Zouein FA, et al. The Angiotensin II Type 1 (AT1) Receptor and Cardiac Hypertrophy: Did we have it wrong all along? An ongoing issue is whether angiotensin II (Ang II) has direct growth promoting effects on the heart. This has relevance for whether ACE inhibitors and AT1 receptor blockers offer additional benefit in preventing adverse cardiac remodeling in hypertension. In a recent study, two strains of mice were infused with Ang II. Ang II caused hypertrophy and hypertension in the strain lacking Ang II type 1 (AT1) receptors in the heart and conduit vessels, but not in the strain with no AT1 receptors in resistance vessels. This supports the conclusion that blood pressure is more important in determining cardiac hypertrophy than direct AT1 activation by Ang II, when the two are rapidly and simultaneously introduced. Surprisingly, mice with no cardiac AT1 receptor expression developed ventricular dilation and eccentric hypertrophy with pressure overload, in contrast to wild type mice, suggesting that cardiac AT1 receptors protect against high blood pressure. This interpretation revives issues related to β-arrestin-biased signaling and mechanosensitivity of AT1 receptors. Synthetic nanobodies, based on the variable regions of camelid-derived heavy chain-only antibodies, could be used to explore the therapeutic potential of exploiting different activation states of AT1 under stress conditions, such as hypertension and heart failure. At the very least, this experimental approach is likely to reveal new facets of AT1 receptor signaling in the heart.