USA – Deste congresso eu selecionei 5 apresentações envolvendo a distrofia muscular; quatro delas se referem ao uso de inibidores da fosfodiesterase 5 como o sildenafil e tadalafil, drogas comercializadas para tratamento de disfunção erétil. Na distrofia muscular de Duchenne/Becker e nos modelos experimentais inúmeros trabalhos tem demonstrado o benefício cardíaco destas drogas. O quinto trabalho tem uma importância grande pois mostra que uma alteração observada no ecocardiograma de adolescentes com distrofia muscular de Duchenne se relaciona com pior prognóstico cardíaco da doença: a presença de não compactação do ventrículo esquerdo estaria relacionada com pior prognóstico da doença.
O resumo em inglês destas pesquisas pode ser lido abaixo:
A) Phosphodiesterase Modulation of Cardiomyopathy in Murine and Canine Models of Muscular Dystrophy Treated With Sildenafil and Tadalafil
Chonyang L Albert, Hosp of the Univ of Pennsylvania, Philadelphia, PA; Meg Sleeper, Univ of Pennsylvania Sch of Veterinary Med, Philadelphia, PA; H. Lee Sweeney, Univ of Pennsylvania, Philadelphia, PA
Patients with Duchenne muscular dystrophy (DMD) suffer from a myriad of musculoskeletal, respiratory, and cardiac symptoms.Cardiomyopathy is the second most common cause of death in DMD patients. The development of cardiomyopathy in these patients is often insidious, but untreated, many patients progress to overt heart failure. Current therapies used to treat the cardiomyopathy of DMD have been poorly studied since many of the same medications are used empirically from patients with congestive heart failure, despite the different underlying mechanical causes of heart failure in DMD patients. Using a well-established murine model of DMD, we treated mdx mice with phosphodiesterase-5 (PDE-5) inhibitors (sildenafil or tadalafil) for a duration of 1 month and 8 months. Treatment response was measured by dobutamine stress echocardiography parameters, proteomic expression, and histologic studies. We saw an increase in protein kinase G (PKG) levels in the sildenafil and tadalafil treated mice hearts, afterboth 1 month and 8 months of treatment, which suggests that the PDE-5 inhibitors’ mechanism of action is active in the heart. This was accompanied by a low level of atrial natriuretic peptide in the treated hearts compared to the untreated hearts at 8 months. Our results suggest that PDE-5 inhibition modulates and down-regulates the pro-fibrotic and pro-inflammatory cascade in the dystrophic mdx heart through TGF beta and SMAD2/3 pathways in an ERK-independent manner. Moreover, in a canine study in which dogs affected with golden retriever muscular dystrophy were treated with one of these 2 drugs for one month, both PDE-5 inhibitors resulted in improved left ventricular strain as measured with cardiac magnetic resonance imaging. There are some differences between the effects of the two PDE-5 inhibitors which is likely attributable to differences in the potency and specificity of these two agents at PDE5 inhibition. Further studies will continue to elucidate the role of PDE-5 inhibitors in the treatment of the dilated cardiomyopathy of DMD.
B) Sildenafil Prevents Progressive Hypertrophy and Normalizes the Enhanced Slow Force Response in Dystrophic Myocardium
Peter P Rainer, Kinya Seo, Dong I Lee, Scarlett Hao, Djahida Bedja, David A Kass, Johns Hopkins Sch of Med, Baltimore, MD
Duchenne Muscular Dystrophy (DMD) is a frequent and devastating disease that affects both skeletal muscle and the heart, resulting in cardiomyopathy in virtually all patients. Key features include nNOS-dysregulation and excessive Ca2+ entry upon mechanical stress. A possible source of increased Ca2+ entry are mechano-sensitive TRPC channels. As TRPC3/6 channels can be suppressed by PKG phosphorylation, we hypothesized that augmentation of PKG stimulation ameliorates invivo function coupled to blunting of stretch-activated Ca2+ entry and the slow force response (SFR).
Methods
Mdx, utrophin+/- mice were treated with sildenafil 200mg/kg/d for 2 months and followed-up by echocardiography; gene expression was assessed by qRT-PCR and PDE5 activity by fluorescence polarization. The SFR and Ca2+ transients were assessed in single cardiomyocytes attached to carbon fibers and papillary muscle preparations when exposed to stretch.
Results
Mdx, utrophin+/- mice demonstrated marked hypertrophy when compared to WT or mdx-only mice, with up-regulation of fetal gene expression markers (ANP 4.5±0.8-fold, BNP 2.5±0.4-fold, bMHC 2.8±0.4-fold, p<0.05) and a trend towards up-regulation of TRPC6 (3.4±1.5-fold, p=n.s.). Myocardial PDE5 activity was increased 3.5±0.5-fold over controls (p<0.01). Sildenafil treatment prevented and reversed progressive myocardial hypertrophy, normalized PDE5 activity, decreased fetal gene and TRPC6 expression (all p<0.05). The morphological and molecular changes were accompanied by an enhanced SFR in dystrophic cardiomyocytes. Sildenafil treatment and/or direct TRPC3/6 antagonism using a selective blocker normalized the myocyte SFR (p<0.05).
Conclusion
PDE5 inhibition is effective in preventing progressive hypertrophy and normalizing molecular markers of heart failure in dystrophic hearts. The SFR is enhanced in dystrophic cardiomyocytes and can be normalized by PDE5 inhibition or acute TRPC antagonism. These data support the involvement of TRPC channels in excessive Ca2+ entry and the enhanced SFR, offering a rationale for modifying TRPC Ca2+ entry, either by direct antagonism or by PKG phosphorylation of TRPC channels.
C) Tadalafil Alleviates Functional Muscle Ischemia in Patients with Becker Muscular Dystrophy
Elizabeth A Martin, Bryan L Scott, Ashley E Walker, Jimmy Johannes, Swaminatha V Gurudevan, Cedars Sinai Medical Ctr, Los Angeles, CA; Francine Anene, Robert M Elashoff, UCLA, Los Angeles, CA; Gail D Thomas, Ronald G Victor, Cedars Sinai Medical Ctr, Los Angeles, CA
Becker muscular dystrophy (BMD) is a progressive, ultimately fatal X-linked muscle wasting disease for which there is no treatment. BMD is caused by mutations in the gene encoding dystrophin, a structural cytoskeletal protein that also targets neuronal nitric oxide synthase (nNOSμ) to the sarcolemma. Our past work suggests that sarcolemmal nNOSμ normally is activated when muscles are exercised and the nitric oxide (NO) produced attenuates local alpha-adrenergic vasoconstriction, thereby optimizing muscle perfusion. We asked if this protective mechanism (“functional sympatholysis”) is defective, causing functional ischemia, in BMD patients with dystrophin mutations that disrupt sarcolemmal targeting of nNOSμ and if the ischemia can be alleviated by boosting NO-cGMP signaling with a phophodiesterase (PDE5A) inhibitor (tadalafil).
Methods:
We measured reflex vasoconstriction as decreased forearm muscle oxygenation (ΔHbO2) with near infrared spectroscopy during lower body negative pressure (LBNP, -20 mmHg) at rest and during rhythmic handgrip (HG) at 20% maximum in 10 men with BMD (age: 37 ± 3 years, mean ± SE) and 7 healthy age-matched male controls. Then, men with BMD underwent a randomized placebo-controlled double-blind cross-over trial of single-dose (20 mg) oral tadalafil (clinicaltrials.gov NCT01070511).
Results:
In healthy controls, reflex vasoconstriction was attenuated by 60 ± 8% during HG (ΔHb02: -18 ± 1% vs. -7 ± 2%, P<.01; rest vs. HG), documenting functional sympatholysis. In contrast, untreated BMD patients had no reflex attenuation during HG (ΔHb02: -19 ± 2% vs. -17 ± 2%, P>0.1; rest vs. HG), indicating functional ischemia. Most importantly, tadalafil fully restored sympatholysis in patients with BMD: after tadalafil, reflex vasoconstriction was attenuated by 52 ± 12% during HG (ΔHb02: -17 ± 2% vs. -9 ± 2%, P<0.01; rest vs. HG) whereas placebo had no effect ([[unable to display character: ∆]]HbO2: -18 ± 2% vs. -17 ± 2%, P>0.1; rest vs. HG).
Conclusion:
These data show that tadalafil alleviates functional muscle ischemia in patients with BMD and constitute the first-in-man proof-of-concept for PDE5A inhibition as a putative new treatment strategy for this and possibly other forms of muscular dystrophy accompanied by loss of sarcolemmal nNOSμ.
D) Phosphodiesterase 5A Inhibition Prevents Functional Muscle Ischemia in the Mdx Mouse Model of Duchenne/Becker Muscular Dystrophy
Liang Li, Ronald G Victor, Gail D Thomas, Cedars-Sinai Medical Ctr, Los Angeles, CA
The fatal muscle-wasting diseases Duchenne and Becker muscular dystrophy (DMD, BMD) are caused by mutations in the gene encoding dystrophin, a cytoskeletal protein that provides mechanical support and targets other proteins to the sarcolemma including the muscle-specific variant of neuronal nitric oxide synthase (nNOS). Loss of sarcolemmal nNOS impairs the normal paracrine effect of muscle-derived NO to attenuate α-adrenergic vasoconstriction in exercising muscle and renders the dystrophin-deficient muscles of boys with DMD and mdx mice susceptible to ischemia. We hypothesized that treatment with a phosphodiesterase 5A (PDE5A) inhibitor to reduce cGMP breakdown and enhance the NO signal from residual cytosolic nNOS would prevent functional muscle ischemia in mdx mice.
Methods:
Male C57BL6 or mdx mice (10-14 wks old) were anesthetized and instrumented to measure arterial pressure and femoral artery blood flow responses to intra-arterial delivery of norepinephrine (NE) into the resting and contracting hindlimbs. Mdx mice were studied after acute treatment with vehicle or one of two chemically distinct PDE5A inhibitors: the first generation, short-acting inhibitor zaprinast (4, 8 mg/kg, ip) or the more potent, long-acting inhibitor tadalafil (2, 4, 8, 16 mg/kg, po).
Results:
Compared to responses in the resting hindlimbs, NE-mediated vasoconstriction was appropriately attenuated by 64 ± 6% in the contracting hindlimbs of C57BL6 mice (n = 8), but was reduced only by 7 ± 10% in the contracting hindlimbs of vehicle-treated mdx mice (n = 10; P<0.05 vs BL6), indicating functional ischemia. This NE-induced ischemia in the mdx mice was prevented by PDE5A inhibition: vasoconstrictor responses in the contracting hindlimbs were attenuated by 76 ± 5% with zaprinast (8 mg/kg; n = 10; P<0.05 vs vehicle) and by 69 ± 9% with tadalafil (4 mg/kg; n = 6; P<0.05 vs vehicle).
Conclusion:
These data indicate that PDE5A inhibition prevents NE-induced ischemia in the contracting muscles of mdx mice. A tadalafil dose of 4 mg/kg in the mdx mouse is equivalent to 20 mg in humans, which is the highest FDA-approved dose used to treat erectile dysfunction. These findings suggest a novel potential use for tadalafil to ameliorate functional muscle ischemia in DMD and BMD patients.
E) A Prospective Cohort Study of Left Ventricular Noncompaction in Patients with Duchenne/Becker Muscular Dystrophy
Koichi Kimura, Katsu Takenaka, Aya Ebihara, Kansei Uno, Hiroyuki Morita, The Univ of Tokyo, Tokyo, Japan; Takashi Nakajima, Tetsuo Ozawa, Izumi Aida, Yosuke Yonemochi, Shinya Higuchi, Niigata Natl Hosp, Niigata, Japan; Yasufumi Motoyoshi, Takashi Mikata, Idai Uchida, Shimoshizu Natl Hosp, Chiba, Japan; Tadayuki Ishihara, Tetsuo Komori, Ruriko Kitao, Hakone Natl Hosp, Kanagawa, Japan; Masahiro Terashima, Cardiovascular Imaging Clinic Iidabashi, Tokyo, Japan; Tetsuya Nagata, Shin’ichi Takeda, Natl Ctr of Neurology and Psychiatry, Tokyo, Japan; Yukio Hiroi, Yutaka Yatomi, Kiyoshi Kubota, Ryozo Nagai, The Univ of Tokyo, Tokyo, Japan
Although studies have shown that neuromuscular diseases are most frequently associated with LV noncompaction (LVNC), the prevalence of LVNC varies widely and its prognostic impact remains controversial because most studies conducted to date have been retrospective and lacked adequate controls.
METHODS:
Patients with Duchenne/Becker muscular dystrophy (DMD/BMD) aged 4-64 years old (n=186) were evaluated by echocardiography at the study entry and prospectively followed-up their subsequent courses. The study endpoint was all-cause death and the presence of LVNC was blinded until the end of the study (median follow-up: 46 months; interquartile range: 41-48 months).
RESULTS:
LVNC was diagnosed in 35 (19%) out of the 186 patients. There were no significant differences in the baseline distributions of DMD/BMD type, age, blood pressure, heart rate, medications administered, and follow-up duration between patients with and without LVNC, with the exception of LV function. A worse prognosis was observed (Figure) in patients with LVNC (13/35 died) than in patients without LVNC (22/151 died). Multivariate Cox analysis revealed that LVNC is an independent prognostic factor (relative hazard 2.7 [95% CI: 1.2-6.0]).
CONCLUSION:
LVNC was prevalent in patients with DMD/BMD. The presence of LVNC was significantly associated with higher mortality rate. Neurologists and cardiologists should pay more careful attention to the presence of LVNC.
Fonte: http://distrofiamuscular.net/noticias.htm
