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Early Cardiovascular Changes of Familial Hypertrophic Cardiomyopathy in the Young

Fernlund, Eva LU (2015) In Lund University Faculty of Medicine Doctoral Dissertation Series 2015:134.
Abstract (Swedish)
Popular Abstract in Swedish

Populärvetenskaplig sammanfattning

Familjär hypertrof kardiomyopati (HCM) är den vanligaste ärftliga hjärtsjukdomen som ärvs autosomalt dominant, dvs. ca 50% risk för varje barn i den drabbade familjen. Tidigare studier har visat hög risk för HCM relaterade tillbud inklusive plötslig hjärtdöd (SCD) under barndomen, med en incidens upp till 10 % under de två första decennierna i livet. Fortfarande är HCM den vanligaste orsaken till plötslig hjärtdöd (Sudden Cardiac Death, SCD) hos unga människor och idrottare, sannolikt till följd av allvarlig arytmi, orsakad av strukturella förändringar i hjärtmuskeln. Sjukdomen HCM medför gradvis förtjockning av vänster kammares hjärtmuskelväggar, och... (More)
Popular Abstract in Swedish

Populärvetenskaplig sammanfattning

Familjär hypertrof kardiomyopati (HCM) är den vanligaste ärftliga hjärtsjukdomen som ärvs autosomalt dominant, dvs. ca 50% risk för varje barn i den drabbade familjen. Tidigare studier har visat hög risk för HCM relaterade tillbud inklusive plötslig hjärtdöd (SCD) under barndomen, med en incidens upp till 10 % under de två första decennierna i livet. Fortfarande är HCM den vanligaste orsaken till plötslig hjärtdöd (Sudden Cardiac Death, SCD) hos unga människor och idrottare, sannolikt till följd av allvarlig arytmi, orsakad av strukturella förändringar i hjärtmuskeln. Sjukdomen HCM medför gradvis förtjockning av vänster kammares hjärtmuskelväggar, och med tiden bildas sjukliga substrat i hjärtat som ökar risken för allvarliga hjärthändelser. På grund av sjukdomens progressiva karaktär, kan den vara svår att hitta i yngre åldrar. Att skilja träningsinducerad från sjukdomsassocierad förtjockning av hjärtmuskelväggarna är ofta mycket svårt i de tidiga faserna av HCM, speciellt i unga år. I modern tid måste vi hantera en ökande befolkning med HCM-genotyp men med normal fenotyp och bättre kunna identifiera de faktorer som indikerar allvarligare sjukdomsprogress, samt förbättra vår förmåga att förutse dessa faktorer i tidigare stadier av sjukdomen.

Syftet med dessa studier har varit att med multimodal bild- och funktionsdiagnostik fokusera på tidiga kardiovaskulära förändringar i presymtomatisk fas av HCM hos unga.

Studie I visade förändrad diastolisk funktion hos HCM men också hos HCM-risk individer. Vi påvisade även förändrad mikrovaskulär reaktivitet på acetylkolin, vilket tyder på tidigt förekommande endoteldysfunktion, både hos unga presymtomatiska HCM-risk och HCM patienter, mätt med laser Doppler i perifer cirkulation. De mikrovaskulära förändringarna uppvisade samband med påverkad diastolisk hjärtmuskelfunktion.

Studie II visade minskade myokardiell perfusion (MP) vid adenosin-provokation i icke-fibrotisk hjärtmuskel hos unga HCM patienter, men inte hos HCM-risk individer eller kontroller, tydande på att mikrovaskulär sjukdom kan vara orsaken till minskad MP.

Studie III visade minskad regional genomblödning i förtjockad jämfört med icke- förtjockad hjärtmuskel och ännu lägre genomblödning i områden med fibrotisk och förtjockad hjärtmuskel hos unga HCM patienter. Adenosin-inducerad stress visade att hypoperfunderade områden var större än områden med LGE (fibros), indikerande att hypoperfusion kan vara en känsligare markör för att identifiera sjuk hjärtmuskel vid HCM.

Studie IV påvisade förändrade nivåer av cirkulerande biomarkörer vilka återspeglar remodellering av hjärtmuskeln, microfibros, vaskulära förändringar och endotel påverkan även i ett tidigt skede av HCM hos unga.

Studie V visade att en 2-parameter kombination av 12-avlednings A-EKG var betydligt mer känsligt och mer specifikt jämfört med åldersspecifika, konventionella EKG-kriterier för detektion av MYBPC3-HCM och att särskilja dessa patienter från friska kontroller samt ungdomsatleter. (Less)
Abstract
Familial hypertrophic cardiomyopathy (HCM) is the most common inherited heart disease, transmitted in an autosomal dominant fashion, i.e. 50% risk for transmission of the disease-causing mutation to each child of the affected family. Previous studies reveal a high risk for HCM related cardiac events including sudden cardiac death (SCD) during childhood, with a peak incidence of up to 10% during the first two decades of life. HCM remains the most common cause of sudden cardiac death in young people and athletes, probably due to fatal arrhythmias mainly caused by structural and functional changes in the myocardium leading to increased risk for major cardiac events. In young athletes, the distinction between physiological and pathological... (More)
Familial hypertrophic cardiomyopathy (HCM) is the most common inherited heart disease, transmitted in an autosomal dominant fashion, i.e. 50% risk for transmission of the disease-causing mutation to each child of the affected family. Previous studies reveal a high risk for HCM related cardiac events including sudden cardiac death (SCD) during childhood, with a peak incidence of up to 10% during the first two decades of life. HCM remains the most common cause of sudden cardiac death in young people and athletes, probably due to fatal arrhythmias mainly caused by structural and functional changes in the myocardium leading to increased risk for major cardiac events. In young athletes, the distinction between physiological and pathological hypertrophy is often very challenging. The diagnosis of HCM in childhood is more difficult in its early phases, due to the progressive nature of the disease and the lack of HCM symptoms. The increasing population with HCM genotype with little or no detectable myocardial hypertrophy along with the increased risk for cardiac events even in these individuals are important aspects that emphasize the stringent need to improve early diagnosis of HCM in the young. In these studies, we sought to investigate indices of early cardiovascular changes in young individuals with or without myocardial hypertrophy on echocardiography.

Study I showed altered diastolic function both in HCM and HCM-risk individuals vs. controls and young athletes. There were altered microvascular responses to acetylcholine, indicating an early endothelial dysfunction present in both the HCM-risk and HCM patients, measured by laser Doppler of peripheral circulation. These microvascular changes were associated with abnormalities in diastolic myocardial function measured by TDI.

Study II demonstrated decreased myocardial perfusion (MP) during adenosine induced hyperemia in non-fibrotic myocardium even without diastolic dysfunction in young HCM patients, but not subjects at risk or controls, indicating that microvascular disease can be the cause of MP decrease.

Study III showed decreased regional perfusion in hypertrophied compared to non-hypertrophied myocardium and even lower perfusion in areas of fibrotic, hypertrophied myocardium in young HCM patients. The adenosine stress-induced hypoperfused areas were found larger than regions with LGE (fibrosis), indicating that hypoperfusion may be a more sensitive marker of diseased myocardium.

Study IV suggests adverse changes of circulating biomarkers reflecting myocardial matrix remodeling, microfibrosis and vascular endotheliopathy in the early stage of hypertrophic cardiomyopathy in the young.

Study V showed the superiority of the 2-parameter 12-lead A-ECG score, which is significantly more sensitive and specific than pooled, age-specific conventional ECG criteria for detecting MYBPC3-HCM and in distinguishing such patients from healthy controls, including endurance-trained athletes. (Less)
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author
supervisor
opponent
  • Prof Simpson, John, Evelina Children´s Hospital, Guy´s and St. Thomas, London, United Kingdom
organization
publishing date
type
Thesis
publication status
published
subject
keywords
A-ECG. SCD., advanced ECG, CMR, Tissue Doppler, Echocardiography, Microcirculation, LaserDoppler, Athletes heart, HCM, hypertrophic cardiomyopathy, Familial hypertrophic cardiomyopathy
in
Lund University Faculty of Medicine Doctoral Dissertation Series
volume
2015:134
pages
166 pages
publisher
Paediatrics, Faculty of Medicine, Lund University
defense location
Belfrage Hall, BMC D15, Klinikgatan 32, Lund
defense date
2015-12-18 14:00
ISSN
1652-8220
ISBN
978-91-7619-214-6
language
English
LU publication?
yes
id
6ce1549a-a5e2-4888-bac2-19e9e7c17fbc (old id 8231646)
date added to LUP
2015-11-30 08:50:03
date last changed
2016-09-19 08:44:46
@phdthesis{6ce1549a-a5e2-4888-bac2-19e9e7c17fbc,
  abstract     = {Familial hypertrophic cardiomyopathy (HCM) is the most common inherited heart disease, transmitted in an autosomal dominant fashion, i.e. 50% risk for transmission of the disease-causing mutation to each child of the affected family. Previous studies reveal a high risk for HCM related cardiac events including sudden cardiac death (SCD) during childhood, with a peak incidence of up to 10% during the first two decades of life. HCM remains the most common cause of sudden cardiac death in young people and athletes, probably due to fatal arrhythmias mainly caused by structural and functional changes in the myocardium leading to increased risk for major cardiac events. In young athletes, the distinction between physiological and pathological hypertrophy is often very challenging. The diagnosis of HCM in childhood is more difficult in its early phases, due to the progressive nature of the disease and the lack of HCM symptoms. The increasing population with HCM genotype with little or no detectable myocardial hypertrophy along with the increased risk for cardiac events even in these individuals are important aspects that emphasize the stringent need to improve early diagnosis of HCM in the young. In these studies, we sought to investigate indices of early cardiovascular changes in young individuals with or without myocardial hypertrophy on echocardiography. <br/><br>
Study I showed altered diastolic function both in HCM and HCM-risk individuals vs. controls and young athletes. There were altered microvascular responses to acetylcholine, indicating an early endothelial dysfunction present in both the HCM-risk and HCM patients, measured by laser Doppler of peripheral circulation. These microvascular changes were associated with abnormalities in diastolic myocardial function measured by TDI. <br/><br>
Study II demonstrated decreased myocardial perfusion (MP) during adenosine induced hyperemia in non-fibrotic myocardium even without diastolic dysfunction in young HCM patients, but not subjects at risk or controls, indicating that microvascular disease can be the cause of MP decrease. <br/><br>
Study III showed decreased regional perfusion in hypertrophied compared to non-hypertrophied myocardium and even lower perfusion in areas of fibrotic, hypertrophied myocardium in young HCM patients. The adenosine stress-induced hypoperfused areas were found larger than regions with LGE (fibrosis), indicating that hypoperfusion may be a more sensitive marker of diseased myocardium. <br/><br>
Study IV suggests adverse changes of circulating biomarkers reflecting myocardial matrix remodeling, microfibrosis and vascular endotheliopathy in the early stage of hypertrophic cardiomyopathy in the young. <br/><br>
Study V showed the superiority of the 2-parameter 12-lead A-ECG score, which is significantly more sensitive and specific than pooled, age-specific conventional ECG criteria for detecting MYBPC3-HCM and in distinguishing such patients from healthy controls, including endurance-trained athletes.},
  author       = {Fernlund, Eva},
  isbn         = {978-91-7619-214-6},
  issn         = {1652-8220},
  keyword      = {A-ECG. SCD.,advanced ECG,CMR,Tissue Doppler,Echocardiography,Microcirculation,LaserDoppler,Athletes heart,HCM,hypertrophic cardiomyopathy,Familial hypertrophic cardiomyopathy},
  language     = {eng},
  pages        = {166},
  publisher    = {Paediatrics, Faculty of Medicine, Lund University},
  school       = {Lund University},
  series       = {Lund University Faculty of Medicine Doctoral Dissertation Series},
  title        = {Early Cardiovascular Changes of Familial Hypertrophic Cardiomyopathy in the Young},
  volume       = {2015:134},
  year         = {2015},
}