Department of Cardiology and Pneumology, Georg-August-University Goettingen, Robert-Koch-Str. 40, 37075 Göttingen, Germany.
Circulation. 2010 Sep 7;122(10):993-1003. doi: 10.1161/CIRCULATIONAHA.110.943431. Epub 2010 Aug 23.
Hemodynamic load regulates myocardial function and gene expression. We tested the hypothesis that afterload and preload, despite similar average load, result in different phenotypes.
Afterload and preload were compared in mice with transverse aortic constriction (TAC) and aortocaval shunt (shunt). Compared with sham mice, 6 hours after surgery, systolic wall stress (afterload) was increased in TAC mice (+40%; P<0.05), diastolic wall stress (preload) was increased in shunt (+277%; P<0.05) and TAC mice (+74%; P<0.05), and mean total wall stress was similarly increased in TAC (69%) and shunt mice (67%) (P=NS, TAC versus shunt; each P<0.05 versus sham). At 1 week, left ventricular weight/tibia length was significantly increased by 22% in TAC and 29% in shunt mice (P=NS, TAC versus shunt). After 24 hours and 1 week, calcium/calmodulin-dependent protein kinase II signaling was increased in TAC. This resulted in altered calcium cycling, including increased L-type calcium current, calcium transients, fractional sarcoplasmic reticulum calcium release, and calcium spark frequency. In shunt mice, Akt phosphorylation was increased. TAC was associated with inflammation, fibrosis, and cardiomyocyte apoptosis. The latter was significantly reduced in calcium/calmodulin-dependent protein kinase IIdelta-knockout TAC mice. A total of 157 mRNAs and 13 microRNAs were differentially regulated in TAC versus shunt mice. After 8 weeks, fractional shortening was lower and mortality was higher in TAC versus shunt mice.
Afterload results in maladaptive fibrotic hypertrophy with calcium/calmodulin-dependent protein kinase II-dependent altered calcium cycling and apoptosis. Preload is associated with Akt activation without fibrosis, little apoptosis, better function, and lower mortality. This indicates that different loads result in distinct phenotype differences that may require specific pharmacological interventions.
血流动力学负荷调节心肌功能和基因表达。我们检验了这样一个假设，即在主动脉缩窄（TAC）和腔静脉分流（分流）的情况下，尽管平均负荷相似，但后负荷和前负荷会导致不同的表型。
在 TAC 小鼠和腔静脉分流小鼠中比较了后负荷和前负荷。与假手术组相比，手术后 6 小时，TAC 小鼠的收缩期壁应力（后负荷）增加了 40%（P<0.05），分流组（前负荷）增加了 277%（P<0.05）和 TAC 小鼠（前负荷）增加了 74%（P<0.05），TAC 和分流小鼠的平均总壁应力均显著增加（TAC 增加 69%，分流增加 67%）（P=NS，TAC 与分流相比；P<0.05，与假手术组相比）。1 周时，TAC 和分流小鼠的左心室重量/胫骨长度分别显著增加 22%和 29%（P=NS，TAC 与分流相比）。在 24 小时和 1 周时，TAC 中的钙/钙调蛋白依赖性蛋白激酶 II 信号增加。这导致钙循环改变，包括增加 L 型钙电流、钙瞬变、肌浆网钙释放分数、钙火花频率。在分流组中，Akt 磷酸化增加。TAC 与炎症、纤维化和心肌细胞凋亡有关。在钙/钙调蛋白依赖性蛋白激酶 II 缺失型 TAC 小鼠中，后者显著减少。TAC 与分流小鼠相比，有 157 个 mRNAs 和 13 个 microRNAs 差异表达。8 周后，TAC 小鼠的短轴缩短分数降低，死亡率高于分流小鼠。
后负荷导致适应性纤维性肥大，伴有钙/钙调蛋白依赖性蛋白激酶 II 依赖性钙循环改变和细胞凋亡。前负荷与 Akt 激活有关，无纤维化，凋亡较少，功能较好，死亡率较低。这表明，不同的负荷会导致不同的表型差异，可能需要特定的药物干预。
