Heterogeneous transmural gene expression of calcium-handling proteins and natriuretic peptides in the failing human heart.

See article by Prestle et al. [17] (pages 323 –331) in this of active sarcomeres, this can occur at the expense of issue. metabolism, is only temporary and eventually decompensates. Similarly, ischemic cardiomyopathy can be associThe realization that a non-uniform distribution of wall ated with wall thinning and dilation resulting from loss of stress across the ventricular wall can have transmural contractile sarcomeres. As wall stress increases with effects on cardiac function has been of intense interest to dilation, the time allowed for endocardial perfusion dephysiologists, cardiologists and engineers since Woods creases. This is complicated by the increase in myocardial published his application of the law of LaPlace [11] over a oxygen consumption, which is directly related to the century ago [25]. Using the simplified model, LaPlace [11] increase in wall stress [19]. Thus, the dilated heart is in a found that, in a thin vessel, tension (stress in a structure higher energy-consuming state than the normal heart. with minimum thickness) is directly related to the internal Consequently, the endocardium may be in a constant state pressure and the radius of the vessel (T5P3r). When this of energy supply /demand imbalance in the failing heart. relationship is applied to a simplified model of the heart, The vulnerability of the endocardium to mismatched either a sphere or an ellipsoid shape, the wall thickness can energy supply /demand may be magnified by an alteration 21 be taken into consideration, leading to the conclusion that in subcellular Ca regulation. In heart failure, reductions the stress (force over an area with thickness) at the in cardiac function have been associated in part with an 21 endocardial surface is greater than at the epicardial surface; attenuation in intracellular Ca handling. Gwathmey et al. for a review, see [26]. Mirsky [13] proposed that the [6] demonstrated over a decade ago, using aequorin, that 21 classical theory underestimated endocardial stress by as intracellular Ca transients in muscles from heart failure much as tenfold, suggesting a marked transmural gradient patients were prolonged and exhibited a secondary of wall stress in the heart. This gradient leaves the ‘‘hump’’, which was construed as being the result of 21 endocardium vulnerable to increases in intraventricular prolonged intracellular Ca elevation. The reason for this pressure. Anatomically, the endocardial coronary vessels increase appears to be a reduction in sarcoplasmic re21 are derived from epicardial vessels that penetrate perpenticulum Ca ATPase (SERCA2a), leading to a reduced 21 dicular to the wall to perfuse the endocardium. Consereaccumulation of intracellular Ca [12,24]. Models of quently, during systole, the transmural gradient of stress aortic banding-induced cardiac hypertrophy have also increases the potential for reduced endocardial perfusion, shown that increases in wall stress are associated with leading to an energy supply /demand imbalance. However, reductions in myocyte shortening velocities, prolongation 21 the length of diastole is sufficient to overcome this of Ca transients and relaxation times, leading to reducvulnerability in the normal heart. tions in the cardiac index [2]. These effects are magnified with heart failure since Since increases in wall stress can induce a reduction in 21 ventricular dilation has the negative effect of increasing the subcellular function associated with Ca regulatory proradius of the ventricle, thus raising wall stress even if teins, there is no reason to believe that across the ventricuintraventricular pressure remains constant. Although the lar wall where there is a gradient stress from the endoheart initially compensates by hypertrophy, thus reducing cardium to the epicardium, there should also be a similar wall stress by distributing the stress over a greater number gradation of function. Few studies have examined transmural gradients of function, but slight reductions in 21 *Tel.: 11-215-652-7828; fax: 11-215-652-3811. endocardial myofibrillar Ca ATPase activity [10] and