RESUMEN
Becker muscular dystrophy (BMD) is a progressive X-linked muscle wasting disease for which there is no treatment. BMD is caused by in-frame mutations in the gene encoding dystrophin, a structural cytoskeletal protein that also targets other proteins to the sarcolemma. Among these is neuronal nitric oxide synthase mu (nNOSµ), which requires specific spectrin-like repeats (SR16/17) in dystrophin's rod domain and the adaptor protein α-syntrophin for sarcolemmal targeting. When healthy skeletal muscle is exercised, sarcolemmal nNOSµ-derived nitric oxide (NO) attenuates α-adrenergic vasoconstriction, thus optimizing perfusion. In the mdx mouse model of dystrophinopathy, this protective mechanism (functional sympatholysis) is defective, resulting in functional muscle ischaemia. Treatment with a NO-donating non-steroidal anti-inflammatory drug (NSAID) alleviates this ischaemia and improves the murine dystrophic phenotype. In the present study, we report that, in 13 men with BMD, sympatholysis is defective mainly in patients whose mutations disrupt sarcolemmal targeting of nNOSµ, with the vasoconstrictor response measured as a decrease in muscle oxygenation (near infrared spectroscopy) to reflex sympathetic activation. Then, in a single-arm, open-label trial in 11 BMD patients and a double-blind, placebo-controlled cross-over trial in six patients, we show that acute treatment with oral sodium nitrate, an inorganic NO donor without a NSIAD moiety, restores sympatholysis and improves post-exercise hyperaemia (Doppler ultrasound). By contrast, sodium nitrate improves neither sympatholysis, nor hyperaemia in healthy controls. Thus, a simple NO donor recapitulates the vasoregulatory actions of sarcolemmal nNOS in BMD patients, and constitutes a putative novel therapy for this disease.
Asunto(s)
Isquemia/tratamiento farmacológico , Músculo Esquelético/irrigación sanguínea , Distrofia Muscular de Duchenne/tratamiento farmacológico , Nitratos/uso terapéutico , Simpaticolíticos/uso terapéutico , Administración Oral , Adolescente , Adulto , Humanos , Masculino , Persona de Mediana Edad , Distrofia Muscular de Duchenne/metabolismo , Nitratos/administración & dosificación , Óxido Nítrico/metabolismo , Óxido Nítrico Sintasa de Tipo I/genética , Óxido Nítrico Sintasa de Tipo I/metabolismo , Oxígeno/metabolismo , Simpaticolíticos/administración & dosificación , VasoconstricciónRESUMEN
OBJECTIVE: A small but significant proportion of patients with atrial fibrillation or atrial flutter (AF) develop left atrial appendage thrombus (LAAT) despite non-vitamin K antagonist oral anticoagulant (NOAC) prescription. This study examines clinical and echocardiographic risk factors associated with LAAT by transesophageal echocardiogram (TEE) despite NOAC use in patients with non-valvular AF, to inform the decision whether a TEE should be performed prior to cardioversion. METHODS: We compared clinical and echocardiographic characteristics of patients with LAAT despite NOAC prescription for >3 weeks (n = 38) with a consecutive sample of patients on NOAC without LAAT (n = 101). RESULTS: The prevalence of LAAT despite NOAC prescription was 2.6%. Left atrial dilation (adjusted odds ratio [aOR] 3.310, 95% CI 1.144-9.580, p = 0.02) and greater CHA2DS2-VASC score (per-point increase, aOR 1.293, 1.027-1.628, p = 0.03) increased the odds for LAAT. Higher LVEF (per 5%, aOR 0.834, 0.704-0.987, p = 0.03) and presence of severe mitral regurgitation (aOR 0.147, 0.048-0.446, p = 0.002) were protective against LAAT. LAA emptying velocities were also independently associated with presence of LAAT (aOR per 10 cm/s, 0.46, 0.27-0.77). CONCLUSION: Left atrial dilation, greater CHA2DS2-VASC score, absence of severe mitral regurgitation and lower left ventricular ejection fraction are associated with LAAT despite NOAC therapy. In addition to suspected NOAC noncompliance, presence of such high-risk features may warrant pre-cardioversion TEE. Similarly, in patients with LVEF > 50% and CHA2DS2-VASC < 2, risk of LAAT was exceedingly low and thus TEE before cardioversion is low-yield.