Copyright © 2004, European Society of Cardiology
Pathophysiology of heart failure: more bricks in the "crumbling sarcolemmal scaffolding" paradigm?
Intervet Pharma R&D, BP 67131, F-49071 Beaucouzé Cédex, France
* Tel.: +33 2 41 22 8269; fax: +33 2 41 8228. Email address: stephane.baudet{at}intervet.com
Received 16 November 2004; accepted 17 November 2004
See article by Takahashi et al. (pages 356–365) in this issue.
Despite major progress in the pharmacological management of congestive heart failure (CHF), life expectancy of patients suffering from CHF remains low [1]. Progress in the treatment of CHF (currently based on diuretics, angiotensin-converting enzyme inhibitors (ACEI) or angiotensin II (Ang II) type 1 receptor (AT1R) blockers (ARB), and β-blockers [1]) has relied on the recognition of the primary role of the adrenergic and renin–angiotensin–aldosterone (RAA) systems, which are initially activated to compensate for the decreased cardiac output, but which, in the long run, aggravate myocardial performance, therefore perpetuating the vicious circle of the CHF process [2].
The myocardium is one final target of the deleterious effects of catecholamines and Ang II. This has led to the carrying out of studies aimed at understanding the damage done to cardiac myocytes and the potential beneficial effects of molecules protecting, directly or indirectly (through haemodynamic changes), the myocardium. Such studies at the myocyte level are still rare and mostly conducted in animal models of CHF [3]. Despite the variety of CHF models, major convergent findings have been disclosed. These include modified expression or activity of proteins involved in the excitation–contraction–coupling process and its neurohormonal modulation: ion channels (voltage-activated potassium channels), transduction pathway components (such as decreased expression of β1-adrenergic receptors, increased expression of Gi protein), intracellular calcium-regulating proteins (decreased expression of sarcoplasmic reticulum calcium ATPase, increased expression of the sarcolemmal Na/Ca exchanger, altered function of the ryanodine receptor) [4,5].
In contrast to the extensive research on mechanisms underlying deficient contractile function, studies on the structural integrity of the failing myocyte are rare. In particular, the sarcolemma plays a crucial role in the myocyte's function. It constitutes a physical but selectively permeable barrier between the extra- and intracellular medium that must resist intraventricular haemodynamic changes and accommodates the myocytes lifelong contractile activity. Sarcolemmal disruption obviously leads to major imbalance in electrolytes and metabolite fluxes that eventually lead to myocyte death. Evidence builds up to demonstrate that sarcolemmal integrity should be regarded as a key component of the CHF's vicious circle paradigm [6,7].
Sarcolemmal integrity is maintained thanks to a network of several proteins that span between actin and basal lamina proteins, commonly referred as the dystrophin-related protein (DRP) complex, that include dystrophin (DYS, that binds to F-actin), dystroglycans (
and β), sarcoglycans (SG; , β, 
, 
and 
), syntrophins, sarcospan and dystrobrevin [7]. In support of the "fragile sarcolemma" hypothesis in CHF is the finding that CHF develops in mammals presenting mutations in DYS or -SG (BIO 4.16 and TO-2 hamster strains) [7–9]. Whether a causal link does exist remains a matter of debate. Nevertheless, recent experimental work has shown beneficial clinical and survival effects of virally mediated -SG transfer in TO-2 hamsters [6]. This theory would be supported if the involvement of a fragile DRP scaffolding in a non-genetic model of CHF could be demonstrated.
Accordingly, in this issue of Cardiovascular Research, Takahashi et al. [10] assessed whether the DRP profile was altered in a non-genetic and well-characterised [11,12] model of heart failure in rats (coronary artery ligation, CAL) and whether current drugs used in the management of heart failure, the ACEI trandolapril or the ARB candesartan, had any beneficial impact not only on the function of CAL rat hearts, but also on the integrity of the DRP complex, in the viable left ventricular myocardium. Functional investigation demonstrated compensated myocardial function 2 weeks post-CAL but depressed contractility 8 weeks post-CAL. At this same time, reduced expression of DYS and -SG proteins was found, as were increased expression and proteolytic activity of the calcium-activated proteases m- and µ-calpains, with unchanged content of calpastatin, their endogenous inhibitor. An essential finding was that, within the DRP complex, DYS and -SG were selective targets of calpains, thereby consolidating the link between a modified DRP profile and increased calcium-activated proteolytic activity. Existence of this relationship was further strengthened by the reversal of the changes in DRP profile and calpain expression and activities by treatment with trandolapril or candesartan initiated 2 weeks post-CAL. Myocardial content of other sarcoglycans was not changed by CAL or CAL+ treatment nor was calpastatin expression (although a trend for an increase was apparent). Of relevance, the decreased content of DYS and -SG was not due to attenuated expression of their respective mRNA (which actually either increased or remain unchanged in CAL rats compared to controls, whether or not the rats were treated). These results all converge to support the hypothesis of specific calcium-activated proteolysis of DYS and -SG. Importantly, from a functional standpoint, the authors demonstrated that left ventricular end-diastolic pressure was strongly correlated with either the DRP or -SG content of the viable left ventricular myocardium of 8-weeks post-CAL rats and that treatment with either trandolapril or candesartan maintained this correlation.
This elegant and extensive study brings exciting results in that a defect in the DRP complex is also involved in the progression of CHF in a non-genetic model. It brings additional support to the pathophysiological hypothesis of a decreased content of one or several DRP (here -SG and DYS) in the myocyte that would make the sarcolemma more susceptible to physical damage due to contractile activity and haemodynamic overload, promoting penetration of calcium within the sarcoplasm [6,7]. Calcium would subsequently activate calpains, which, amongst other substrates, would digest specific DRP, leading to further sarcolemmal weakening [6].
Two limitations of the study by Takahashi et al. can be raised. Firstly, the pharmacological treatment was started late after CAL (15 days), whereas, if the model was to reproduce some aspects of human ischaemia, treatment with an ACE inhibitor or an ARB should have been started as soon as possible after the ischaemic insult. Two weeks in the absence of any treatment will have most likely favoured a long-lasting excessive workload of the viable myocardium and thereby triggered a clear-cut modification in the DRP profile. Earlier treatment may not have disclosed such molecular remodelling. Secondly, the fate of other constituents of the DRP was not looked for in this model. Digestion of DYS and -SG may therefore be necessary but not sufficient for CHF to evolve in this model.
This work also raises new questions. For instance, the molecular pathways explaining the beneficial effects of trandolapril and candesartan need investigation. In fact, the results could reasonably be explained by decreased availability or binding of Ang II on the AT1R, but may also be a result of increased production of bradykinin (trandolapril's effects) with subsequent binding to the bradykinin B2 receptor, or binding of Ang II to the AT2 receptor (candesartan's effects). Interestingly, the B2 and AT2 receptors share common transduction pathways (in particular, NO/cGMP) [13]. In this context, co-administration of a B2 receptor blocker with trandolapril or of an AT2 receptor blocker with candesartan could attenuate or reverse the beneficial effects of the ACEI or ARB. In this same rat CAL model, beneficial effects of the virally mediated transfer [6] of -SG or DYS (or another DRP) could also reinforce the sarcolemmal paradigm, as would be the expression of parvalbumin [14], a large-capacity calcium binding protein (to give further support to the "calcium" side of the mechanism). Finally, this hypothesis will require confirmation in other models of heart failure induced, for instance, by tachypacing.
In conclusion, experimental evidence is mounting to indicate that maintenance of sarcolemmal integrity and control of calcium-activated proteolytic activity are potential targets in the pharmacological management of heart failure.
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