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Tadalafil Treatment Delays the Onset of Cardiomyopathy in Dystrophin ‐ Deficient Hearts

View Article: PubMed Central - PubMed

ABSTRACT

Background: Cardiomyopathy is a leading cause of mortality among Duchenne muscular dystrophy patients and lacks effective therapies. Phosphodiesterase type 5 is implicated in dystrophic pathology, and the phosphodiesterase type 5 inhibitor tadalafil has recently been studied in a clinical trial for Duchenne muscular dystrophy.

Methods and results: Tadalafil was evaluated for the prevention of cardiomyopathy in the mdx mouse and golden retriever muscular dystrophy dog models of Duchenne muscular dystrophy. Tadalafil blunted the adrenergic response in mdx hearts during a 30‐minute dobutamine challenge, which coincided with cardioprotective signaling, reduced induction of μ‐calpain levels, and decreased sarcomeric protein proteolysis. Dogs with golden retriever muscular dystrophy began daily tadalafil treatment prior to detectable cardiomyopathy and demonstrated preserved cardiac function, as assessed by echocardiography and magnetic resonance imaging at ages 18, 21, and 25 months. Tadalafil treatment improved golden retriever muscular dystrophy histopathological features, decreased levels of the cation channel TRPC6, increased total threonine phosphorylation status of TRPC6, decreased m‐calpain levels and indicators of calpain target proteolysis, and elevated levels of utrophin. In addition, we showed that Duchenne muscular dystrophy patient myocardium exhibited increased TRPC6, m‐calpain, and calpain cleavage products compared with control human myocardium.

Conclusions: Prophylactic use of tadalafil delays the onset of dystrophic cardiomyopathy, which is likely attributed to modulation of TRPC6 levels and permeability and inhibition of protease content and activity. Consequently, phosphodiesterase type 5 inhibition is a candidate therapy for slowing the development of cardiomyopathy in Duchenne muscular dystrophy patients.

No MeSH data available.


Related in: MedlinePlus

Tadalafil reduces histopathology in golden retriever muscular dystrophy (GRMD) hearts. Representative images of Masson's trichrome–stained left ventricle (LV), interventricular septum (IVS), and right ventricle (RV) from untreated and tadalafil‐treated GRMD dogs at 25 months.
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jah31697-fig-0006: Tadalafil reduces histopathology in golden retriever muscular dystrophy (GRMD) hearts. Representative images of Masson's trichrome–stained left ventricle (LV), interventricular septum (IVS), and right ventricle (RV) from untreated and tadalafil‐treated GRMD dogs at 25 months.

Mentions: Tadalafil also improved GRMD cardiac histopathology. Masson's trichrome staining of the LV, interventricular septum, and RV (Figure 6) revealed that at age 25 months, untreated GRMD LV (approximately segments 5–6) and interventricular septum (approximately segment 2–3) were largely characterized by disorganized cardiomyocytes, prominent myocardial interstitial and perivascular fibrosis, and large fibrous or fat deposits throughout the myocardium, whereas the RV showed substantial myocardial deterioration and fibrous/fat deposition. Tadalafil reduced most signs of pathology, with comparatively mild perivascular fibrosis being the prominent feature in the LV and interventricular septum and perivascular‐restricted fibrous/fat deposition in the RV, thus agreeing with the functional benefits of tadalafil treatment for dystrophic myocardium. Reductions in fibronectin levels in tadalafil‐treated LVs (Figure 7B) agree with this observed difference in fibrosis.


Tadalafil Treatment Delays the Onset of Cardiomyopathy in Dystrophin ‐ Deficient Hearts
Tadalafil reduces histopathology in golden retriever muscular dystrophy (GRMD) hearts. Representative images of Masson's trichrome–stained left ventricle (LV), interventricular septum (IVS), and right ventricle (RV) from untreated and tadalafil‐treated GRMD dogs at 25 months.
© Copyright Policy - creativeCommonsBy-nc
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC5015305&req=5

jah31697-fig-0006: Tadalafil reduces histopathology in golden retriever muscular dystrophy (GRMD) hearts. Representative images of Masson's trichrome–stained left ventricle (LV), interventricular septum (IVS), and right ventricle (RV) from untreated and tadalafil‐treated GRMD dogs at 25 months.
Mentions: Tadalafil also improved GRMD cardiac histopathology. Masson's trichrome staining of the LV, interventricular septum, and RV (Figure 6) revealed that at age 25 months, untreated GRMD LV (approximately segments 5–6) and interventricular septum (approximately segment 2–3) were largely characterized by disorganized cardiomyocytes, prominent myocardial interstitial and perivascular fibrosis, and large fibrous or fat deposits throughout the myocardium, whereas the RV showed substantial myocardial deterioration and fibrous/fat deposition. Tadalafil reduced most signs of pathology, with comparatively mild perivascular fibrosis being the prominent feature in the LV and interventricular septum and perivascular‐restricted fibrous/fat deposition in the RV, thus agreeing with the functional benefits of tadalafil treatment for dystrophic myocardium. Reductions in fibronectin levels in tadalafil‐treated LVs (Figure 7B) agree with this observed difference in fibrosis.

View Article: PubMed Central - PubMed

ABSTRACT

Background: Cardiomyopathy is a leading cause of mortality among Duchenne muscular dystrophy patients and lacks effective therapies. Phosphodiesterase type 5 is implicated in dystrophic pathology, and the phosphodiesterase type 5 inhibitor tadalafil has recently been studied in a clinical trial for Duchenne muscular dystrophy.

Methods and results: Tadalafil was evaluated for the prevention of cardiomyopathy in the mdx mouse and golden retriever muscular dystrophy dog models of Duchenne muscular dystrophy. Tadalafil blunted the adrenergic response in mdx hearts during a 30‐minute dobutamine challenge, which coincided with cardioprotective signaling, reduced induction of μ‐calpain levels, and decreased sarcomeric protein proteolysis. Dogs with golden retriever muscular dystrophy began daily tadalafil treatment prior to detectable cardiomyopathy and demonstrated preserved cardiac function, as assessed by echocardiography and magnetic resonance imaging at ages 18, 21, and 25 months. Tadalafil treatment improved golden retriever muscular dystrophy histopathological features, decreased levels of the cation channel TRPC6, increased total threonine phosphorylation status of TRPC6, decreased m‐calpain levels and indicators of calpain target proteolysis, and elevated levels of utrophin. In addition, we showed that Duchenne muscular dystrophy patient myocardium exhibited increased TRPC6, m‐calpain, and calpain cleavage products compared with control human myocardium.

Conclusions: Prophylactic use of tadalafil delays the onset of dystrophic cardiomyopathy, which is likely attributed to modulation of TRPC6 levels and permeability and inhibition of protease content and activity. Consequently, phosphodiesterase type 5 inhibition is a candidate therapy for slowing the development of cardiomyopathy in Duchenne muscular dystrophy patients.

No MeSH data available.


Related in: MedlinePlus