Zespół hipoplastycznego lewego serca
Patofizjologia i mechanizm

Zespół hipoplastycznego lewego serca (HLHS) to ciężka wada wrodzona charakteryzująca się niedorozwojem lewej komory, zastawki aortalnej, mitralnej oraz aorty wstępującej, stanowiąca 2-4% wszystkich wrodzonych wad serca. Wyróżnia się trzy warianty anatomiczne: atrezję zastawki mitralnej i aortalnej (MA-AA), stenozy zastawki mitralnej i atrezji zastawki aortalnej (MS-AA) oraz stenozy obu zastawek (MS-AS). Hemodynamika HLHS cechuje się brakiem przepływu przez lewą komorę i zastawkę aortalną, co skutkuje wstecznym przepływem z lewego do prawego przedsionka, powiększeniem prawej komory i pnia płucnego oraz koniecznością, by prawa komora pełniła funkcję komory systemowej i płucnej. Etiologia HLHS jest wieloczynnikowa, obejmująca mutacje genów takich jak GJA1, HAND1, NKX2.5 oraz loci 10q22 i 6q23, a także defekty endokardium i zaburzenia mitochondrialne, co potwierdzają modele zwierzęce i badania molekularne. Hipoplazja lewej komory powstaje między 4 a 8 tygodniem ciąży, a mechanizmy patogenetyczne obejmują zarówno zaburzenia przepływu krwi („no flow, no grow”), jak i pierwotne defekty rozwojowe mięśnia sercowego i endokardium.

  1. Patofizjologia zespołu hipoplastycznego lewego serca
    1. Spektrum anatomiczne i patofizjologiczne
    2. Etiologia i czynniki ryzyka
  2. Mechanizmy rozwoju HLHS
    1. Teoria „no flow, no grow”
    2. Hipoteza pierwotnej wady rozwojowej
    3. Rola endokardium
    4. Defekty wewnątrzkomórkowe
  3. Rozwój i patofizjologia HLHS w okresie płodowym
    1. Rozwój płodowy HLHS
    2. Rola przepływu krwi w rozwoju serca
    3. Współczesne zrozumienie rozwoju HLHS
  4. Implikacje dla rozumienia i leczenia HLHS
    1. Potencjalne kierunki terapeutyczne
    2. Zaawansowane terapie eksperymentalne
    3. Prenatalna interwencja
    4. Znaczenie badań nad HLHS
    5. Kolejne rozdziały

Patofizjologia zespołu hipoplastycznego lewego serca

Zespół hipoplastycznego lewego serca (ang. Hypoplastic Left Heart Syndrome, HLHS) to ciężka, zagrażająca życiu wrodzona wada serca charakteryzująca się znacznym niedorozwojem struktur lewej części serca, w tym lewej komory, zastawki aortalnej, zastawki mitralnej oraz aorty wstępującej.12 HLHS stanowi 2-4% wszystkich wrodzonych wad serca i jest drugą najczęstszą wadą obstrukcyjną lewego serca.3 Ciężkość zespołu wynika z faktu, że bez odpowiedniego leczenia stan ten jest zawsze śmiertelny.45

Spektrum anatomiczne i patofizjologiczne

HLHS obejmuje spektrum nieprawidłowości anatomicznych charakteryzujących się znacznym niedorozwojem lewej komory i aorty wstępującej.6 W zależności od stopnia nasilenia wady, można wyróżnić trzy główne warianty anatomiczne:7

  • Atrezja zastawki mitralnej i atrezja zastawki aortalnej (MA-AA) – najcięższa postać, w której nie występuje przepływ krwi do lewej komory
  • Stenoza zastawki mitralnej i atrezja zastawki aortalnej (MS-AA) – krew może napełniać lewą komorę, ale nie może być dostarczana do krążenia systemowego przez hipoplastyczną aortę wstępującą
  • Stenoza zastawki mitralnej i stenoza zastawki aortalnej (MS-AS) – najłagodniejsza postać, w której lewa komora może dostarczać pewną ilość krwi do krążenia systemowego, jednak wydajność jest niewystarczająca

8

Hemodynamicznie, krew nie może przepływać przez lewą komorę i zastawkę aortalną, co powoduje wsteczny przepływ z lewego przedsionka przez otwór owalny do prawego przedsionka. Prowadzi to do powiększenia prawego przedsionka, prawej komory i pnia płucnego.9 Ze względu na hipoplazję lewego serca, prawa komora zaopatruje zarówno krążenie płucne, jak i systemowe. Żyły płucne mogą być prawidłowe lub powiększone. Objętość krwi i ciśnienie w prawym sercu są podwyższone, podczas gdy lewy przedsionek, lewa komora i aorta są zmniejszone.10

Etiologia i czynniki ryzyka

Etiologia HLHS jest wieloczynnikowa, obejmująca kombinację czynników genetycznych, środowiskowych i prawdopodobnie epigenetycznych.1112 Większość przypadków HLHS występuje sporadycznie, co oznacza, że pojawiają się u pacjentów bez rodzinnego wywiadu w kierunku tej wady.13 Jednakże istnieją dowody na genetyczne podłoże HLHS, ponieważ wykazano, że jest dziedziczny i związany z określonymi mutacjami genów.14

Loci genetyczne powiązane z HLHS obejmują:15

  • GJA1 (connexin 43)
  • HAND1
  • NKX2.5
  • 10q22
  • 6q23

Analiza genetyczna myszy z HLHS wskazuje, że zespół ten jest genetycznie heterogenny, z wielogenową etiologią.16 Badania na myszach z mutacją Ohia wykazały, że HLHS może być wywołany przez mutacje w dwóch genach: Sap130, białku związanym z Sin3a w kompleksie deacetylazy histonowej (HDAC), oraz Pcdha9, protokadherynie pośredniczącej w adhezji komórka-komórka.17 Hipoplazja lewej komory była wywoływana przez mutację Sap130, co potwierdzono w modelu zebrafish z mutacją sap130a.18

Co interesujące, nieoczekiwane odkrycie mutacji w modyfikatorach chromatyny i składnikach szlaku Ras/MAPK we wszystkich 8 liniach myszy z HLHS sugeruje, że modyfikatory chromatyny w połączeniu z zaburzoną sygnalizacją Ras/MAPK mogą przyczyniać się do hipoplazji lewej komory i złożonej genetyki HLHS.19

Mechanizmy rozwoju HLHS

Teoria „no flow, no grow”

Popularna teoria zwana hipotezą „no flow, no grow” (brak przepływu, brak wzrostu) sugeruje, że pierwotne anatomiczne wady zastawek aortalnej i mitralnej prowadzą do zniekształceń lewej komory i jej drogi odpływu.20 Głównym czynnikiem jest przeszkoda w odpływie z lewej komory spowodowana zwężeniem lub atrezją zastawki aortalnej podczas rozwoju płodu.21

Ta przeszkoda powoduje zwiększenie obciążenia następczego lewej komory, wywołując przerost, a następnie hamując wzrost komory, co prowadzi do hipoplazji.22 Podwyższone ciśnienie w lewym przedsionku spowodowane niewystarczającym odpływem z lewej komory powoduje dwukierunkowy przepływ lub odwrócenie przepływu przez otwór owalny, co nasila hipoplazję.23

Zwężenie lub atrezja zastawki mitralnej może podobnie ograniczać napływ do lewej komory, prowadząc do zmniejszonego obciążenia wstępnego, obniżonego ciśnienia i niedorozwoju lewej komory oraz powiązanych struktur.24 W przypadku zwężenia zastawki aortalnej, które występuje podczas rozwoju płodu, dochodzi do dodatkowego obciążenia lewej komory in utero. Może to ostatecznie prowadzić do zmniejszonej perfuzji przez lewą komorę, co prawdopodobnie hamuje wzrost komory.25

Kilka dowodów sugeruje, że zmniejszony przepływ krwi przez lewe serce jest istotny w patogenezie HLHS.26 Wyniki z chirurgicznie wywołanego modelu mysiego HLHS pokazują, że zmniejszony przepływ krwi przez lewe serce po zamknięciu komunikacji międzykomorowej może prowadzić do rozwoju zespołu hipoplastycznego lewego serca.27

Hipoteza pierwotnej wady rozwojowej

Druga teoria sugeruje, że hipoplazja lewej komory jest pierwotnym mechanizmem.28 Istnieją coraz liczniejsze dowody wskazujące, że hipoplazja lewej komory wynika z pierwotnego defektu w rozwoju komory.29 W tym kontekście zespół hipoplastycznego lewego serca można postrzegać jako noworodkową formę kardiomiopatii.30

Zgodnie z tą hipotezą, mutacje w co najmniej jednym genie, a mianowicie NKX2-5, zgłoszono w związku zarówno z hipoplazją lewego serca, jak i kardiomiopatią.31 Na poziomie komórkowym zaobserwowano zwiększone zwłóknienie związane z dezorganizacją kardiomiocytów w tkance uzyskanej z eksplantowanych serc niemowląt.32

Kluczowe pytanie dotyczy tego, czy odkrycia te są wtórne, czyli spowodowane niedokrwieniem wynikającym ze zmienionych warunków hemodynamicznych, czy są częścią pierwotnego procesu chorobowego, który podkreśla hipoplazję komory.33

Rola endokardium

Utrata funkcji endokardium prowadząca do początkowego zatrzymania wzrostu rozwijającej się lewej komory może być krytycznym wczesnym krokiem w patogenezie zespołu.34 Badania sugerują, że defekty endokardium mają istotny udział w etiologii HLHS.35

Ponieważ HLHS charakteryzuje się nieprawidłowościami strukturalnymi zastawek i niedorozwojem lewej komory, spekulowano, że defekt w endokardium może być mechanizmem leżącym u podstaw HLHS.36 Badania Miao i Tian odkryły mechanizm, który pomaga wyjaśnić wrodzone wady serca obserwowane u pacjentów z HLHS (tj. obecność wadliwych komórek endokardium powoduje upośledzenie rozwoju endokardium).37

Defekty wewnątrzkomórkowe

Badania na modelach zwierzęcych HLHS ujawniają ważne czynniki przyczyniające się do rozwoju tej wady, takie jak dysfunkcja mitochondrialna i zaburzenia we wczesnych etapach rozwoju embrionalnego.38 Myszy mutanty HLHS wykazują dysfunkcję metaboliczną z towarzyszącym zatrzymaniem cyklu komórkowego i defektami różnicowania kardiomiocytów.39

Badania na zebrafish z uszkodzonymi ortologami białka wiążącego RNA RBFOX2, genu powiązanego z HLHS u ludzi, wykazały wady układu sercowo-naczyniowego pokrywające się z tymi u pacjentów z HLHS, w tym niewydolność komory, zastawek i aorty.40 Mechanistycznie, zaobserwowano zmniejszoną ekspresję i alternatywny splicing komponentów sarkomeru i mitochondriów, które upośledzają odpowiednio montaż sarkomeru i oddychanie mitochondrialne.41

Wyniki te wspierają nowy paradygmat patogenezy HLHS, który koncentruje się na wewnętrznych defektach mięśnia sercowego.4243 Dane wykazują, że białka Rbfox są niezbędne do montażu sarkomeru, ultrastruktury mitochondrialnej, ekspresji genów łańcucha transportu elektronów i produkcji ATP, co przy defekcie upośledza funkcję pompy kardiomiocytów i wzrost komórek.44

Rozwój i patofizjologia HLHS w okresie płodowym

Rozwój płodowy HLHS

Pierwotny defekt w HLHS powstaje podczas embriogenezy, między 4 a 8 tygodniem ciąży, z powodu nieprawidłowego rozwoju struktur lewej strony serca.45 Główne czynniki prowadzące do tego defektu to atrezja lub krytyczne zwężenie zastawek aortalnej lub mitralnej, co skutkuje hipoplazją lewej komory, aorty wstępującej i łuku aorty.46

Niewystarczający przepływ krwi przez lewe serce podczas rozwoju płodu przyczynia się do hipoplazji, podczas gdy wewnętrzne defekty genetyczne mogą upośledzać proliferację komórek, różnicowanie lub szlaki sygnałowe krytyczne dla normalnej morfogenezy serca.47

Nowe dowody sugerują, że siły mechaniczne wywierane przez przepływ krwi i zawartość tlenu mogą niezależnie pośredniczyć we wzroście i przebudowie struktur lewego serca poprzez programy wrażliwe na bodźce mechaniczne i wykrywające hipoksję.48

Rola przepływu krwi w rozwoju serca

Podczas rozwoju serca odpowiedni przepływ krwi przez daną strukturę jest w dużej mierze odpowiedzialny za wzrost tej struktury.49 Przy małym lub zerowym przepływie krwi z powodu atrezji zastawki aortalnej i mitralnej, wzrost lewej komory nie następuje.50

Podobnie, wzrost aorty wstępującej nie występuje z powodu braku wyrzutu z lewej komory. Aorta wstępująca jest perfundowana w sposób wsteczny z przewodu tętniczego, funkcjonując jedynie jako wspólna tętnica wieńcowa.51

Inną postulowaną przyczyną jest nieprawidłowe ustawienie przegrody międzyprzedsionkowej w lewą stronę, co może ograniczać napełnianie lewej komory.52 Zmiany w przepływie krwi prowadzą do rozwoju nieprawidłowości strukturalnych serca związanych z tym zespołem.53

Współczesne zrozumienie rozwoju HLHS

Najnowsze badania sugerują, że zaburzenia przepływu krwi są ważnym czynnikiem przyczynowym w patogenezie tej choroby i że część przypadków może rozwijać się w okresie płodowym, a nie we wczesnym okresie embrionalnym.54

Zrozumienie podstawy, dlaczego w niektórych przypadkach rozwój komory podczas życia płodowego może przebiegać normalnie w obecności zwężenia aorty, mogłoby dostarczyć kluczowych informacji o tym, jak sam zespół można zapobiec.55

Nieprawidłowy wzrost mózgu, zwłaszcza struktur istoty białej, staje się wykrywalny już w drugim trymestrze ciąży, a zmniejszony wsteczny przepływ krwi przez hipoplastyczny łuk aorty został uznany za potencjalny czynnik przyczynowy.56

Implikacje dla rozumienia i leczenia HLHS

Potencjalne kierunki terapeutyczne

Badania mechanizmów komórkowych i molekularnych napędzających hipoplazję komory w HLHS mogą pomóc w identyfikacji nowych celów terapeutycznych dla interwencji płodowej w celu odzyskania wzrostu lewej komory.57

W chwili obecnej, ostateczne przeżycie pacjentów z HLHS wymaga etapowych procedur chirurgicznych, które umożliwiają prawej komorze funkcjonowanie jako komora systemowa i ustanowienie kontrolowanego źródła przepływu krwi płucnej.58

U niektórych niemowląt z HLHS, szczególnie tych z ciężką dysfunkcją zastawki trójdzielnej lub komory, przeszczep serca jest uznawany za procedurę z wyboru.59

Zaawansowane terapie eksperymentalne

Terapia komórkami macierzystymi jako procedura eksperymentalna oferuje nadzieję dla osób z HLHS, wprowadzając koncepcję dostarczania izolowanych komórek do miejsca uszkodzenia lub zmiany w celu naprawy i regeneracji.60

Zasada terapii komórkami macierzystymi opiera się na przekonaniu, że ich dostarczenie w miejsce uszkodzenia może spowodować regenerację lub gojenie, możliwe poprzez uwalnianie czynników parakrynnych, transfer mitochondrialny, egzosomy/pęcherzyki pozakomórkowe oraz rekonstytucję niszy sercowej, a także odgrywać rolę przeciwwłóknieniową i przeciwapoptotyczną.61

Szereg badań przedklinicznych i prób klinicznych przeprowadzonych z użyciem różnych typów komórek macierzystych i różnych dróg podawania u noworodków i dorosłych wykazało skuteczność komórek macierzystych w regeneracji uszkodzonej tkanki mięśnia sercowego i zmniejszaniu niewydolności serca.62

Prenatalna interwencja

Innowacyjnym podejściem w leczeniu HLHS jest interwencja prenatalna. U naszego pacjenta, prenatalna postępująca hipoplazja lewego serca związana z restrykcyjnym otworem owalnym (FO) sugerowała prawdopodobieństwo mechanizmu związanego z przepływem.63

Dodatkowo, poporodowa poprawa hipoplastycznego lewego serca w obecności funkcjonalnego ubytku przegrody międzykomorowej (PM-VSD) wzmocniła podejrzenie mechanizmu zewnętrznego.64

Pre- lub poporodowe interwencyjne utworzenie ubytku przegrody międzyprzedsionkowej (ASD) lub VSD jest proponowaną metodą leczenia HLHS u wybranych pacjentów.65

Znaczenie badań nad HLHS

Zrozumienie pełnego zakresu czynników prowadzących do rozwoju HLHS i możliwość przetestowania skuteczności nowych interwencji chirurgicznych jest wyzwaniem bez solidnych modeli choroby, które odtwarzają fizjologię i hemodynamikę HLHS.66

Chociaż istnieje wiele doniesień o mechanicznym zablokowaniu przepływu w celu wywołania HLHS, wiadomo, że czynniki genetyczne odgrywają rolę w rozwoju HLHS u ludzi.67 Modele genetycznego indukowania HLHS są jednak znacznie rzadsze.68

W sumie, modele zwierzęce dostarczają różnych metod odtwarzania fenotypu HLHS. Pomimo różnic specyficznych dla gatunku, upośledzenie przepływu krwi przez lewe serce w środkowym okresie ciąży było wielokrotnie wykorzystywane do odtworzenia fenotypu podobnego do HLHS, z modelami powtarzającymi cechy HLHS, w tym hipoplazję lewego serca, hipoplazję aorty wstępującej i zwiększone odkładanie kolagenu w śródbłonku.69

Modele genetyczne HLHS zaczynają dostarczać wglądu w istotne genetyczne czynniki przyczyniające się do hipoplazji lewego serca, takie jak niezależne od przepływu upośledzenie proliferacji, rozwój zastawek, rozwój łożyska i transport składników odżywczych.70

Kolejne rozdziały

Zapraszamy do dalszego czytania naszego leksykonu.

Wybierz kolejny rozdział z menu poniżej, aby otworzyć nową podstronę kompedium wiedzy i uzyskać szczegółowe informację o leku, substancji lub chorobie.

  1. 10.04.2026
  2. www.leksykon.com.pl

Materiały źródłowe

  • #1 Hypoplastic Left Heart Syndrome – StatPearls – NCBI Bookshelf
    https://www.ncbi.nlm.nih.gov/books/NBK554576/
    Hypoplastic left heart syndrome (HLHS) is a rare but severe congenital heart defect characterized by underdevelopment of left-sided heart structures, including the left ventricle, aortic valve, mitral valve, and ascending aorta. […] The etiology of HLHS is multifactorial, involving a combination of genetic, environmental, and possibly epigenetic influences. […] The primary defect in HLHS arises during embryogenesis, between weeks 4 and 8 of gestation, due to abnormal development of the left-sided heart structures. […] The main factors leading to this defect are atresia or critical stenosis of the aortic or mitral valves, resulting in hypoplasia of the LV, ascending aorta, and aortic arch. […] Insufficient blood flow through the left heart during fetal development contributes to hypoplasia, while intrinsic genetic defects may impair cellular proliferation, differentiation, or signaling pathways critical for normal heart morphogenesis.
  • #2 Hypoplastic Left Heart Syndrome – Pediatrics – Merck Manual Professional Edition
    https://www.merckmanuals.com/professional/pediatrics/congenital-cardiovascular-anomalies/hypoplastic-left-heart-syndrome
    Hypoplastic left heart syndrome consists of hypoplasia of the left ventricle and ascending aorta, maldevelopment and hypoplasia of the aortic and mitral valves (frequently aortic atresia is present), an atrial septal defect, and a patent ductus arteriosus. […] Hypoplastic left heart syndrome (HLHS) accounts for 2 to 4% of congenital heart anomalies and is the second most common left heart obstructive lesion. Because the mitral valve, left ventricle, and aortic valve are hypoplastic (often with aortic atresia), oxygenated blood coming into the left atrium from the lungs is diverted across the atrial communication into the right heart, where it mixes with desaturated systemic venous return. […] Diagnosis of hypoplastic left heart syndrome is suspected clinically, particularly in neonates with metabolic acidosis that worsens after receiving oxygen; oxygen lowers pulmonary vascular resistance and thus increases the relative proportion of the right ventricle output that flows to the lungs rather than through the patent ductus arteriosus to the body.
  • #3 Hypoplastic Left Heart Syndrome – Pediatrics – Merck Manual Professional Edition
    https://www.merckmanuals.com/professional/pediatrics/congenital-cardiovascular-anomalies/hypoplastic-left-heart-syndrome
    Hypoplastic left heart syndrome consists of hypoplasia of the left ventricle and ascending aorta, maldevelopment and hypoplasia of the aortic and mitral valves (frequently aortic atresia is present), an atrial septal defect, and a patent ductus arteriosus. […] Hypoplastic left heart syndrome (HLHS) accounts for 2 to 4% of congenital heart anomalies and is the second most common left heart obstructive lesion. Because the mitral valve, left ventricle, and aortic valve are hypoplastic (often with aortic atresia), oxygenated blood coming into the left atrium from the lungs is diverted across the atrial communication into the right heart, where it mixes with desaturated systemic venous return. […] Diagnosis of hypoplastic left heart syndrome is suspected clinically, particularly in neonates with metabolic acidosis that worsens after receiving oxygen; oxygen lowers pulmonary vascular resistance and thus increases the relative proportion of the right ventricle output that flows to the lungs rather than through the patent ductus arteriosus to the body.
  • #4 Hypoplastic left heart syndrome | Radiology Reference Article | Radiopaedia.org
    https://radiopaedia.org/articles/hypoplastic-left-heart-syndrome?lang=us
    Hypoplastic left heart syndrome (HLHS) is a cyanotic congenital cardiac anomaly where affected individuals can have profound cyanosis and cardiac failure. […] Hypoplastic left heart syndrome results from the underdevelopment of left heart structures including left ventricle, mitral valve: stenosis/atresia, aortic valve: atresia/hypoplasia, ascending aortic root/arch. […] Hypoplastic left heart syndrome is fatal if untreated.
  • #5 Hypoplastic left heart syndrome | Orphanet Journal of Rare Diseases | Full Text
    https://ojrd.biomedcentral.com/articles/10.1186/1750-1172-2-23
    Hypoplastic left heart syndrome (HLHS) refers to the abnormal development of the left-sided cardiac structures, resulting in obstruction to blood flow from the left ventricular outflow tract. […] The embryologic cause of the disease, as in the case of most congenital cardiac defects, is not fully known. […] The embryologic cause, as in the case of most congenitally malformed hearts, is not fully known. Early epidemiologic studies report a multifactorial influence to be the cause of up to 90% of cardiac anomalies, with a recurrence rate in further offspring of 2% to 6%. […] In the case of hypoplasia of the left heart, the resulting multiple anomalies may result from either the multifactorial factors described above, or from a reduction of left ventricular inflow or outflow during fetal development.
  • #6 Pediatric Hypoplastic Left Heart Syndrome: Background, Pathophysiology, Etiology
    https://emedicine.medscape.com/article/890196-overview
    The term hypoplastic left heart syndrome (HLHS), initially proposed by Noonan and Nadas, describes a spectrum of cardiac abnormalities characterized by marked hypoplasia of the left ventricle and ascending aorta. […] Hypoplasia of the left heart structures is noted, with enlargement and hypertrophy of the right heart. Similar to other congenital heart defects, hypoplastic left heart syndrome also has a spectrum of severity. […] The exact cause of hypoplastic left heart syndrome is unknown. Although familial cases with autosomal recessive inheritance have been reported, hypoplastic left heart syndrome is generally postulated to follow multifactorial mode of inheritance. […] Most likely, the primary abnormality occurs during aortic and mitral valve development. During cardiac development, adequate flow of blood through a structure is largely responsible for the growth of that structure. With little or no blood flow because of aortic and mitral valve atresia, growth of the left ventricle does not occur.
  • #7 Pathogenesis and Pathophysiology of Hypoplastic Left Heart Syndrome | Open Access Journals
    https://www.rroij.com/open-access/pathogenesis-and-pathophysiology-of-hypoplastic-left-heart-syndrome.php?aid=93273
    Aortic stenosis provides one illustration of this. The left ventricle experiences additional stress in utero as a result of aortic stenosis that develops during fetal development. This may eventually result in decreased left ventricle perfusion, which is thought to impede ventricular growth. […] A number of cardiac anomalies can occur in HLHS patients, eventually resulting in a small left ventricle that is unable to provide sufficient blood flow to the rest of the body. The disease can be classified into three main anatomic variants based on whether the aortic and mitral valves are stenotic or atresiastic. […] The most severe form of HLHS is called Mitral Atresia and Aortic Atresia (MA-AA). In this condition, there is no blood flow to the left ventricle, so there is no chance of left ventricular output. In the Mitral Stenosis and Aortic Atresia (MS-AA) subtype blood can fill the left ventricle, but it can’t be provided to the fundamental flow by means of the hypoplastic rising aorta. The Mitral Stenosis and Aortic Stenosis (MS-AS) subtype is the mildest form. Even though the left ventricle is able to provide some blood flow to the rest of the body in these patients, the left ventricular systemic output is still insufficient overall.
  • #8 Pathogenesis and Pathophysiology of Hypoplastic Left Heart Syndrome | Open Access Journals
    https://www.rroij.com/open-access/pathogenesis-and-pathophysiology-of-hypoplastic-left-heart-syndrome.php?aid=93273
    Aortic stenosis provides one illustration of this. The left ventricle experiences additional stress in utero as a result of aortic stenosis that develops during fetal development. This may eventually result in decreased left ventricle perfusion, which is thought to impede ventricular growth. […] A number of cardiac anomalies can occur in HLHS patients, eventually resulting in a small left ventricle that is unable to provide sufficient blood flow to the rest of the body. The disease can be classified into three main anatomic variants based on whether the aortic and mitral valves are stenotic or atresiastic. […] The most severe form of HLHS is called Mitral Atresia and Aortic Atresia (MA-AA). In this condition, there is no blood flow to the left ventricle, so there is no chance of left ventricular output. In the Mitral Stenosis and Aortic Atresia (MS-AA) subtype blood can fill the left ventricle, but it can’t be provided to the fundamental flow by means of the hypoplastic rising aorta. The Mitral Stenosis and Aortic Stenosis (MS-AS) subtype is the mildest form. Even though the left ventricle is able to provide some blood flow to the rest of the body in these patients, the left ventricular systemic output is still insufficient overall.
  • #9 Hypoplastic Left Heart Syndrome | Radiology Key
    https://radiologykey.com/hypoplastic-left-heart-syndrome/
    Hemodynamically, blood is unable to pass through the left ventricle and aortic valve and therefore is shunted in a retrograde manner from the left atrium, through the foramen ovale, and back into the right atrium. This results in an increase in the size of the right atrium, right ventricle, and main pulmonary artery. […] Because of the left heart hypoplasia, the right ventricle supplies both the pulmonary and systemic circulations. The pulmonary veins may be either normal or increased in size. The blood volume and pressure in the right heart are elevated. The left atrium, left ventricle, and aorta are all decreased in size. In severe cases of hypoplasia of the ascending aorta, the coronary arteries are perfused in a retrograde manner by the ductus arteriosus. […] HLHS results in cardiac function similar to that seen in univentricular hearts. The increased right ventricular pressure, together with inadequate flow out of the left atrium, results in elevated pulmonary venous pressure and pulmonary congestion.
  • #10 Hypoplastic Left Heart Syndrome | Radiology Key
    https://radiologykey.com/hypoplastic-left-heart-syndrome/
    Hemodynamically, blood is unable to pass through the left ventricle and aortic valve and therefore is shunted in a retrograde manner from the left atrium, through the foramen ovale, and back into the right atrium. This results in an increase in the size of the right atrium, right ventricle, and main pulmonary artery. […] Because of the left heart hypoplasia, the right ventricle supplies both the pulmonary and systemic circulations. The pulmonary veins may be either normal or increased in size. The blood volume and pressure in the right heart are elevated. The left atrium, left ventricle, and aorta are all decreased in size. In severe cases of hypoplasia of the ascending aorta, the coronary arteries are perfused in a retrograde manner by the ductus arteriosus. […] HLHS results in cardiac function similar to that seen in univentricular hearts. The increased right ventricular pressure, together with inadequate flow out of the left atrium, results in elevated pulmonary venous pressure and pulmonary congestion.
  • #11 Hypoplastic Left Heart Syndrome – StatPearls – NCBI Bookshelf
    https://www.ncbi.nlm.nih.gov/books/NBK554576/
    Hypoplastic left heart syndrome (HLHS) is a rare but severe congenital heart defect characterized by underdevelopment of left-sided heart structures, including the left ventricle, aortic valve, mitral valve, and ascending aorta. […] The etiology of HLHS is multifactorial, involving a combination of genetic, environmental, and possibly epigenetic influences. […] The primary defect in HLHS arises during embryogenesis, between weeks 4 and 8 of gestation, due to abnormal development of the left-sided heart structures. […] The main factors leading to this defect are atresia or critical stenosis of the aortic or mitral valves, resulting in hypoplasia of the LV, ascending aorta, and aortic arch. […] Insufficient blood flow through the left heart during fetal development contributes to hypoplasia, while intrinsic genetic defects may impair cellular proliferation, differentiation, or signaling pathways critical for normal heart morphogenesis.
  • #12 Hypoplastic left heart syndrome – Wikipedia
    https://en.wikipedia.org/wiki/Hypoplastic_left_heart_syndrome
    Hypoplastic left heart syndrome (HLHS) is a rare congenital heart defect in which the left side of the heart is severely underdeveloped and incapable of supporting the systemic circulation. […] The etiology is believed to be multifactorial resulting from a combination of genetic mutations and defects resulting in altered blood flow in the heart. […] The majority of HLHS cases are sporadic meaning they arise in patients with no family history of HLHS. […] Some cases may have a genetic component, as HLHS has been shown to be heritable and associated with specific gene mutations. […] Possible contributing factors may include intrauterine infarction, infectious changes, and a selective left ventricular cardiomyopathy. […] Genetic loci associated with HLHS include GJA1 (connexin 43), HAND1, NKX2.5, 10q22, and 6q23.
  • #13 Hypoplastic left heart syndrome – Wikipedia
    https://en.wikipedia.org/wiki/Hypoplastic_left_heart_syndrome
    Hypoplastic left heart syndrome (HLHS) is a rare congenital heart defect in which the left side of the heart is severely underdeveloped and incapable of supporting the systemic circulation. […] The etiology is believed to be multifactorial resulting from a combination of genetic mutations and defects resulting in altered blood flow in the heart. […] The majority of HLHS cases are sporadic meaning they arise in patients with no family history of HLHS. […] Some cases may have a genetic component, as HLHS has been shown to be heritable and associated with specific gene mutations. […] Possible contributing factors may include intrauterine infarction, infectious changes, and a selective left ventricular cardiomyopathy. […] Genetic loci associated with HLHS include GJA1 (connexin 43), HAND1, NKX2.5, 10q22, and 6q23.
  • #14 Hypoplastic left heart syndrome – Wikipedia
    https://en.wikipedia.org/wiki/Hypoplastic_left_heart_syndrome
    Hypoplastic left heart syndrome (HLHS) is a rare congenital heart defect in which the left side of the heart is severely underdeveloped and incapable of supporting the systemic circulation. […] The etiology is believed to be multifactorial resulting from a combination of genetic mutations and defects resulting in altered blood flow in the heart. […] The majority of HLHS cases are sporadic meaning they arise in patients with no family history of HLHS. […] Some cases may have a genetic component, as HLHS has been shown to be heritable and associated with specific gene mutations. […] Possible contributing factors may include intrauterine infarction, infectious changes, and a selective left ventricular cardiomyopathy. […] Genetic loci associated with HLHS include GJA1 (connexin 43), HAND1, NKX2.5, 10q22, and 6q23.
  • #15 Hypoplastic left heart syndrome – Wikipedia
    https://en.wikipedia.org/wiki/Hypoplastic_left_heart_syndrome
    Hypoplastic left heart syndrome (HLHS) is a rare congenital heart defect in which the left side of the heart is severely underdeveloped and incapable of supporting the systemic circulation. […] The etiology is believed to be multifactorial resulting from a combination of genetic mutations and defects resulting in altered blood flow in the heart. […] The majority of HLHS cases are sporadic meaning they arise in patients with no family history of HLHS. […] Some cases may have a genetic component, as HLHS has been shown to be heritable and associated with specific gene mutations. […] Possible contributing factors may include intrauterine infarction, infectious changes, and a selective left ventricular cardiomyopathy. […] Genetic loci associated with HLHS include GJA1 (connexin 43), HAND1, NKX2.5, 10q22, and 6q23.
  • #16 Hypoplastic Left Heart Syndrome | IntechOpen
    https://www.intechopen.com/chapters/81680
    While the causes for the poor cardiac outcomes are multifactorial, our study in a mouse model of HLHS uncovers important contributing factors related to mitochondrial dysfunction. […] The complex genetics of HLHS is further supported by analysis of HLHS mutant mice through the usage of a large-forward genetic screen. […] The results indicate that HLHS is genetically heterogeneous with a multi-genetic etiology. […] This entails closure of the mitochondrial permeability transition pore (mPTP) and formation of a mitochondrial transmembrane potential (m) mediating oxidative phosphorylation. […] These findings suggest systemic defects impact mitochondrial respiration in SV-CHD patients.
  • #17
    https://grantome.com/grant/NIH/R01-HL142788-03S1
    Hypoplastic Left Heart Syndrome (HLHS) is a congenital heart defect (CHD) characterized by a small left ventricle (LV) and hypoplastic aorta and aortic/mitral valves. A genetic etiology for HLHS is strongly indicated by high recurrence risk, but the genetic underpinning for HLHS is poorly understood. Clinical studies suggest HLHS is multigenic and genetically heterogeneous. Insights into the genetics of HLHS has come from our recent recovery of the first mouse models of HLHS from a large-scale mouse mutagenesis screen. […] Detailed analysis of one mutant mouse line, Ohia, showed HLSH is elicited by mutations in two genes: Sap130, a Sin3a associated protein in the chromatin modifying histone deacetylase complex (HDAC), and Pcdha9, a protocadherin mediating cell-cell adhesion. The LV hypoplasia was shown to be elicited by the Sap130 mutation, a finding confirmed with replication of a small ventricle phenotype in a CRISPR generated sap130a zebrafish mutant. The LV hypoplasia was associated with a cardiomyocyte cell proliferation defect and cardiomyocyte cell cycle arrest.
  • #18
    https://grantome.com/grant/NIH/R01-HL142788-03S1
    Hypoplastic Left Heart Syndrome (HLHS) is a congenital heart defect (CHD) characterized by a small left ventricle (LV) and hypoplastic aorta and aortic/mitral valves. A genetic etiology for HLHS is strongly indicated by high recurrence risk, but the genetic underpinning for HLHS is poorly understood. Clinical studies suggest HLHS is multigenic and genetically heterogeneous. Insights into the genetics of HLHS has come from our recent recovery of the first mouse models of HLHS from a large-scale mouse mutagenesis screen. […] Detailed analysis of one mutant mouse line, Ohia, showed HLSH is elicited by mutations in two genes: Sap130, a Sin3a associated protein in the chromatin modifying histone deacetylase complex (HDAC), and Pcdha9, a protocadherin mediating cell-cell adhesion. The LV hypoplasia was shown to be elicited by the Sap130 mutation, a finding confirmed with replication of a small ventricle phenotype in a CRISPR generated sap130a zebrafish mutant. The LV hypoplasia was associated with a cardiomyocyte cell proliferation defect and cardiomyocyte cell cycle arrest.
  • #19
    https://grantome.com/grant/NIH/R01-HL142788-03S1
    In this study, we will investigate the cellular and molecular mechanisms and genetic interactions driving the LV hypoplasia in HLHS, leveraging the unique strengths of the zebrafish and mouse models. […] This study is motivated by the unexpected recovery of mutations in chromatin modifiers and Ras/MAPK pathway components in all 8 HLHS mouse lines, suggesting chromatin modifiers in combination with dysregulated Ras/MAPK signaling may contribute to the LV hypoplasia and complex genetics of HLHS. Together these studies will help to elucidate the cellular and molecular mechanisms driving the ventricular hypoplasia in HLHS, findings that may yield new therapeutic targets for fetal intervention to recover LV growth. […] The objective of this proposal is to delineate the cellular, molecular and genetic mechanisms of ventricular hypoplasia in hypoplastic left heart syndrome (HLHS), a congenital defect with marked hypoplasia of the left ventricle that essentially leaves the conceptus with only a single pumping chamber. These studies will use the zebrafish and mouse models, leveraging the unique advantages of each model system to elucidate the developmental mechanisms driving the ventricular hypoplasia and thus help identify new druggable targets amenable to fetal intervention for recovery of LV growth.
  • #20 Hypoplastic left heart syndrome – Wikipedia
    https://en.wikipedia.org/wiki/Hypoplastic_left_heart_syndrome
    A popular theory termed the „no flow, no grow” hypothesis suggest that primary anatomic defects of the aortic and mitral valves lead to malformations of the left ventricle and its outflow tract. […] Outflow tract obstruction leads to left ventricular hypertrophy and reduction in the left ventricular lumen. […] Aortic stenosis that occurs during fetal development results in added stress on the left ventricle in utero. This can eventually lead to decreased perfusion through the left ventricle which is believed to inhibit ventricular growth.
  • #21 Hypoplastic Left Heart Syndrome – StatPearls – NCBI Bookshelf
    https://www.ncbi.nlm.nih.gov/books/NBK554576/
    The condition arises from multifactorial etiologies, with the main factor being an obstruction to LV outflow caused by aortic stenosis or atresia during fetal development. […] This obstruction increases LV afterload, causing hypertrophy and subsequently inhibiting ventricular growth, resulting in hypoplasia. […] Increased left atrial pressure due to inadequate LV egress causes bidirectional flow or reversal through the foramen ovale, exacerbating hypoplasia. […] Mitral stenosis or atresia can similarly limit LV inflow, leading to decreased preload, reduced pressure, and underdevelopment of the LV and associated structures.
  • #22 Hypoplastic Left Heart Syndrome – StatPearls – NCBI Bookshelf
    https://www.ncbi.nlm.nih.gov/books/NBK554576/
    The condition arises from multifactorial etiologies, with the main factor being an obstruction to LV outflow caused by aortic stenosis or atresia during fetal development. […] This obstruction increases LV afterload, causing hypertrophy and subsequently inhibiting ventricular growth, resulting in hypoplasia. […] Increased left atrial pressure due to inadequate LV egress causes bidirectional flow or reversal through the foramen ovale, exacerbating hypoplasia. […] Mitral stenosis or atresia can similarly limit LV inflow, leading to decreased preload, reduced pressure, and underdevelopment of the LV and associated structures.
  • #23 Hypoplastic Left Heart Syndrome – StatPearls – NCBI Bookshelf
    https://www.ncbi.nlm.nih.gov/books/NBK554576/
    The condition arises from multifactorial etiologies, with the main factor being an obstruction to LV outflow caused by aortic stenosis or atresia during fetal development. […] This obstruction increases LV afterload, causing hypertrophy and subsequently inhibiting ventricular growth, resulting in hypoplasia. […] Increased left atrial pressure due to inadequate LV egress causes bidirectional flow or reversal through the foramen ovale, exacerbating hypoplasia. […] Mitral stenosis or atresia can similarly limit LV inflow, leading to decreased preload, reduced pressure, and underdevelopment of the LV and associated structures.
  • #24 Hypoplastic Left Heart Syndrome – StatPearls – NCBI Bookshelf
    https://www.ncbi.nlm.nih.gov/books/NBK554576/
    The condition arises from multifactorial etiologies, with the main factor being an obstruction to LV outflow caused by aortic stenosis or atresia during fetal development. […] This obstruction increases LV afterload, causing hypertrophy and subsequently inhibiting ventricular growth, resulting in hypoplasia. […] Increased left atrial pressure due to inadequate LV egress causes bidirectional flow or reversal through the foramen ovale, exacerbating hypoplasia. […] Mitral stenosis or atresia can similarly limit LV inflow, leading to decreased preload, reduced pressure, and underdevelopment of the LV and associated structures.
  • #25 Hypoplastic left heart syndrome – Wikipedia
    https://en.wikipedia.org/wiki/Hypoplastic_left_heart_syndrome
    A popular theory termed the „no flow, no grow” hypothesis suggest that primary anatomic defects of the aortic and mitral valves lead to malformations of the left ventricle and its outflow tract. […] Outflow tract obstruction leads to left ventricular hypertrophy and reduction in the left ventricular lumen. […] Aortic stenosis that occurs during fetal development results in added stress on the left ventricle in utero. This can eventually lead to decreased perfusion through the left ventricle which is believed to inhibit ventricular growth.
  • #26 Flow-Mediated Factors in the Pathogenesis of Hypoplastic Left Heart Syndrome
    https://www.mdpi.com/2308-3425/9/5/154
    Hypoplastic left heart syndrome (HLHS) is a life-threatening congenital heart disease that is characterized by severe underdevelopment of left heart structures. […] A major barrier in developing effective treatments is that the etiology of HLHS is largely unknown. Here, we discuss how intracardiac blood flow disturbances are an important causal factor in the pathogenesis of impaired left heart growth. […] Several lines of evidence suggest that decreased blood flow through the left heart is important in the pathogenesis of HLHS. […] While these clinical findings and animal studies support the idea that decreased blood flow can lead to decreased growth of left heart structures, the history and pathogenesis of HLHS in utero is still unknown. […] Our results thus give support to the “no-flow, no-grow” hypothesis of HLHS and indicate that (i) decreased blood flow through the left heart can lead to growth failure and (ii) a subset of HLHS cases likely occur in the fetal period post-cardiogenesis, rather than in the embryonic period.
  • #27 Flow-Mediated Factors in the Pathogenesis of Hypoplastic Left Heart Syndrome
    https://www.mdpi.com/2308-3425/9/5/154
    Emerging evidence suggests that the mechanical forces imparted by blood flow and oxygenation content can independently mediate growth and remodeling of left heart structures through mechanosensitive and hypoxia-sensing programs. […] The findings from the surgically induced mouse model of HLHS shows that decreased blood through the left heart following the closure of interventricular communication can lead to the development of hypoplastic left heart syndrome. […] This suggests that blood flow perturbations are an important causal factor in the pathogenesis of this disease and that a subset of cases may develop in the fetal rather than the early embryonic period.
  • #28 Hypoplastic Left Heart Syndrome: A New Paradigm for an Old Disease?
    https://www.mdpi.com/2308-3425/6/1/10
    Two contrasting theories have been proposed to explain the pathogenesis. The first, which implicates abnormal flow, suggests that the reduced size of the left ventricular cavity is secondary to decreased flow across the mitral valve, with decreased growth of the distal left-sided structures. […] The second theory implicates the hypoplasia of the left ventricle as the primary mechanism. […] Consistent with this hypothesis, mutations in at least one gene, namely NKX2-5, have been reported in association with both hypoplasia of the left heart and cardiomyopathy. […] At the cellular level, increased fibrosis associated with disarray of the cardiomyocytes has been observed in tissue obtained from explanted hearts from infants. […] The critical question remains as to whether the findings are secondary, in other words due to ischemia from altered hemodynamics, or are part of the primary disease process which underscores the ventricular hypoplasia.
  • #29 Hypoplastic Left Heart Syndrome: A New Paradigm for an Old Disease?
    https://www.mdpi.com/2308-3425/6/1/10
    Hypoplastic left heart syndrome occurs in up to 3% of all infants born with congenital heart disease and is a leading cause of death in this population. […] Although there is strong evidence for a genetic component, a specific genetic cause is only known in a small subset of patients, consistent with a multifactorial etiology for the syndrome. […] The most commonly held view is that the “decreased” growth of the left ventricle is due to a decreased flow during a critical period of ventricular development. […] There is a growing body of evidence, nonetheless, indicating that the hypoplasia of the left ventricle is due to a primary defect in ventricular development. […] In this regard, hypoplastic left heart syndrome could be viewed as a neonatal form of cardiomyopathy. […] We also discuss the role of the endocardium in the development of the ventricular hypoplasia, which may provide a mechanistic basis for how impaired flow to the developing ventricle leads to the anatomical changes seen in the syndrome.
  • #30 Hypoplastic Left Heart Syndrome: A New Paradigm for an Old Disease?
    https://www.mdpi.com/2308-3425/6/1/10
    Hypoplastic left heart syndrome occurs in up to 3% of all infants born with congenital heart disease and is a leading cause of death in this population. […] Although there is strong evidence for a genetic component, a specific genetic cause is only known in a small subset of patients, consistent with a multifactorial etiology for the syndrome. […] The most commonly held view is that the “decreased” growth of the left ventricle is due to a decreased flow during a critical period of ventricular development. […] There is a growing body of evidence, nonetheless, indicating that the hypoplasia of the left ventricle is due to a primary defect in ventricular development. […] In this regard, hypoplastic left heart syndrome could be viewed as a neonatal form of cardiomyopathy. […] We also discuss the role of the endocardium in the development of the ventricular hypoplasia, which may provide a mechanistic basis for how impaired flow to the developing ventricle leads to the anatomical changes seen in the syndrome.
  • #31 Hypoplastic Left Heart Syndrome: A New Paradigm for an Old Disease?
    https://www.mdpi.com/2308-3425/6/1/10
    Two contrasting theories have been proposed to explain the pathogenesis. The first, which implicates abnormal flow, suggests that the reduced size of the left ventricular cavity is secondary to decreased flow across the mitral valve, with decreased growth of the distal left-sided structures. […] The second theory implicates the hypoplasia of the left ventricle as the primary mechanism. […] Consistent with this hypothesis, mutations in at least one gene, namely NKX2-5, have been reported in association with both hypoplasia of the left heart and cardiomyopathy. […] At the cellular level, increased fibrosis associated with disarray of the cardiomyocytes has been observed in tissue obtained from explanted hearts from infants. […] The critical question remains as to whether the findings are secondary, in other words due to ischemia from altered hemodynamics, or are part of the primary disease process which underscores the ventricular hypoplasia.
  • #32 Hypoplastic Left Heart Syndrome: A New Paradigm for an Old Disease?
    https://www.mdpi.com/2308-3425/6/1/10
    Two contrasting theories have been proposed to explain the pathogenesis. The first, which implicates abnormal flow, suggests that the reduced size of the left ventricular cavity is secondary to decreased flow across the mitral valve, with decreased growth of the distal left-sided structures. […] The second theory implicates the hypoplasia of the left ventricle as the primary mechanism. […] Consistent with this hypothesis, mutations in at least one gene, namely NKX2-5, have been reported in association with both hypoplasia of the left heart and cardiomyopathy. […] At the cellular level, increased fibrosis associated with disarray of the cardiomyocytes has been observed in tissue obtained from explanted hearts from infants. […] The critical question remains as to whether the findings are secondary, in other words due to ischemia from altered hemodynamics, or are part of the primary disease process which underscores the ventricular hypoplasia.
  • #33 Hypoplastic Left Heart Syndrome: A New Paradigm for an Old Disease?
    https://www.mdpi.com/2308-3425/6/1/10
    Two contrasting theories have been proposed to explain the pathogenesis. The first, which implicates abnormal flow, suggests that the reduced size of the left ventricular cavity is secondary to decreased flow across the mitral valve, with decreased growth of the distal left-sided structures. […] The second theory implicates the hypoplasia of the left ventricle as the primary mechanism. […] Consistent with this hypothesis, mutations in at least one gene, namely NKX2-5, have been reported in association with both hypoplasia of the left heart and cardiomyopathy. […] At the cellular level, increased fibrosis associated with disarray of the cardiomyocytes has been observed in tissue obtained from explanted hearts from infants. […] The critical question remains as to whether the findings are secondary, in other words due to ischemia from altered hemodynamics, or are part of the primary disease process which underscores the ventricular hypoplasia.
  • #34 Hypoplastic Left Heart Syndrome: A New Paradigm for an Old Disease?
    https://www.mdpi.com/2308-3425/6/1/10
    Loss of endocardial function leading to an initial arrest of growth of the developing left ventricle may be a critical early step in the pathogenesis of the syndrome. […] Understanding the basis for why, in some cases, ventricular development during fetal life can proceed normally in the presence of aortic stenosis could provide critical insights into how the syndrome itself could be prevented. […] Much remains to be learned, therefore, about the pathogenesis of hypoplastic left heart syndrome.
  • #35 A Subset of Cells That Can Break Your Heart | Stanford Cardiovascular Institute | Stanford Medicine
    https://med.stanford.edu/cvi/mission/news_center/articles_announcements/a-subset-of-cells-that-can-break-your-heart.html
    Hypoplastic left heart syndrome (HLHS) is characterized by the underdevelopment of heart valves as well as the left ventricle, the main pumping chamber of the heart. […] However, the cause for why these hearts develop abnormally is not well understood. Scientists have long sought the mechanism responsible for the developmental abnormalities in the heart muscle of HLHS patients, however, the cells that exhibit deficits that could help explain the malformation seen in HLHS hearts remain elusive. […] Since HLHS is characterized by structural abnormalities in the valves and under-development of the left ventricle, it has been speculated that a defect in the endocardium may be the mechanism underlying HLHS. […] Miao and Tian et als study, recently reported in Cell Stem Cell, has uncovered a mechanism that helps to explain the congenital heart defects seen in HLHS patients (i.e. the presence of faulty endocardial cells causes developmental impairment in the endocardium). Not only does this study help explain the cause of HLHS, but it suggests that approaches that focus on endocardial function could be a fruitful avenue for treating other heart diseases.
  • #36 A Subset of Cells That Can Break Your Heart | Stanford Cardiovascular Institute | Stanford Medicine
    https://med.stanford.edu/cvi/mission/news_center/articles_announcements/a-subset-of-cells-that-can-break-your-heart.html
    Hypoplastic left heart syndrome (HLHS) is characterized by the underdevelopment of heart valves as well as the left ventricle, the main pumping chamber of the heart. […] However, the cause for why these hearts develop abnormally is not well understood. Scientists have long sought the mechanism responsible for the developmental abnormalities in the heart muscle of HLHS patients, however, the cells that exhibit deficits that could help explain the malformation seen in HLHS hearts remain elusive. […] Since HLHS is characterized by structural abnormalities in the valves and under-development of the left ventricle, it has been speculated that a defect in the endocardium may be the mechanism underlying HLHS. […] Miao and Tian et als study, recently reported in Cell Stem Cell, has uncovered a mechanism that helps to explain the congenital heart defects seen in HLHS patients (i.e. the presence of faulty endocardial cells causes developmental impairment in the endocardium). Not only does this study help explain the cause of HLHS, but it suggests that approaches that focus on endocardial function could be a fruitful avenue for treating other heart diseases.
  • #37 A Subset of Cells That Can Break Your Heart | Stanford Cardiovascular Institute | Stanford Medicine
    https://med.stanford.edu/cvi/mission/news_center/articles_announcements/a-subset-of-cells-that-can-break-your-heart.html
    Hypoplastic left heart syndrome (HLHS) is characterized by the underdevelopment of heart valves as well as the left ventricle, the main pumping chamber of the heart. […] However, the cause for why these hearts develop abnormally is not well understood. Scientists have long sought the mechanism responsible for the developmental abnormalities in the heart muscle of HLHS patients, however, the cells that exhibit deficits that could help explain the malformation seen in HLHS hearts remain elusive. […] Since HLHS is characterized by structural abnormalities in the valves and under-development of the left ventricle, it has been speculated that a defect in the endocardium may be the mechanism underlying HLHS. […] Miao and Tian et als study, recently reported in Cell Stem Cell, has uncovered a mechanism that helps to explain the congenital heart defects seen in HLHS patients (i.e. the presence of faulty endocardial cells causes developmental impairment in the endocardium). Not only does this study help explain the cause of HLHS, but it suggests that approaches that focus on endocardial function could be a fruitful avenue for treating other heart diseases.
  • #38 Hypoplastic Left Heart Syndrome | IntechOpen
    https://www.intechopen.com/chapters/81680
    Hypoplastic left heart syndrome (HLHS) is a complex congenital heart disease (CHD) involving hypoplasia of the left ventricle (LV), aorta (Ao), and mitral valve. […] The causes for such high morbidity and mortality are not well understood, but the majority of deaths are directly or indirectly related to cardiovascular/hemodynamics causes. Studies in a mouse model of HLHS uncover important contributing factors for single-ventricle patients such as the patients intrinsic factors related to mitochondrial dysfunction, and derangements in the early stages of embryonic development. The HLHS mutant mice were noted to have metabolic dysfunction accompanied by cell cycle arrest and cardiomyocyte differentiation defects. […] Moreover, strong evidence of the genetic etiology of HLHS has come from the observation that HLHS has a high recurrence risk and is associated with various chromosomal abnormalities.
  • #39 Hypoplastic Left Heart Syndrome | IntechOpen
    https://www.intechopen.com/chapters/81680
    Hypoplastic left heart syndrome (HLHS) is a complex congenital heart disease (CHD) involving hypoplasia of the left ventricle (LV), aorta (Ao), and mitral valve. […] The causes for such high morbidity and mortality are not well understood, but the majority of deaths are directly or indirectly related to cardiovascular/hemodynamics causes. Studies in a mouse model of HLHS uncover important contributing factors for single-ventricle patients such as the patients intrinsic factors related to mitochondrial dysfunction, and derangements in the early stages of embryonic development. The HLHS mutant mice were noted to have metabolic dysfunction accompanied by cell cycle arrest and cardiomyocyte differentiation defects. […] Moreover, strong evidence of the genetic etiology of HLHS has come from the observation that HLHS has a high recurrence risk and is associated with various chromosomal abnormalities.
  • #40 Intrinsic myocardial defects underlie an Rbfox-deficient zebrafish model of hypoplastic left heart syndrome | Nature Communications
    https://www.nature.com/articles/s41467-022-32982-x
    Hypoplastic left heart syndrome (HLHS) is characterized by underdevelopment of left sided structures including the ventricle, valves, and aorta. […] Here, we report that zebrafish lacking two orthologs of the RNA binding protein RBFOX2, a gene linked to HLHS in humans, display cardiovascular defects overlapping those in HLHS patients including ventricular, valve, and aortic deficiencies. […] Mechanistically, we find diminished expression and alternative splicing of sarcomere and mitochondrial components that compromise sarcomere assembly and mitochondrial respiration, respectively. […] This work supports an emerging paradigm for HLHS pathogenesis that centers on myocardial intrinsic defects. […] Here, we used CRISPR-Cas9 genome editing to create zebrafish lacking Rbfox1l and Rbfox2.
  • #41 Intrinsic myocardial defects underlie an Rbfox-deficient zebrafish model of hypoplastic left heart syndrome | Nature Communications
    https://www.nature.com/articles/s41467-022-32982-x
    Hypoplastic left heart syndrome (HLHS) is characterized by underdevelopment of left sided structures including the ventricle, valves, and aorta. […] Here, we report that zebrafish lacking two orthologs of the RNA binding protein RBFOX2, a gene linked to HLHS in humans, display cardiovascular defects overlapping those in HLHS patients including ventricular, valve, and aortic deficiencies. […] Mechanistically, we find diminished expression and alternative splicing of sarcomere and mitochondrial components that compromise sarcomere assembly and mitochondrial respiration, respectively. […] This work supports an emerging paradigm for HLHS pathogenesis that centers on myocardial intrinsic defects. […] Here, we used CRISPR-Cas9 genome editing to create zebrafish lacking Rbfox1l and Rbfox2.
  • #42 Intrinsic myocardial defects underlie an Rbfox-deficient zebrafish model of hypoplastic left heart syndrome | Nature Communications
    https://www.nature.com/articles/s41467-022-32982-x
    Hypoplastic left heart syndrome (HLHS) is characterized by underdevelopment of left sided structures including the ventricle, valves, and aorta. […] Here, we report that zebrafish lacking two orthologs of the RNA binding protein RBFOX2, a gene linked to HLHS in humans, display cardiovascular defects overlapping those in HLHS patients including ventricular, valve, and aortic deficiencies. […] Mechanistically, we find diminished expression and alternative splicing of sarcomere and mitochondrial components that compromise sarcomere assembly and mitochondrial respiration, respectively. […] This work supports an emerging paradigm for HLHS pathogenesis that centers on myocardial intrinsic defects. […] Here, we used CRISPR-Cas9 genome editing to create zebrafish lacking Rbfox1l and Rbfox2.
  • #43 Intrinsic myocardial defects underlie an Rbfox-deficient zebrafish model of hypoplastic left heart syndrome | Nature Communications
    https://www.nature.com/articles/s41467-022-32982-x
    Together, these data demonstrate that Rbfox proteins are essential for sarcomere assembly in vivo and suggest that this defect contributes to the functional deficiency observed in DKO hearts. […] These data demonstrate that Rbfox proteins are essential for sarcomere assembly, mitochondrial ultrastructure, electron transport chain gene expression, and ATP production, which when defective compromises cardiomyocyte pump function and cell growth. […] Taken together, our data highlight that mutations in Rbfox2 orthologs are sufficient to cause the full spectrum of HLHS-like phenotypes in zebrafish through a primary functional deficiency and underscore the need for whole animal modeling of this complicated disease. […] Overall, our study supports an emerging paradigm for HLHS pathogenesis that centers on myocardial intrinsic abnormalities.
  • #44 Intrinsic myocardial defects underlie an Rbfox-deficient zebrafish model of hypoplastic left heart syndrome | Nature Communications
    https://www.nature.com/articles/s41467-022-32982-x
    Together, these data demonstrate that Rbfox proteins are essential for sarcomere assembly in vivo and suggest that this defect contributes to the functional deficiency observed in DKO hearts. […] These data demonstrate that Rbfox proteins are essential for sarcomere assembly, mitochondrial ultrastructure, electron transport chain gene expression, and ATP production, which when defective compromises cardiomyocyte pump function and cell growth. […] Taken together, our data highlight that mutations in Rbfox2 orthologs are sufficient to cause the full spectrum of HLHS-like phenotypes in zebrafish through a primary functional deficiency and underscore the need for whole animal modeling of this complicated disease. […] Overall, our study supports an emerging paradigm for HLHS pathogenesis that centers on myocardial intrinsic abnormalities.
  • #45 Hypoplastic Left Heart Syndrome – StatPearls – NCBI Bookshelf
    https://www.ncbi.nlm.nih.gov/books/NBK554576/
    Hypoplastic left heart syndrome (HLHS) is a rare but severe congenital heart defect characterized by underdevelopment of left-sided heart structures, including the left ventricle, aortic valve, mitral valve, and ascending aorta. […] The etiology of HLHS is multifactorial, involving a combination of genetic, environmental, and possibly epigenetic influences. […] The primary defect in HLHS arises during embryogenesis, between weeks 4 and 8 of gestation, due to abnormal development of the left-sided heart structures. […] The main factors leading to this defect are atresia or critical stenosis of the aortic or mitral valves, resulting in hypoplasia of the LV, ascending aorta, and aortic arch. […] Insufficient blood flow through the left heart during fetal development contributes to hypoplasia, while intrinsic genetic defects may impair cellular proliferation, differentiation, or signaling pathways critical for normal heart morphogenesis.
  • #46 Hypoplastic Left Heart Syndrome – StatPearls – NCBI Bookshelf
    https://www.ncbi.nlm.nih.gov/books/NBK554576/
    Hypoplastic left heart syndrome (HLHS) is a rare but severe congenital heart defect characterized by underdevelopment of left-sided heart structures, including the left ventricle, aortic valve, mitral valve, and ascending aorta. […] The etiology of HLHS is multifactorial, involving a combination of genetic, environmental, and possibly epigenetic influences. […] The primary defect in HLHS arises during embryogenesis, between weeks 4 and 8 of gestation, due to abnormal development of the left-sided heart structures. […] The main factors leading to this defect are atresia or critical stenosis of the aortic or mitral valves, resulting in hypoplasia of the LV, ascending aorta, and aortic arch. […] Insufficient blood flow through the left heart during fetal development contributes to hypoplasia, while intrinsic genetic defects may impair cellular proliferation, differentiation, or signaling pathways critical for normal heart morphogenesis.
  • #47 Hypoplastic Left Heart Syndrome – StatPearls – NCBI Bookshelf
    https://www.ncbi.nlm.nih.gov/books/NBK554576/
    Hypoplastic left heart syndrome (HLHS) is a rare but severe congenital heart defect characterized by underdevelopment of left-sided heart structures, including the left ventricle, aortic valve, mitral valve, and ascending aorta. […] The etiology of HLHS is multifactorial, involving a combination of genetic, environmental, and possibly epigenetic influences. […] The primary defect in HLHS arises during embryogenesis, between weeks 4 and 8 of gestation, due to abnormal development of the left-sided heart structures. […] The main factors leading to this defect are atresia or critical stenosis of the aortic or mitral valves, resulting in hypoplasia of the LV, ascending aorta, and aortic arch. […] Insufficient blood flow through the left heart during fetal development contributes to hypoplasia, while intrinsic genetic defects may impair cellular proliferation, differentiation, or signaling pathways critical for normal heart morphogenesis.
  • #48 Flow-Mediated Factors in the Pathogenesis of Hypoplastic Left Heart Syndrome
    https://www.mdpi.com/2308-3425/9/5/154
    Emerging evidence suggests that the mechanical forces imparted by blood flow and oxygenation content can independently mediate growth and remodeling of left heart structures through mechanosensitive and hypoxia-sensing programs. […] The findings from the surgically induced mouse model of HLHS shows that decreased blood through the left heart following the closure of interventricular communication can lead to the development of hypoplastic left heart syndrome. […] This suggests that blood flow perturbations are an important causal factor in the pathogenesis of this disease and that a subset of cases may develop in the fetal rather than the early embryonic period.
  • #49 Pediatric Hypoplastic Left Heart Syndrome: Background, Pathophysiology, Etiology
    https://emedicine.medscape.com/article/890196-overview
    The term hypoplastic left heart syndrome (HLHS), initially proposed by Noonan and Nadas, describes a spectrum of cardiac abnormalities characterized by marked hypoplasia of the left ventricle and ascending aorta. […] Hypoplasia of the left heart structures is noted, with enlargement and hypertrophy of the right heart. Similar to other congenital heart defects, hypoplastic left heart syndrome also has a spectrum of severity. […] The exact cause of hypoplastic left heart syndrome is unknown. Although familial cases with autosomal recessive inheritance have been reported, hypoplastic left heart syndrome is generally postulated to follow multifactorial mode of inheritance. […] Most likely, the primary abnormality occurs during aortic and mitral valve development. During cardiac development, adequate flow of blood through a structure is largely responsible for the growth of that structure. With little or no blood flow because of aortic and mitral valve atresia, growth of the left ventricle does not occur.
  • #50 Pediatric Hypoplastic Left Heart Syndrome: Background, Pathophysiology, Etiology
    https://emedicine.medscape.com/article/890196-overview
    The term hypoplastic left heart syndrome (HLHS), initially proposed by Noonan and Nadas, describes a spectrum of cardiac abnormalities characterized by marked hypoplasia of the left ventricle and ascending aorta. […] Hypoplasia of the left heart structures is noted, with enlargement and hypertrophy of the right heart. Similar to other congenital heart defects, hypoplastic left heart syndrome also has a spectrum of severity. […] The exact cause of hypoplastic left heart syndrome is unknown. Although familial cases with autosomal recessive inheritance have been reported, hypoplastic left heart syndrome is generally postulated to follow multifactorial mode of inheritance. […] Most likely, the primary abnormality occurs during aortic and mitral valve development. During cardiac development, adequate flow of blood through a structure is largely responsible for the growth of that structure. With little or no blood flow because of aortic and mitral valve atresia, growth of the left ventricle does not occur.
  • #51 Pediatric Hypoplastic Left Heart Syndrome: Background, Pathophysiology, Etiology
    https://emedicine.medscape.com/article/890196-overview
    Similarly, growth of the ascending aorta does not occur because of lack of left ventricular output. The ascending aorta is perfused in retrograde manner from the ductus arteriosus functioning only as a common coronary artery. […] Another postulated cause is misalignment of the atrial septum to the left. […] More recent studies suggest that hypoplastic left heart syndrome is genetically heterogeneous and hypoplastic left heart syndrome and bicuspid aortic valve are genetically related.
  • #52 Hypoplastic Left Heart Syndrome | Radiology Key
    https://radiologykey.com/hypoplastic-left-heart-syndrome/
    Malalignment of the interatrial septum toward the left has also been proposed as a mechanism of interfering with left ventricular filling, resulting in poor development of that chamber. Another explanation for HLHS is that fusion of the endocardial cushions occurs but fails to produce a valve. It may also be due to an overgrowth of the ventral atrioventricular cushion, which deprives the ascending aorta of adequate blood flow. The resultant change in flow leads to the development of the structural cardiac anomalies associated with this syndrome. […] A third hypothesis is that the causative factor is a rudimentary left atrium and, consequently, diminished blood flow to the mitral portion of the atrioventricular canal. The left ventricle and aorta or aortic valve thus fail to develop properly because of the decreased blood flow through the lumen. The left ventricle will be small, the aortic valve may be stenotic, and coarctation of the aorta may result. Aortic stenosis or atresia may be valvular, subvalvular, or supravalvular.
  • #53 Hypoplastic Left Heart Syndrome | Radiology Key
    https://radiologykey.com/hypoplastic-left-heart-syndrome/
    Malalignment of the interatrial septum toward the left has also been proposed as a mechanism of interfering with left ventricular filling, resulting in poor development of that chamber. Another explanation for HLHS is that fusion of the endocardial cushions occurs but fails to produce a valve. It may also be due to an overgrowth of the ventral atrioventricular cushion, which deprives the ascending aorta of adequate blood flow. The resultant change in flow leads to the development of the structural cardiac anomalies associated with this syndrome. […] A third hypothesis is that the causative factor is a rudimentary left atrium and, consequently, diminished blood flow to the mitral portion of the atrioventricular canal. The left ventricle and aorta or aortic valve thus fail to develop properly because of the decreased blood flow through the lumen. The left ventricle will be small, the aortic valve may be stenotic, and coarctation of the aorta may result. Aortic stenosis or atresia may be valvular, subvalvular, or supravalvular.
  • #54 Flow-Mediated Factors in the Pathogenesis of Hypoplastic Left Heart Syndrome
    https://www.mdpi.com/2308-3425/9/5/154
    Emerging evidence suggests that the mechanical forces imparted by blood flow and oxygenation content can independently mediate growth and remodeling of left heart structures through mechanosensitive and hypoxia-sensing programs. […] The findings from the surgically induced mouse model of HLHS shows that decreased blood through the left heart following the closure of interventricular communication can lead to the development of hypoplastic left heart syndrome. […] This suggests that blood flow perturbations are an important causal factor in the pathogenesis of this disease and that a subset of cases may develop in the fetal rather than the early embryonic period.
  • #55 Hypoplastic Left Heart Syndrome: A New Paradigm for an Old Disease?
    https://www.mdpi.com/2308-3425/6/1/10
    Loss of endocardial function leading to an initial arrest of growth of the developing left ventricle may be a critical early step in the pathogenesis of the syndrome. […] Understanding the basis for why, in some cases, ventricular development during fetal life can proceed normally in the presence of aortic stenosis could provide critical insights into how the syndrome itself could be prevented. […] Much remains to be learned, therefore, about the pathogenesis of hypoplastic left heart syndrome.
  • #56 Neurodevelopmental outcome in hypoplastic left heart syndrome after hybrid procedure – Reich – Translational Pediatrics
    https://tp.amegroups.org/article/view/25235/html
    Antenatal brain maturational delay has been described to play an important role in this altered cerebral development. […] In fetuses with HLHS, abnormal brain growth, especially of the white matter structures, becomes detectable as early as the second trimester and reduced retrograde blood flow via the hypoplastic aortic arch has been hypothesized to be a culprit factor. […] It has been postulated that prevalence and severity of developmental disabilities further increase, if open-heart surgery is required during the neonatal period, since hypoxic/ischemic conditions, coagulation imbalances, inflammatory processes, and anesthetic drugs related to surgeries may further delay brain maturation and increase the risk of secondary acquired structural brain injury. […] It has been postulated that the Hybrid procedure might be beneficial in terms of protecting the premature brain.
  • #57
    https://grantome.com/grant/NIH/R01-HL142788-03S1
    In this study, we will investigate the cellular and molecular mechanisms and genetic interactions driving the LV hypoplasia in HLHS, leveraging the unique strengths of the zebrafish and mouse models. […] This study is motivated by the unexpected recovery of mutations in chromatin modifiers and Ras/MAPK pathway components in all 8 HLHS mouse lines, suggesting chromatin modifiers in combination with dysregulated Ras/MAPK signaling may contribute to the LV hypoplasia and complex genetics of HLHS. Together these studies will help to elucidate the cellular and molecular mechanisms driving the ventricular hypoplasia in HLHS, findings that may yield new therapeutic targets for fetal intervention to recover LV growth. […] The objective of this proposal is to delineate the cellular, molecular and genetic mechanisms of ventricular hypoplasia in hypoplastic left heart syndrome (HLHS), a congenital defect with marked hypoplasia of the left ventricle that essentially leaves the conceptus with only a single pumping chamber. These studies will use the zebrafish and mouse models, leveraging the unique advantages of each model system to elucidate the developmental mechanisms driving the ventricular hypoplasia and thus help identify new druggable targets amenable to fetal intervention for recovery of LV growth.
  • #58 Hypoplastic Left Heart Syndrome – Pediatrics – Merck Manual Professional Edition
    https://www.merckmanuals.com/professional/pediatrics/congenital-cardiovascular-anomalies/hypoplastic-left-heart-syndrome
    Survival ultimately requires staged surgical procedures that enable the right ventricle to function as the systemic ventricle and establishing a controlled source of pulmonary blood flow. […] In some infants with hypoplastic left heart syndrome, particularly those with severe tricuspid valve or ventricular dysfunction, heart transplantation is considered the procedure of choice; however, prostaglandin E1 infusion must be continued along with careful management of pulmonary and systemic vascular resistance until a donor heart is available.
  • #59 Hypoplastic Left Heart Syndrome – Pediatrics – Merck Manual Professional Edition
    https://www.merckmanuals.com/professional/pediatrics/congenital-cardiovascular-anomalies/hypoplastic-left-heart-syndrome
    Survival ultimately requires staged surgical procedures that enable the right ventricle to function as the systemic ventricle and establishing a controlled source of pulmonary blood flow. […] In some infants with hypoplastic left heart syndrome, particularly those with severe tricuspid valve or ventricular dysfunction, heart transplantation is considered the procedure of choice; however, prostaglandin E1 infusion must be continued along with careful management of pulmonary and systemic vascular resistance until a donor heart is available.
  • #60
    https://journals.lww.com/aopc/fulltext/2024/17020/regenerating_the_ailing_heart__stem_cell_therapies.6.aspx
    Hypoplastic left heart syndrome (HLHS) is a complex congenital heart defect (CHD) characterized by a spectrum of underdeveloped left-sided cardiac structures. […] The etiology of HLHS is multifactorial and is associated with chromosomal disorders such as Turner syndrome, DiGeorge syndrome, and Down syndrome and genetic causes such as mutations in genes encoding signaling pathways and transcription factors that hinder the proliferation, differentiation, and maturation of cardiac progenitor cells (CPCs), resulting in underdevelopment of the left heart structures and diminished contractility of cardiomyocytes. […] Researchers have also hypothesized that altered blood flow is responsible for the underdevelopment of cardiac structures seen in HLHS. […] Due to the limitations of standard management of HLHS, stem cell therapy, as an experimental procedure, offers hope for individuals with HLHS with the concept of delivering isolated cells to the site of injury or lesion for repair and regeneration.
  • #61
    https://journals.lww.com/aopc/fulltext/2024/17020/regenerating_the_ailing_heart__stem_cell_therapies.6.aspx
    Several types of stem cells are currently being explored for their potential application in treating HLHS. […] The principle of stem cell therapy is rooted in the belief that their delivery at the site of damage or injury can cause regeneration or healing, possibly by the release of paracrine factors, mitochondrial transfer, exosomes/extracellular vesicles, and reconstitution of cardiac niche and also play an antifibrotic and anti-apoptotic role. […] In HLHS, the effects of subclinical RV dysfunction are more pronounced due to under-development of the left side of the heart, leading to gross structural and microscopic changes in RV resulting in pressure and volume overload, and are often exacerbated by surgeries and ongoing physiologic demands. […] These studies have highlighted the potential roles of stem cells in various models of RV dysfunction, which are relevant to single-ventricular pathophysiology as observed in CHDs like HLHS.
  • #62
    https://journals.lww.com/aopc/fulltext/2024/17020/regenerating_the_ailing_heart__stem_cell_therapies.6.aspx
    The translation of findings from stem cell therapy studies for HLHS into clinical application faces several challenges. […] While palliative surgical interventions have extended the lifespan of affected individuals by creating an effective systemic right ventricular pump, persistent challenges in terms of quality of life and survival occur due to the development of RV overload-related dysfunction and failure. […] Several preclinical studies and clinical trials conducted using different types of stem cells and various administration routes in neonates and adults have demonstrated the efficacy of stem cells in regenerating damaged myocardial tissue and reducing heart failure. […] The emerging technologies related to stem cells have the potential to bring about a revolutionary transformation in the treatment of various CHDs in the pediatric population, with a particular focus on HLHS.
  • #63 Spontaneously Corrected Hypoplastic Left Heart: A Case Report and Exceptional Opportunity to Discuss Etiology with Novel Therapeutic Vision
    https://journalaim.com/Article/aim-31185
    Hypoplastic left heart syndrome (HLHS) is a relatively prevalent fetal echocardiography finding in complex congenital heart diseases. Current studies indicate that intrinsic and extrinsic mechanisms could be involved in the development of left heart hypoplasia. Left ventricular inflow or outflow disorders may cause left heart hypoplasia. […] In our patient, prenatal progressive left heart hypoplasia associated with restrictive foramen oval (FO) suggested the likelihood of a flow-mediated mechanism. Additionally, postnatal improvement of the hypoplastic left heart in the presence of a functional perimembranous ventricular septal defect (PM-VSD) reinforced the suspicion of an extrinsic mechanism. Pre- or postnatal interventional creation of an atrial septal defect (ASD) or VSD is our proposed method for HLHS in selected patients.
  • #64 Spontaneously Corrected Hypoplastic Left Heart: A Case Report and Exceptional Opportunity to Discuss Etiology with Novel Therapeutic Vision
    https://journalaim.com/Article/aim-31185
    Hypoplastic left heart syndrome (HLHS) is a relatively prevalent fetal echocardiography finding in complex congenital heart diseases. Current studies indicate that intrinsic and extrinsic mechanisms could be involved in the development of left heart hypoplasia. Left ventricular inflow or outflow disorders may cause left heart hypoplasia. […] In our patient, prenatal progressive left heart hypoplasia associated with restrictive foramen oval (FO) suggested the likelihood of a flow-mediated mechanism. Additionally, postnatal improvement of the hypoplastic left heart in the presence of a functional perimembranous ventricular septal defect (PM-VSD) reinforced the suspicion of an extrinsic mechanism. Pre- or postnatal interventional creation of an atrial septal defect (ASD) or VSD is our proposed method for HLHS in selected patients.
  • #65 Spontaneously Corrected Hypoplastic Left Heart: A Case Report and Exceptional Opportunity to Discuss Etiology with Novel Therapeutic Vision
    https://journalaim.com/Article/aim-31185
    Hypoplastic left heart syndrome (HLHS) is a relatively prevalent fetal echocardiography finding in complex congenital heart diseases. Current studies indicate that intrinsic and extrinsic mechanisms could be involved in the development of left heart hypoplasia. Left ventricular inflow or outflow disorders may cause left heart hypoplasia. […] In our patient, prenatal progressive left heart hypoplasia associated with restrictive foramen oval (FO) suggested the likelihood of a flow-mediated mechanism. Additionally, postnatal improvement of the hypoplastic left heart in the presence of a functional perimembranous ventricular septal defect (PM-VSD) reinforced the suspicion of an extrinsic mechanism. Pre- or postnatal interventional creation of an atrial septal defect (ASD) or VSD is our proposed method for HLHS in selected patients.
  • #66
    https://link.springer.com/article/10.1007/s11886-024-02122-6
    Understanding the full extent of insults that lead to the development of HLHS and the ability to test the efficacy of new surgical interventions is challenging without robust disease models that recapitulate HLHS physiology and hemodynamics. […] While there are multiple reports using mechanical flow obstruction to induce HLHS, genetic factors are known to play a role in human HLHS development. […] However, models of genetic induction of HLHS are much scarcer. […] Overall, these animal models provide various methods of recapitulating HLHS phenotype. […] Despite the species-specific differences between models, mid-gestation impairment of left heart blood flow was repeatedly used to recapitulate an HLHS-like phenotype with models recapitulating HLHS features including left heart hypoplasia, ascending aorta hypoplasia, and increased endocardial collagen deposition.
  • #67
    https://link.springer.com/article/10.1007/s11886-024-02122-6
    Understanding the full extent of insults that lead to the development of HLHS and the ability to test the efficacy of new surgical interventions is challenging without robust disease models that recapitulate HLHS physiology and hemodynamics. […] While there are multiple reports using mechanical flow obstruction to induce HLHS, genetic factors are known to play a role in human HLHS development. […] However, models of genetic induction of HLHS are much scarcer. […] Overall, these animal models provide various methods of recapitulating HLHS phenotype. […] Despite the species-specific differences between models, mid-gestation impairment of left heart blood flow was repeatedly used to recapitulate an HLHS-like phenotype with models recapitulating HLHS features including left heart hypoplasia, ascending aorta hypoplasia, and increased endocardial collagen deposition.
  • #68
    https://link.springer.com/article/10.1007/s11886-024-02122-6
    Understanding the full extent of insults that lead to the development of HLHS and the ability to test the efficacy of new surgical interventions is challenging without robust disease models that recapitulate HLHS physiology and hemodynamics. […] While there are multiple reports using mechanical flow obstruction to induce HLHS, genetic factors are known to play a role in human HLHS development. […] However, models of genetic induction of HLHS are much scarcer. […] Overall, these animal models provide various methods of recapitulating HLHS phenotype. […] Despite the species-specific differences between models, mid-gestation impairment of left heart blood flow was repeatedly used to recapitulate an HLHS-like phenotype with models recapitulating HLHS features including left heart hypoplasia, ascending aorta hypoplasia, and increased endocardial collagen deposition.
  • #69
    https://link.springer.com/article/10.1007/s11886-024-02122-6
    Understanding the full extent of insults that lead to the development of HLHS and the ability to test the efficacy of new surgical interventions is challenging without robust disease models that recapitulate HLHS physiology and hemodynamics. […] While there are multiple reports using mechanical flow obstruction to induce HLHS, genetic factors are known to play a role in human HLHS development. […] However, models of genetic induction of HLHS are much scarcer. […] Overall, these animal models provide various methods of recapitulating HLHS phenotype. […] Despite the species-specific differences between models, mid-gestation impairment of left heart blood flow was repeatedly used to recapitulate an HLHS-like phenotype with models recapitulating HLHS features including left heart hypoplasia, ascending aorta hypoplasia, and increased endocardial collagen deposition.
  • #70
    https://link.springer.com/article/10.1007/s11886-024-02122-6
    However, genetic models of HLHS are beginning to provide insight into the significant genetic contributors to left heart hypoplasia such as flow-independent impaired proliferation, valve development, placental development, and nutrient transportation. […] In vitro studies aimed at understanding the pathogenesis of HLHS have primarily utilized human induced pluripotent stem cells (hiPSCs) differentiated into cardiac lineages, and more recently, on CRISPR/Cas9-mediated genetic manipulation of HLHS-associated pathogenic variants. […] These methodologies offer several significant advantages over traditional animal models. […] This genetic and cellular model proposes a potential mechanism into the pathogenesis of MYH6-related HLHS via sarcomere disorganization that likely causes decreased atrial contractility and promotes hypoplastic left ventricular development.

Zobacz więcej

embriogeneza czynnik parakrynny otwór owalny pęcherzyk pozakomórkowy obciążenie następcze wrodzona wada serca hipoteza no flow no grow atrezja zastawki mitralnej powiększenie prawego przedsionka łańcuch transportu elektronów zespół hipoplastycznego lewego serca deacetylaza histonowa komunikacja międzykomorowa lewa komora terapia komórkami macierzystymi kardiomiopatia mutacja genu zastawka aortalna aorta wstępująca niedorozwój struktur serca ubytek przegrody międzyprzedsionkowej lewy przedsionek oddychanie mitochondrialne ubytek przegrody międzykomorowej dysfunkcja mitochondrialna krążenie płucne szlak RAS/MAPK zastawka mitralna