The enhanced activity of the cardiac Na⁺/H⁺ exchanger (NHE-1) after myocardial stretch is considered a key step of the intracellular signaling pathway leading to the slow force response to stretch as well as an early signal for the development of cardiac hypertrophy. We propose that the chain of events triggered by stretch begins with the release of small amounts of Angiotensin II (Ang II)/endothelin (ET) and ends with the increase in intracellular Ca²⁺ concentration ([Ca²⁺]_i) through the Na⁺/Ca²⁺ exchanger in reverse mode (NCX_rev), which triggers cardiac hypertrophy by activation of widely recognized Ca²⁺-dependent intracellular signaling pathways.