Evgeny Tsimerinov

Tadalafil alleviates muscle ischemia in patients with Becker muscular dystrophy

The phosphodiesterase 5A inhibitor tadalafil restores normal blood flow regulation in exercising skeletal muscle of patients with Becker muscular dystrophy. A Shot in the Arm for Muscular Dystrophy Becker muscular dystrophy (BMD), characterized by progressive skeletal muscle wasting, is caused by mutations in the muscle protein dystrophin. Preclinical research in the dystrophin-deficient mdx mouse model of a related disease Duchenne muscular dystrophy shows that inhibitors of phosphodiesterase 5 (PDE5)—which boosts guanosine 3′,5′-monophosphate (cGMP), the downstream target of nitric oxide (NO) in vascular smooth muscle—alleviate some features of the dystrophic phenotype including vasospasm of skeletal muscle microvessels that can lead to muscle injury and fatigue. The challenge is to determine whether these compelling results in mice can be translated to benefit human patients with muscular dystrophy. In a new study, Martin et al. assessed exercise-induced attenuation of reflex sympathetic vasoconstriction in the muscles of 10 patients with BMD and 7 age-matched healthy male controls. This is a protective mechanism that optimizes perfusion of skeletal muscle to meet the metabolic demands of exercise. Reflex vasoconstriction was induced by simulated orthostatic stress and was measured as the decrease in forearm muscle oxygenation using near-infrared spectroscopy. The authors took the measurements when the forearm muscles were rested or lightly exercised in the form of a rhythmic handgrip. First, the investigators showed that exercise-induced attenuation of reflex vasoconstriction was defective in 9 of 10 patients with BMD in whom the common dystrophin mutations disrupt targeting of neuronal NO synthase (nNOS) to the muscle sarcolemma (the response was preserved in one patient in whom nNOS was localized to the muscle sarcolemma). Then, in a double-blind randomized placebo-controlled crossover trial, the authors showed that normal blood flow regulation was fully restored in eight of nine patients by a single oral 20-mg dose of the drug tadalafil, a specific PDE5 inhibitor. These findings support an essential role for sarcolemmal nNOS in modulating sympathetic vasoconstriction in exercising human skeletal muscles and implicate PDE5 inhibition as a putative therapeutic strategy for treating BMD. Becker muscular dystrophy (BMD) is a progressive X-linked muscle wasting disease for which there is no treatment. Like Duchenne muscular dystrophy (DMD), BMD is caused by mutations in the gene encoding dystrophin, a structural cytoskeletal protein that also targets other proteins to the muscle sarcolemma. Among these is neuronal nitric oxide synthase (nNOSμ), which requires certain spectrin-like repeats in dystrophin’s rod domain and the adaptor protein α-syntrophin to be targeted to the sarcolemma. When healthy skeletal muscle is subjected to exercise, sarcolemmal nNOSμ-derived NO attenuates local α-adrenergic vasoconstriction, thereby optimizing perfusion of muscle. We found previously that this protective mechanism is defective—causing functional muscle ischemia—in dystrophin-deficient muscles of the mdx mouse (a model of DMD) and of children with DMD, in whom nNOSμ is mislocalized to the cytosol instead of the sarcolemma. We report that this protective mechanism also is defective in men with BMD in whom the most common dystrophin mutations disrupt sarcolemmal targeting of nNOSμ. In these men, the vasoconstrictor response, measured as a decrease in muscle oxygenation, to reflex sympathetic activation is not appropriately attenuated during exercise of the dystrophic muscles. In a randomized placebo-controlled crossover trial, we show that functional muscle ischemia is alleviated and normal blood flow regulation is fully restored in the muscles of men with BMD by boosting NO-cGMP (guanosine 3′,5′-monophosphate) signaling with a single dose of the drug tadalafil, a phosphodiesterase 5A inhibitor. These results further support an essential role for sarcolemmal nNOSμ in the normal modulation of sympathetic vasoconstriction in exercising human skeletal muscle and implicate the NO-cGMP pathway as a putative new target for treating BMD.

Sodium nitrate alleviates functional muscle ischaemia in patients with Becker muscular dystrophy

Dystrophin deficiency disrupts sarcolemmal targeting of neuronal nitric oxide synathase, resulting in functional muscle ischaemia. Chronic treatment of dystrophic mice with an inorganic nitric oxide (NO) donor alleviates this ischaemia and improves many features of the dystrophic phenotype. The present study translates this preclinical work by showing that a single oral dose of sodium nitrate,which serves as a NO donor when reduced to circulating nitrite by the commensal bacteria in the oral cavity, alleviates functional muscle ischaemia and restores normal blood flow regulation in human patients with dystrophinopathy. The results of the present study further support the mechanistic hypothesis that circulating nitrite serves as an alternative NO donor when reduced by deoxyhaemoglobin and/or deoxymyoglobin in exercising muscle.

Gastrointestinal and Urologic Sphincter Dysfunction in Stiff Person Syndrome.

Objectives: Stiff person syndrome is a neurologic disorder characterized by axial rigidity leading to progressive disability, with broad clinical spectrum. Methods: We report 2 cases with unique clinical presentation. Results: Two young men suffered progressive urinary retention requiring bladder catheterization, anorectal spasms and constipation, complicated subsequently with lower extremity trigger-induced spasms, and gait instability. Associated symptoms revealed brainstem involvement (vertigo, diplopia, and cranial neuropathies) and dysautonomia (abnormal sweating and orthostatic hypotension). Anal manometry demonstrated incomplete relaxation of the anal sphincter. The first case was associated with diabetes mellitus type I, did not respond to classical therapies, but was responsive to rituximab. The second case responded to intravenous immunoglobulin infusions. Paraneoplastic profiles were negative, and anti-GAD65 antibody titers remained elevated despite successful therapeutic responses. Conclusions: We want to raise awareness that stiff person syndrome can present with esophageal, anorectal, and urethral sphincter disturbance. Rituximab is a good therapeutic option in intractable cases.

Recurrent Ischemic Strokes and Headaches Originating from Lambl's Excrescences: A Case-Report

Determining recurrent stroke etiology and subsequent therapeutic approaches is an important, but not always straightforward task. Lambl’s Excrescences (LE) are cardiac valve strands that can be a source of recurrent cerebral ischemic events. We report the case of a 60 year old female that was seen in neurologic consultation for recurrent ischemic strokes. The patient developed migraine headache with complex auras at the age of 59. She reported three admissions for ischemic strokes in the past year. Stroke work-ups were unrevealing. The patient remained on daily Aspirin. Upon current admission, a brain MRI showed a combination of sub acute and chronic infarcts in diverse brain areas bilaterally. Further diagnostic evaluation revealed a relatively unremarkable CT head and neck angiogram. Transcranial Doppler (TCD) showed increased pulsatility index throughout the insonated vessels. Transesophageal echocardiogram (TEE) showed a trileaflet aortic valve with a 10 mm long thin fibrin strand prolapsing into the left ventricle outflow tract in diastole, meeting echocardiographic criteria for an LE. The patient refused anticoagulation and surgical intervention. She opted instead for a combination of two antiplatelet agents. Recurrent cerebral infarcts presenting concurrently with late-age onset migraine with aura should raise a clinical suspicion of cardiogenic valvular etiology. The use of TEE in evaluating patients with unexplained recurrent stroke is imperative so that LE is not missed. Anti-platelet agents, anti-coagulants, and cardiothoracic surgical intervention are proposed in the literature for the management of long-term complications associated with LE. Asymptomatic patients should be monitored, counseled, and made aware of LE complications, neurological symptoms, and alarm signals. Migraine headaches associated with LE should raise a red flag and prompt treatment with anti-platelet agents.