Pathophysiology and Therapy of Cardiac Dysfunction in Duchenne Muscular Dystrophy

Daniel P. Judge; David A. Kass; W. Reid Thompson; Kathryn R. Wagner


Am J Cardiovasc Drugs. 2011;11(5):287-294. 

In This Article

7. Emerging Pharmacologic Strategies for Cardiac Dysfunction

7.1 Phosphodiesterase-5 Inhibition with Sildenafil

The lack of functional dystrophin impacts various associated signaling molecules. Dystrophin localizes to the sarcolemma in myocytes and is associated with a large complex of proteins and glycoproteins known as the DGC.[11] This complex forms a link between the cytoskeleton and ECM. Nitric oxide is produced by three isoforms of nitric oxide synthase, termed neuronal (nNOS), inducible (iNOS), and endothelial (eNOS). Importantly, nNOS localizes to the myocyte sarcolemma and binds to α1-syntrophin in the membrane dystrophin-cytoskeleton complex.[32] Although nNOS was given its name because it was first localized to the brain, it is expressed highly in muscle.[33,34] In the setting of dystrophin deficiency, nNOS is absent from the sarcolemma in mdx mice.[35] Several experiments supported the idea that dystrophin deficiency leads to reduced cardiac and skeletal muscle function through loss of nNOS and cGMP.[36–38]

The link between nNOS and dystrophin deficiency likely involves direct binding of the protein to members of the DGC, specifically α-syntrophin, though this dislocalization has also been observed with disuse muscle atrophy syndromes where the dystrophin complex remains intact.[39] Furthermore, deletion of nNOS itself does not induce muscular dystrophy nor change the underlying mdx phenotype, giving rise to the notion that a second primary mechanism is critical to explain the disease.[40,41]

The 'second hit' has been broadly described as membrane destabilization associated with the lack of a functional DGC.[42] The DGC combines dystrophin with the membrane sarcoglycan protein complex, and intracellular binding proteins, α-syntrophin and dystrobrevin. Cells lacking dystrophin fail to assemble a functional macrostructure. When subjected to mechanical stress, affected muscle exhibits increased intracellular entry of cations, particularly calcium, and this may induce subsequent cellular injury and death by stimulating damaging proteases such as calpain, and increasing mitochondrial calcium uptake to alter energy metabolism and increase generation of reactive oxygen species.[43–45] While first suspected to pass via rents in the surface membrane, growing evidence suggests excess calcium trafficking passes via non-selective non-voltage-gated cation channels, all members of the superfamily of transient receptor potential canonical channels (TRPCs). Much of this evidence comes from studies in the mdx mouse model of DMD where up-regulation of a stretch-activated inward Ca2+ channel current has been demonstrated.[46–48]

Human DMD muscle also displays changes in TRPC channel expression, though channel activity is lesswell known.TRPC1was the first channel suggested to underlie the current, but recent studies support other members, notably TRPC3.[49–52] TRPC3 and its homologous channel TRPC6 are both receptor-activated channels in that they are directly activated by diacylglycerol induced by Gq/11 receptor-coupled stimulation.[53] Both are also activated by mechanical stretch (as is the Gq receptor).[54] Importantly, a recent study found that dystrophic skeletalmuscle in mice lacking dystrophin or a-sarcoglycan is ameliorated by transgenic co-expression of a dominant negative TRPC3.[52]

Nucleotide phosphodiesterases (PDEs) catalyze the hydrolysis of cyclic nucleotide monophosphates and thereby regulate downstream signaling by cAMP and cGMP. Cyclic GMP is produced by guanylate cyclase from GTP and serves as a mediator of nitric oxide and natriuretic peptide stimulation, inducing vasodilation and increasing blood flow.[55] PDE5 was first purified and characterized in rat lung, with subsequent human studies showing its activity in many organs including heart.[56,57]

The vasorelaxant properties of PDE5 inhibition were initially investigated using pharmacologic agents with a goal of reducing BP or treating angina pectoris by augmenting vascular cGMP. These studies revealed safety, but little cardiovascular impact in normal controls. However, penile erections were eventually recognized as a common side effect, resulting in the development and US FDA approval of drugs for the treatment of erectile dysfunction.[58] High levels of PDE5A expression in lung and pulmonary vasculature later led to clinical trials demonstrating that PDE5 inhibition with sildenafil is safe and effective for the treatment of pulmonary hypertension.[59]

In cardiac tissue, PDE5 inhibition has little effect on basal cardiac function but modulates responses to various stimuli. Ischemic preconditioning is favorably induced by sildenafil.[60] In addition, PDE5 inhibition prominentlymodulates adrenergic-stimulated cardiac contractility and pressure-overload hypertrophy.[61,62] This hypertrophy is not only prevented, but is also reversed after early development.[62] Besides morphologic responses, cardiac contractility can be improved by sildenafil during thoracic aortic constriction (TAC), and measures of diastolic ventricular relaxation such as Tau (time constant of ventricular relaxation) are also normalized by sildenafil during TAC.[62] The expression of several mediators of ventricular hypertrophy in response to TAC, such as calcineurin, ERK1/2, and Akt, are also suppressed by sildenafil, suggesting that PDE5 inhibition may serve as a central target for modulation of multiple different sources of cardiac hypertrophy.[62] Various chronic cardiovascular diseases such as heart failure are associated with increased cGMP in response to sustained activation of natriuretic peptides (NPs), and PDE5 upregulation occurs as a countering mechanism.[63] This has direct implications for both the systolic and diastolic cardiac dysfunction that develops among individuals with DMD.[8]

In summary, several lines of evidence support the concept that enhanced cGMP levels by inhibition of PDE5 will ameliorate the deficiency in NOS signaling resulting from the loss of dystrophin. Increased TRPC channel activation with consequent myocyte calcium overload and damage occurs in the setting of dystrophin deficiency, and PDE5 inhibition blocks TRPC channel activation and associated Cn/NFAT activation signaling by PKG-dependent channel phosphorylation.[64] A recent report on the ability of sildenafil to reverse cardiac dysfunction in the dystrophin-deficient mdx strain of mice further supports this hypothesis.[65] Furthermore, a small trial of sildenafil in humans with systolic heart failure showed favorable effects on both systolic and diastolic LV function, cardiac remodeling, and cardiac performance.[66] A clinical trial, REVERSE-DMD (Revatio for Heart Disease of Duchenne Muscular Dystrophy), is currently enrolling participants to assess the efficacy of sildenafil as a treatment for DMD-associated cardiac dysfunction ( identifier:NCT01168908). Figure 1 shows the interactions among pathways that can be modulated to treat cardiac dysfunction in cardiomyopathy due to dystrophin deficiency or absence.

Figure 1.

Schematic representation of the pathways that are targeted for therapies to improve cardiac dysfunction. Note that dystrophin binds to the glycoprotein complex and neuronal nitric oxide synthase (nNOS). Inhibition of phosphodiesterase-5 (PDE5) by sildenafil blocks the conversion of cyclic GMP (cGMP) to GMP and increases cGMP to increase protein kinase G (PKG). Aldo = aldosterone; ang II = angiotensin II; AT1 = angiotensin II type 1 receptor; βAR= β-adrenoceptor; epi = epinephrine; K-ATP = adenosine triphosphate-sensitive potassium channel; MCR= mineralocorticoid receptor; mito = mitochondria; NO= nitric oxide; sGC= soluble guanylate cyclase; TRP= transient receptor potential.

7.2 Poloxamer-188

Dystrophin deficiency leads to increased micro-tearing of both cardiac and skeletal muscle in response to mechanical stress.[67] While micro-tears occur in normal and dystrophic muscle, their occurrence is more common in DMD and the repair of such injury is impaired.[67] This likely contributes to increased calcium influx and abnormal calcium homeostasis in muscle without dystrophin. Investigators have focused on the structural deficiency of dystrophin and investigated the use of a surfactant called poloxamer-188 (poly[ethylene oxide]80-poly[propylene oxide]27-poly[ethylene oxide]80) to help seal membrane ruptures. In isolated cardiomyocytes obtained from mdx mice, poloxamer-188 improved compliance and response to stretch, with normalization of intracellular calcium levels.[67] Pre-treatment of mdx mice with an intravenous infusion of poloxamer-188 improved both the hemodynamic response to dobutamine infusion and survival by preventing acute dobutamine-induced heart failure. In a larger animal model of DMD, a strain of golden retriever muscular dystrophy (GRMD) dogs with a mutation in the dystrophin gene, cardiomyopathy is worse than in mdx mice.[68] Recently, poloxamer-188 treatment was reported in this strain of dogs.[69] Compared with saline, treatment with a continuous 8-week infusion of poloxamer-188 prevented both LV dilation and increases in cardiac troponin I in theGRMDdogs.[69]


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