Angiotensin‐dependent autonomic dysregulation precedes dilated cardiomyopathy in a mouse model of muscular dystrophy

Abstract

Sarcoglycan mutations cause muscular dystrophy. Patients with muscular dystrophy develop autonomic dysregulation and dilated cardiomyopathy (DCM), but the temporal relationship and mechanism of autonomic dysregulation are not well understood. We hypothesized that activation of the renin-angiotensin system (RAS) causes autonomic dysregulation prior to development of DCM in sarcoglycan-delta (Sgcd) deficient mice, and that the severity of autonomic dysfunction at a young age predicts the severity of DCM at older ages. At 10-12 weeks of age, when left ventricular function assessed by echocardiography remained normal, Sgcd−/− mice exhibited decreases in arterial pressure, locomotor activity, baroreflex sensitivity (BRS) and cardiovagal tone, and increased sympathetic tone compared with age-matched C57BL/6 control mice (P<0.05). Systemic and skeletal muscle RAS were activated, and angiotensin II type 1 receptor (AT1R) expression, superoxide and fibrosis were increased in dystrophic skeletal muscle (P<0.05). Treatment with the AT1R blocker losartan for 7-9 weeks beginning at 3 weeks of age prevented or strongly attenuated the abnormalities in Sgcd−/− mice (P<0.05). Repeated assessment of phenotypes between 10 and 75 weeks of age demonstrated worsening of autonomic function, progressive cardiac dysfunction and DCM, and increased mortality in Sgcd−/− mice. High sympathetic tone predicted subsequent left ventricular dysfunction. We conclude that RAS activation causes severe autonomic dysregulation in young Sgcd−/− mice, which portends a worse long-term prognosis. Therapeutic targeting of RAS at a young age may improve autonomic function and slow disease progression in muscular dystrophy.

Baroreflex sensitivity in facioscapulohumeral muscular dystrophy

“…In a mouse model of Duchenne muscular dystrophy, Chu et al ( 2002 ). observed an attenuated BRS, while Sabharwal et al ( 2015 ) reported that autonomic dysfunction preceded pathological cardiac hypertrophy in their mouse model of muscular dystrophy. Cardiac abnormalities in adults with FSHD that have been observed include left ventricular myocardial thickening (Finsterer et al, 2005 ) and abnormal ECG readings in the form of biatrial P‐waves, impaired sinoatrial node and atrioventricular node conduction, as well as atrial flutter or fibrillation (Laforêt et al, 1998 ; Stevenson et al, 1990 ).…”

Role of the Renin-Angiotensin-Aldosterone System in Dystrophin-Deficient Cardiomyopathy

“…It has been shown that autonomic dysfunction caused by activation of RAAS and manifested as reduced heart rate variability or inappropriate sinus tachycardia, is present at early stages of the disease and worsens progressively with age. Of note, the precocity and severity of this autonomic dysfunction predicts the severity of DDC at older ages and ANG2/AT1R blockade reduces oxidative stress and fibrosis and improved improves autonomic function and cardiac functionality in dystrophic mice [88][89][90].…”

“…Besides inhibiting MF, losartan also showed important beneficial and protective cardiovascular and metabolic effects, being associated with decreased LDH, AST, BUN and triglyceride levels and increased high-density lipoprotein (HDL) levels. Sabharwal et al [88][89][90] provided interesting evidence when studied the effects of ARBs on the autonomic dysregulation casted by ANG2 in dystrophic Sgcd−/− mice. They found that early autonomic dysfunction precedes and predicts the severity of LV dysfunction and mortality.…”

Role of the Renin–Angiotensin–Aldosterone System in Dystrophin-Deficient Cardiomyopathy

“…Sabharwal et al [ 88 , 89 , 90 ] provided interesting evidence when studied the effects of ARBs on the autonomic dysregulation casted by ANG2 in dystrophic Sgcd−/− mice. They found that early autonomic dysfunction precedes and predicts the severity of LV dysfunction and mortality.…”

“…AngioTable 2. is also essential in order to maintain and perpetuate the profibrotic response, providing a source for a positive auto-feedback. Abbreviations: ACE: angiotensin-converting-enzyme; Akt: protein kinase B; ALK5: activin receptor-like kinase-1; Ang I: angiotensin I; ANG II: angiotensin II; CCN2/CTGF: connective tissue growth factor; ET1: endothelin-1; ETA: endothelin receptor A; JNK: Jun N-Terminal Kinase; LAP: latency-associated peptides; MMPs: matrix metalloproteinases; NADH: reduced nicotinamide adenine dinucleotide; PDGF: platelet derived growth factor; PI3: phosphoinositide 3; ROS: reactive oxygen species; Smad3/4: mothers against decapentaplegic homolog ¾; TFG-β: transforming growth factor-beta; TNF-α: tumour necrosis factor alpha; α-SMA: alpha-smooth muscle actin; βFGF: basic fibroblast growth factor the severity of DDC at older ages and ANG2/AT1R blockade reduces oxidative stress and fibrosis and improved improves autonomic function and cardiac functionality in dystrophic mice [ 88 , 89 , 90 ].…”