Atrial remodelling in hypertensive heart disease: role of Na+ homeostasis and contractility
Arterial hypertension causes hypertensive heart disease. Constant mechanical stress and activation of neurohormonal systems cause structural and functional changes in the myocardium termed “remodelling”. Remodelling is beneficial in the beginning of the disease development; however, with time it bec...
Pharmakologie und Toxikologie
|Online Access:||PDF Full Text|
No Tags, Be the first to tag this record!
|Summary:||Arterial hypertension causes hypertensive heart disease. Constant mechanical stress and activation of neurohormonal systems cause structural and functional changes in the myocardium termed “remodelling”. Remodelling is beneficial in the beginning of the disease development; however, with time it becomes detrimental and impairs cardiac function. Remodelling of the myocardium occurs in hypertension, atrial fibrillation and heart failure. These cardiac diseases are tightly linked by the mechanisms of pathological remodelling and induce development and maintenance of one another. Ventricular remodelling has been studied intensively in hypertensive heart disease, however, atrial remodelling has been studied much less and is only poorly understood. Physiology of cardiac myocytes relies on balanced intracellular Na+ homeostasis. Na+ is involved in many cellular processes, such as action potential initiation, Ca2+ homeostasis, intracellular pH, metabolism and contractility. In the first part of the thesis I investigated ionic (Na+ homeostasis) and functional (contractility) atrial remodelling in an animal model of hypertensive heart disease – spontaneously hypertensive rats (SHR). In early hypertension, SHR exhibited elevated blood pressure and isolated left ventricular hypertrophy. The atria were not hypertrophied. Contractility of atrial myocytes and intracellular Na+ concentration ([Na+]i) were both unaltered. Expression of most Na+-handling proteins was unaffected in the atria of SHR. In advanced hypertension, SHR exhibited further progression of left ventricular hypertrophy and signs of heart failure. Left atria were hypertrophied. The contractility of atrial myocytes was reduced. [Na+]i was significantly decreased together with increased expression of the α 1 subunit of Na+/K+-ATPase. Expression of Na+/H+-exchanger was increased, suggesting activation of pro-hypertrophic pathways. Comparison of SHR with and without signs of heart failure (i.e. increased lung weight) revealed development of right ventricular hypertrophy and progression of bi-atrial hypertrophy in SHR with heart failure. Moreover, the impairment of atrial myocyte contractility progressed. However, [Na+]i and the expression of major Na+-handling proteins were not changed during the transition to heart failure. In addition to studies on atrial myocytes, we performed measurements of [Na+]i and contractility of ventricular myocytes from old SHR. In contrast to our findings in the atria, no impairment of contractility or changes in [Na+]i were observed in the ventricular myocytes, indicating atria-specific remodelling. Taken together, the presented results indicate that in early hypertension no significant signs of atrial remodelling in terms of contractility and Na+ homeostasis were found. However, in advanced hypertensive heart disease there was atria-specific functional atrial remodelling, which might contribute to the transition from compensated left ventricular hypertrophy to heart failure. Atrial ionic remodelling is an important factor in the development and maintenance of atrial fibrillation. The role of intracellular Na+ homeostasis in these processes is not understood. In the second part of the thesis, I investigated expression of Na+-handling proteins in right atrial tissue of patients suffering from paroxysmal and chronic atrial fibrillation compared to patients with sinus rhythm. The results indicated that the expression of Na+-handling proteins, including Na+ channels, Na+/H+ exchanger, alpha subunits of Na+/K+-ATPase, phospholemman, was not altered in either paroxysmal or chronic atrial fibrillation. The expression of β 1 subunit of Na+/K+-ATPase was significantly reduced in chronic atrial fibrillation. However, the functional consequences of this change require further investigation. Endothelin-1 plays an important role in the regulation of blood pressure and cardiac physiology. Enhancement of endothelin-1 system activity contributes to cardiac maladaptive remodelling, including disturbances in Ca2+ and Na+ homeostasis in cardiac myocytes. At the age of 7 months, SHR exhibit enhanced endothelin-1 signalling and altered Ca2+ handling. Therefore, in the third part of the thesis we investigated the effect of endothelin-1 receptor blockage on blood pressure and expression and phosphorylation of Ca2+-handling proteins, as well as the expression of proteins involved in endothelin-1 signalling in the atria of SHR. The results revealed that the blockage of endothelin receptors by 8 weeks treatment with macitentan (novel dual endothelin A and endothelin B receptor antagonist) did not lower blood pressure in SHR. Expression and phosphorylation of major Ca2+-handling proteins and endothelin-1 signalling proteins were both unaffected. Thus, the blockage of endothelin receptors did not cause any major changes in atrial Ca2+ remodelling in SHR|
|Physical Description:||166 Pages|