscle fibers, making it a more natural measure of LV function.
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and function. Although CMR is considered the gold standard imaging modality for assessment of cardiac structure and function9, it has its disadvantages in terms of availability, time-consumption,
and costs. 2D TTE is a widely available, bedside, time- and cost-effective alternative for CMR, and the current standard clinical care10. A large bias exists between CMR and 2D TTE in quantification
of LV structure and function measurements11. There are major differences in techniques to
measure myocardial strain between TTE and CMR. TTE makes use of so-called speckle tracking, which uses algorithms to track speckles frame-to-frame throughout the cardiac cycle12. The CMR
variant of speckle tracking is named feature tracking, which tracks tissue motion between the epicardial and endocardial borders using optical flow measures13.
Left ventricular remodeling
Cardiac remodeling is defined by consensus as genome expression, molecular, cellular and interstitial changes to the heart after cardiac injury that are manifested clinically as changes in size, shape and function of the heart14. It precedes the clinical syndrome of heart failure and can be
used to identify individuals at risk15.
Structural LV remodeling, changes in size or shape of the heart, can be measured using parameters
such as LV mass and LVEDV. LV hypertrophy is defined as an absolute increase in LV mass, and arguably the most important finding of cardiac remodeling16. LV hypertrophy has been frequently
associated with adverse outcomes such as heart failure and cardiovascular death17-19. A 4-tiered
classification based on LV mass and LVEDV has been proposed to distinguish between types of remodeling, each associated with a specific phenotype and risk profile17,20. Concentric remodeling
refers to a normal LV mass but a small LVEDV, and therefore an increased LV mass to volume ratio. Concentric hypertrophy refers to an increased absolute LV mass with a normal LVEDV, similarly to concentric remodeling resulting in an increased LV mass to volume ratio. Eccentric hypertrophy is an increased LV mass and LVEDV, which results in a normal LV mass to volume ratio. Eccentric hypertrophy is considered a more physiological type of remodeling, associated with physical activity, and frequently observed in (elite) athletes21.
Different from structural LV remodeling, functional LV remodeling can be evaluated using LVEF
and measures of LV myocardial strain and is a key part of clinical care, e.g. to make indications for pharmacotherapy and implantable cardioverter-defibrillator implantation in heart failure patients7,22. A recent meta-analysis of patients with various cardiovascular diseases revealed that
global longitudinal strain was superior to LVEF in predicting mortality, when using baseline measurements, and also when using changes over time23. In clinical practice however, global
longitudinal strain measurements are not yet widely used, because evidence for treatment is usually based on results from clinical trials that used LVEF measurements to define study groups.
The parameters most suitable to assess diastolic function and diagnostic thresholds for diastolic dysfunction remain a much debated subject24. Parameters such as myocardial tissue relaxation and
ventricular inflow patterns have modest sensitivity and specificity to classify disease severity25,26.
Left ventricular remodeling after myocardial infarction
A typical example of LV remodeling that is well studied is after damage due to myocardial infarction. Typical for remodeling after myocardial infarction is an increase in LV volumes, especially LVESV, and a more spherical LV shape27. Theoretically, dilatation can be beneficial
by maintaining stroke volume through the Frank-Starling mechanism. However, LV dilatation increases wall stress and extends the burden on the remaining myocytes, leading to subendocardial myocardial ischemia and ultimately causing more damage28. Moreover, impaired LV contractility
and reduced cardiac output activates neurohormonal pathways29. These pathways are thought to
act as a way to maintain cardiac output through inotropic and chronotropic effects but result in an increased workload for the remaining myocytes, leading to progressive adverse remodeling. When left untreated, adverse left remodeling will ultimately lead to heart failure. Both functional and structural measures of adverse LV remodeling are associated with mortality and cardiovascular events after myocardial infarction30-33. Drug therapies targeting neurohormonal pathways have
shown to attenuate LV remodeling, which is associated with reduced long-term mortality34.
The association between attenuation of LV remodeling and improved outcome led to the hypothesis that surgical restoration of the original volume and ellipsoid shape of the LV could be beneficial in cases of severe LV remodeling. The first surgical attempt at LV restoration was the aneurysmectomy with a linear suture, first described by Cooley et al. in 195835 and developed
over the years36. In more recent years, many devices have also been developed that make use of
a transcatheter approach37.
Novel methods in cardiovascular research
Recently, novel research methods have emerged that can be applied to gain more insights into the mechanisms underlying cardiovascular disease that traditional research methods could not have revealed. The field of genetics makes it possible to distinguish between effects from a person’s genetic makeup, the genotype, and effects from external factors during someone’s lifetime. Effects from a person’s genetic makeup can be explored by studying the effects of individual single-nucleotide polymorphisms (SNPs), which are variations in single nucleotides at a specific position in the genome. In some cases, SNPs can alter the level of expression of a gene, and/or change the function of the protein that it codes for. Genome-wide association studies (GWAS) have been designed to discover SNPs that are related to phenotypes, which include a wide range of cardiovascular risk factors and cardiovascular diseases38. Each SNP that
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has been associated with a phenotype in a GWAS has a specific effect size which reflects how much it affects the phenotype. In individuals that have underwent DNA sequencing, the sum of the effect sizes of a range of SNPs multiplied by the number of alleles (0, 1, or 2) can be used to generate an individual’s genetic risk score for that specific phenotype. As SNPs are randomly assigned to an individual at conception, genetic variants can be used to assess the causality of a relationship, similar to a randomized controlled trial. Studies that use SNPs and genetic risk scores to assess the causality of a relationship are known as Mendelian randomization analyses. These studies are especially valuable in untangling the etiology of complex processes such as cardiac remodeling. Coinciding with the surge in popularity of genetics and other forms of big data, artificial intelligence (AI) emerged as a popular method of analyzing data. AI is a very broad concept encompassing the simulation of human intelligence processes by machines. Deep learning (DL) is an important subset of AI methods that has achieved great success in imaging analyses. DL has been applied in a wide range of imaging modalities including TTE and CMR for classification of image orientation39, segmentation of cardiac structures and volumes40, and
AIMS OF THIS THESIS
The aim of this thesis is to improve early detection of LV remodeling, through understanding of how cardiovascular risk factors and myocardial infarction cause LV remodeling and by proposing practical implementations for clinical practice.
Part I: Cardiovascular risk factors
In Chapter 2, the effect of smoking on LV structure and function is investigated, using a nested
matched case-control study design and selecting a relatively healthy population of UK Biobank participants to reduce the effects of confounding factors. In Chapter 3, a novel Mendelian
randomization approach is used to investigate the effects of a lifelong exposure to a raised SBP on LV structure and function, to provide evidence for a causal relationship between raised SBP and adverse LV remodeling.
Part II: Myocardial infarction
Whereas the presence of cardiovascular risk factors is associated with a relatively limited extent
of LV remodeling, in Chapter 4, predictors of structural LV remodeling after ST-elevation
myocardial infarction are investigated, in which especially LVEF and LVESV are more severely affected. In addition to LV volumes and mass, we also investigate predictors of remote (non-infarcted) LV wall thickness. After myocardial infarction, both TTE and CMR are frequently used to assess LV remodeling, but cannot be compared directly due to wide limits of agreement and underestimation of LV volumes and overestimation of LV mass when comparing 2D TTE to CMR, as we demonstrate in Chapter 5. Furthermore, potential sources of bias between imaging
modalities are investigated using a novel approach of applying linear regression on the absolute difference (bias) between measurements. Chapter 6 reviews the empirical evidence supporting
LV restoration devices, which were designed to restore the LV to its original ellipsoid shape after myocardial infarction, hoping to improve functional status and reduce the incidence of heart failure hospitalizations and other cardiovascular events.
Part III: Improvements
In Chapter 7, the determinants of LV volumes in the general population are studied. Evidence
is provided that the commonly applied indexation of LV volumes to BSA or height is suboptimal and new methods of indexation that can be used to reduce interindividual differences and improve early detection of pathologic dimensions are proposed. In Chapter 8, the most commonly used
methods of deep learning are described, and methods to deploy artificial intelligence to improve the (early) detection of LV remodeling are postulated.
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