Sex differences in remodeling and diastolic dysfunction in patients with hypertrophic cardiomyopathy: From bench to bedside

Lisa Antonia Maria Nijenkamp

Research output: ThesisPhd-Thesis - Research and graduation internal

Abstract

CHAPTER ONE gives a more in depth introduction to hypertrophic cardiomyopathy and this thesis in general. We have studied the influences of sex and genotype on diastolic dysfunction and cardiac remodeling. High-myofilament calcium sensitivity has been proposed as a disease trigger as discussed in CHAPTER TWO. Myofilament length-dependent activation is impaired in stage II HCM patients with a missense mutation. A blunted response to β-adrenergic receptor stimulation might explain the hypophosphorylation in HCM patients and may represent a mechanism underlying the development of HCM. CHAPTER THREE gives an introduction to sex-differences in the pathophysiology of the heart. The “Classic” Stage In CHAPTER FOUR we studied sex-differences in diastolic function and included patients with a thick filament mutation; β-myosin heavy chain (MYH7) and cardiac myosin binding protein C (MYBPC3). We found that at the time of myectomy women are older than men and show a higher grade of diastolic dysfunction. Both indexed left atrial and interventricular septum diameters were larger in women compared to men. In addition to the differences in clinical parameters we also found distinct structural and cellular sex-dependent changes. A shift was observed from the stiff titin isoform to the more compliant isoform of titin, particularly in female HCM patients. Moreover, there is a significant relation between titin compliance and diastolic dysfunction. Furthermore, women showed a twofold higher amount of fibrosis compared to HCM men. In CHAPTER FIVE we investigated if the observed sex-differences apply to all HCM patients by including thin filament mutations and HCM patients without an underlying sarcomere gene mutation. We found smaller IVS thickness in THIN filament and SMN patients compared to HCM patients with THICK filament mutations. SMN patients are on average 10 years older compared to SMP HCM patients, although diastolic dysfunction seems less impaired. Cellular changes, such as fibrosis, capillary density and titin ratio are less altered in SMN patients. The sex-differences reported in previous chapters apply to the overall HCM patient group: women are older, show worse diastolic dysfunction and show worse cellular changes that might influence diastolic dysfunction. Fibrosis and titin ratio are increased and capillary density is lower in women compared to HCM men. End Stage HCM While most patients show obstructive hypertrophy and a relatively stable clinical phenotype (stage II), a small group of patients progresses to end-stage HCM (stage IV). It is unclear which factors underlie this transition. In CHAPTER SIX we have studied the differences between stage II and stage IV HCM. Passive tension, titin compliance and amount of fibrosis were comparable between the two disease stages, while capillary density was even lower in stage IV compared to stage II HCM patients. Our study points to microvascular ischemia and fibrosis as main mechanisms of disease progression rather than sarcomere dysfunction. Mutation Carrier The absolute thickness of the interventricular septum (IVS) is comparable between women and men; however, when corrected for body surface area, women show greater IVS thickness compared to men. Because women are older at diagnosis and have worse diastolic dysfunction we hypothesized that women are in fact in a more advanced disease stage (stage III). In CHAPTER SEVEN we studied cardiac dimensions of stage I HCM patients to obtain “base-line” parameters via MRI. Even corrected for body surface area female hearts were smaller compared to male stage I HCM hearts. This supports our hypothesis that HCM women are in a more advanced disease stage at diagnosis. To reach the diagnostic threshold, a left ventricular wall thickness of ≥15mm, they require relatively more hypertrophy. CHAPTER EIGHT highlights several recent observations from the DOSIS consortium and collaborators which may ultimately be relevant for clinical practice.
Original languageEnglish
QualificationDoctor of Philosophy
Awarding Institution
  • Vrije Universiteit Amsterdam
Supervisors/Advisors
  • van der Velden, Jolanda, Supervisor
  • Kuster, Diederik, Co-supervisor
Award date1 Jul 2021
Place of Publications.l.
Publisher
Print ISBNs9789464164664
Publication statusPublished - 2 Jul 2021

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