Kardiomiopatia rozstrzeniowa – Patofizjologia i mechanizm

Kardiomiopatia rozstrzeniowa
Patofizjologia i mechanizm

Kardiomiopatia rozstrzeniowa (DCM) charakteryzuje się poszerzeniem i rozciągnięciem komór serca oraz upośledzeniem funkcji skurczowej, definiowanym jako frakcja wyrzutowa lewej komory (LVEF) poniżej 40% lub frakcja skracania mniejsza niż 25%. Etiologia DCM jest heterogenna, z 30-40% przypadków o podłożu genetycznym, obejmującym mutacje w ponad 50 genach kodujących białka sarkomerowe, cytoszkieletowe, otoczkę jądrową oraz kanały jonowe. Szczególną rolę odgrywają mutacje w genie TTN (około 25% przypadków) oraz LMNA, które prowadzą do dysfunkcji mechanicznej i strukturalnej kardiomiocytów. Patogeneza DCM obejmuje deficyt generowania siły, zaburzenia homeostazy wapniowej, stres retikulum endoplazmatycznego, stres oksydacyjny, zapalenie oraz nieprawidłową przebudowę macierzy pozakomórkowej, co skutkuje progresywną niewydolnością serca i ryzykiem nagłej śmierci sercowej. Wczesne mechanizmy kompensacyjne, takie jak aktywacja układu współczulnego i RAAS, z czasem prowadzą do niekorzystnej przebudowy komór i pogorszenia funkcji skurczowej.

Definicja i patofizjologia kardiomiopatii rozstrzeniowej

Kardiomiopatia rozstrzeniowa (DCM – Dilated Cardiomyopathy) to choroba mięśnia sercowego charakteryzująca się poszerzeniem i rozciągnięciem jednej lub obu komór serca wraz z upośledzeniem funkcji skurczowej, definiowanej jako frakcja wyrzutowa lewej komory (LVEF) poniżej 40% lub frakcja skracania mniejsza niż 25%.¹ Choroba ta jest rozpoznawana po wykluczeniu nieprawidłowych warunków obciążenia (takich jak nadciśnienie tętnicze i choroba zastawkowa serca) lub choroby wieńcowej.²³ DCM stanowi jedną z głównych przyczyn niewydolności serca i nagłej śmierci sercowej.⁴

Charakterystyczną cechą patofizjologiczną kardiomiopatii rozstrzeniowej jest dysfunkcja skurczowa. Patogeneza obejmuje kilka mechanizmów, w tym: zwiększone przeciążenie hemodynamiczne, przebudowę komór, nadmierną stymulację neurohumoralną, nieprawidłowy obieg wapnia w miocytach, nadmierną lub niewystarczającą proliferację macierzy pozakomórkowej oraz przyspieszoną apoptozę komórek.⁵ Choć początkowo te mechanizmy kompensacyjne są korzystne w początkowych stadiach niewydolności serca, z czasem prowadzą do błędnego koła pogarszającej się niewydolności serca.⁶

Podłoże genetyczne DCM

Przyczyny genetyczne stanowią 30-40% przypadków kardiomiopatii rozstrzeniowej i dotyczą genów kodujących heterogenną grupę cząsteczek uczestniczących w generowaniu siły, transmisji siły, integralności sarkomeru, strukturze cytoszkieletu i jądra komórkowego, homeostazy elektrolitowej, funkcji mitochondrialnej oraz transkrypcji.⁷⁸ Dotychczas zidentyfikowano ponad 50 genów związanych z dziedziczną postacią DCM.⁹¹⁰

Kardiomiopatia rozstrzeniowa zwykle występuje jako choroba autosomalna dominująca, chociaż opisywano również dziedziczenie w postaci recesywnej, sprzężonej z chromosomem X oraz mitochondrialnej.¹¹¹² Najczęstsze mutacje występują w genach kodujących białka sarkomeryczne oraz w genach związanych z otoczką jądrową i cytoszkieletem.¹³

Ostatnie badania wykazały, że mutacje w olbrzymim białku titinie są odpowiedzialne za około 25% przypadków DCM.¹⁴ Gen TTN na chromosomie 2 został wcześniej powiązany z rodzinną postacią DCM, a te ustalenia zostały potwierdzone w badaniach na modelach zwierzęcych.¹⁵

Mechanizmy patogenetyczne DCM

Różnorodne ścieżki patogenetyczne zostały zaproponowane, aby wyjaśnić rozwój kardiomiopatii rozstrzeniowej, w zależności od dotkniętych genów i zaburzonych wewnątrzkomórkowych struktur lub szlaków.¹⁶ Głównymi mechanizmami dysfunkcji komorowej w DCM są:

Zaburzenia białek sarkomerycznych

Deficyt w generowaniu siły (kardiomiopatia sarkomeryczna) wynika z mutacji w genach kodujących titinę, miozynę, aktynę, troponinę i tropomiozynę. Prowadzi to do ekspresji nieprawidłowo funkcjonujących białek, powodując dysfunkcję miokardium i DCM.¹⁷ Mechanizm działania niektórych mutacji sarkomerycznych w DCM polega na dominującej negatywności.¹⁸

Niedawne badania wykazały, że mutacje w genach kodujących białka sarkomeryczne powodują zmniejszoną wrażliwość miokardium na jony wapnia. Badania z użyciem modeli transgenicznych myszy wykazały kluczową rolę zmniejszonej wrażliwości na wapń w rozwoju DCM.¹⁹

Defekty otoczki jądrowej

Laminopatie charakteryzują się różnym stopniem zajęcia serca i mięśni szkieletowych.²⁰ Mutacje w genach LMNA zostały powiązane z rodzinną kardiomiopatią rozstrzeniową. Najnowsze badania wykazały, że pęknięcia otoczki jądrowej występują często w modelach choroby, zanim serce zacznie słabnąć.²¹ Odkryto, że prawie 50% komórek mięśnia sercowego w modelach choroby ma pęknięcia otoczki jądrowej w porównaniu do prawie zerowego wskaźnika w normalnych sercach, co sugeruje, że pęknięcie jądrowe jest prawdopodobnie przyczyną choroby.²²

Deficyt w transmisji siły

Kardiomiopatie cytoszkieletowe wynikają z mutacji w białkach cytoszkieletu, takich jak filaminy, dystrofina, desmina, d-sarkoglikan i winkulina. Są one odpowiedzialne za dystrofie mięśniowe, które często towarzyszą DCM.²³ Mutacje w dystrofinie i sarkoglikanie powodują chorobę mięśni szkieletowych i kardiomiopatię, więc niewydolność serca u tych pacjentów jest dodatkowo skomplikowana przez hipowentylację z powodu osłabienia mięśni oddechowych.²⁴

Zaburzenia połączeń międzykomórkowych

Upośledzone połączenia komórka-komórka (kardiomiopatie desmosomalne) wynikają z mutacji w genach kodujących białka desmosomalne, które są odpowiedzialne za arytmogenną prawokomorową kardiomiopatię (ARVC) oraz DCM, z częstością występowania do 13% w kohorcie pacjentów z DCM.²⁵

Deficyt produkcji energii

Kardiomiopatie mitochondrialne charakteryzują się defektami w fosforylacji oksydacyjnej, które skutkują niewystarczającą produkcją energii w postaci ATP.²⁶ Mutacje w genach mitochondrialnych mogą prowadzić do nieprawidłowej produkcji energii w komórkach mięśnia sercowego, co przyczynia się do rozwoju kardiomiopatii rozstrzeniowej.²⁷

Zaburzenia cyklu wapniowego

Cytoplazmatyczny Ca²⁺ odgrywa kluczową rolę w kurczeniu serca, wywołując interakcję między miozyną a aktyną.²⁸ Mutacje w genie fosfolambanu zostały opisane w przypadkach DCM.²⁹ Badania strukturalne kompleksów PKA-fosfolamban ujawniły, że mutacje w pozycjach 9, 14 i 18 fosfolambanu mają wspólny mechanizm chorobowy związany ze zmniejszoną fosforylacją przez PKA.³⁰ Niższe poziomy fosforylacji fosfolambanu w komórkach serca prowadzą do większego hamowania SERCA, zmniejszając kurczliwość mięśnia sercowego i szybkość relaksacji.³¹

Zaburzenia kanałów jonowych

Mutacje w genach kanałów jonowych (SCN5A, ABCC9) są zwykle związane z różnymi zaburzeniami arytmicznymi, ale mogą również prowadzić do DCM.³²

Mechanizmy wtórne w rozwoju DCM

Przebudowa (remodeling) mięśnia sercowego

DCM charakteryzuje się histologicznie rozlanym włóknieniem, kompensacyjnym przerostem pozostałych miocytów i utratą miocytów.³³ Przerost miocytów jest stymulowany przez stymulację katecholaminergiczną, aktywację integryn przez miocyty i fibroblasty na skutek rozciągania, przekazywanie sygnałów wewnątrzkomórkowych za pośrednictwem białek G oraz sieci mikro-RNA.³⁴

W miarę postępu choroby dochodzi do postępującego rozszerzania się komór, przyczyniając się do znacznej niedomykalności zastawki trójdzielnej i mitralnej, co dodatkowo obniża frakcję wyrzutową i zwiększa napięcie ściany komory oraz objętość końcowoskurczową.³⁵ Zgodnie z prawem Laplace’a, zwiększona średnica zwiększa napięcie ściany i powoduje dalszą niekorzystną mechaniczną dysfunkcję.³⁶

Aktywacja układu neurohumoralnego

Niewydolność serca wynika ze zwiększonej aktywności układu współczulnego, ale również dochodzi do patologicznej aktywacji układu renina-angiotensyna-aldosteron (RAAS).³⁷³⁸ Aktywacja RAAS jest krytycznym aspektem zmian neurohormonalnych u osób z przewlekłą niewydolnością serca. Angiotensyna II wzmacnia działanie noradrenaliny poprzez zwiększenie systemowego oporu naczyniowego.³⁹

Ostatecznie angiotensyna II przyczynia się do przebudowy serca, promując przerost miocytów i apoptozę oraz zmiany strukturalne i biochemiczne w macierzy pozakomórkowej.⁴⁰ We wczesnych stadiach mechanizmy kompensacyjne obejmują zwiększenie częstości akcji serca i napięcia obwodowego układu naczyniowego. Jednak te mechanizmy kompensacyjne prowadzą do geometrycznej przebudowy komór i ostatecznie do nasilenia uszkodzenia mięśnia sercowego.⁴¹

Zapalenie i odpowiedź immunologiczna

Zapalenie może również odgrywać rolę w patofizjologii DCM. Wiele badań wykazało wzrost różnych mediatorów zapalnych (np. czynnika martwicy nowotworów (TNF), interleukiny (IL) 1 beta).⁴² TNF ma negatywny efekt inotropowy toksyczny dla miokardium, który jest związany z niekorzystną przebudową komór w DCM.⁴³

Centralne znaczenie w rozwoju niewydolności serca u psów z kardiomiopatią rozstrzeniową ma aktywacja układu neurohumoralnego i zapalenie o podłożu immunologicznym. Rozwój przewlekłej niewydolności serca u psów z kardiomiopatią rozstrzeniową jest spowodowany postępującą utratą kardiomiocytów, apoptozą, przebudową lewej komory, dysfunkcją skurczową i rozkurczową, arytmiami, zmniejszonym przepływem krwi do mózgu, zajęciem innych kluczowych narządów wewnętrznych i dysbiozą jelitową.⁴⁴

Badania wykazały obecność przeciwciał przeciwko receptorowi beta1-adrenergicznemu, które są wykrywane u znacznej liczby pacjentów z „idiopatyczną” DCM. Mogą one zwiększać stężenie wewnątrzkomórkowego cAMP i wewnątrzkomórkowego Ca²⁺, co często prowadzi do przejściowej nadmiernej wydajności serca, a następnie do osłabionej funkcji serca i niewydolności serca.⁴⁵

Macierz pozakomórkowa i włóknienie

Macierz pozakomórkowa w sercu zapewnia rusztowanie, w którym znajdują się kurczliwe kardiomiocyty; zawiera błonę podstawną, sieć kolagenu, proteoglikany i glikozaminoglikany.⁴⁶ Jest to raczej dynamiczny system, który jest stale odnawialny. W przypadku uszkodzenia serca lub uszkodzenia pozasercowego, regulacja macierzy pozakomórkowej prawdopodobnie odgrywa ważną rolę w przebudowie komór i zwłóknieniu.⁴⁷

Włóknienie serca, charakteryzujące się nagromadzeniem kolagenu po śmierci kardiomiocytów, występuje we wczesnej fazie progresji DCM, zwiększając sztywność serca, zmniejszając wydajność miokardium i zwiększając ryzyko niewydolności serca, nagłej śmierci sercowej i złośliwych arytmii.⁴⁸ Kilka szlaków molekularnych i czynników humoralnych, w tym transformujący czynnik wzrostu beta (TGF-β), układ renina-angiotensyna-aldosteron, TNF-α, IL-1β i IL-6, odgrywa kluczową rolę w modulowaniu procesu profibrotycznego.⁴⁹

Stres retikulum endoplazmatycznego

W ostatniej dekadzie wykazano, że stres retikulum endoplazmatycznego (ER) jest zaangażowany w patogenezę DCM, wśród innych chorób układu sercowo-naczyniowego. Retikulum endoplazmatyczne odpowiada za syntezę, składanie i kontrolę jakości większości białek w komórce. Zaburzenia tej homeostazy prowadzą do akumulacji źle sfałdowanych i niesfałdowanych białek, procesu znanego jako stres ER. Stres ER wywołuje proces zwany odpowiedzią na nieprawidłowo sfałdowane białka (UPR), który koryguje defekt fałdowania białek i przywraca homeostazę ER. Jednak jeśli UPR nie może przywrócić tej równowagi, przyjmuje niekorzystną rolę i wywołuje apoptozę.⁵⁰

Stres oksydacyjny

Stres oksydacyjny definiuje się jako nadmierną produkcję reaktywnych form tlenu (ROS) w stosunku do obrony antyoksydacyjnej. W warunkach fizjologicznych sygnalizacja ROS w sercu pełni podstawową funkcję w homeostazie komórek; jednak nadmierna produkcja ROS została powiązana z patofizjologią DCM i niewydolności serca. Niedawne odkrycia sugerują istnienie wzajemnych powiązań między stresem oksydacyjnym a stresem ER. W kontekście DCM, badania Toro i współpracowników dostarczyły dowodów, że miR-16-5p może stanowić kluczowy element pośredniczący w interakcji między stresem ER za pośrednictwem ATF6 a produkcją ROS w sercu.⁵¹

Autofagia i apoptoza

Autofagia okazała się kluczowym elementem w patologii DCM. Jest to zachowany proces zaangażowany w utrzymanie homeostazy komórkowej, eliminujący dysfunkcyjne długożyjące białka cytoplazmatyczne i organelle w sposób zależny od lizosomów.⁵²

Proces apoptozy jest wyzwalany przez wewnętrzny szlak mitochondrialny i zewnętrzny szlak receptora śmierci komórkowej powierzchni. U pacjentów z DCM obserwuje się apoptozę kardiomiocytów i zwiększoną przestrzeń międzykomórkową wypełnioną tkanką ziarnistą złożoną z makrofagów, komórek śródbłonka i fibroblastów.⁵³

Podwójne uderzenie – interakcja podłoża genetycznego z czynnikami środowiskowymi

Badania wskazują na ścisłą interakcję między tłem genetycznym a ekspozycją środowiskową, co może prowadzić do różnych fenotypowych manifestacji choroby (tzw. hipoteza podwójnego uderzenia).⁵⁴ Czynniki niegenetyczne również wpływają na wystąpienie DCM, a rosnące dowody łączą tło genetyczne z jednoczesnym występowaniem niegenetycznych czynników wyzwalających lub przyspieszających, zwiększając skrajną złożoność patofizjologii DCM.⁵⁵

Wśród czynników niegenetycznych, które mogą przyczynić się do rozwoju DCM, należy wymienić: infekcje wirusowe (szczególnie wywołane przez wirusy coxsackie B i adenowirusy), które zostały powiązane z rozwojem kardiomiopatii rozstrzeniowej, prawdopodobnie poprzez indukcję odpowiedzi zapalnych i autoimmunizacyjnych w mięśniu sercowym⁵⁶, a także przewlekłe nadużywanie alkoholu, które może prowadzić do alkoholowej kardiomiopatii, formy kardiomiopatii rozstrzeniowej charakteryzującej się włóknieniem i przerostem mięśnia sercowego.⁵⁷

Nowe kierunki w badaniach i leczeniu DCM

Postępy w zarządzaniu DCM zmierzają w kierunku podejścia medycyny precyzyjnej do diagnostyki i leczenia.⁵⁸ Przyszłe badania i alokacja zasobów będą koncentrować się na identyfikacji modyfikujących chorobę metod leczenia DCM, które obejmują terapie ukierunkowane molekularnie i terapie genowe.⁵⁹

Nowatorskie terapie dla leczenia rodzinnej kardiomiopatii rozstrzeniowej (DCM) są niewystarczające. Czynniki wyzwalające progresję choroby zwykle występują z powodu specyficznych wariantów genów, które wpływają na produkcję białek sarkomerycznych/cytoszkieletowych. Generalnie warianty te powodują zmniejszenie napięcia przez miofilamenty, co prowadzi do nieprawidłowości sygnalizacyjnych w mikrośrodowisku, które z czasem skutkują strukturalnymi i funkcjonalnymi nieprawidłowościami adaptacyjnymi, prowadzącymi do niewydolności serca.⁶⁰

Testy wykrywające pęknięcia otoczki jądrowej mogą potencjalnie służyć jako wczesny wskaźnik DCM, co może umożliwić wcześniejszą interwencję w celu zapobieżenia niewydolności serca. Zapobieganie pęknięciom lub znalezienie sposobów na ich naprawę mogłoby spowolnić lub nawet zapobiec postępowi choroby.⁶¹

Ostatecznie lepsze zrozumienie złożonych mechanizmów patogenetycznych kardiomiopatii rozstrzeniowej na poziomie molekularnym, komórkowym i genetycznym jest niezbędne do opracowania skuteczniejszych strategii diagnostycznych i terapeutycznych dla tej często wyniszczającej choroby serca.

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Materiały źródłowe

#1 Causes of dilated cardiomyopathy – UpToDate
https://www.uptodate.com/contents/causes-of-dilated-cardiomyopathy
Dilated cardiomyopathy (DCM) is characterized by dilation and impaired contraction of one or both ventricles. […] A diagnosis of dilated cardiomyopathy requires evidence of dilation and impaired contraction of the left ventricle or both ventricles (eg, left ventricular ejection fraction <40 percent or fractional shortening less than 25 percent). [...] The disease is considered idiopathic if primary and secondary causes of heart disease (eg, myocarditis and coronary artery disease) are excluded by evaluation including history and physical examination, laboratory testing, coronary angiography (to exclude >50 percent obstruction of one or more coronary arteries), echocardiography, and endomyocardial biopsy when indicated. […] Symptoms of heart failure (progressive dyspnea with exertion, impaired exercise capacity, orthopnea, paroxysmal nocturnal dyspnea, and peripheral edema) are most common.
#2 Dilated cardiomyopathy | Nature Reviews Disease Primers
https://www.nature.com/articles/s41572-019-0084-1
Dilated cardiomyopathy (DCM) is a clinical diagnosis characterized by left ventricular or biventricular dilation and impaired contraction that is not explained by abnormal loading conditions (for example, hypertension and valvular heart disease) or coronary artery disease. […] Mutations in several genes can cause DCM, including genes encoding structural components of the sarcomere and desmosome. […] Nongenetic forms of DCM can result from different aetiologies, including inflammation of the myocardium due to an infection (mostly viral); exposure to drugs, toxins or allergens; and systemic endocrine or autoimmune diseases. […] The heterogeneous aetiology and clinical presentation of DCM make a correct and timely diagnosis challenging. […] Echocardiography and other imaging techniques are required to assess ventricular dysfunction and adverse myocardial remodelling, and immunological and histological analyses of an endomyocardial biopsy sample are indicated when inflammation or infection is suspected.
#3 Diverse Concepts in Definitions of Dilated Cardiomyopathy: Theory and Practice | Myers | Cardiology Research
https://cardiologyres.org/index.php/Cardiologyres/article/view/1679/1646
DCM was classified as primary cardiomyopathy with mixed (genetic and/or acquired) etiology. […] The broad definition of DCM is left or biventricular systolic dysfunction, often associated with dilation, in the absence of abnormal loading conditions or significant coronary artery disease. […] The challenge for the proper diagnostics of DCM in routine clinical practice is the evolving understanding of the disease and changing definitions and diagnostic criteria. […] The definition of DCM in this 2008 ESC guideline is as follows: DCM is defined by the presence of left ventricular dilatation and left ventricular systolic dysfunction in the absence of abnormal loading conditions (hypertension (HTN), valve disease) or coronary artery disease sufficient to cause global systolic impairment. […] The same ESC Working Group that published the above guidelines further revised the definition of DCM in a separate document published in 2016.
#4 KEGG PATHWAY: hsa05414
https://www.genome.jp/dbget-bin/www_bget?pathway+hsa05414
Dilated cardiomyopathy (DCM) is a heart muscle disease characterised by dilation and impaired contraction of the left or both ventricles that results in progressive heart failure and sudden cardiac death from ventricular arrhythmia. […] The pathophysiology may be separated into two categories: defects in force generation and defects in force transmission. […] Current hypotheses regarding causes of „idiopathic” DCM focus on myocarditis induced by enterovirus and subsequent autoimmune myocardium impairments. […] Antibodies to the beta1-adrenergic receptor (beta1AR), which are detected in a substantial number of patients with „idiopathic” DCM, may increase the concentration of intracellular cAMP and intracellular Ca2+, a condition often leading to a transient hyper-performance of the heart followed by depressed heart function and heart failure.
#5 Pathophysiology – Dilated Cardiomyopathy – NCBI Bookshelf
https://www.ncbi.nlm.nih.gov/books/NBK553848/
The hallmark pathophysiologic feature of dilated cardiomyopathy is systolic dysfunction. Several pathogenetic mechanisms appear to be operative. These include increased hemodynamic overload, ventricular remodeling, excessive neurohumoral stimulation, abnormal myocyte calcium cycling, excessive or inadequate proliferation of the extracellular matrix, accelerated apoptosis, and genetic mutations. Although beneficial in the early stages of heart failure, these compensatory mechanisms eventually lead to a vicious cycle of worsening heart failure. […] Genetic causes account for 30-40% of DCM and involve genes that encode a heterogeneous group of molecules that participate in force generation, force transmission, sarcomere integrity, cytoskeletal and nuclear architecture, electrolyte homeostasis, mitochondrial function, and transcription.
#6 Dilated cardiomyopathy pathophysiology – wikidoc
https://www.wikidoc.org/index.php/Dilated_cardiomyopathy_pathophysiology
Dilated cardiomyopathy usually results from a failed physiological response to myocyte injury. Myocyte injury can generally end in one of three outcomes: Immediate myocyte cell death, delayed myocyte cell death (apoptosis), or pathological compensatory response. The third outcome usually results in a cycle that occurs as follows: […] Myocyte injury […] Hypertrophy of the remaining myocytes to increased wall stress […] Hyperadrenergic response […] Dynamic remodeling of the interstitial myocardial skeleton (e.g. fibrosis) […] Reduced diastolic function and increased ventricular dilatation […] Distortion of valvular apparatus […] Increased ventricular afterload […] Initiating the process of heart failure that causes more myocyte injury.
#7 Pathophysiology – Dilated Cardiomyopathy – NCBI Bookshelf
https://www.ncbi.nlm.nih.gov/books/NBK553848/
The hallmark pathophysiologic feature of dilated cardiomyopathy is systolic dysfunction. Several pathogenetic mechanisms appear to be operative. These include increased hemodynamic overload, ventricular remodeling, excessive neurohumoral stimulation, abnormal myocyte calcium cycling, excessive or inadequate proliferation of the extracellular matrix, accelerated apoptosis, and genetic mutations. Although beneficial in the early stages of heart failure, these compensatory mechanisms eventually lead to a vicious cycle of worsening heart failure. […] Genetic causes account for 30-40% of DCM and involve genes that encode a heterogeneous group of molecules that participate in force generation, force transmission, sarcomere integrity, cytoskeletal and nuclear architecture, electrolyte homeostasis, mitochondrial function, and transcription.
#8
https://profilesrns.times.uh.edu/profile/358446
Dilated cardiomyopathy (DCM) is a disease of cardiac muscle characterized by left ventricular dilation and systolic dysfunction. DCM is believed to be caused by mutations in cytoskeletal and sarcomeric proteins in 30-40% of all cases. Understanding how these mutations lead to the development of DCM is lacking, although most known DCM-linked mutations of sarcomeric proteins desensitize cardiac muscle to Ca2+. […] The objective of the proposed project is to determine whether we can generate a mutation in cTnC not discovered in nature and then introduce it into mouse myocardium to recreate the phenotype of DCM. […] The novel knock-in mouse model will enable us to evaluate the role of desensitizing cTnC to Ca2+ in triggering the pathogenesis of DCM. […] Specific Aim 2: Determine whether decreasing the Ca2+ sensitivity of cTnC leads to pathogenesis of DCM. This aim will test the hypothesis that decreasing the Ca2+ sensitivity of cTnC (by accelerating the rate of Ca2+ dissociation) leads to the development of DCM. […] The proposed research will provide a deeper insight into the molecular mechanism of DCM.
#9 Current Pathophysiological and Genetic Aspects of Dilated Cardiomyopathy | IntechOpen
https://www.intechopen.com/chapters/65320
Most commonly, familial DCM is inherited as an autosomal dominant pattern. […] Mutations in genes encoding sarcomeric, cytoskeletal, desmosomal, nuclear membrane, mitochondrial, and RNA-binding proteins have all been linked to DCM. […] The most common mutations occur in genes encoding sarcomeric proteins and in genes related to the nuclear envelope and the cytoskeleton.
#10
https://www.jci.org/articles/view/62862
Genetic mutations account for a significant percentage of cardiomyopathies, which are a leading cause of congestive heart failure. […] In contrast, dilated cardiomyopathy (DCM) is far more genetically heterogeneous, with mutations in genes encoding cytoskeletal, nucleoskeletal, mitochondrial, and calcium-handling proteins. DCM is characterized by enlarged ventricular dimensions and impaired systolic and diastolic function. […] More than 50 single genes are linked to inherited DCM, including many genes that also link to HCM. […] The mechanism of action for some sarcomeric DCM mutations is dominant negative. […] Most recently, mutations in the giant protein titin were estimated to be responsible for approximately 25% of DCM. […] The TTN gene at chromosome 2 was previously linked to familial DCM, and those findings have been reinforced by studies in animal models.
#11 Current Pathophysiological and Genetic Aspects of Dilated Cardiomyopathy | IntechOpen
https://www.intechopen.com/chapters/65320
Most commonly, familial DCM is inherited as an autosomal dominant pattern. […] Mutations in genes encoding sarcomeric, cytoskeletal, desmosomal, nuclear membrane, mitochondrial, and RNA-binding proteins have all been linked to DCM. […] The most common mutations occur in genes encoding sarcomeric proteins and in genes related to the nuclear envelope and the cytoskeleton.
#12 Genetics of dilated cardiomyopathy – UpToDate
https://www.uptodate.com/contents/genetics-of-dilated-cardiomyopathy
Dilated cardiomyopathy (DCM) is a common cause of heart failure (HF) and is the most common diagnosis in patients referred for cardiac transplantation. DCM is characterized by dilatation and systolic dysfunction of one or both ventricles. […] Family-based studies of first-degree relatives during the 1990s established that familial dilated cardiomyopathy (familial DCM) can be identified in 20 to 35 percent of patients diagnosed with IDC by clinical screening (electrocardiography, echocardiography) of family members. Most familial DCM is transmitted in an autosomal dominant inheritance pattern, although all inheritance patterns have been identified (autosomal recessive, X-linked, and mitochondrial). […] Developments have dramatically and favorably affected efforts to identify and understand the genetic basis of DCM, including the enormous impact of next generation sequencing (NGS) and the availability of very large databases of exome or genome sequences that can be used as reference sequences in gene discovery programs (eg, the Exome Study Project, Exome Variant Server, the Thousand Genomes Project, the Exome Aggregation Consortium [ExAC], and the Genome Aggregation Database [gnomAD]). Extensive discovery studies over the past 20 years have identified rare variants in numerous genes.
#13 Current Pathophysiological and Genetic Aspects of Dilated Cardiomyopathy | IntechOpen
https://www.intechopen.com/chapters/65320
Most commonly, familial DCM is inherited as an autosomal dominant pattern. […] Mutations in genes encoding sarcomeric, cytoskeletal, desmosomal, nuclear membrane, mitochondrial, and RNA-binding proteins have all been linked to DCM. […] The most common mutations occur in genes encoding sarcomeric proteins and in genes related to the nuclear envelope and the cytoskeleton.
#14
https://www.jci.org/articles/view/62862
Genetic mutations account for a significant percentage of cardiomyopathies, which are a leading cause of congestive heart failure. […] In contrast, dilated cardiomyopathy (DCM) is far more genetically heterogeneous, with mutations in genes encoding cytoskeletal, nucleoskeletal, mitochondrial, and calcium-handling proteins. DCM is characterized by enlarged ventricular dimensions and impaired systolic and diastolic function. […] More than 50 single genes are linked to inherited DCM, including many genes that also link to HCM. […] The mechanism of action for some sarcomeric DCM mutations is dominant negative. […] Most recently, mutations in the giant protein titin were estimated to be responsible for approximately 25% of DCM. […] The TTN gene at chromosome 2 was previously linked to familial DCM, and those findings have been reinforced by studies in animal models.
#15
https://www.jci.org/articles/view/62862
Genetic mutations account for a significant percentage of cardiomyopathies, which are a leading cause of congestive heart failure. […] In contrast, dilated cardiomyopathy (DCM) is far more genetically heterogeneous, with mutations in genes encoding cytoskeletal, nucleoskeletal, mitochondrial, and calcium-handling proteins. DCM is characterized by enlarged ventricular dimensions and impaired systolic and diastolic function. […] More than 50 single genes are linked to inherited DCM, including many genes that also link to HCM. […] The mechanism of action for some sarcomeric DCM mutations is dominant negative. […] Most recently, mutations in the giant protein titin were estimated to be responsible for approximately 25% of DCM. […] The TTN gene at chromosome 2 was previously linked to familial DCM, and those findings have been reinforced by studies in animal models.
#16 Pathophysiology – Dilated Cardiomyopathy – NCBI Bookshelf
https://www.ncbi.nlm.nih.gov/books/NBK553848/
A great diversity of pathogenetic pathways has been hypothesized to explain the development of DCM, depending on the affected genes and the dislodged intracellular structures or pathways. […] Genetic mutations suggest several mechanisms of ventricular dysfunction in DCM as follows: […] Deficit in force generation (sarcomere DCM): Mutations within genes encoding titin, myosin, actin, troponin, and tropomyosin result in the expression of abnormally functioning proteins, thus leading to myocardial dysfunction and DCM. […] Defects in nuclear envelope (laminopathies): These diseases are characterized by variable degrees of heart and skeletal muscle involvement. […] Deficit in force transmission (cytoskeletal cardiomyopathies): Mutations involving protein members of the cytoskeletal apparatus, like filamins, dystrophin, desmin, d-sarcoglycan, and vinculin, are responsible for muscular dystrophies, which are often associated with DCM.
#17 Pathophysiology – Dilated Cardiomyopathy – NCBI Bookshelf
https://www.ncbi.nlm.nih.gov/books/NBK553848/
A great diversity of pathogenetic pathways has been hypothesized to explain the development of DCM, depending on the affected genes and the dislodged intracellular structures or pathways. […] Genetic mutations suggest several mechanisms of ventricular dysfunction in DCM as follows: […] Deficit in force generation (sarcomere DCM): Mutations within genes encoding titin, myosin, actin, troponin, and tropomyosin result in the expression of abnormally functioning proteins, thus leading to myocardial dysfunction and DCM. […] Defects in nuclear envelope (laminopathies): These diseases are characterized by variable degrees of heart and skeletal muscle involvement. […] Deficit in force transmission (cytoskeletal cardiomyopathies): Mutations involving protein members of the cytoskeletal apparatus, like filamins, dystrophin, desmin, d-sarcoglycan, and vinculin, are responsible for muscular dystrophies, which are often associated with DCM.
#18
https://www.jci.org/articles/view/62862
Genetic mutations account for a significant percentage of cardiomyopathies, which are a leading cause of congestive heart failure. […] In contrast, dilated cardiomyopathy (DCM) is far more genetically heterogeneous, with mutations in genes encoding cytoskeletal, nucleoskeletal, mitochondrial, and calcium-handling proteins. DCM is characterized by enlarged ventricular dimensions and impaired systolic and diastolic function. […] More than 50 single genes are linked to inherited DCM, including many genes that also link to HCM. […] The mechanism of action for some sarcomeric DCM mutations is dominant negative. […] Most recently, mutations in the giant protein titin were estimated to be responsible for approximately 25% of DCM. […] The TTN gene at chromosome 2 was previously linked to familial DCM, and those findings have been reinforced by studies in animal models.
#19
https://profilesrns.times.uh.edu/profile/358446
Dilated cardiomyopathy (DCM) is a disease of cardiac muscle characterized by left ventricular dilation and systolic dysfunction. DCM is believed to be caused by mutations in cytoskeletal and sarcomeric proteins in 30-40% of all cases. Understanding how these mutations lead to the development of DCM is lacking, although most known DCM-linked mutations of sarcomeric proteins desensitize cardiac muscle to Ca2+. […] The objective of the proposed project is to determine whether we can generate a mutation in cTnC not discovered in nature and then introduce it into mouse myocardium to recreate the phenotype of DCM. […] The novel knock-in mouse model will enable us to evaluate the role of desensitizing cTnC to Ca2+ in triggering the pathogenesis of DCM. […] Specific Aim 2: Determine whether decreasing the Ca2+ sensitivity of cTnC leads to pathogenesis of DCM. This aim will test the hypothesis that decreasing the Ca2+ sensitivity of cTnC (by accelerating the rate of Ca2+ dissociation) leads to the development of DCM. […] The proposed research will provide a deeper insight into the molecular mechanism of DCM.
#20 Pathophysiology – Dilated Cardiomyopathy – NCBI Bookshelf
https://www.ncbi.nlm.nih.gov/books/NBK553848/
A great diversity of pathogenetic pathways has been hypothesized to explain the development of DCM, depending on the affected genes and the dislodged intracellular structures or pathways. […] Genetic mutations suggest several mechanisms of ventricular dysfunction in DCM as follows: […] Deficit in force generation (sarcomere DCM): Mutations within genes encoding titin, myosin, actin, troponin, and tropomyosin result in the expression of abnormally functioning proteins, thus leading to myocardial dysfunction and DCM. […] Defects in nuclear envelope (laminopathies): These diseases are characterized by variable degrees of heart and skeletal muscle involvement. […] Deficit in force transmission (cytoskeletal cardiomyopathies): Mutations involving protein members of the cytoskeletal apparatus, like filamins, dystrophin, desmin, d-sarcoglycan, and vinculin, are responsible for muscular dystrophies, which are often associated with DCM.
#21 Study Challenges Current Thinking About Mechanisms of Dilated Cardiomyopathy – Research Horizons
https://scienceblog.cincinnatichildrens.org/study-challenges-current-thinking-about-mechanisms-of-dilated-cardiomyopathy/
Research in Cell Reports led by experts at Cincinnati Childrenâs reveals nuclear envelope ruptures in heart muscle driving the disease. […] The study focuses on LMNA-related DCM, a genetically inherited form of the disease. […] This work is the first to establish that nuclear envelope rupture occurs frequently in the disease model heart before the heart starts becoming weak. […] We found that almost 50% of heart muscle cells in the disease model heart have nuclear envelope ruptures compared to near zero found in normal hearts. This suggests that nuclear rupture is likely a disease cause. […] The most striking finding from observing the gene-edited mice was that nuclear envelope ruptures triggered by the lack of Lamin A/C proteins began occurring before any other signs of heart disease, and ultimately involved surprisingly high numbers of muscle cells.
#22 Study Challenges Current Thinking About Mechanisms of Dilated Cardiomyopathy – Research Horizons
https://scienceblog.cincinnatichildrens.org/study-challenges-current-thinking-about-mechanisms-of-dilated-cardiomyopathy/
Research in Cell Reports led by experts at Cincinnati Childrenâs reveals nuclear envelope ruptures in heart muscle driving the disease. […] The study focuses on LMNA-related DCM, a genetically inherited form of the disease. […] This work is the first to establish that nuclear envelope rupture occurs frequently in the disease model heart before the heart starts becoming weak. […] We found that almost 50% of heart muscle cells in the disease model heart have nuclear envelope ruptures compared to near zero found in normal hearts. This suggests that nuclear rupture is likely a disease cause. […] The most striking finding from observing the gene-edited mice was that nuclear envelope ruptures triggered by the lack of Lamin A/C proteins began occurring before any other signs of heart disease, and ultimately involved surprisingly high numbers of muscle cells.
#23 Pathophysiology – Dilated Cardiomyopathy – NCBI Bookshelf
https://www.ncbi.nlm.nih.gov/books/NBK553848/
A great diversity of pathogenetic pathways has been hypothesized to explain the development of DCM, depending on the affected genes and the dislodged intracellular structures or pathways. […] Genetic mutations suggest several mechanisms of ventricular dysfunction in DCM as follows: […] Deficit in force generation (sarcomere DCM): Mutations within genes encoding titin, myosin, actin, troponin, and tropomyosin result in the expression of abnormally functioning proteins, thus leading to myocardial dysfunction and DCM. […] Defects in nuclear envelope (laminopathies): These diseases are characterized by variable degrees of heart and skeletal muscle involvement. […] Deficit in force transmission (cytoskeletal cardiomyopathies): Mutations involving protein members of the cytoskeletal apparatus, like filamins, dystrophin, desmin, d-sarcoglycan, and vinculin, are responsible for muscular dystrophies, which are often associated with DCM.
#24
https://www.jci.org/articles/view/62862
A larger heart, such as that dilated from regurgitant valve disease, may be more susceptible to impaired elastic recoil or a reduction in titin signaling from mutations ablating the titin kinase domain. […] It is notable that HCM subjects had a strikingly lower percentage of TTN frameshifting mutations in the Herman study, possibly supporting the idea that HCM sarcomere mutations along with TTN frameshifting mutations predispose to DCM. […] Mutations in dystrophin and the sarcoglycan produce skeletal muscle disease and cardiomyopathy, and so heart failure in these patients is further compromised by hypoventilation from respiratory muscle weakness.
#25 Pathophysiology – Dilated Cardiomyopathy – NCBI Bookshelf
https://www.ncbi.nlm.nih.gov/books/NBK553848/
Deficit in protein post-translational modifications (glycosylation processes-cardiomyopathies): An example comes from dolichol kinase gene mutations, resulting in impairment of protein glycosylation processes inside the cell organelles, thus manifesting as syndromic conditions with hypertrophic phenotype and as non-syndromic DCM phenotype. […] Impaired cell-to-cell adhesion (desmosomal cardiomyopathies): Mutations in genes encoding desmosomal proteins are responsible for arrhythmogenic right ventricular Cardiomyopathy (ARVC) and also for DCM, with a prevalence of up to 13% in a DCM cohort. […] Deficit in energy production (mitochondrial cardiomyopathies): They are characterized by defects in the oxidative phosphorylation that result in deficient energy production in the form of ATP. […] Calcium-cycling abnormalities: A DCM mutation has been described in the phospholamban gene.
#26 Pathophysiology – Dilated Cardiomyopathy – NCBI Bookshelf
https://www.ncbi.nlm.nih.gov/books/NBK553848/
Deficit in protein post-translational modifications (glycosylation processes-cardiomyopathies): An example comes from dolichol kinase gene mutations, resulting in impairment of protein glycosylation processes inside the cell organelles, thus manifesting as syndromic conditions with hypertrophic phenotype and as non-syndromic DCM phenotype. […] Impaired cell-to-cell adhesion (desmosomal cardiomyopathies): Mutations in genes encoding desmosomal proteins are responsible for arrhythmogenic right ventricular Cardiomyopathy (ARVC) and also for DCM, with a prevalence of up to 13% in a DCM cohort. […] Deficit in energy production (mitochondrial cardiomyopathies): They are characterized by defects in the oxidative phosphorylation that result in deficient energy production in the form of ATP. […] Calcium-cycling abnormalities: A DCM mutation has been described in the phospholamban gene.
#27 The Role of MicroRNAs in Dilated Cardiomyopathy: New Insights for an Old Entity
https://www.mdpi.com/1422-0067/23/21/13573
Over the last decade, ER stress has been shown to be involved in DCM pathogenesis, among other CVDs. The ER is responsible for the synthesis, folding, and quality control of most proteins in the cell. Perturbations of this homoeostasis lead to an accumulation of misfolded and unfolded proteins, a process known as ER stress. ER stress induces a process termed the unfolded protein response (UPR), which corrects the protein-folding defect and reestablishes ER homoeostasis. However, if the UPR fails to restore this balance, the UPR assumes an adverse role and triggers apoptosis. […] Numerous studies have reported a link between miRNAs and ER stress in the heart, as miRNAs and members of the ER stress pathway can modulate each other in CVD. […] Various miRNAs have been described to contribute to distinct CVDs, such as HF, ischemic heart diseases, cardiac hypertrophy and diabetic cardiomyopathy, through the regulation of relevant signaling pathways and mitochondrial function-related proteins.
#28 Pathophysiology – Dilated Cardiomyopathy – NCBI Bookshelf
https://www.ncbi.nlm.nih.gov/books/NBK553848/
The extracellular matrix is a rather dynamic system that is constantly turned over. In the setting of cardiac or extracardiac injury, regulation of extracellular matrix likely plays an important role in ventricular remodeling and fibrosis. […] Cytoplasmic Ca2+ has a key role in cardiac contraction triggering the interaction of the myosin-thick and actin-thin myofilament. During the depolarization of the myocyte, Ca2+ enters the myocyte through L-type Ca2+ channels known as transverse tubules, which are close to the sarcoplasmic reticulum (SR) and stimulates the release of much greater quantities of Ca2+ from the SR into the cytoplasm through the Ca2+ release channels, the ryanodine receptors (RyR2).
#29 Pathophysiology – Dilated Cardiomyopathy – NCBI Bookshelf
https://www.ncbi.nlm.nih.gov/books/NBK553848/
Deficit in protein post-translational modifications (glycosylation processes-cardiomyopathies): An example comes from dolichol kinase gene mutations, resulting in impairment of protein glycosylation processes inside the cell organelles, thus manifesting as syndromic conditions with hypertrophic phenotype and as non-syndromic DCM phenotype. […] Impaired cell-to-cell adhesion (desmosomal cardiomyopathies): Mutations in genes encoding desmosomal proteins are responsible for arrhythmogenic right ventricular Cardiomyopathy (ARVC) and also for DCM, with a prevalence of up to 13% in a DCM cohort. […] Deficit in energy production (mitochondrial cardiomyopathies): They are characterized by defects in the oxidative phosphorylation that result in deficient energy production in the form of ATP. […] Calcium-cycling abnormalities: A DCM mutation has been described in the phospholamban gene.
#30 Structures of PKAâphospholamban complexes reveal a mechanism of familial dilated cardiomyopathy | eLife
https://elifesciences.org/articles/75346
Several mutations identified in phospholamban (PLN) have been linked to familial dilated cardiomyopathy (DCM) and heart failure, yet the underlying molecular mechanism remains controversial. […] Our structures, combined with the results from other biophysical and biochemical assays, reveal a common disease mechanism: the mutations in PLN reduce its phosphorylation level by changing its conformation and weakening its interactions with PKA. […] To date DCM mutations associated with PLN include R9C, R9H, R9L, R14, R14I, and I18T. […] However, its neighborhood contains the critical PKA and CaMKII phosphorylation sites, Ser16 and Thr17, respectively, suggesting a connection between altered regulation of phosphorylation and DCM phenotype. […] Our data also support the idea that other PLN mutations in the neighborhood, including DCM-related mutations at the 9th, 14th, and 18th positions, share a common disease mechanism related to reduced PKA phosphorylation.
#31 Structures of PKAâphospholamban complexes reveal a mechanism of familial dilated cardiomyopathy | eLife
https://elifesciences.org/articles/75346
Our work supports a model in which the mutations at positions 9, 14, and 18 of PLN share a common disease mechanism. […] Lower phosphorylation levels of PLN in cardiac cells would lead to greater inhibition of SERCA, decreasing heart muscle contractility and relaxation rate. […] While catalytic efficiency of PKAc with PLN R9C only decreases by ~twofold, a corresponding change in phosphorylation level of PLN could be consistent with the relatively mild symptoms of DCM. […] Thus, our explanation for the differences between the two structures is as follows: 3O7L presents a 2:1 (PKAc:PLN) complex structure, where the PLN peptide was trapped between two PKAc molecules from the same ASU, and the crystal contacts force the substrate into an unnatural pose that reduces the binding affinity of the nucleotide; our monomeric structure, which was generated using different crystallization conditions, presents a 1:1 (PKAc:PLN) complex structure, consistent with the native solution behavior and with a fully occupied nucleotide-binding site.
#32 Pathophysiology – Dilated Cardiomyopathy – NCBI Bookshelf
https://www.ncbi.nlm.nih.gov/books/NBK553848/
Ion channel abnormalities: Mutations in ion channel genes (SCN5A, ABCC9) are typically associated with a variety of arrhythmic disorders. […] Spliceosomal defects: RBM20 is an RNA binding protein involved in alternative splicing process. […] Epigenetic perturbation: Missense mutation in GATAD1 gene is associated with DCM. […] Protein misfolding disease: Mutations in presenilin genes have been recently identified in patients with DCM. […] RAS-MAPK pathway disruption: Mutations in RAF-1 gene are responsible for rare variants of childhood-onset, non-syndromic DCM. […] DCM is histologically characterized by diffuse fibrosis, compensatory hypertrophy of the other myocytes, and myocyte dropout. Myocyte hypertrophy is promoted by catecholaminergic stimulation, stretch activation of integrins by myocyte and fibroblast, G protein-mediated intracellular signaling, and micro-RNA networks.
#33 Pathophysiology – Dilated Cardiomyopathy – NCBI Bookshelf
https://www.ncbi.nlm.nih.gov/books/NBK553848/
Ion channel abnormalities: Mutations in ion channel genes (SCN5A, ABCC9) are typically associated with a variety of arrhythmic disorders. […] Spliceosomal defects: RBM20 is an RNA binding protein involved in alternative splicing process. […] Epigenetic perturbation: Missense mutation in GATAD1 gene is associated with DCM. […] Protein misfolding disease: Mutations in presenilin genes have been recently identified in patients with DCM. […] RAS-MAPK pathway disruption: Mutations in RAF-1 gene are responsible for rare variants of childhood-onset, non-syndromic DCM. […] DCM is histologically characterized by diffuse fibrosis, compensatory hypertrophy of the other myocytes, and myocyte dropout. Myocyte hypertrophy is promoted by catecholaminergic stimulation, stretch activation of integrins by myocyte and fibroblast, G protein-mediated intracellular signaling, and micro-RNA networks.
#34 Pathophysiology – Dilated Cardiomyopathy – NCBI Bookshelf
https://www.ncbi.nlm.nih.gov/books/NBK553848/
Ion channel abnormalities: Mutations in ion channel genes (SCN5A, ABCC9) are typically associated with a variety of arrhythmic disorders. […] Spliceosomal defects: RBM20 is an RNA binding protein involved in alternative splicing process. […] Epigenetic perturbation: Missense mutation in GATAD1 gene is associated with DCM. […] Protein misfolding disease: Mutations in presenilin genes have been recently identified in patients with DCM. […] RAS-MAPK pathway disruption: Mutations in RAF-1 gene are responsible for rare variants of childhood-onset, non-syndromic DCM. […] DCM is histologically characterized by diffuse fibrosis, compensatory hypertrophy of the other myocytes, and myocyte dropout. Myocyte hypertrophy is promoted by catecholaminergic stimulation, stretch activation of integrins by myocyte and fibroblast, G protein-mediated intracellular signaling, and micro-RNA networks.
#35 Dilated Cardiomyopathy – StatPearls – NCBI Bookshelf
https://www.ncbi.nlm.nih.gov/books/NBK441911/
The progressive dilatation of the ventricles leads to significant tricuspid and mitral valve insufficiency, which further lower the ejection fraction and increase the ventricular wall stress and end systolic volumes. Early compensatory mechanisms include an increase in heart rate and tone of the peripheral vascular system. However, these compensatory mechanisms lead to geometric remodeling of the ventricles and eventually this leads to worsening of the myocardial injury. At the same time, there is neurohumoral activation of the renin-angiotensin aldosterone system and an increase in circulating levels of catecholamines. In addition, levels of natriuretic peptides are also increased. Eventually these compensatory mechanisms become overwhelmed and the heart fails. […] Histologic examination or the myocardium typically shows nonspecific changes of fibrosis and hypertrophy. It also reveals myocardial injury with a marked infiltrate by inflammatory cells.
#36 Dilated and Restrictive Cardiomyopathies
https://www.clevelandclinicmeded.com/medicalpubs/diseasemanagement/cardiology/dilated-restrictive-cardiomyopathy/
Dilated cardiomyopathy represents the final common morphologic outcome of various biologic insults. The combination of myocyte injury and necrosis associated with myocardial fibrosis results in impaired mechanical function. Many cases are a result of direct toxicity (eg, alcohol) or mechanical insults (eg, chronic volume overload in mitral valvular regurgitation). With myocyte failure and cytoskeletal uncoupling, the chambers become dilated. According to Laplace’s law, increased diameter increases wall stress and causes further mechanical disadvantage. Thus, myocardial dysfunction can cause a vicious cycle leading to more myocardial dysfunction in a process termed adverse ventricular remodeling, which is an important therapeutic target. […] No specific genetic abnormality is known to cause dilated cardiomyopathy though numerous genetic abnormalities have been found. There are many putative mechanisms in the development of familial cardiomyopathy beyond the scope of this chapter. All forms of Mendelian inheritance have been observed, including autosomal dominant, recessive, X-linked, and mitochondrial (matrilinear).
#37 Pathophysiology – Dilated Cardiomyopathy – NCBI Bookshelf
https://www.ncbi.nlm.nih.gov/books/NBK553848/
HF results from increased sympathetic nervous activity, but the renin-angiotensin-aldosterone system (RAAS) is also pathologically activated. […] Finally, ATII contributes to cardiac remodeling promoting myocyte hypertrophy and apoptosis and structural and biochemical alterations in the ECM. […] Inflammation may also play a role in pathophysiology of DCM. Many studies have shown an increase in different inflammatory mediators (e.g., tumor necrosis factor (TNF), interleukin (IL) 1beta). […] TNF, for example, has a negative inotropic toxic effect on the myocardium that is connected to adverse ventricular remodeling in DCM. […] The extracellular matrix in the heart provides the scaffolding within which contractile cardiomyocytes are housed; it contains a basement membrane, collagen network, proteoglycans, and glycosaminoglycans.
#38 Dilated Cardiomyopathy (DCM): Practice Essentials, Background, Pathophysiology
https://emedicine.medscape.com/article/152696-overview
DCM is characterized by ventricular chamber enlargement and systolic dysfunction with greater left ventricular (LV) cavity size with little or no wall hypertrophy. […] The enlargement of the remaining heart chambers is primarily due to LV failure, but it may be secondary to the primary cardiomyopathic process. DCMs are associated with both systolic and diastolic dysfunction. The decrease in systolic function is by far the primary abnormality due to adverse myocardial remodeling that eventually leads to an increase in the end-diastolic and end-systolic volumes. […] Genetic mutations that affect desmin (cytoskeleton), lamin C (nuclear membrane), or myosin (contractile proteins) have been found in association with DCM. […] Decreased cardiac output with resultant reductions in organ perfusion results in neurohormonal activation, including stimulation of the adrenergic nervous system and the renin-angiotensin-aldosterone system (RAAS).
#39 Dilated Cardiomyopathy (DCM): Practice Essentials, Background, Pathophysiology
https://emedicine.medscape.com/article/152696-overview
Activation of the RAAS is a critical aspect of neurohormonal alterations in persons with chronic HF. Angiotensin II potentiates the effects of norepinephrine by increasing systemic vascular resistance. […] Tissue necrosis factor-alpha (TNF-alpha) is involved in all forms of cardiac injury. In cardiomyopathies, TNF-alpha has been implicated in the progressive worsening of ventricular function, but the complete mechanism of its actions is poorly understood. […] Elevated levels of several interleukins have been found in patients with left ventricular dysfunction. Interleukin (IL)-1b has been shown to depress myocardial function. […] The exact mechanism for myocardial injury in viral cardiomyopathy is controversial. Several mechanisms have been proposed based on animal models. Viruses affect myocardiocytes by direct cytotoxic effects and by cell-mediated (T-helper cells) destruction of myofibers. […] The body’s compensatory mechanisms for a failing heart are eventually overwhelmed. Compensation for decreased cardiac output cannot be sustained without inducing further decompensation.
#40 Pathophysiology – Dilated Cardiomyopathy – NCBI Bookshelf
https://www.ncbi.nlm.nih.gov/books/NBK553848/
HF results from increased sympathetic nervous activity, but the renin-angiotensin-aldosterone system (RAAS) is also pathologically activated. […] Finally, ATII contributes to cardiac remodeling promoting myocyte hypertrophy and apoptosis and structural and biochemical alterations in the ECM. […] Inflammation may also play a role in pathophysiology of DCM. Many studies have shown an increase in different inflammatory mediators (e.g., tumor necrosis factor (TNF), interleukin (IL) 1beta). […] TNF, for example, has a negative inotropic toxic effect on the myocardium that is connected to adverse ventricular remodeling in DCM. […] The extracellular matrix in the heart provides the scaffolding within which contractile cardiomyocytes are housed; it contains a basement membrane, collagen network, proteoglycans, and glycosaminoglycans.
#41 Dilated Cardiomyopathy – StatPearls – NCBI Bookshelf
https://www.ncbi.nlm.nih.gov/books/NBK441911/
The progressive dilatation of the ventricles leads to significant tricuspid and mitral valve insufficiency, which further lower the ejection fraction and increase the ventricular wall stress and end systolic volumes. Early compensatory mechanisms include an increase in heart rate and tone of the peripheral vascular system. However, these compensatory mechanisms lead to geometric remodeling of the ventricles and eventually this leads to worsening of the myocardial injury. At the same time, there is neurohumoral activation of the renin-angiotensin aldosterone system and an increase in circulating levels of catecholamines. In addition, levels of natriuretic peptides are also increased. Eventually these compensatory mechanisms become overwhelmed and the heart fails. […] Histologic examination or the myocardium typically shows nonspecific changes of fibrosis and hypertrophy. It also reveals myocardial injury with a marked infiltrate by inflammatory cells.
#42 Pathophysiology – Dilated Cardiomyopathy – NCBI Bookshelf
https://www.ncbi.nlm.nih.gov/books/NBK553848/
HF results from increased sympathetic nervous activity, but the renin-angiotensin-aldosterone system (RAAS) is also pathologically activated. […] Finally, ATII contributes to cardiac remodeling promoting myocyte hypertrophy and apoptosis and structural and biochemical alterations in the ECM. […] Inflammation may also play a role in pathophysiology of DCM. Many studies have shown an increase in different inflammatory mediators (e.g., tumor necrosis factor (TNF), interleukin (IL) 1beta). […] TNF, for example, has a negative inotropic toxic effect on the myocardium that is connected to adverse ventricular remodeling in DCM. […] The extracellular matrix in the heart provides the scaffolding within which contractile cardiomyocytes are housed; it contains a basement membrane, collagen network, proteoglycans, and glycosaminoglycans.
#43 Pathophysiology – Dilated Cardiomyopathy – NCBI Bookshelf
https://www.ncbi.nlm.nih.gov/books/NBK553848/
HF results from increased sympathetic nervous activity, but the renin-angiotensin-aldosterone system (RAAS) is also pathologically activated. […] Finally, ATII contributes to cardiac remodeling promoting myocyte hypertrophy and apoptosis and structural and biochemical alterations in the ECM. […] Inflammation may also play a role in pathophysiology of DCM. Many studies have shown an increase in different inflammatory mediators (e.g., tumor necrosis factor (TNF), interleukin (IL) 1beta). […] TNF, for example, has a negative inotropic toxic effect on the myocardium that is connected to adverse ventricular remodeling in DCM. […] The extracellular matrix in the heart provides the scaffolding within which contractile cardiomyocytes are housed; it contains a basement membrane, collagen network, proteoglycans, and glycosaminoglycans.
#44 Immune-inflammatory concept of the pathogenesis of chronic heart failure in dogs with dilated cardiomyopathy
https://www.veterinaryworld.org/Vol.12/September-2019/21.html
The central component of heart failure syndrome in dogs with dilated cardiomyopathy is the activation of the neurohumoral system and immune-mediated inflammation. The development of CHF in dogs with dilated cardiomyopathy is caused by the progressive loss of cardiomyocytes, apoptosis, remodeling of the left ventricle, systolic and diastolic dysfunction, arrhythmias, reduced cerebral blood flow, involvement of other key internal organs, and intestinal dysbiosis.
#45 KEGG PATHWAY: hsa05414
https://www.genome.jp/dbget-bin/www_bget?pathway+hsa05414
Dilated cardiomyopathy (DCM) is a heart muscle disease characterised by dilation and impaired contraction of the left or both ventricles that results in progressive heart failure and sudden cardiac death from ventricular arrhythmia. […] The pathophysiology may be separated into two categories: defects in force generation and defects in force transmission. […] Current hypotheses regarding causes of „idiopathic” DCM focus on myocarditis induced by enterovirus and subsequent autoimmune myocardium impairments. […] Antibodies to the beta1-adrenergic receptor (beta1AR), which are detected in a substantial number of patients with „idiopathic” DCM, may increase the concentration of intracellular cAMP and intracellular Ca2+, a condition often leading to a transient hyper-performance of the heart followed by depressed heart function and heart failure.
#46 Pathophysiology – Dilated Cardiomyopathy – NCBI Bookshelf
https://www.ncbi.nlm.nih.gov/books/NBK553848/
HF results from increased sympathetic nervous activity, but the renin-angiotensin-aldosterone system (RAAS) is also pathologically activated. […] Finally, ATII contributes to cardiac remodeling promoting myocyte hypertrophy and apoptosis and structural and biochemical alterations in the ECM. […] Inflammation may also play a role in pathophysiology of DCM. Many studies have shown an increase in different inflammatory mediators (e.g., tumor necrosis factor (TNF), interleukin (IL) 1beta). […] TNF, for example, has a negative inotropic toxic effect on the myocardium that is connected to adverse ventricular remodeling in DCM. […] The extracellular matrix in the heart provides the scaffolding within which contractile cardiomyocytes are housed; it contains a basement membrane, collagen network, proteoglycans, and glycosaminoglycans.
#47 Pathophysiology – Dilated Cardiomyopathy – NCBI Bookshelf
https://www.ncbi.nlm.nih.gov/books/NBK553848/
The extracellular matrix is a rather dynamic system that is constantly turned over. In the setting of cardiac or extracardiac injury, regulation of extracellular matrix likely plays an important role in ventricular remodeling and fibrosis. […] Cytoplasmic Ca2+ has a key role in cardiac contraction triggering the interaction of the myosin-thick and actin-thin myofilament. During the depolarization of the myocyte, Ca2+ enters the myocyte through L-type Ca2+ channels known as transverse tubules, which are close to the sarcoplasmic reticulum (SR) and stimulates the release of much greater quantities of Ca2+ from the SR into the cytoplasm through the Ca2+ release channels, the ryanodine receptors (RyR2).
#48 The Role of MicroRNAs in Dilated Cardiomyopathy: New Insights for an Old Entity
https://www.mdpi.com/1422-0067/23/21/13573
Autophagy has emerged as a key player in DCM pathology. Autophagy is a conserved process involved in maintaining cellular homeostasis, eliminating dysfunctional long-lived cytosolic proteins and organelles in a lysosomal-dependent way. […] The apoptotic process is triggered by the intrinsic mitochondrial pathway and the extrinsic cell surface death receptor pathway. […] Patients with DCM show cardiomyocyte apoptosis and increased intercellular space filled with granulation tissue composed of macrophages, endothelial cells and fibroblasts. […] Cardiac fibrosis, characterized by accumulation of collagen following cardiomyocyte death, occurs early in the progression of DCM, increasing cardiac rigidity, decreasing myocardial performance, and enhancing the risk of HF, sudden cardiac death and malignant arrhythmias. […] Several molecular pathways and humoral factors, including transforming growth factor beta (TGF-Î²), the renin-angiotensin-aldosterone system, TNF-Î±, IL-1Î², and IL-6, have been reported to play a key role in modulating the profibrotic process.
#49 The Role of MicroRNAs in Dilated Cardiomyopathy: New Insights for an Old Entity
https://www.mdpi.com/1422-0067/23/21/13573
Autophagy has emerged as a key player in DCM pathology. Autophagy is a conserved process involved in maintaining cellular homeostasis, eliminating dysfunctional long-lived cytosolic proteins and organelles in a lysosomal-dependent way. […] The apoptotic process is triggered by the intrinsic mitochondrial pathway and the extrinsic cell surface death receptor pathway. […] Patients with DCM show cardiomyocyte apoptosis and increased intercellular space filled with granulation tissue composed of macrophages, endothelial cells and fibroblasts. […] Cardiac fibrosis, characterized by accumulation of collagen following cardiomyocyte death, occurs early in the progression of DCM, increasing cardiac rigidity, decreasing myocardial performance, and enhancing the risk of HF, sudden cardiac death and malignant arrhythmias. […] Several molecular pathways and humoral factors, including transforming growth factor beta (TGF-Î²), the renin-angiotensin-aldosterone system, TNF-Î±, IL-1Î², and IL-6, have been reported to play a key role in modulating the profibrotic process.
#50 The Role of MicroRNAs in Dilated Cardiomyopathy: New Insights for an Old Entity
https://www.mdpi.com/1422-0067/23/21/13573
Over the last decade, ER stress has been shown to be involved in DCM pathogenesis, among other CVDs. The ER is responsible for the synthesis, folding, and quality control of most proteins in the cell. Perturbations of this homoeostasis lead to an accumulation of misfolded and unfolded proteins, a process known as ER stress. ER stress induces a process termed the unfolded protein response (UPR), which corrects the protein-folding defect and reestablishes ER homoeostasis. However, if the UPR fails to restore this balance, the UPR assumes an adverse role and triggers apoptosis. […] Numerous studies have reported a link between miRNAs and ER stress in the heart, as miRNAs and members of the ER stress pathway can modulate each other in CVD. […] Various miRNAs have been described to contribute to distinct CVDs, such as HF, ischemic heart diseases, cardiac hypertrophy and diabetic cardiomyopathy, through the regulation of relevant signaling pathways and mitochondrial function-related proteins.
#51 The Role of MicroRNAs in Dilated Cardiomyopathy: New Insights for an Old Entity
https://www.mdpi.com/1422-0067/23/21/13573
In this regard, several studies that used transgenic mice with overexpressed specific miRNA activity have demonstrated a crucial role in the initiation and progression of DCM through regulating genes involved in the maintenance of mitochondrial function. […] Oxidative stress is defined as the excess production of ROS relative to antioxidant defense. Under physiological conditions, cardiac ROS signaling plays a fundamental function in cell homeostasis; however, excess ROS production has been associated with the pathophysiology of DCM and HF. […] Recent findings suggest a crosstalk between oxidative stress and ER stress. In the context of DCM, Toro et al. provided evidence that miR-16-5p may constitute a key player, mediating the crosstalk between ATF6-mediated ER stress and ROS production in the heart.
#52 The Role of MicroRNAs in Dilated Cardiomyopathy: New Insights for an Old Entity
https://www.mdpi.com/1422-0067/23/21/13573
Autophagy has emerged as a key player in DCM pathology. Autophagy is a conserved process involved in maintaining cellular homeostasis, eliminating dysfunctional long-lived cytosolic proteins and organelles in a lysosomal-dependent way. […] The apoptotic process is triggered by the intrinsic mitochondrial pathway and the extrinsic cell surface death receptor pathway. […] Patients with DCM show cardiomyocyte apoptosis and increased intercellular space filled with granulation tissue composed of macrophages, endothelial cells and fibroblasts. […] Cardiac fibrosis, characterized by accumulation of collagen following cardiomyocyte death, occurs early in the progression of DCM, increasing cardiac rigidity, decreasing myocardial performance, and enhancing the risk of HF, sudden cardiac death and malignant arrhythmias. […] Several molecular pathways and humoral factors, including transforming growth factor beta (TGF-Î²), the renin-angiotensin-aldosterone system, TNF-Î±, IL-1Î², and IL-6, have been reported to play a key role in modulating the profibrotic process.
#53 The Role of MicroRNAs in Dilated Cardiomyopathy: New Insights for an Old Entity
https://www.mdpi.com/1422-0067/23/21/13573
Autophagy has emerged as a key player in DCM pathology. Autophagy is a conserved process involved in maintaining cellular homeostasis, eliminating dysfunctional long-lived cytosolic proteins and organelles in a lysosomal-dependent way. […] The apoptotic process is triggered by the intrinsic mitochondrial pathway and the extrinsic cell surface death receptor pathway. […] Patients with DCM show cardiomyocyte apoptosis and increased intercellular space filled with granulation tissue composed of macrophages, endothelial cells and fibroblasts. […] Cardiac fibrosis, characterized by accumulation of collagen following cardiomyocyte death, occurs early in the progression of DCM, increasing cardiac rigidity, decreasing myocardial performance, and enhancing the risk of HF, sudden cardiac death and malignant arrhythmias. […] Several molecular pathways and humoral factors, including transforming growth factor beta (TGF-Î²), the renin-angiotensin-aldosterone system, TNF-Î±, IL-1Î², and IL-6, have been reported to play a key role in modulating the profibrotic process.
#54 Pathophysiology of dilated cardiomyopathy: from mechanisms to precision medicine | Nature Reviews Cardiology
https://www.nature.com/articles/s41569-024-01074-2
Dilated cardiomyopathy (DCM) is a complex disease with multiple causes and various pathogenic mechanisms. […] Non-genetic factors also influence the onset of DCM, and growing evidence links genetic background with concomitant non-genetic triggers or precipitating factors, increasing the extreme complexity of the pathophysiology of DCM. […] This Review covers the spectrum of pathophysiological mechanisms in DCM, from monogenic causes to the coexistence of genetic abnormalities and triggering environmental factors (the two-hit hypothesis). […] A strong interaction exists between the genetic background and environmental exposures, which can lead to different phenotypic manifestations of the disease (that is, the two-hit hypothesis). […] Advances in the management of DCM are moving towards a precision medicine approach to the diagnostic work-up and treatment. […] Future research and resource allocation will focus on the identification of disease-modifying treatments for DCM, which include molecular targeted and gene therapies.
#55 Pathophysiology of dilated cardiomyopathy: from mechanisms to precision medicine | CoLab
https://colab.ws/articles/10.1038%2Fs41569-024-01074-2
Dilated cardiomyopathy (DCM) is a complex disease with multiple causes and various pathogenic mechanisms. […] Non-genetic factors also influence the onset of DCM, and growing evidence links genetic background with concomitant non-genetic triggers or precipitating factors, increasing the extreme complexity of the pathophysiology of DCM. […] This Review covers the spectrum of pathophysiological mechanisms in DCM, from monogenic causes to the coexistence of genetic abnormalities and triggering environmental factors (the two-hit hypothesis). […] In this Review, Mestroni and colleagues provide an overview of the pathophysiological mechanisms underlying dilated cardiomyopathy, including both genetic and non-genetic causes.
#56 Understanding the Pathogenesis of Cardiomyopathy
https://www.longdom.org/open-access/understanding-the-pathogenesis-of-cardiomyopathy-100174.html
Understanding the Pathogenesis of Cardiomyopathy […] Cardiomyopathy is a condition characterized by damage or dysfunction of the heart muscle, which leads to impaired heart function and sometimes heart failure. […] The pathogenesis of cardiomyopathy is complex and multifactorial, involving genetic, environmental, and lifestyle factors that can interact and trigger a cascade of events leading to the development of the disease. […] Mutations in genes encoding for cytoskeletal proteins, such as DES and LMNA, are more commonly associated with dilated cardiomyopathy. […] Viral infections, particularly those caused by Coxsackie B virus and adenovirus, have been linked to the development of dilated cardiomyopathy, possibly through the induction of inflammatory and autoimmune responses in the heart muscle. […] Chronic alcohol abuse, in particular, can lead to alcoholic cardiomyopathy, a form of dilated cardiomyopathy characterized by fibrosis and hypertrophy of the heart muscle.
#57 Understanding the Pathogenesis of Cardiomyopathy
https://www.longdom.org/open-access/understanding-the-pathogenesis-of-cardiomyopathy-100174.html
Understanding the Pathogenesis of Cardiomyopathy […] Cardiomyopathy is a condition characterized by damage or dysfunction of the heart muscle, which leads to impaired heart function and sometimes heart failure. […] The pathogenesis of cardiomyopathy is complex and multifactorial, involving genetic, environmental, and lifestyle factors that can interact and trigger a cascade of events leading to the development of the disease. […] Mutations in genes encoding for cytoskeletal proteins, such as DES and LMNA, are more commonly associated with dilated cardiomyopathy. […] Viral infections, particularly those caused by Coxsackie B virus and adenovirus, have been linked to the development of dilated cardiomyopathy, possibly through the induction of inflammatory and autoimmune responses in the heart muscle. […] Chronic alcohol abuse, in particular, can lead to alcoholic cardiomyopathy, a form of dilated cardiomyopathy characterized by fibrosis and hypertrophy of the heart muscle.
#58 Pathophysiology of dilated cardiomyopathy: from mechanisms to precision medicine | Nature Reviews Cardiology
https://www.nature.com/articles/s41569-024-01074-2
Dilated cardiomyopathy (DCM) is a complex disease with multiple causes and various pathogenic mechanisms. […] Non-genetic factors also influence the onset of DCM, and growing evidence links genetic background with concomitant non-genetic triggers or precipitating factors, increasing the extreme complexity of the pathophysiology of DCM. […] This Review covers the spectrum of pathophysiological mechanisms in DCM, from monogenic causes to the coexistence of genetic abnormalities and triggering environmental factors (the two-hit hypothesis). […] A strong interaction exists between the genetic background and environmental exposures, which can lead to different phenotypic manifestations of the disease (that is, the two-hit hypothesis). […] Advances in the management of DCM are moving towards a precision medicine approach to the diagnostic work-up and treatment. […] Future research and resource allocation will focus on the identification of disease-modifying treatments for DCM, which include molecular targeted and gene therapies.
#59 Pathophysiology of dilated cardiomyopathy: from mechanisms to precision medicine | Nature Reviews Cardiology
https://www.nature.com/articles/s41569-024-01074-2
Dilated cardiomyopathy (DCM) is a complex disease with multiple causes and various pathogenic mechanisms. […] Non-genetic factors also influence the onset of DCM, and growing evidence links genetic background with concomitant non-genetic triggers or precipitating factors, increasing the extreme complexity of the pathophysiology of DCM. […] This Review covers the spectrum of pathophysiological mechanisms in DCM, from monogenic causes to the coexistence of genetic abnormalities and triggering environmental factors (the two-hit hypothesis). […] A strong interaction exists between the genetic background and environmental exposures, which can lead to different phenotypic manifestations of the disease (that is, the two-hit hypothesis). […] Advances in the management of DCM are moving towards a precision medicine approach to the diagnostic work-up and treatment. […] Future research and resource allocation will focus on the identification of disease-modifying treatments for DCM, which include molecular targeted and gene therapies.
#60 Emerging Concepts of Mechanisms Controlling Cardiac Tension: Focus on Familial Dilated Cardiomyopathy (DCM) and Sarcomere-Directed Therapies
https://www.mdpi.com/2227-9059/12/5/999
Novel therapies for the treatment of familial dilated cardiomyopathy (DCM) are lacking. Triggers for the progression of the disorder commonly occur due to specific gene variants that affect the production of sarcomeric/cytoskeletal proteins. Generally, these variants cause a decrease in tension by the myofilaments, resulting in signaling abnormalities within the micro-environment, which over time result in structural and functional maladaptations, leading to heart failure (HF). […] Current concepts support the hypothesis that the mutant sarcomere proteins induce a causal depression in the tension-time integral (TTI) of linear preparations of cardiac muscle. However, molecular mechanisms underlying tension generation particularly concerning mutant proteins and their impact on sarcomere molecular signaling are currently controversial.
#61 Study Challenges Current Thinking About Mechanisms of Dilated Cardiomyopathy – Research Horizons
https://scienceblog.cincinnatichildrens.org/study-challenges-current-thinking-about-mechanisms-of-dilated-cardiomyopathy/
Until this study, many heart experts believed that nuclear envelope ruptures cause DCM by activating an immune response mechanism known as the cGAS-STING pathway. […] However, that pathway was not activated in these mice, despite the high rates of nuclear envelope ruptures. Instead, the research team identified extracellular matrix (ECM) signaling from cardiomyocytes to fibroblasts as a key player in disrupting heart function. […] Tests to detect nuclear envelope rupture potentially could serve as an early indicator of DCM, which might allow earlier intervention to head off heart failure. Preventing the ruptures, or finding ways to repair them, could slow or even prevent the progression of disease. […] Meanwhile, nuclear envelope ruptures may be at the root of other âlaminopathiesâ such as progeria (a rare premature aging disease linked to defective lamin A proteins) as well as some muscular dystrophies and lipodystrophies.