Żyły rozsiane – Patofizjologia i mechanizm

Żyły rozsiane
Patofizjologia i mechanizm

Żyły rozsiane (varicose veins) to patologicznie rozszerzone i kręte żyły powierzchowne, najczęściej kończyn dolnych, wynikające z niewydolności zastawek żylnych i przewlekłego nadciśnienia żylnego. Patogeneza obejmuje utratę elastyczności ściany żyły, co uniemożliwia prawidłowe zamknięcie zastawek, prowadząc do refluksu i dalszego rozciągania żył. Na poziomie mikroskopowym obserwuje się przerost intimy, infiltrację leukocytów i komórek tucznych, fragmentację elastyny oraz zmniejszenie kolagenu typu III, co jest związane z zaburzeniami metaloproteinaz macierzy (MMP) i ich inhibitorów (TIMP). Stan zapalny, hipoksja w niszy zastawkowej oraz czynniki genetyczne (m.in. mutacje FOXC2, NOTCH3, CFB) odgrywają kluczową rolę w progresji choroby. Czynniki ryzyka to m.in. płeć żeńska, ciąża (żyły rozsiane rozwijają się u 28% ciężarnych), otyłość, długotrwałe stanie, wysoki wzrost oraz refluks żylny miednicy. Niewydolność żył przeszywających potęguje nadciśnienie i rozszerzenie żył powierzchownych, co prowadzi do charakterystycznego klinicznego obrazu żylaków.

Patogeneza Żył Rozsianych (Varicose Veins)

Podstawowy mechanizm patogenetyczny
Mechanizm wstecznego przepływu
Zmiany w ścianie żylnej
Rola stanu zapalnego
<a href="#rola-hipoksji-i-stresu-oksydacyjnego”>Rola hipoksji i stresu oksydacyjnego

Czynniki ryzyka i mechanizmy predysponujące

Predyspozycje genetyczne
Wpływ hormonów i ciąży
Wzrost jako czynnik ryzyka
Otyłość i przedłużone stanie

Rola niewydolności zastawek w mechanizmie rozwoju żył rozsianych

Pierwotna niewydolność zastawek
Rola żył perforujących
Zmiany w mikrokrążeniu

Zmiany molekularne i komórkowe w żyłach rozsianych

Rola metaloproteinaz macierzy
Zmiany w składzie kolagenu
Rola genów i epigenetyki
Rola zmian fenotypowych w komórach mięśni gładkich

Skutki nadciśnienia żylnego i błędne koło patofizjologiczne

Błędne koło w patogenezie
Rola refluksu żylnego
Rola deformacji żylaków

Podsumowanie mechanizmów patogenetycznych

Kolejne rozdziały

Patogeneza Żył Rozsianych (Varicose Veins)

Żyły rozsiane (varicose veins) to rozszerzone, kręte żyły podskórne umożliwiające wsteczny przepływ krwi. Najczęściej występują w kończynach dolnych i mogą być pierwotne lub wtórne do patologii żył głębokich. System żyły odpiszczelowej wielkiej (GSV) jest najczęściej zajęty, podczas gdy żyła odpiszczelowa mała (SSV) jest dotknięta w około 20% przypadków.¹ Chociaż dokładny mechanizm powstawania żył rozsianych na poziomie mikroskopowym jest nadal kwestionowany, zasadniczy defekt makroskopowo jest generalnie uznawany za niewydolność zastawek żylnych, co prowadzi do rozszerzenia i wydłużenia żył powierzchownych, które stają się kręte.²³

Podstawowy mechanizm patogenetyczny

Głównym czynnikiem przyczyniającym się do rozwoju i progresji żył rozsianych jest długotrwałe nadciśnienie żylne, które zwiększa średnicę żył powierzchownych, co prowadzi do dalszej niewydolności zastawek.⁴ Dokładna patofizjologia jest złożona, ale obejmuje predyspozycję genetyczną, niewydolne zastawki, osłabienie ścian naczyń oraz zwiększone ciśnienie wewnątrzżylne.⁵ W większości przypadków dysfunkcja zastawek jest spowodowana utratą elastyczności w ścianie żyły, co powoduje, że płatki zastawek nie mogą się prawidłowo zamknąć.⁶

W prawidłowych warunkach krew żylna płynie od układu powierzchownego do głębokiego i w górę nogi w kierunku serca. Jednokierunkowe zastawki żylne znajdują się zarówno w systemie powierzchownym, jak i głębokim oraz w żyłach przeszywających. Niewydolność w którymkolwiek z tych zastawek może prowadzić do zakłócenia jednokierunkowego przepływu krwi w kierunku serca, powodując ambulatoryjne nadciśnienie żylne.⁷ Ponadto niewydolność w jednym systemie często prowadzi do niewydolności w innym.

Mechanizm wstecznego przepływu

Gdy zastawki żylne stają się niewydolne, zamiast przepływu krwi od dystalnych do proksymalnych części i od powierzchownych do głębokich, niewydolne zastawki pozwalają na przepływ krwi w przeciwnym kierunku. Ze zwiększonym ciśnieniem na dotknięty układ żylny, większe żyły mogą stać się wydłużone i kręte.⁸ Naprężenie ścinające na komórkach śródbłonka żylnego z powodu odwróconego lub burzliwego przepływu krwi oraz stan zapalny są również ważnymi czynnikami etiologicznymi w chorobie żylnej.⁹

W najczęstszym scenariuszu, pojedynczy zastawek żylny ulega uszkodzeniu i tworzy przeciek wysokociśnieniowy między układem głębokim a powierzchownym. Wysokie ciśnienie w układzie powierzchownym powoduje miejscowe rozszerzenie, co prowadzi do sekwencyjnej niewydolności (poprzez nadmierne rozciąganie) innych pobliskich zastawek w żyłach powierzchownych.¹⁰

Wraz z narastającą liczbą niewydolnych zastawek, wysokie ciśnienie jest przekazywane do coraz szerszej sieci rozszerzonych żył powierzchownych w zjawisku rekrutacji. Z czasem duża liczba niewydolnych żył powierzchownych nabiera typowego rozszerzonego i krętego wyglądu żylaków.¹¹

Zmiany w ścianie żylnej

Na poziomie mikroskopowym żyły rozsiane wykazują obszary przerostu intimy i blaszki z infiltracją leukocytów i komórek tucznych. Obserwuje się fragmentację włókien elastyny, a całkowita zawartość elastyny i kolagenu typu III jest zmniejszona. Te nieprawidłowości macierzy zewnątrzkomórkowej mogą być regulowane przez zaburzenia produkcji metaloproteinaz macierzy (MMP) i ich tkankowych inhibitorów (TIMP).¹²

Kliniczne i histologiczne cechy żył rozsianych są wynikiem zakłócenia normalnej struktury architektonicznej ściany żylnej w wyniku remodelingu macierzy zewnątrzkomórkowej w odpowiedzi na zwiększone rozciąganie żylne i zmienione naprężenie ścinające.¹³ Chociaż wiele genów, czynników wzrostu, proteaz i ich inhibitorów znanych z modulowania macierzy zewnątrzkomórkowej zostało zaangażowanych w patogenezę żył rozsianych, ich etiologia pozostaje nieznana.¹⁴

Rola stanu zapalnego

Częstą przyczyną żył rozsianych jest przewlekły stan zapalny, który może mieć podłoże genetyczne i prowadzić do uszkodzenia zastawek w żyłach kończyn dolnych. Mediatory zapalne przyciągają i aktywują neutrofile, prowadząc do ich infiltracji ściany żylnej i rozpoczynając uszkodzenie składników macierzy zewnątrzkomórkowej.¹⁵

Liczne badania wykazały, że czynniki wzrostu wydzielane przez makrofagi, cytokiny prozapalne, metaloproteinazy macierzy (MMP) i cząsteczki adhezyjne są zaangażowane w etiologię żył rozsianych.¹⁶ Wykazano, że żyły rozsiane charakteryzują się większą infiltracją komórek zapalnych w porównaniu do normalnej żyły.¹⁷

Zmiany w naprężeniu ścinającym prowadzące do aktywacji, adhezji leukocytów i migracji przez śródbłonek przyczyniają się do stanu zapalnego i późniejszej przebudowy ściany żylnej i zastawek.¹⁸ U pacjentów z żyłami rozsianymi wykazano obecność wielu cząsteczek zapalnych, cytokin, chemokin, czynników wazoaktywnych, selektyn i prekursorów prozakrzepowych.¹⁹

hipoksji-i-stresu-oksydacyjnego”>Rola hipoksji i stresu oksydacyjnego

Uważa się, że powstawanie żył rozsianych jest spowodowane dysfunkcją zastawek i refluksem żylnym, co prowadzi do zastoju żylnego i hipoksji. Hipoksja najpierw wpływa na zatokę i jest stałym zjawiskiem w niszy zastawkowej.²⁰

Niektóre mediatory prozapalne uwalniane lokalnie w wyniku hipoksji mogą aktywować nocyceptory zlokalizowane w ścianie żylnej i w tkance łącznej tworzącej przestrzeń okołożylną, w bliskim kontakcie z mikrokrążeniem.²¹

Te same procesy, które prawdopodobnie generują ból w chorobie żylnej, wydają się być również zaangażowane w dłuższej perspektywie w proces remodelingu żył rozsianych, zdefiniowany jako wszystkie jakościowe i ilościowe zmiany w komórkowych i macierzowych składnikach ściany żylnej.²²

Czynniki ryzyka i mechanizmy predysponujące

Predyspozycje genetyczne

Istnieją pewne zaburzenia genetyczne i mutacje, które predysponują do niewydolności żylnej i rozwoju żylaków (FOXC2, NOTCH3). Jednak te choroby są rzadkie, podczas gdy żyły rozsiane są powszechne.²³ Znaczenie czynników genetycznych w etiologii żył rozsianych zostało podkreślone w pracach duńskich i szwedzkich naukowców, którzy na podstawie zebranych informacji o rodzicach i rodzeństwie 250 pacjentów doszli do wniosku, że determinacja choroby przez jeden gen jest mało prawdopodobna, a dziedziczenie wydaje się być wieloczynnikowe.²⁴

W 1974 roku czechosłowaccy naukowcy Matousek i Prerovsky oszacowali, że dziedziczność pierwotnych żył rozsianych wynosi do 50% przy założeniu hipotezy dziedziczenia wielogenowego.²⁵ W 1998 roku chińscy naukowcy Guo i Guo, na podstawie wyników analizy genetycznej choroby żylnej, doszli do wniosku, że w większości przypadków choroba ta jest zgodna z autosomalnym dominującym dziedziczeniem o niepełnej penetracji, podczas gdy niektóre przypadki były sporadyczne, co skłoniło ich do założenia możliwego również modelu recesywnego.²⁶

Wpływ hormonów i ciąży

Stwierdzono, że kobiety są bardziej narażone na rozwój żył rozsianych. Wysunięto hipotezę, że estrogen odgrywa rolę w tym procesie. Estrogen powoduje zwiększone rozluźnienie żył, ograniczając prawidłowe zamykanie zastawek.²⁷

Podczas ciąży zachodzi kilka zmian fizjologicznych, które pomagają zapewnić płodowi odpowiednie odżywianie i zwiększają szanse na jego przeżycie. Rozszerzenie wewnątrznaczyniowej objętości krwi jest jedną z tych zmian.²⁸ Żyły rozsiane rozwijają się po raz pierwszy u nawet 28% ciąż. Chociaż dokładny mechanizm nie jest w pełni znany, prawdopodobnie jest to kombinacja efektów hormonalnych i obstrukcji odpływu żylnego z nóg przez powiększoną macicę.²⁹

Wzrost jako czynnik ryzyka

W największym genetycznym badaniu żył rozsianych, jakie kiedykolwiek przeprowadzono, badacze ze Stanford i ich współpracownicy dostarczyli dowodów, że wysoki wzrost jest czynnikiem ryzyka tego schorzenia.³⁰ „Geny, które przewidują wzrost osoby, mogą być przyczyną tego związku między wzrostem a żyłami rozsianymi i mogą dostarczyć wskazówek do leczenia tego schorzenia”, powiedział Nicholas Leeper, MD, profesor nadzwyczajny chirurgii i medycyny sercowo-naczyniowej na Uniwersytecie Stanford.³¹

Badanie potwierdziło również, że operacje na nogach, historia rodzinna, brak ruchu, palenie i terapia hormonalna są czynnikami ryzyka. Ale korelacja, którą znaleźli między wzrostem a tym schorzeniem, była nieoczekiwana.³² „Nasze wyniki zdecydowanie sugerują, że wzrost jest przyczyną, a nie tylko skorelowanym czynnikiem, ale podstawowym mechanizmem prowadzącym do żył rozsianych”, powiedział Ingelsson.³³

Otyłość i przedłużone stanie

Wykazano, że pacjenci z otyłością są związani ze znacznie wyższymi klinicznymi stopniami CEAP w porównaniu do pacjentów bez otyłości, nawet u osób z podobnymi anatomicznymi wzorcami niewydolności żylnej.³⁴

Osoby stojące przez długie godziny mają tendencję do rozwijania żył rozsianych. Przedłużone stanie może zwiększać ciśnienie żylne w nogach.³⁵ Każda aktywność lub warunki, które zwiększają ciśnienie w jamie brzusznej i utrudniają przepływ krwi żylnej z powrotem do serca, mogą obciążać żyły, powodując ich rozszerzenie.³⁶

Rola niewydolności zastawek w mechanizmie rozwoju żył rozsianych

Pierwotna niewydolność zastawek

Pierwotna niewydolność zastawkowa (PVI) jest uważana za spowodowaną utratą elastyny i kolagenu w ścianie, co prowadzi do rozszerzenia i separacji płatków zastawki.³⁷ Najczęstszą kliniczną konsekwencją tego procesu jest rozwój żył rozsianych. Główny czynnik przyczyniający się do rozwoju i progresji żył rozsianych to długotrwałe nadciśnienie żylne, które zwiększa średnicę żył powierzchownych, powodując dalszą niewydolność zastawek.³⁸

W większości przypadków dysfunkcja zastawek wynika z utraty elastyczności w ścianie żyły, powodując niemożność dopasowania płatków zastawki do siebie.³⁹ Gdy zastawka żylna staje się niewydolna, ciśnienie grawitacyjne wzdłuż kolumny krwi na długości żyły tworzy ciśnienie hydrostatyczne, które jest gorsze w bardziej dystalnej części długości żyły.⁴⁰

Rola żył perforujących

Istnieje coraz więcej dowodów na rolę niewydolnych żył przeszywających (lub „perforatorów”) w powstawaniu żył rozsianych i nawracających żył rozsianych.⁴¹ Niewydolność żył przeszywających prowadzi do ciśnienia hydrodynamicznego. Mechanizm pompy łydkowej pomaga opróżnić układ żył głębokich, ale jeśli zastawki żył przeszywających zawiodą, to ciśnienie wytworzone w układzie żył głębokich przez mechanizm pompy łydkowej jest przekazywane do układu powierzchownego za pośrednictwem niewydolnych żył przeszywających.⁴²

Gdy żyła przeszywająca jest pierwotnym miejscem refluksu, rozszerzenie naczynia postępuje zarówno w kierunku proksymalnym, jak i dystalnym. Gdy rozszerzenie osiąga najbardziej proksymalną część żyły, połączenie odpiszczelowo-udowe lub połączenie odpiszczelowo-podkolanowe jest często rekrutowane jako wtórne miejsce refluksu.⁴³

Zmiany w mikrokrążeniu

Główny mechanizm związany z patofizjologią przewlekłej niewydolności żylnej to wzrost ciśnienia żylnego, który jest konsekwencją uszkodzonych zastawek żylnych, naprężeń ścinających i refluksu.⁴⁴ Te czynniki powodują dalsze uszkodzenie zastawek, zwiększając ciśnienie i rozszerzając żyłę.⁴⁵

Zmiany w żyle są przenoszone do mikrokrążenia, zaburzając funkcję komórek śródbłonka i mikrośrodowisko naczyniowe, co z kolei prowadzi do mikroangiopatii żylnej, charakteryzującej się rozszerzeniem i krętością łożysk kapilarnych.⁴⁶

Zmiany molekularne i komórkowe w żyłach rozsianych

Rola metaloproteinaz macierzy

Zmiany w ekspresji mRNA, poziomach białek i aktywności proteolitycznej metaloproteinaz macierzy (MMP) zostały wykryte w żyłach rozsianych. Ekspresja/aktywność MMP może być modulowana przez ciśnienie hydrostatyczne żył, hipoksję, metabolity tkankowe i stan zapalny. MMP z kolei zwiększają proteolizę różnych substratów białkowych w macierzy zewnątrzkomórkowej, szczególnie kolagenu i elastyny, prowadząc do osłabienia ściany żylnej.⁴⁷

MMP mogą również wpływać na funkcję śródbłonka i mechanizmy skurczu mięśni gładkich naczyń (VSM). MMP mogą również wpływać na proliferację, migrację, różnicowanie i/lub apoptozę komórek mięśni gładkich naczyń (VSM).⁴⁸

MMP mogą promować rozszerzenie żylne poprzez zwiększenie uwalniania wazodylatatorów pochodzenia śródbłonkowego i aktywację kanałów potasowych, prowadząc do hiperpolaryzacji i rozluźnienia mięśni gładkich.⁴⁹

Zmiany w składzie kolagenu

Badania ujawniły znaczącą separację między komórkami mięśni gładkich w ścianie żył rozsianych oraz obecność nieprawidłowej amorficznej macierzy zewnątrzkomórkowej i wakuoli wewnątrzplazmatycznych, co może odzwierciedlać „niezwykłe” możliwe role wydzielnicze i fagocytarne komórek mięśni gładkich. To może dostarczyć ważnego wyjaśnienia dla nieprawidłowej funkcji kurczliwej tych komórek w żyłach rozsianych.⁵⁰

W tej patogenezie oczywiste jest, że nadciśnienie żylne, niewydolność zastawek i zmiany strukturalne w ścianie żylnej są ze sobą powiązane. Nadciśnienie żylne, które forsuje i uszkadza ścianę żylną, wywołuje odpowiedzi niedokrwienne i zapalne z rozszerzeniem i niewydolnością zastawek w ścianie żylnej. W odpowiedzi na tę sytuację aktywowane są różne mechanizmy molekularne poprzez stymulację. W miarę postępu choroby mechanizmy molekularne inicjują zmiany w histomorfologii ściany żylnej.⁵¹

Rola genów i epigenetyki

Rola genetyki w tym kontekście nie może być przeceniona, ponieważ genetyka jest jedną z części składowych, ogólnie rzecz biorąc, tworzenia białka z DNA, gdzie zaangażowane są zarówno procesy biochemiczne, jak i molekularne (tj. replikacja, transkrypcja i translacja, z czego i jak białko jest syntezowane). Ponadto epigenetyka może odgrywać równie ważną rolę.⁵²

Pierwsze zakrojone na szeroką skalę badanie asocjacji genetycznej dla pierwotnych żył rozsianych przeprowadzone w naszym laboratorium na populacji rosyjskiej z wykorzystaniem genotypowania eksomu zidentyfikowało obiecujący sygnał asocjacji na chromosomie 6 w obrębie klasycznego regionu podregion III głównego kompleksu zgodności tkankowej, przy czym najbardziej statystycznie istotne powiązanie wykazano w analizie łączonej (etap odkrycia i replikacji) dla polimorfizmu rs4151657 w genie CFB (czynnik dopełniacza B), co wskazuje na udział układu odpornościowego w patogenezie żył rozsianych.⁵³

Geny potencjalnie zaangażowane w patogenezę żył rozsianych	Funkcja/Rola
FOXC2	Związany z rozwojem naczyń i zastawek żylnych
NOTCH3	Wpływa na różnicowanie komórek śródbłonka
CFB (czynnik dopełniacza B)	Wskazuje na udział układu odpornościowego
PLP2, DACT3, LRRC25	Związane z progresją i regresją żył rozsianych
PILRA, MSX1, APOD	Związane z progresją i regresją żył rozsianych

Rola zmian fenotypowych w komórach mięśni gładkich

Wykazano, że żyły pacjentów z żyłami rozsianymi różnią się m.in. właściwościami elastycznymi w porównaniu do żył zdrowych osób.⁵⁴ Ekspresja kilku genów związanych z angiogenezą, przerostem naczyniowym i regulacją żylną wpływa na częstość występowania przewlekłej niewydolności żylnej.⁵⁵

Udowodniono, że DACT3 jest ściśle zaangażowany w proliferację, cykl komórkowy, migrację i przejście fenotypowe komórek mięśni gładkich naczyń (VSMCs), regulując tym samym progresję żył rozsianych.⁵⁶ Wykazano, że DACT3 jest zaangażowany w negatywną regulację kanonicznego szlaku sygnalizacyjnego Wnt oraz negatywną regulację wzrostu komórek.⁵⁷ Nadekspresja DACT3 znacząco hamuje proliferację VSMCs i opóźnia ich przejście z fazy G0/G1 do fazy S.⁵⁸

Zmiana fenotypowa VSMCs głęboko wpływa na początek i progresję żył rozsianych.⁵⁹ Zrozumienie mechanizmów komunikacji mitochondrialnej i jądrowej może rzucić światło na złożoną etiologię choroby, a także na implikacje strategii terapeutycznych w celu zwiększenia funkcji mitochondrialnej.⁶⁰

Skutki nadciśnienia żylnego i błędne koło patofizjologiczne

Błędne koło w patogenezie

Po wystąpieniu nadciśnienia żylnego, dysfunkcja żylna nadal pogarsza się poprzez błędne koło. Zastój krwi i nadciśnienie żylne prowadzą do rozszerzenia żylnego, które następnie powoduje większą niewydolność zastawkową. Z czasem, wraz z większym miejscowym rozszerzeniem, inne sąsiednie zastawki sekwencyjnie zawodzą, a po awarii serii zastawek cały powierzchowny układ żylny staje się niewydolny.⁶¹

Objawy kliniczne żył rozsianych, żył siatkowatych i teleangiektazji wynikają z nadciśnienia w powierzchownym układzie żylnym, które rozprzestrzenia się do żył obocznych i żył dopływowych, powodując rozszerzone kręte struktury. Metody leczenia są ukierunkowane na korygowanie nadciśnienia powierzchownego żylnego.⁶²

Obecność i wielkość widocznych żylaków nie są wiarygodnymi wskaźnikami objętości lub ciśnienia refluksu żylnego. Żyła, która jest ograniczona w płaszczyznach powięziowych lub jest zagrzebana pod tkanką podskórną, może przenosić ogromne ilości refluksu wysokociśnieniowego bez bycia w ogóle widoczną. I odwrotnie, nawet niewielki wzrost ciśnienia może ostatecznie wywołać masywne rozszerzenie w innym przypadku normalnej żyły powierzchownej, która przenosi bardzo mały przepływ.⁶³

Rola refluksu żylnego

Reflux żylny jest znaczącą przyczyną. Badania wykazały również znaczenie refluksu żylnego miednicy (PVR) w rozwoju żył rozsianych. Żyły rozsiane w nogach mogą być spowodowane refluksem żyły jajnikowej. Zarówno refluks żyły jajnikowej, jak i żyły biodrowej wewnętrznej powoduje żyły rozsiane nóg. Stan ten dotyczy 14% kobiet z żyłami rozsianymi lub 20% kobiet, które miały poród pochwowy i mają żyły rozsiane nóg. Ponadto dowody sugerują, że niepowodzenie w poszukiwaniu i leczeniu refluksu żylnego miednicy może być przyczyną nawracających żył rozsianych.⁶⁴

Bez względu na przyczynę, to odwrócenie przepływu krwi wytwarza nadciśnienie żylne w kończynach dolnych, co z kolei powoduje wzrost średnicy żylnej, który prowadzi do niewydolności zastawkowej.⁶⁵ Powoduje to odwrócenie przepływu krwi z układu głębokiego do powierzchownego systemu żylnego przez niewydolne żyły komunikujące.⁶⁶ Żyły powierzchowne reagują na zwiększone ciśnienie, rozszerzając się, aby pomieścić zwiększony przepływ krwi.⁶⁷

Rola deformacji żylaków

Niemniej jednak deformacje żył rozsianych same w sobie będą sprzyjać rozwojowi procesu, zwiększając deteriorację całego naczynia (błędne koło).⁶⁸ Hipoksja najpierw wpływa na zatokę i, jak wspomniano wcześniej, jest stałym zjawiskiem w niszy zastawkowej.⁶⁹

Zdarzenie pierwotne nie leży już w ścianie żyły. Nie zapobiega to wtórnym głównym nieprawidłowościom mechanicznym w naczyniu przed pogorszeniem, a nawet wywołaniem zmian.⁷⁰ Podsumowując, związek między zaburzeniem hemodynamicznym z powodu dysfunkcji zastawek żylnych, krążącymi komórkami krwi, ścianą żylną i procesami biochemicznymi jest ustalony w odniesieniu do etiologii żył rozsianych.⁷¹

Podsumowanie mechanizmów patogenetycznych

Żyły rozsiane (varicose veins) są wynikiem złożonego procesu patofizjologicznego, w którym kluczową rolę odgrywa nadciśnienie żylne, prowadzące do dysfunkcji zastawek i przebudowy ściany żylnej. Proces rozpoczyna się od pierwotnej niewydolności zastawek lub osłabienia ściany żylnej, co prowadzi do wstecznego przepływu krwi i zwiększonego ciśnienia w układzie żylnym powierzchownym.⁷²⁷³

Na poziomie komórkowym i molekularnym obserwuje się zmiany w macierzy zewnątrzkomórkowej, ze zmniejszoną zawartością elastyny i kolagenu, co prowadzi do osłabienia ściany żylnej. W proces ten zaangażowane są metaloproteinazy macierzy (MMP) oraz ich inhibitory, których zaburzenie przyczynia się do przebudowy ściany naczynia.⁷⁴⁷⁵

Stan zapalny odgrywa istotną rolę w patogenezie, z infiltracją leukocytów i komórek tucznych w ścianie żylnej oraz zwiększoną ekspresją cytokin prozapalnych. Czynniki te, wraz z hipoksją wynikającą z zastoju żylnego, przyczyniają się do dalszego uszkodzenia zastawek i ściany żylnej.⁷⁶⁷⁷

Predyspozycje genetyczne, wpływ hormonów (szczególnie u kobiet w ciąży), przedłużone stanie, otyłość oraz wysoki wzrost są istotnymi czynnikami ryzyka rozwoju żył rozsianych. Wszystkie te czynniki wpływają na mechanizmy patogenetyczne, prowadząc do klinicznego obrazu rozszerzonych, krętych żył powierzchownych.⁷⁸⁷⁹⁸⁰

Zrozumienie tych złożonych mechanizmów patogenetycznych jest kluczowe dla opracowania skutecznych strategii profilaktycznych i terapeutycznych w leczeniu żył rozsianych.⁸¹⁸²

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Materiały źródłowe

#1 Pathophysiology and Principles of Management of Varicose Veins – Mechanisms of Vascular Disease – NCBI Bookshelf
https://www.ncbi.nlm.nih.gov/books/NBK534256/
Varicose veins (VV) are dilated, tortuous subcutaneous veins that permit reverse flow. They are most commonly found in the lower limb and may be primary, or secondary to deep venous pathology. The GSV system is most frequently affected with the SSV being involved in about 20% of cases. The aetiology of VV at a microscopic level is still disputed but the essential defect macroscopically is generally agreed to be the failure of venous valve closure resulting in the superficial veins becoming dilated, elongated and tortuous. The main factor contributing to the development and progression of varicose veins is sustained venous hypertension that increases the diameter of the superficial veins resulting in further valve incompetence. […] Failure of valve closure leading to valve incompetence and reflux may affect the deep and/or superficial venous systems and may be primary or secondary. Primary valvular incompetence (PVI) is believed to be due to loss of mural elastin and collagen, which leads to dilatation and separation of the valve leaflets. The commonest clinical consequence of this process is the development of VV.
#2 Pathophysiology and Principles of Management of Varicose Veins – Mechanisms of Vascular Disease – NCBI Bookshelf
https://www.ncbi.nlm.nih.gov/books/NBK534256/
Varicose veins (VV) are dilated, tortuous subcutaneous veins that permit reverse flow. They are most commonly found in the lower limb and may be primary, or secondary to deep venous pathology. The GSV system is most frequently affected with the SSV being involved in about 20% of cases. The aetiology of VV at a microscopic level is still disputed but the essential defect macroscopically is generally agreed to be the failure of venous valve closure resulting in the superficial veins becoming dilated, elongated and tortuous. The main factor contributing to the development and progression of varicose veins is sustained venous hypertension that increases the diameter of the superficial veins resulting in further valve incompetence. […] Failure of valve closure leading to valve incompetence and reflux may affect the deep and/or superficial venous systems and may be primary or secondary. Primary valvular incompetence (PVI) is believed to be due to loss of mural elastin and collagen, which leads to dilatation and separation of the valve leaflets. The commonest clinical consequence of this process is the development of VV.
#3 Varicose Veins: Diagnosis and Treatment | AAFP
https://www.aafp.org/pubs/afp/issues/2019/0601/p682.html
Varicose veins are twisted, dilated veins most commonly located on the lower extremities. The exact pathophysiology is debated, but it involves a genetic predisposition, incompetent valves, weakened vascular walls, and increased intravenous pressure. […] Venous disease resulting in valvular reflux appears to be the underlying cause of varicose veins. The exact pathophysiology is debated, but it involves a genetic predisposition, incompetent valves, weakened vascular walls, and increased intravenous pressure. In most cases, the valvular dysfunction is presumed to be caused by a loss of elasticity in the vein wall, with failure of the valve leaflets to fit together. Rather than blood flowing from distal to proximal and superficial to deep, failed or incompetent valves allow blood to flow in the reverse direction. With increased pressure on the affected venous system, the larger veins may become elongated and tortuous. Shear stress on venous endothelial cells due to reversed or turbulent blood flow and inflammation are also important etiologic factors for venous disease.
#4 Pathophysiology and Principles of Management of Varicose Veins – Mechanisms of Vascular Disease – NCBI Bookshelf
https://www.ncbi.nlm.nih.gov/books/NBK534256/
Varicose veins (VV) are dilated, tortuous subcutaneous veins that permit reverse flow. They are most commonly found in the lower limb and may be primary, or secondary to deep venous pathology. The GSV system is most frequently affected with the SSV being involved in about 20% of cases. The aetiology of VV at a microscopic level is still disputed but the essential defect macroscopically is generally agreed to be the failure of venous valve closure resulting in the superficial veins becoming dilated, elongated and tortuous. The main factor contributing to the development and progression of varicose veins is sustained venous hypertension that increases the diameter of the superficial veins resulting in further valve incompetence. […] Failure of valve closure leading to valve incompetence and reflux may affect the deep and/or superficial venous systems and may be primary or secondary. Primary valvular incompetence (PVI) is believed to be due to loss of mural elastin and collagen, which leads to dilatation and separation of the valve leaflets. The commonest clinical consequence of this process is the development of VV.
#5 Varicose Veins: Diagnosis and Treatment | AAFP
https://www.aafp.org/pubs/afp/issues/2019/0601/p682.html
Varicose veins are twisted, dilated veins most commonly located on the lower extremities. The exact pathophysiology is debated, but it involves a genetic predisposition, incompetent valves, weakened vascular walls, and increased intravenous pressure. […] Venous disease resulting in valvular reflux appears to be the underlying cause of varicose veins. The exact pathophysiology is debated, but it involves a genetic predisposition, incompetent valves, weakened vascular walls, and increased intravenous pressure. In most cases, the valvular dysfunction is presumed to be caused by a loss of elasticity in the vein wall, with failure of the valve leaflets to fit together. Rather than blood flowing from distal to proximal and superficial to deep, failed or incompetent valves allow blood to flow in the reverse direction. With increased pressure on the affected venous system, the larger veins may become elongated and tortuous. Shear stress on venous endothelial cells due to reversed or turbulent blood flow and inflammation are also important etiologic factors for venous disease.
#6 Management of Varicose Veins | AAFP
https://www.aafp.org/pubs/afp/issues/2008/1201/p1289.html
Varicose veins are twisted, dilated veins most commonly located on the lower extremities. The exact pathophysiology is debated, but it involves a genetic predisposition, incompetent valves, weakened vascular walls, and increased intravenous pressure. […] Venous disease resulting in valve reflux appears to be the underlying pathophysiology for the formation of varicose veins. […] Failed or incompetent valves in the venous system allow blood to flow in the reverse direction. […] With increased pressure on the local venous system, the larger affected veins may become elongated and tortuous. […] In most cases the valvular dysfunction is presumed to be caused by a loss of elasticity in the vein wall, with failure of the valve leaflets to fit together. […] Shear forces and inflammation have recently been recognized as important etiologic factors for venous disease.
#7 Varicose Vein Surgery: Practice Essentials, Anatomy, Pathophysiology
https://emedicine.medscape.com/article/462579-overview
Varicose veins are simply dilated, tortuous veins of the subcutaneous/superficial venous system. However, the pathophysiology behind their formation is complicated and involves the concept of ambulatory venous hypertension. To understand this process, it is necessary to be familiar with the anatomy of the lower-extremity venous system, as outlined above. […] In healthy veins, the flow of venous blood is through the superficial system into the deep system and up the leg and toward the heart. One-way venous valves are found in both systems and the perforating veins. Incompetence in any of these valves can lead to a disruption in the unidirectional flow of blood toward the heart and result in ambulatory venous hypertension. […] Furthermore, incompetence in one system can often lead to incompetence in another. Incompetence in the superficial venous system alone usually results from failure at valves located at the SFJ and the SPJ. The gravitational weight of the column of blood along the length of the vein creates hydrostatic pressure, which is worse at the more distal aspect of the length of vein.
#8 Varicose Veins: Diagnosis and Treatment | AAFP
https://www.aafp.org/pubs/afp/issues/2019/0601/p682.html
Varicose veins are twisted, dilated veins most commonly located on the lower extremities. The exact pathophysiology is debated, but it involves a genetic predisposition, incompetent valves, weakened vascular walls, and increased intravenous pressure. […] Venous disease resulting in valvular reflux appears to be the underlying cause of varicose veins. The exact pathophysiology is debated, but it involves a genetic predisposition, incompetent valves, weakened vascular walls, and increased intravenous pressure. In most cases, the valvular dysfunction is presumed to be caused by a loss of elasticity in the vein wall, with failure of the valve leaflets to fit together. Rather than blood flowing from distal to proximal and superficial to deep, failed or incompetent valves allow blood to flow in the reverse direction. With increased pressure on the affected venous system, the larger veins may become elongated and tortuous. Shear stress on venous endothelial cells due to reversed or turbulent blood flow and inflammation are also important etiologic factors for venous disease.
#9 Varicose Veins: Diagnosis and Treatment | AAFP
https://www.aafp.org/pubs/afp/issues/2019/0601/p682.html
Varicose veins are twisted, dilated veins most commonly located on the lower extremities. The exact pathophysiology is debated, but it involves a genetic predisposition, incompetent valves, weakened vascular walls, and increased intravenous pressure. […] Venous disease resulting in valvular reflux appears to be the underlying cause of varicose veins. The exact pathophysiology is debated, but it involves a genetic predisposition, incompetent valves, weakened vascular walls, and increased intravenous pressure. In most cases, the valvular dysfunction is presumed to be caused by a loss of elasticity in the vein wall, with failure of the valve leaflets to fit together. Rather than blood flowing from distal to proximal and superficial to deep, failed or incompetent valves allow blood to flow in the reverse direction. With increased pressure on the affected venous system, the larger veins may become elongated and tortuous. Shear stress on venous endothelial cells due to reversed or turbulent blood flow and inflammation are also important etiologic factors for venous disease.
#10 Varicose Veins and Spider Veins: Practice Essentials, Background, Pathophysiology
https://emedicine.medscape.com/article/1085530-overview
Varicose veins and spider veins are normal veins that have dilated under the influence of increased venous pressure. […] Elevated venous pressure most often is the result of venous insufficiency due to valve incompetence in the deep or superficial veins. Varicose veins are the undesirable pathways by which venous blood refluxes back into the congested extremity. Ablation of the varicose pathways invariably improves overall venous circulation. […] Most commonly, superficial venous valve failure results from excessive dilatation of a vein from high pressure of reverse flow within the superficial venous system. […] In the most common scenario, a single venous valve fails and creates a high-pressure leak between the deep and superficial systems. High pressure within the superficial system causes local dilatation, which leads to sequential failure (through over-stretching) of other nearby valves in the superficial veins.
#11 Varicose Veins and Spider Veins: Practice Essentials, Background, Pathophysiology
https://emedicine.medscape.com/article/1085530-overview
As increasing numbers of valves fail under the strain, high pressure is communicated into a widening network of dilated superficial veins in a recruitment phenomenon. Over time, large numbers of incompetent superficial veins acquire the typical dilated and tortuous appearance of varicosities. […] The sequelae of venous insufficiency are related to the venous pressure and to the volume of venous blood that is carried in a retrograde direction through incompetent veins. Unfortunately, the presence and size of visible varicosities are not reliable indicators of the volume or pressure of venous reflux. […] Most patients with venous insufficiency have subjective symptoms that may include pain, soreness, burning, aching, throbbing, cramping, muscle fatigue, and restless legs. Over time, chronic venous insufficiency leads to cutaneous and soft tissue breakdown that can be debilitating.
#12 Pathophysiology and Principles of Management of Varicose Veins – Mechanisms of Vascular Disease – NCBI Bookshelf
https://www.ncbi.nlm.nih.gov/books/NBK534256/
The molecular biology of varicose veins has recently been reviewed. The aetiology of varicose veins is undoubtedly multi-factorial. There are some genetic disorders and mutations that predispose to venous incompetence and development of varicosities (FOXC2, NOTCH3). However these diseases are rare whilst varicose veins are common. […] In recent years there has been much research to define the structural and molecular events that accompany the formation of varicose veins, with an overall underlying hypothesis that varicose vein formation is most likely due to a structural, cellular or molecular abnormality within the vein wall. On a gross level, varicose veins exhibit intimal hyperplastic areas and underlying plaques with infiltration of leukocytes and mast cells. There is fragmentation of elastin fibres and the total content of elastin and Type III collagen is reduced. These extracellular matrix abnormalities may be regulated by disordered MMP and TIMP production.
#13 Pathogenesis of varicose veins and implications for clinical management – PubMed
https://pubmed.ncbi.nlm.nih.gov/17976322/
Varicose veins (VVs) classically result from venous hypertension owing to incompetence of the major communications between the superficial and deep veins of the lower extremity. […] In a significant number of patients, there is no demonstrable truncal saphenous reflux and varicosities are the result of isolated perforating and nonsaphenous vein incompetence. […] The clinical and histologic features of VVs are the result of disruption of the normal architectural structure of the venous wall as a consequence of remodeling of the extracellular matrix (ECM) in response to increased venous distention and altered hemodynamic shear stress. […] Although a number of genes, growth factors, proteases, and their inhibitors known to modulate the ECM have been implicated in the pathogenesis of VVs, their etiology remains unknown.
#14 Pathogenesis of varicose veins and implications for clinical management – PubMed
https://pubmed.ncbi.nlm.nih.gov/17976322/
Varicose veins (VVs) classically result from venous hypertension owing to incompetence of the major communications between the superficial and deep veins of the lower extremity. […] In a significant number of patients, there is no demonstrable truncal saphenous reflux and varicosities are the result of isolated perforating and nonsaphenous vein incompetence. […] The clinical and histologic features of VVs are the result of disruption of the normal architectural structure of the venous wall as a consequence of remodeling of the extracellular matrix (ECM) in response to increased venous distention and altered hemodynamic shear stress. […] Although a number of genes, growth factors, proteases, and their inhibitors known to modulate the ECM have been implicated in the pathogenesis of VVs, their etiology remains unknown.
#15 Factors Influencing Venous Remodeling in the Development of Varicose Veins of the Lower Limbs
https://www.mdpi.com/1422-0067/25/3/1560
One of the early symptoms of chronic venous disease (CVD) is varicose veins (VV) of the lower limbs. […] The aim of this review is to present current knowledge on CVD, including the pathophysiology and mechanisms related to vein wall remodeling. […] It is believed that the formation of varicose veins is caused by valve dysfunction and venous reflux, which consequently leads to venous stasis and hypoxia. […] A common cause of varicose veins is chronic inflammation, which may have a genetic basis and can cause damage to the valves in the veins of the lower limbs. […] Inflammatory mediators attract and activate neutrophils, leading to their infiltration of the venous wall, and initiate damage to extracellular matrix components. […] Numerous studies have shown that growth factors secreted by macrophages, pro-inflammatory cytokines, matrix metalloproteinases (MMPs), and adhesion molecules are involved in the etiology of varicose veins.
#16 Factors Influencing Venous Remodeling in the Development of Varicose Veins of the Lower Limbs
https://www.mdpi.com/1422-0067/25/3/1560
One of the early symptoms of chronic venous disease (CVD) is varicose veins (VV) of the lower limbs. […] The aim of this review is to present current knowledge on CVD, including the pathophysiology and mechanisms related to vein wall remodeling. […] It is believed that the formation of varicose veins is caused by valve dysfunction and venous reflux, which consequently leads to venous stasis and hypoxia. […] A common cause of varicose veins is chronic inflammation, which may have a genetic basis and can cause damage to the valves in the veins of the lower limbs. […] Inflammatory mediators attract and activate neutrophils, leading to their infiltration of the venous wall, and initiate damage to extracellular matrix components. […] Numerous studies have shown that growth factors secreted by macrophages, pro-inflammatory cytokines, matrix metalloproteinases (MMPs), and adhesion molecules are involved in the etiology of varicose veins.
#17 Factors Influencing Venous Remodeling in the Development of Varicose Veins of the Lower Limbs
https://www.mdpi.com/1422-0067/25/3/1560
It has been shown that varicose veins are characterized by a greater infiltration of inflammatory cells compared to the normal vein. […] Changes in shear stress leading to activation, leukocyte adhesion, and migration across the endothelium contribute to inflammation and subsequent remodeling of the venous wall and valves. […] The main mechanism associated with the pathophysiology of chronic venous insufficiency is an increase in venous pressure, which is a consequence of damaged venous valves, shear stresses, and reflux. […] These factors cause further damage to the valves, increasing pressure and dilating the vein. […] Changes in the vein are transferred to microcirculation, disturbing the function of endothelial cells and the vascular microenvironment, which in turn leads to venous microangiopathy, characterized by dilatation and tortuosity of the capillary beds.
#18 Factors Influencing Venous Remodeling in the Development of Varicose Veins of the Lower Limbs
https://www.mdpi.com/1422-0067/25/3/1560
It has been shown that varicose veins are characterized by a greater infiltration of inflammatory cells compared to the normal vein. […] Changes in shear stress leading to activation, leukocyte adhesion, and migration across the endothelium contribute to inflammation and subsequent remodeling of the venous wall and valves. […] The main mechanism associated with the pathophysiology of chronic venous insufficiency is an increase in venous pressure, which is a consequence of damaged venous valves, shear stresses, and reflux. […] These factors cause further damage to the valves, increasing pressure and dilating the vein. […] Changes in the vein are transferred to microcirculation, disturbing the function of endothelial cells and the vascular microenvironment, which in turn leads to venous microangiopathy, characterized by dilatation and tortuosity of the capillary beds.
#19 Factors Influencing Venous Remodeling in the Development of Varicose Veins of the Lower Limbs
https://www.mdpi.com/1422-0067/25/3/1560
In patients with varicose veins, the presence of many inflammatory molecules, cytokines, chemokines, vasoactive factors, selectins, and prothrombotic precursors has been demonstrated. […] The pathophysiology of CVD is characterized by different clinical stages, starting with the clinical class C0s, which includes patients without visible or palpable symptoms of a venous disease. […] The main cause of CVeD is remodeling of the vein wall and damage to the valves, which is a consequence of blood stasis, hypoxia, and interaction of the endothelium with white blood cells. […] The formation of varicose veins can cause changes leading to prothrombotic syndrome followed by deep vein thrombosis. […] In turn, skin changes and ulcerations are caused by venous hypertension, which is transferred to the microcirculation.
#20 Recent findings in the pathogenesis of venous wall degradation – Servier – PhlebolymphologyServier – Phlebolymphology
https://www.phlebolymphology.org/recent-findings-in-the-pathogenesis-of-venous-wall-degradation/
Recent studies show that the link between valvular dysfunction and remodeling involves early activation of aseptic inflammation, which triggers cellular and enzymatic processes. […] Once valvular damage is done, it produces venous, and then cutaneous, damage. […] Nevertheless, varicose vein deformities will themselves promote development of the process, enhancing deterioration of the entire vessel (a vicious circle). […] Hypoxia first affects the sinus, and as seen before is a constant finding in the valvular nidus. […] The primary event no longer lies in the wall of the vein. This does not prevent secondary major mechanical abnormalities in the vessel from worsening and even inducing alterations. […] In summary, the link between a hemodynamic disorder due to dysfunction of venous valves, circulating blood cells, the venous wall, and biochemical processes is established with regard to the etiology of varicose veins.
#21 Pathophysiology of pain in venous disease – Servier – PhlebolymphologyServier – Phlebolymphology
https://www.phlebolymphology.org/pathophysiology-of-pain-in-venous-disease/
Some proinflammatory mediators released locally as the result of hypoxia can activate nociceptors located in the venous wall and in the connective tissue that forms the perivenous space, in close contact with the microcirculation. […] This algogenic action of bradykinin is potentiated by the local administration of prostaglandin E2. […] Based on these data, the hypothesis can be formulated that such a cascade of reactions, by an auto-amplification process, can lead to the local release of a true inflammatory mixture, which can activate venous and perivenous nociceptors, as well as extravasation of plasma with transmural and tissue edema. […] In agreement with this hypothesis, Howlader and Smith have previously demonstrated that nitric oxide concentrations measured in blood collected in the saphenous vein or in a vein in the dorsal aspect of the foot were significantly higher in patients with the most severe stage of venous disease.
#22 Pathophysiology of pain in venous disease – Servier – PhlebolymphologyServier – Phlebolymphology
https://www.phlebolymphology.org/pathophysiology-of-pain-in-venous-disease/
Interestingly, the same processes assumed to generate pain in venous disease also seem to be involved in the longer term in the process of varicose vein remodeling, defined as all of the qualitative and quantitative alterations in the cellular and matrix components of the venous wall. […] The starting point for these mechanisms probably is local hypoxia associated with capillary stasis. […] Evidence for such an inflammatory reaction in patients with varicose veins has accumulated dramatically over the last five years, and the biochemical changes identified suggest that endothelial cells and neutrophils are the source of this local inflammation. […] The presence of neutrophils, monocytes, and activated T lymphocytes, the accumulation of macrophages and mast cells, the expression of adhesion molecules on the surface of leukocytes and endothelial cells, the synthesis of cytokines and prothrombotic factors are all indicators of inflammation in venous disease.
#23 Pathophysiology and Principles of Management of Varicose Veins – Mechanisms of Vascular Disease – NCBI Bookshelf
https://www.ncbi.nlm.nih.gov/books/NBK534256/
The molecular biology of varicose veins has recently been reviewed. The aetiology of varicose veins is undoubtedly multi-factorial. There are some genetic disorders and mutations that predispose to venous incompetence and development of varicosities (FOXC2, NOTCH3). However these diseases are rare whilst varicose veins are common. […] In recent years there has been much research to define the structural and molecular events that accompany the formation of varicose veins, with an overall underlying hypothesis that varicose vein formation is most likely due to a structural, cellular or molecular abnormality within the vein wall. On a gross level, varicose veins exhibit intimal hyperplastic areas and underlying plaques with infiltration of leukocytes and mast cells. There is fragmentation of elastin fibres and the total content of elastin and Type III collagen is reduced. These extracellular matrix abnormalities may be regulated by disordered MMP and TIMP production.
#24 The genetic constituent of varicose vein pathogenesis as a key for future treatment option development
https://www.oaepublish.com/articles/2574-1209.2021.17
The significance of genetic factors in the etiology of VVD was also emphasized in the works of the Danish and Swedish scientists Hauge and Gundersen, who, based on the information they collected about the parents and siblings of 250 patients, concluded that the determination of the disease by one gene is unlikely, and inheritance seems to be multifactorial. […] In 1974, Czechoslovakian scientists Matousek and Prerovsky estimated the heritability of primary varicose veins is up to 50% upon assuming the hypothesis of polygenic inheritance. […] A little later, in 1998, Chinese scientists Guo and Guo, based on the results of the genetic analysis of VVD, concluded that in most cases this disease is compatible with an autosomal dominant inheritance of incomplete penetrance, while some of the cases were sporadic, which prompted them to assume a recessive model possible as well.
#25 The genetic constituent of varicose vein pathogenesis as a key for future treatment option development
https://www.oaepublish.com/articles/2574-1209.2021.17
The significance of genetic factors in the etiology of VVD was also emphasized in the works of the Danish and Swedish scientists Hauge and Gundersen, who, based on the information they collected about the parents and siblings of 250 patients, concluded that the determination of the disease by one gene is unlikely, and inheritance seems to be multifactorial. […] In 1974, Czechoslovakian scientists Matousek and Prerovsky estimated the heritability of primary varicose veins is up to 50% upon assuming the hypothesis of polygenic inheritance. […] A little later, in 1998, Chinese scientists Guo and Guo, based on the results of the genetic analysis of VVD, concluded that in most cases this disease is compatible with an autosomal dominant inheritance of incomplete penetrance, while some of the cases were sporadic, which prompted them to assume a recessive model possible as well.
#26 The genetic constituent of varicose vein pathogenesis as a key for future treatment option development
https://www.oaepublish.com/articles/2574-1209.2021.17
The significance of genetic factors in the etiology of VVD was also emphasized in the works of the Danish and Swedish scientists Hauge and Gundersen, who, based on the information they collected about the parents and siblings of 250 patients, concluded that the determination of the disease by one gene is unlikely, and inheritance seems to be multifactorial. […] In 1974, Czechoslovakian scientists Matousek and Prerovsky estimated the heritability of primary varicose veins is up to 50% upon assuming the hypothesis of polygenic inheritance. […] A little later, in 1998, Chinese scientists Guo and Guo, based on the results of the genetic analysis of VVD, concluded that in most cases this disease is compatible with an autosomal dominant inheritance of incomplete penetrance, while some of the cases were sporadic, which prompted them to assume a recessive model possible as well.
#27 Varicose veins pathophysiology – wikidoc
https://www.wikidoc.org/index.php/Varicose_veins_pathophysiology
Varicose veins originate from sustained raised blood pressure in the superficial veins. Veins are normally gated by a one-way bicuspid valve system that prevents the backward flow of blood. […] The pathogenesis of varicose veins is multifactorial. Most of the risk factors for varicose veins either cause the weakening/destruction of valves of perforating veins or cause raise the overall pressure in the veins. […] With advancing age, the valves of the veins are exposed to wear and tear. This can lead to the development of the incompetence of the one-way valves that regulate the venous blood flow. This leads to backward leaking of pressure from deep veins to the superficial veins. This leads to increased prevalence of varicose veins in the elderly. […] It has been found that females are more prone to develop varicose veins. It has been hypothesized that estrogen plays are role in this. Estrogen caused increased relaxation of veins, limiting proper closure of the valves.
#28 Varicose veins pathophysiology – wikidoc
https://www.wikidoc.org/index.php/Varicose_veins_pathophysiology
During pregnancy, several physiologic changes occur. These changes help make sure that the fetus gets proper nutrition and increase the chances of its survival. The expansion of intravascular blood volume is one of these changes. […] Positive family history is present in a lot of cases varicose veins. The association seems to be more with prevalence rather than incidence. […] Obese patients have been to be associated with significantly higher CEAP clinical stages as compared to non-obese patients even in people with similar anatomical patterns of venous incompetence. […] People in prolonged hours of standing tend to develop Varicose veins. Prolonged standing can raise the venous pressure in the legs.
#29 Middletown Vein & Aesthetic Center (MVAC) – Connecticut Vein Care Specialists
https://www.ctveins.com/for-patients/venous-disease/chronic-venous-insufficiency
Chronic venous insufficiency (CVI) is a condition that occurs when the valve in the leg veins do not work well which along with enlargement of the vein itself make it difficult for blood to return to the heart from the legs. As a result, the blood pools in the legs causing varicose veins, swelling, pain, and sometimes, ulcerations. […] Symptoms in patients with varicose veins can be disproportionate to the amount and size of varicose veins that are visible. Patients with small varicose veins may have more complaints than those with larger varicose veins. Varicose vein pain is generally worse with prolonged standing and with warmer temperatures. It can also be worse during certain times of the menstrual cycle. Venous related pain may also be exacerbated by exercise, which is referred to as venous claudication. […] Varicose veins first develop in up to 28% of pregnancies. Although the exact mechanism is not fully known, it is likely a combination of hormonal effects and the obstruction of venous outflow from the legs by the enlarged uterus.
#30 Height may be risk factor for varicose veins | News Center
https://med.stanford.edu/news/all-news/2018/09/height-may-be-risk-factor-for-varicose-veins.html
In the largest genetic study of varicose veins ever completed, Stanford researchers and their collaborators provide evidence that being tall is a risk factor for the condition. […] „Genes that predict a person’s height may be at the root of this link between height and varicose veins and may provide clues for treating the condition,” said Nicholas Leeper, MD, associate professor of surgery and of cardiovascular medicine at Stanford. […] The study also confirmed that surgery on the legs, family history, lack of movement, smoking and hormone therapy are risk factors. But the correlation they found between height and the condition was unexpected, the researchers said. […] „Our results strongly suggest height is a cause, not just a correlated factor, but an underlying mechanism leading to varicose veins,” Ingelsson said.
#31 Height may be risk factor for varicose veins | News Center
https://med.stanford.edu/news/all-news/2018/09/height-may-be-risk-factor-for-varicose-veins.html
In the largest genetic study of varicose veins ever completed, Stanford researchers and their collaborators provide evidence that being tall is a risk factor for the condition. […] „Genes that predict a person’s height may be at the root of this link between height and varicose veins and may provide clues for treating the condition,” said Nicholas Leeper, MD, associate professor of surgery and of cardiovascular medicine at Stanford. […] The study also confirmed that surgery on the legs, family history, lack of movement, smoking and hormone therapy are risk factors. But the correlation they found between height and the condition was unexpected, the researchers said. […] „Our results strongly suggest height is a cause, not just a correlated factor, but an underlying mechanism leading to varicose veins,” Ingelsson said.
#32 Height may be risk factor for varicose veins | News Center
https://med.stanford.edu/news/all-news/2018/09/height-may-be-risk-factor-for-varicose-veins.html
In the largest genetic study of varicose veins ever completed, Stanford researchers and their collaborators provide evidence that being tall is a risk factor for the condition. […] „Genes that predict a person’s height may be at the root of this link between height and varicose veins and may provide clues for treating the condition,” said Nicholas Leeper, MD, associate professor of surgery and of cardiovascular medicine at Stanford. […] The study also confirmed that surgery on the legs, family history, lack of movement, smoking and hormone therapy are risk factors. But the correlation they found between height and the condition was unexpected, the researchers said. […] „Our results strongly suggest height is a cause, not just a correlated factor, but an underlying mechanism leading to varicose veins,” Ingelsson said.
#33 Height may be risk factor for varicose veins | News Center
https://med.stanford.edu/news/all-news/2018/09/height-may-be-risk-factor-for-varicose-veins.html
In the largest genetic study of varicose veins ever completed, Stanford researchers and their collaborators provide evidence that being tall is a risk factor for the condition. […] „Genes that predict a person’s height may be at the root of this link between height and varicose veins and may provide clues for treating the condition,” said Nicholas Leeper, MD, associate professor of surgery and of cardiovascular medicine at Stanford. […] The study also confirmed that surgery on the legs, family history, lack of movement, smoking and hormone therapy are risk factors. But the correlation they found between height and the condition was unexpected, the researchers said. […] „Our results strongly suggest height is a cause, not just a correlated factor, but an underlying mechanism leading to varicose veins,” Ingelsson said.
#34 Varicose veins pathophysiology – wikidoc
https://www.wikidoc.org/index.php/Varicose_veins_pathophysiology
During pregnancy, several physiologic changes occur. These changes help make sure that the fetus gets proper nutrition and increase the chances of its survival. The expansion of intravascular blood volume is one of these changes. […] Positive family history is present in a lot of cases varicose veins. The association seems to be more with prevalence rather than incidence. […] Obese patients have been to be associated with significantly higher CEAP clinical stages as compared to non-obese patients even in people with similar anatomical patterns of venous incompetence. […] People in prolonged hours of standing tend to develop Varicose veins. Prolonged standing can raise the venous pressure in the legs.
#35 Varicose veins pathophysiology – wikidoc
https://www.wikidoc.org/index.php/Varicose_veins_pathophysiology
During pregnancy, several physiologic changes occur. These changes help make sure that the fetus gets proper nutrition and increase the chances of its survival. The expansion of intravascular blood volume is one of these changes. […] Positive family history is present in a lot of cases varicose veins. The association seems to be more with prevalence rather than incidence. […] Obese patients have been to be associated with significantly higher CEAP clinical stages as compared to non-obese patients even in people with similar anatomical patterns of venous incompetence. […] People in prolonged hours of standing tend to develop Varicose veins. Prolonged standing can raise the venous pressure in the legs.
#36 Varicose and Telangiectatic Leg Veins – Endovascular Today
https://evtoday.com/articles/2007-oct/EVT1007_05-php
The most common predisposing factor for the development of unwanted leg veins is family history. […] Any activity or condition that increases abdominal pressure and impedes the flow of venous blood back to the heart may put strain on the veins, causing them to dilate. […] Varicose and telangiectatic veins arise from and may also be a cutaneous marker for an underlying reversal of venous blood flow known as venous insufficiency. […] Regardless of the cause, this reversal of blood flow produces venous hypertension in the lower extremities, which in turn produces an increase in venous diameter that leads to valvular insufficiency. […] This results in a reversal of blood flow from the deep to the superficial venous system through incompetent communicating veins. […] The superficial veins respond to increased pressure by dilating to accommodate the increased blood flow.
#37 Pathophysiology and Principles of Management of Varicose Veins – Mechanisms of Vascular Disease – NCBI Bookshelf
https://www.ncbi.nlm.nih.gov/books/NBK534256/
Varicose veins (VV) are dilated, tortuous subcutaneous veins that permit reverse flow. They are most commonly found in the lower limb and may be primary, or secondary to deep venous pathology. The GSV system is most frequently affected with the SSV being involved in about 20% of cases. The aetiology of VV at a microscopic level is still disputed but the essential defect macroscopically is generally agreed to be the failure of venous valve closure resulting in the superficial veins becoming dilated, elongated and tortuous. The main factor contributing to the development and progression of varicose veins is sustained venous hypertension that increases the diameter of the superficial veins resulting in further valve incompetence. […] Failure of valve closure leading to valve incompetence and reflux may affect the deep and/or superficial venous systems and may be primary or secondary. Primary valvular incompetence (PVI) is believed to be due to loss of mural elastin and collagen, which leads to dilatation and separation of the valve leaflets. The commonest clinical consequence of this process is the development of VV.
#38 Pathophysiology and Principles of Management of Varicose Veins – Mechanisms of Vascular Disease – NCBI Bookshelf
https://www.ncbi.nlm.nih.gov/books/NBK534256/
Varicose veins (VV) are dilated, tortuous subcutaneous veins that permit reverse flow. They are most commonly found in the lower limb and may be primary, or secondary to deep venous pathology. The GSV system is most frequently affected with the SSV being involved in about 20% of cases. The aetiology of VV at a microscopic level is still disputed but the essential defect macroscopically is generally agreed to be the failure of venous valve closure resulting in the superficial veins becoming dilated, elongated and tortuous. The main factor contributing to the development and progression of varicose veins is sustained venous hypertension that increases the diameter of the superficial veins resulting in further valve incompetence. […] Failure of valve closure leading to valve incompetence and reflux may affect the deep and/or superficial venous systems and may be primary or secondary. Primary valvular incompetence (PVI) is believed to be due to loss of mural elastin and collagen, which leads to dilatation and separation of the valve leaflets. The commonest clinical consequence of this process is the development of VV.
#39 Varicose Veins: Diagnosis and Treatment | AAFP
https://www.aafp.org/pubs/afp/issues/2019/0601/p682.html
Varicose veins are twisted, dilated veins most commonly located on the lower extremities. The exact pathophysiology is debated, but it involves a genetic predisposition, incompetent valves, weakened vascular walls, and increased intravenous pressure. […] Venous disease resulting in valvular reflux appears to be the underlying cause of varicose veins. The exact pathophysiology is debated, but it involves a genetic predisposition, incompetent valves, weakened vascular walls, and increased intravenous pressure. In most cases, the valvular dysfunction is presumed to be caused by a loss of elasticity in the vein wall, with failure of the valve leaflets to fit together. Rather than blood flowing from distal to proximal and superficial to deep, failed or incompetent valves allow blood to flow in the reverse direction. With increased pressure on the affected venous system, the larger veins may become elongated and tortuous. Shear stress on venous endothelial cells due to reversed or turbulent blood flow and inflammation are also important etiologic factors for venous disease.
#40 Varicose Vein Surgery: Practice Essentials, Anatomy, Pathophysiology
https://emedicine.medscape.com/article/462579-overview
Varicose veins are simply dilated, tortuous veins of the subcutaneous/superficial venous system. However, the pathophysiology behind their formation is complicated and involves the concept of ambulatory venous hypertension. To understand this process, it is necessary to be familiar with the anatomy of the lower-extremity venous system, as outlined above. […] In healthy veins, the flow of venous blood is through the superficial system into the deep system and up the leg and toward the heart. One-way venous valves are found in both systems and the perforating veins. Incompetence in any of these valves can lead to a disruption in the unidirectional flow of blood toward the heart and result in ambulatory venous hypertension. […] Furthermore, incompetence in one system can often lead to incompetence in another. Incompetence in the superficial venous system alone usually results from failure at valves located at the SFJ and the SPJ. The gravitational weight of the column of blood along the length of the vein creates hydrostatic pressure, which is worse at the more distal aspect of the length of vein.
#41 Varicose veins – Wikipedia
https://en.wikipedia.org/wiki/Varicose_veins
There is increasing evidence for the role of incompetent perforator veins (or „perforators”) in the formation of varicose veins and recurrent varicose veins. […] Varicose veins could also be caused by hyperhomocysteinemia in the body, which can degrade and inhibit the formation of the three main structural components of the artery: collagen, elastin and the proteoglycans. Homocysteine permanently degrades cysteine disulfide bridges and lysine amino acid residues in proteins, gradually affecting function and structure. Simply put, homocysteine is a 'corrosive’ of long-living proteins, i.e. collagen or elastin, or lifelong proteins, i.e. fibrillin. These long-term effects are difficult to establish in clinical trials focusing on groups with existing artery decline.
#42 Varicose Vein Surgery: Practice Essentials, Anatomy, Pathophysiology
https://emedicine.medscape.com/article/462579-overview
Incompetence of the perforating veins leads to hydrodynamic pressure. The calf pump mechanism helps to empty the deep venous system, but if perforating vein valves fail, then the pressure generated in the deep venous system by the calf pump mechanism are transmitted into the superficial system via the incompetent perforating veins. […] Once venous hypertension is present, the venous dysfunction continues to worsen through a vicious circle. Pooled blood and venous hypertension leads to venous dilatation, which then causes greater valvular insufficiency. Over time, with more local dilatation, other adjacent valves sequentially fail, and after a series of valves has failed, the entire superficial venous system is incompetent. […] The clinical findings of varicose veins, reticular veins, and telangiectasias are due to the hypertension in the superficial venous system that spreads to collateral veins and tributary veins, causing dilated tortuous structures. Treatment modalities are geared towards correcting the superficial venous hypertension.
#43 Varicose Vein Surgery: Practice Essentials, Anatomy, Pathophysiology
https://emedicine.medscape.com/article/462579-overview
Reflux at or near the SFJ does not always come through the terminal valve of the GSV, nor does it always involve the entire trunk of the GSV. Reflux can enter the GSV below the subterminal valve or even immediately below the junction, passing through a failed subterminal valve to mimic true SFJ incompetence. Reflux can also pass directly into any of the other veins that join the GSV at that level, or it may pass a few centimeters along the GSV and then abandon the GSV for another branch vessel. […] When a perforating vein is the primary site of reflux, dilatation of the vessel proceeds both proximally and distally. When dilatation reaches the most proximal portion of the vein, the SFJ or the SPJ is often recruited as a secondary point of reflux. Although most large varices are tributaries off of an incompetent GSV or SSV, failed perforating veins or connecting veins can also give rise to independent varices in the GSV distribution without involving the saphenous system itself. Identifying the originating point and the primary pathway of reflux in the thigh is often difficult, which is why DUS has become so helpful in varicose vein workup.
#44 Factors Influencing Venous Remodeling in the Development of Varicose Veins of the Lower Limbs
https://www.mdpi.com/1422-0067/25/3/1560
It has been shown that varicose veins are characterized by a greater infiltration of inflammatory cells compared to the normal vein. […] Changes in shear stress leading to activation, leukocyte adhesion, and migration across the endothelium contribute to inflammation and subsequent remodeling of the venous wall and valves. […] The main mechanism associated with the pathophysiology of chronic venous insufficiency is an increase in venous pressure, which is a consequence of damaged venous valves, shear stresses, and reflux. […] These factors cause further damage to the valves, increasing pressure and dilating the vein. […] Changes in the vein are transferred to microcirculation, disturbing the function of endothelial cells and the vascular microenvironment, which in turn leads to venous microangiopathy, characterized by dilatation and tortuosity of the capillary beds.
#45 Factors Influencing Venous Remodeling in the Development of Varicose Veins of the Lower Limbs
https://www.mdpi.com/1422-0067/25/3/1560
It has been shown that varicose veins are characterized by a greater infiltration of inflammatory cells compared to the normal vein. […] Changes in shear stress leading to activation, leukocyte adhesion, and migration across the endothelium contribute to inflammation and subsequent remodeling of the venous wall and valves. […] The main mechanism associated with the pathophysiology of chronic venous insufficiency is an increase in venous pressure, which is a consequence of damaged venous valves, shear stresses, and reflux. […] These factors cause further damage to the valves, increasing pressure and dilating the vein. […] Changes in the vein are transferred to microcirculation, disturbing the function of endothelial cells and the vascular microenvironment, which in turn leads to venous microangiopathy, characterized by dilatation and tortuosity of the capillary beds.
#46 Factors Influencing Venous Remodeling in the Development of Varicose Veins of the Lower Limbs
https://www.mdpi.com/1422-0067/25/3/1560
It has been shown that varicose veins are characterized by a greater infiltration of inflammatory cells compared to the normal vein. […] Changes in shear stress leading to activation, leukocyte adhesion, and migration across the endothelium contribute to inflammation and subsequent remodeling of the venous wall and valves. […] The main mechanism associated with the pathophysiology of chronic venous insufficiency is an increase in venous pressure, which is a consequence of damaged venous valves, shear stresses, and reflux. […] These factors cause further damage to the valves, increasing pressure and dilating the vein. […] Changes in the vein are transferred to microcirculation, disturbing the function of endothelial cells and the vascular microenvironment, which in turn leads to venous microangiopathy, characterized by dilatation and tortuosity of the capillary beds.
#47 Mechanisms of lower extremity vein dysfunction in chronic venous disease and implications in management of varicose veins
https://www.oaepublish.com/articles/2574-1209.2021.16
Chronic venous disease (CVD) is a common venous disorder of the lower extremities. CVD can be manifested as varicose veins (VVs), with dilated and tortuous veins, dysfunctional valves and venous reflux. […] Alterations in the mRNA expression, protein levels and proteolytic activity of matrix metalloproteinases (MMPs) have been detected in VVs and VLU. MMP expression/activity can be modulated by venous hydrostatic pressure, hypoxia, tissue metabolites, and inflammation. MMPs in turn increase proteolysis of different protein substrates in the extracellular matrix particularly collagen and elastin, leading to weakening of the vein wall. […] Changes in the levels/activity of matrix metalloproteinases (MMPs) have also been detected in VVs. MMPs are Zn2+-dependent endopeptidases that cause degradation of different protein substrates in the extracellular matrix (ECM). MMP mRNA expression, protein levels and proteolytic activity can be modulated by numerous factors including venous hydrostatic pressure, hypoxia, tissue metabolites and the inflammatory response. MMPs could promote remodeling of venous tissue through proteolytic degradation of different components of ECM.
#48 Mechanisms of lower extremity vein dysfunction in chronic venous disease and implications in management of varicose veins
https://www.oaepublish.com/articles/2574-1209.2021.16
MMPs have also been shown to affect endothelial function and VSM contraction mechanisms. […] MMPs could also affect vascular smooth muscle (VSM) cell proliferation, migration, differentiation and/or apoptosis. […] MMPs could promote venous dilation by increasing the release of endothelium-derived vasodilators and activating potassium channels, leading to smooth muscle hyperpolarization and relaxation. […] MMPs could also increase ECM turnover, but also cause endothelial cell dysfunction and reduce VSM contraction mechanisms, leading to progression of venous dilation and VVs. […] MMPs are negatively controlled by endogenous tissue inhibitors of metalloproteinases (TIMPs), and an imbalance between MMPs and TIMPs could contribute to venous dysfunction and CVD.
#49 Mechanisms of lower extremity vein dysfunction in chronic venous disease and implications in management of varicose veins
https://www.oaepublish.com/articles/2574-1209.2021.16
MMPs have also been shown to affect endothelial function and VSM contraction mechanisms. […] MMPs could also affect vascular smooth muscle (VSM) cell proliferation, migration, differentiation and/or apoptosis. […] MMPs could promote venous dilation by increasing the release of endothelium-derived vasodilators and activating potassium channels, leading to smooth muscle hyperpolarization and relaxation. […] MMPs could also increase ECM turnover, but also cause endothelial cell dysfunction and reduce VSM contraction mechanisms, leading to progression of venous dilation and VVs. […] MMPs are negatively controlled by endogenous tissue inhibitors of metalloproteinases (TIMPs), and an imbalance between MMPs and TIMPs could contribute to venous dysfunction and CVD.
#50 (PDF) Pathogenesis of varicose veins
https://www.academia.edu/27884289/Pathogenesis_of_varicose_veins
The exact etiology of Varicose Veins is not clearly known. The fact that the human race gets Varicose Veins at all is probably due to our evolutionary adoption of the erect posture. The superficial veins of the legs being between three and four feet below the heart, and unsupported except by connective tissue are in poor position to withstand continuous venous hypertension and so they become enlarged and tortuous i.e., varicose. […] revealed a significant separation among smooth muscle cells in the wall of VVs, and the presence of an abnormal amorphous extracellular matrix and intracytoplasmic vacuoles could reflect 'unusual’ possible secretory and phagocytic roles of smooth muscle cells. This could provide an important explanation for the abnormal contractile function of these cells in VVs.
#51
https://journals.lww.com/njcp/fulltext/2022/25030/what_is_the_relationship_of_varicose_vein.14.aspx
In this study, the densities of collagen 1 and collagen 4, which are an effective vascular component in the remodelling of varicose veins, were investigated. […] The change in the density of collagen types plays an important role in vein wall remodeling. […] Despite the high prevalence of VV disease, the biological mechanisms underlying its pathogenesis have not been fully clarified. In pathogenesis, it is obvious that venous hypertension, valvular insufficiency, and structural changes in the vein wall are intertwined. Venous hypertension, which forces and damages the vein wall, elicits ischemic and inflammatory responses with dilation and valvular insufficiency in the vein wall. In response to this situation, various molecular mechanisms are activated by stimulation. As the disease progresses, molecular mechanisms initiate changes in vein wall histomorphology.
#52 The genetic constituent of varicose vein pathogenesis as a key for future treatment option development
https://www.oaepublish.com/articles/2574-1209.2021.17
This perspective focuses primarily on the fundamental part of phlebology, where most attention is paid to the genetic aspects of the pathogenesis of varicose vein disease and where the main breakthrough advances in this area of research are discussed. […] Varicose vein disease (VVD)-the main nosological form of chronic venous diseases-is a multifactorial disease. Risk factors for developing venous pathologies include genetic factors and environmental factors. […] The role of genetics in this context can hardly be overestimated, since genetics is one of the constituent parts, in general, of the nucleation of a protein from DNA, where both biochemical and molecular biological processes are involved (i.e., replication, transcription and translation, from what and how protein is synthesized). Moreover, epigenetics can play an equally important role.
#53 The genetic constituent of varicose vein pathogenesis as a key for future treatment option development
https://www.oaepublish.com/articles/2574-1209.2021.17
The first large-scale genetic association study for primary varicose veins performed in our laboratory on the Russian population using exome genotyping identified a promising association signal at chromosome 6 within classical major histocompatibility complex class III subregion, with the most statistically significant association being shown in a combined analysis (discovery and replication stages) for polymorphism rs4151657 in the CFB (complement factor B) gene, which points to immune system involvement in VV pathogenesis. […] Understanding the mechanisms of mitochondrial and nuclear communication may shed light on the complex etiology of the disease, as well as the implications of therapeutic strategies to increase mitochondrial function. […] In 2020, a Russian group of scientists performed a scrutinizing review based on the literature data and their own works and postulated that: (a) primary varicose transformation of superficial veins develops as a result of remodeling of their walls; (b) vein wall remodeling is based on a complex of molecular processes determined by genetic predisposition; (c) vein wall remodeling is reversible, i.e., the dilated and altered vein can return to its original (healthy) state; and (d) varicose veins can probably be successfully cured pharmacologically with no surgical interventions needed.
#54 Factors Influencing Venous Remodeling in the Development of Varicose Veins of the Lower Limbs
https://www.mdpi.com/1422-0067/25/3/1560
Chronic venous insufficiency is caused by abnormalities in the wall structure and dysfunction of the venous valves, as well as disorders resulting from previous deep vein thrombosis. […] It has been shown that the veins of patients with varicose veins differ, among other things, in their elastic properties compared to the veins of healthy people. […] The expression of several genes related to angiogenesis, vascular hyperplasia, and venous regulation influences the incidence of CVI. […] In addition, inflammation, changes in mRNA expression, protein levels, and the proteolytic activity of matrix metalloproteinases (MMPs) have been found in VV and VLU. […] Altered venous hemodynamic triggers proteolytic remodeling of the venous wall and inflammatory processes as well as degradation of the protective endothelial glycocalyx, resulting in a wide spectrum of clinical symptoms ranging from varicose veins to venous ulcers, which have been termed chronic venous disorders (CVeD).
#55 Factors Influencing Venous Remodeling in the Development of Varicose Veins of the Lower Limbs
https://www.mdpi.com/1422-0067/25/3/1560
Chronic venous insufficiency is caused by abnormalities in the wall structure and dysfunction of the venous valves, as well as disorders resulting from previous deep vein thrombosis. […] It has been shown that the veins of patients with varicose veins differ, among other things, in their elastic properties compared to the veins of healthy people. […] The expression of several genes related to angiogenesis, vascular hyperplasia, and venous regulation influences the incidence of CVI. […] In addition, inflammation, changes in mRNA expression, protein levels, and the proteolytic activity of matrix metalloproteinases (MMPs) have been found in VV and VLU. […] Altered venous hemodynamic triggers proteolytic remodeling of the venous wall and inflammatory processes as well as degradation of the protective endothelial glycocalyx, resulting in a wide spectrum of clinical symptoms ranging from varicose veins to venous ulcers, which have been termed chronic venous disorders (CVeD).
#56 Identification of biological significance of different stages of varicose vein development based on mRNA sequencing | Scientific Reports
https://www.nature.com/articles/s41598-024-73691-3
Normal veins could develop to varicose vein (VV) by some risk factors, and might further progress to shallow vein thrombosis (SVT). […] However, the molecular mechanism of key genes associated with the progression and regression of VV are still not thorough enough. […] Six key genes including PLP2, DACT3, LRRC25, PILRA, MSX1 and APOD that were associated with the progression and regression of VV were screened. […] This study identified six key genes associated with the progression and regression of VV. Among them, DACT3 was proved to hinder VV progression. […] DACT3 was closely involved in the proliferation, cell cycle, migration and phenotype transition of VSMCs, in turn regulating the progression of VV. […] It has been established that DACT3 involved in negative regulation of canonical Wnt signaling pathway and negative regulation of cell growth. […] Overexpression of DACT3 significantly inhibited the proliferation of VSMCs and retarded their transition from G0/G1 to S phase. […] The phenotypic change of VSMCs profoundly affects the onset and progression of VV.
#57 Identification of biological significance of different stages of varicose vein development based on mRNA sequencing | Scientific Reports
https://www.nature.com/articles/s41598-024-73691-3
Normal veins could develop to varicose vein (VV) by some risk factors, and might further progress to shallow vein thrombosis (SVT). […] However, the molecular mechanism of key genes associated with the progression and regression of VV are still not thorough enough. […] Six key genes including PLP2, DACT3, LRRC25, PILRA, MSX1 and APOD that were associated with the progression and regression of VV were screened. […] This study identified six key genes associated with the progression and regression of VV. Among them, DACT3 was proved to hinder VV progression. […] DACT3 was closely involved in the proliferation, cell cycle, migration and phenotype transition of VSMCs, in turn regulating the progression of VV. […] It has been established that DACT3 involved in negative regulation of canonical Wnt signaling pathway and negative regulation of cell growth. […] Overexpression of DACT3 significantly inhibited the proliferation of VSMCs and retarded their transition from G0/G1 to S phase. […] The phenotypic change of VSMCs profoundly affects the onset and progression of VV.
#58 Identification of biological significance of different stages of varicose vein development based on mRNA sequencing | Scientific Reports
https://www.nature.com/articles/s41598-024-73691-3
Normal veins could develop to varicose vein (VV) by some risk factors, and might further progress to shallow vein thrombosis (SVT). […] However, the molecular mechanism of key genes associated with the progression and regression of VV are still not thorough enough. […] Six key genes including PLP2, DACT3, LRRC25, PILRA, MSX1 and APOD that were associated with the progression and regression of VV were screened. […] This study identified six key genes associated with the progression and regression of VV. Among them, DACT3 was proved to hinder VV progression. […] DACT3 was closely involved in the proliferation, cell cycle, migration and phenotype transition of VSMCs, in turn regulating the progression of VV. […] It has been established that DACT3 involved in negative regulation of canonical Wnt signaling pathway and negative regulation of cell growth. […] Overexpression of DACT3 significantly inhibited the proliferation of VSMCs and retarded their transition from G0/G1 to S phase. […] The phenotypic change of VSMCs profoundly affects the onset and progression of VV.
#59 Identification of biological significance of different stages of varicose vein development based on mRNA sequencing | Scientific Reports
https://www.nature.com/articles/s41598-024-73691-3
Normal veins could develop to varicose vein (VV) by some risk factors, and might further progress to shallow vein thrombosis (SVT). […] However, the molecular mechanism of key genes associated with the progression and regression of VV are still not thorough enough. […] Six key genes including PLP2, DACT3, LRRC25, PILRA, MSX1 and APOD that were associated with the progression and regression of VV were screened. […] This study identified six key genes associated with the progression and regression of VV. Among them, DACT3 was proved to hinder VV progression. […] DACT3 was closely involved in the proliferation, cell cycle, migration and phenotype transition of VSMCs, in turn regulating the progression of VV. […] It has been established that DACT3 involved in negative regulation of canonical Wnt signaling pathway and negative regulation of cell growth. […] Overexpression of DACT3 significantly inhibited the proliferation of VSMCs and retarded their transition from G0/G1 to S phase. […] The phenotypic change of VSMCs profoundly affects the onset and progression of VV.
#60 The genetic constituent of varicose vein pathogenesis as a key for future treatment option development
https://www.oaepublish.com/articles/2574-1209.2021.17
The first large-scale genetic association study for primary varicose veins performed in our laboratory on the Russian population using exome genotyping identified a promising association signal at chromosome 6 within classical major histocompatibility complex class III subregion, with the most statistically significant association being shown in a combined analysis (discovery and replication stages) for polymorphism rs4151657 in the CFB (complement factor B) gene, which points to immune system involvement in VV pathogenesis. […] Understanding the mechanisms of mitochondrial and nuclear communication may shed light on the complex etiology of the disease, as well as the implications of therapeutic strategies to increase mitochondrial function. […] In 2020, a Russian group of scientists performed a scrutinizing review based on the literature data and their own works and postulated that: (a) primary varicose transformation of superficial veins develops as a result of remodeling of their walls; (b) vein wall remodeling is based on a complex of molecular processes determined by genetic predisposition; (c) vein wall remodeling is reversible, i.e., the dilated and altered vein can return to its original (healthy) state; and (d) varicose veins can probably be successfully cured pharmacologically with no surgical interventions needed.
#61 Varicose Vein Surgery: Practice Essentials, Anatomy, Pathophysiology
https://emedicine.medscape.com/article/462579-overview
Incompetence of the perforating veins leads to hydrodynamic pressure. The calf pump mechanism helps to empty the deep venous system, but if perforating vein valves fail, then the pressure generated in the deep venous system by the calf pump mechanism are transmitted into the superficial system via the incompetent perforating veins. […] Once venous hypertension is present, the venous dysfunction continues to worsen through a vicious circle. Pooled blood and venous hypertension leads to venous dilatation, which then causes greater valvular insufficiency. Over time, with more local dilatation, other adjacent valves sequentially fail, and after a series of valves has failed, the entire superficial venous system is incompetent. […] The clinical findings of varicose veins, reticular veins, and telangiectasias are due to the hypertension in the superficial venous system that spreads to collateral veins and tributary veins, causing dilated tortuous structures. Treatment modalities are geared towards correcting the superficial venous hypertension.
#62 Varicose Vein Surgery: Practice Essentials, Anatomy, Pathophysiology
https://emedicine.medscape.com/article/462579-overview
Incompetence of the perforating veins leads to hydrodynamic pressure. The calf pump mechanism helps to empty the deep venous system, but if perforating vein valves fail, then the pressure generated in the deep venous system by the calf pump mechanism are transmitted into the superficial system via the incompetent perforating veins. […] Once venous hypertension is present, the venous dysfunction continues to worsen through a vicious circle. Pooled blood and venous hypertension leads to venous dilatation, which then causes greater valvular insufficiency. Over time, with more local dilatation, other adjacent valves sequentially fail, and after a series of valves has failed, the entire superficial venous system is incompetent. […] The clinical findings of varicose veins, reticular veins, and telangiectasias are due to the hypertension in the superficial venous system that spreads to collateral veins and tributary veins, causing dilated tortuous structures. Treatment modalities are geared towards correcting the superficial venous hypertension.
#63 Varicose Vein Surgery: Practice Essentials, Anatomy, Pathophysiology
https://emedicine.medscape.com/article/462579-overview
At times, the degree of venous hypertension does not correlate to the clinical findings. The presence and size of visible varicosities are not reliable indicators of the volume or pressure of venous reflux. A vein that is confined within fascial planes or is buried beneath subcutaneous tissue can carry massive amounts of high-pressure reflux without being visible at all. Conversely, even a small increase in pressure can eventually produce massive dilatation of an otherwise normal superficial vein that carries very little flow. […] In contrast to the superficial veins, the deep veins do not become excessively distended. They can withstand the increased pressure because of their construction and the confining fascia.
#64 Varicose veins – Wikipedia
https://en.wikipedia.org/wiki/Varicose_veins
Varicose veins have no specific cause. Risk factors include obesity, lack of exercise, leg trauma, and family history of the condition. They also develop more commonly during pregnancy. Occasionally they result from chronic venous insufficiency. Underlying causes include weak or damaged valves in the veins. […] Venous reflux is a significant cause. Research has also shown the importance of pelvic vein reflux (PVR) in the development of varicose veins. Varicose veins in the legs could be due to ovarian vein reflux. Both ovarian and internal iliac vein reflux causes leg varicose veins. This condition affects 14% of women with varicose veins or 20% of women who have had vaginal delivery and have leg varicose veins. In addition, evidence suggests that failing to look for and treat pelvic vein reflux can be a cause of recurrent varicose veins.
#65 Varicose and Telangiectatic Leg Veins – Endovascular Today
https://evtoday.com/articles/2007-oct/EVT1007_05-php
The most common predisposing factor for the development of unwanted leg veins is family history. […] Any activity or condition that increases abdominal pressure and impedes the flow of venous blood back to the heart may put strain on the veins, causing them to dilate. […] Varicose and telangiectatic veins arise from and may also be a cutaneous marker for an underlying reversal of venous blood flow known as venous insufficiency. […] Regardless of the cause, this reversal of blood flow produces venous hypertension in the lower extremities, which in turn produces an increase in venous diameter that leads to valvular insufficiency. […] This results in a reversal of blood flow from the deep to the superficial venous system through incompetent communicating veins. […] The superficial veins respond to increased pressure by dilating to accommodate the increased blood flow.
#66 Varicose and Telangiectatic Leg Veins – Endovascular Today
https://evtoday.com/articles/2007-oct/EVT1007_05-php
The most common predisposing factor for the development of unwanted leg veins is family history. […] Any activity or condition that increases abdominal pressure and impedes the flow of venous blood back to the heart may put strain on the veins, causing them to dilate. […] Varicose and telangiectatic veins arise from and may also be a cutaneous marker for an underlying reversal of venous blood flow known as venous insufficiency. […] Regardless of the cause, this reversal of blood flow produces venous hypertension in the lower extremities, which in turn produces an increase in venous diameter that leads to valvular insufficiency. […] This results in a reversal of blood flow from the deep to the superficial venous system through incompetent communicating veins. […] The superficial veins respond to increased pressure by dilating to accommodate the increased blood flow.
#67 Varicose and Telangiectatic Leg Veins – Endovascular Today
https://evtoday.com/articles/2007-oct/EVT1007_05-php
The most common predisposing factor for the development of unwanted leg veins is family history. […] Any activity or condition that increases abdominal pressure and impedes the flow of venous blood back to the heart may put strain on the veins, causing them to dilate. […] Varicose and telangiectatic veins arise from and may also be a cutaneous marker for an underlying reversal of venous blood flow known as venous insufficiency. […] Regardless of the cause, this reversal of blood flow produces venous hypertension in the lower extremities, which in turn produces an increase in venous diameter that leads to valvular insufficiency. […] This results in a reversal of blood flow from the deep to the superficial venous system through incompetent communicating veins. […] The superficial veins respond to increased pressure by dilating to accommodate the increased blood flow.
#68 Recent findings in the pathogenesis of venous wall degradation – Servier – PhlebolymphologyServier – Phlebolymphology
https://www.phlebolymphology.org/recent-findings-in-the-pathogenesis-of-venous-wall-degradation/
Recent studies show that the link between valvular dysfunction and remodeling involves early activation of aseptic inflammation, which triggers cellular and enzymatic processes. […] Once valvular damage is done, it produces venous, and then cutaneous, damage. […] Nevertheless, varicose vein deformities will themselves promote development of the process, enhancing deterioration of the entire vessel (a vicious circle). […] Hypoxia first affects the sinus, and as seen before is a constant finding in the valvular nidus. […] The primary event no longer lies in the wall of the vein. This does not prevent secondary major mechanical abnormalities in the vessel from worsening and even inducing alterations. […] In summary, the link between a hemodynamic disorder due to dysfunction of venous valves, circulating blood cells, the venous wall, and biochemical processes is established with regard to the etiology of varicose veins.
#69 Recent findings in the pathogenesis of venous wall degradation – Servier – PhlebolymphologyServier – Phlebolymphology
https://www.phlebolymphology.org/recent-findings-in-the-pathogenesis-of-venous-wall-degradation/
Recent studies show that the link between valvular dysfunction and remodeling involves early activation of aseptic inflammation, which triggers cellular and enzymatic processes. […] Once valvular damage is done, it produces venous, and then cutaneous, damage. […] Nevertheless, varicose vein deformities will themselves promote development of the process, enhancing deterioration of the entire vessel (a vicious circle). […] Hypoxia first affects the sinus, and as seen before is a constant finding in the valvular nidus. […] The primary event no longer lies in the wall of the vein. This does not prevent secondary major mechanical abnormalities in the vessel from worsening and even inducing alterations. […] In summary, the link between a hemodynamic disorder due to dysfunction of venous valves, circulating blood cells, the venous wall, and biochemical processes is established with regard to the etiology of varicose veins.
#70 Recent findings in the pathogenesis of venous wall degradation – Servier – PhlebolymphologyServier – Phlebolymphology
https://www.phlebolymphology.org/recent-findings-in-the-pathogenesis-of-venous-wall-degradation/
Recent studies show that the link between valvular dysfunction and remodeling involves early activation of aseptic inflammation, which triggers cellular and enzymatic processes. […] Once valvular damage is done, it produces venous, and then cutaneous, damage. […] Nevertheless, varicose vein deformities will themselves promote development of the process, enhancing deterioration of the entire vessel (a vicious circle). […] Hypoxia first affects the sinus, and as seen before is a constant finding in the valvular nidus. […] The primary event no longer lies in the wall of the vein. This does not prevent secondary major mechanical abnormalities in the vessel from worsening and even inducing alterations. […] In summary, the link between a hemodynamic disorder due to dysfunction of venous valves, circulating blood cells, the venous wall, and biochemical processes is established with regard to the etiology of varicose veins.
#71 Recent findings in the pathogenesis of venous wall degradation – Servier – PhlebolymphologyServier – Phlebolymphology
https://www.phlebolymphology.org/recent-findings-in-the-pathogenesis-of-venous-wall-degradation/
Recent studies show that the link between valvular dysfunction and remodeling involves early activation of aseptic inflammation, which triggers cellular and enzymatic processes. […] Once valvular damage is done, it produces venous, and then cutaneous, damage. […] Nevertheless, varicose vein deformities will themselves promote development of the process, enhancing deterioration of the entire vessel (a vicious circle). […] Hypoxia first affects the sinus, and as seen before is a constant finding in the valvular nidus. […] The primary event no longer lies in the wall of the vein. This does not prevent secondary major mechanical abnormalities in the vessel from worsening and even inducing alterations. […] In summary, the link between a hemodynamic disorder due to dysfunction of venous valves, circulating blood cells, the venous wall, and biochemical processes is established with regard to the etiology of varicose veins.
#72 Varicose veins – Symptoms and causes – Mayo Clinic
https://www.mayoclinic.org/diseases-conditions/varicose-veins/symptoms-causes/syc-20350643
Veins return blood from the rest of the body to the heart. To return blood to the heart, the veins in the legs must work against gravity. Weakened valves, also called incompetent valves, within the veins might cause varicose veins. The weakened valves let blood pool in the veins instead of traveling to the heart. When blood pools in the veins, the veins become larger, making them show under the skin. […] Weak or damaged valves can lead to varicose veins. […] Tiny valves in the veins open as blood flows toward the heart, then close to stop blood from flowing backward. If these valves are weak or damaged, blood can flow backward and pool in the veins, causing the veins to stretch or twist.
#73 Recent findings in the pathogenesis of venous wall degradation – Servier – PhlebolymphologyServier – Phlebolymphology
https://www.phlebolymphology.org/recent-findings-in-the-pathogenesis-of-venous-wall-degradation/
Increased venous pressure in the erect position is a constant finding in patients with chronic venous disease. […] The length of time a subject is exposed to elevated venous pressure is a major factor in the progression of venous disease and in the development of varicose veins. […] According to a similar mechanism, this inflammatory chain reaction may extend to large veins, resulting in multilevel valvular deficiencies and increased VHT. […] In summary, alterations in venous valves induced by a leukocyte-mediated inflammatory process appear to be a key factor in the development of varicose veins, and can be inhibited by the micronized flavonoid fraction in MPFF at a dose of 500 mg. […] Therefore, it is evident that venous valve incompetence, whose consequence is an increase in venous pressure, is the major cause of varicose vein disease, and subsequent venous insufficiency and skin disorders, including venous ulceration, the most serious complication.
#74 Pathophysiology and Principles of Management of Varicose Veins – Mechanisms of Vascular Disease – NCBI Bookshelf
https://www.ncbi.nlm.nih.gov/books/NBK534256/
The molecular biology of varicose veins has recently been reviewed. The aetiology of varicose veins is undoubtedly multi-factorial. There are some genetic disorders and mutations that predispose to venous incompetence and development of varicosities (FOXC2, NOTCH3). However these diseases are rare whilst varicose veins are common. […] In recent years there has been much research to define the structural and molecular events that accompany the formation of varicose veins, with an overall underlying hypothesis that varicose vein formation is most likely due to a structural, cellular or molecular abnormality within the vein wall. On a gross level, varicose veins exhibit intimal hyperplastic areas and underlying plaques with infiltration of leukocytes and mast cells. There is fragmentation of elastin fibres and the total content of elastin and Type III collagen is reduced. These extracellular matrix abnormalities may be regulated by disordered MMP and TIMP production.
#75 Mechanisms of lower extremity vein dysfunction in chronic venous disease and implications in management of varicose veins
https://www.oaepublish.com/articles/2574-1209.2021.16
Chronic venous disease (CVD) is a common venous disorder of the lower extremities. CVD can be manifested as varicose veins (VVs), with dilated and tortuous veins, dysfunctional valves and venous reflux. […] Alterations in the mRNA expression, protein levels and proteolytic activity of matrix metalloproteinases (MMPs) have been detected in VVs and VLU. MMP expression/activity can be modulated by venous hydrostatic pressure, hypoxia, tissue metabolites, and inflammation. MMPs in turn increase proteolysis of different protein substrates in the extracellular matrix particularly collagen and elastin, leading to weakening of the vein wall. […] Changes in the levels/activity of matrix metalloproteinases (MMPs) have also been detected in VVs. MMPs are Zn2+-dependent endopeptidases that cause degradation of different protein substrates in the extracellular matrix (ECM). MMP mRNA expression, protein levels and proteolytic activity can be modulated by numerous factors including venous hydrostatic pressure, hypoxia, tissue metabolites and the inflammatory response. MMPs could promote remodeling of venous tissue through proteolytic degradation of different components of ECM.
#76 Factors Influencing Venous Remodeling in the Development of Varicose Veins of the Lower Limbs
https://www.mdpi.com/1422-0067/25/3/1560
One of the early symptoms of chronic venous disease (CVD) is varicose veins (VV) of the lower limbs. […] The aim of this review is to present current knowledge on CVD, including the pathophysiology and mechanisms related to vein wall remodeling. […] It is believed that the formation of varicose veins is caused by valve dysfunction and venous reflux, which consequently leads to venous stasis and hypoxia. […] A common cause of varicose veins is chronic inflammation, which may have a genetic basis and can cause damage to the valves in the veins of the lower limbs. […] Inflammatory mediators attract and activate neutrophils, leading to their infiltration of the venous wall, and initiate damage to extracellular matrix components. […] Numerous studies have shown that growth factors secreted by macrophages, pro-inflammatory cytokines, matrix metalloproteinases (MMPs), and adhesion molecules are involved in the etiology of varicose veins.
#77 Pathophysiology of pain in venous disease – Servier – PhlebolymphologyServier – Phlebolymphology
https://www.phlebolymphology.org/pathophysiology-of-pain-in-venous-disease/
Interestingly, the same processes assumed to generate pain in venous disease also seem to be involved in the longer term in the process of varicose vein remodeling, defined as all of the qualitative and quantitative alterations in the cellular and matrix components of the venous wall. […] The starting point for these mechanisms probably is local hypoxia associated with capillary stasis. […] Evidence for such an inflammatory reaction in patients with varicose veins has accumulated dramatically over the last five years, and the biochemical changes identified suggest that endothelial cells and neutrophils are the source of this local inflammation. […] The presence of neutrophils, monocytes, and activated T lymphocytes, the accumulation of macrophages and mast cells, the expression of adhesion molecules on the surface of leukocytes and endothelial cells, the synthesis of cytokines and prothrombotic factors are all indicators of inflammation in venous disease.
#78 Varicose Veins: Diagnosis and Treatment | AAFP
https://www.aafp.org/pubs/afp/issues/2019/0601/p682.html
Varicose veins are twisted, dilated veins most commonly located on the lower extremities. The exact pathophysiology is debated, but it involves a genetic predisposition, incompetent valves, weakened vascular walls, and increased intravenous pressure. […] Venous disease resulting in valvular reflux appears to be the underlying cause of varicose veins. The exact pathophysiology is debated, but it involves a genetic predisposition, incompetent valves, weakened vascular walls, and increased intravenous pressure. In most cases, the valvular dysfunction is presumed to be caused by a loss of elasticity in the vein wall, with failure of the valve leaflets to fit together. Rather than blood flowing from distal to proximal and superficial to deep, failed or incompetent valves allow blood to flow in the reverse direction. With increased pressure on the affected venous system, the larger veins may become elongated and tortuous. Shear stress on venous endothelial cells due to reversed or turbulent blood flow and inflammation are also important etiologic factors for venous disease.
#79 Height may be risk factor for varicose veins | News Center
https://med.stanford.edu/news/all-news/2018/09/height-may-be-risk-factor-for-varicose-veins.html
In the largest genetic study of varicose veins ever completed, Stanford researchers and their collaborators provide evidence that being tall is a risk factor for the condition. […] „Genes that predict a person’s height may be at the root of this link between height and varicose veins and may provide clues for treating the condition,” said Nicholas Leeper, MD, associate professor of surgery and of cardiovascular medicine at Stanford. […] The study also confirmed that surgery on the legs, family history, lack of movement, smoking and hormone therapy are risk factors. But the correlation they found between height and the condition was unexpected, the researchers said. […] „Our results strongly suggest height is a cause, not just a correlated factor, but an underlying mechanism leading to varicose veins,” Ingelsson said.
#80 Varicose veins pathophysiology – wikidoc
https://www.wikidoc.org/index.php/Varicose_veins_pathophysiology
During pregnancy, several physiologic changes occur. These changes help make sure that the fetus gets proper nutrition and increase the chances of its survival. The expansion of intravascular blood volume is one of these changes. […] Positive family history is present in a lot of cases varicose veins. The association seems to be more with prevalence rather than incidence. […] Obese patients have been to be associated with significantly higher CEAP clinical stages as compared to non-obese patients even in people with similar anatomical patterns of venous incompetence. […] People in prolonged hours of standing tend to develop Varicose veins. Prolonged standing can raise the venous pressure in the legs.
#81 Pathogenesis of varicose veins and implications for clinical management – PubMed
https://pubmed.ncbi.nlm.nih.gov/17976322/
The distinct pathogenic mechanisms involved in the development of VVs have important implications for the management of VVs that include a wide spectrum of treatment modalities ranging from reassurance, alternative medicines, conservative management or compression therapy, and surgical or endovascular therapy.
#82 Pathophysiology and Principles of Management of Varicose Veins – Mechanisms of Vascular Disease – NCBI Bookshelf
https://www.ncbi.nlm.nih.gov/books/NBK534256/
There is certain to be further research in the next few years to further define the vascular biology of varicose veins. There has been some suggestion that this may lead to a medical therapy for varicose veins, although the practicality of this is not immediately apparent. Nevertheless research into the molecular aetiology of varicose veins will continue to define vascular pathways.