As multicellular organisms evolved and increased in size, increasingly complex respiratory and circulatory systems developed to bring in O2 and nutrients and to take out carbon dioxide and waste products. From simple gas exchange via ectoderm in sponges to tracheae in insects, water animals developed gills, while land animals developed lungs. These changes were associated with natural selection of bilateral symmetry, segmentation, and ventral-lateral axes, with locomotion supported by either exoskeletons (invertebrates) or endoskeletons (vertebrates). With increasing size and anatomical complexity, a simple vascular tube developed first in three layered animals, triploblasts, from the lateral plate mesoderm. A pulsating pump moves blood through a simple atrium and ventricle toward gills supplied with branchial arteries in fish and tadpoles; in all mammals and birds, there is a right atrial-ventricular pulmonary circulatory system distinctly for the lungs, and a separate left atrial-ventricular circulatory system for all other organs. Genetic data indicate that some genes for heart development are conserved from insects to mammals. This supports the notion that Nature starts with a basic blueprint which is adapted for fitness and survival during evolution. Embryology, in part, lays out the developmental history of these gradual evolutionary changes. Heart rate is modulated up and down by the autonomic nervous system and contractility is enhanced primarily by the sympathetic nervous system with its cardiac receptors and by other neuromodulators. Coronary vascular tone, or flow, is regulated mostly by local vasodilatory and vasoconstrictive factor from the endothelium. An important vasodilatory factor is nitric oxide, which acts on guanylyl cyclase in vascular cells to convert GTP to GMP; this stimulates K+ channel opening and induces vascular cell membrane hyperpolarization. The O2 supplied to the heart is utilized in the process of making ATP to drive cellular cation pumps and maintain ion homeostasis, to maintain the proton motive force and coupling efficiency, and to power actin-myosin cross bridge cycling. ATP produced in the matrix is exchanged for ADP in the sarcoplasm via adenine nucleotide translocase and stored as creatine phosphate. The human heart processes approximately 30 kg of ATP per day. The hearts and mitochondria of mammals are adapted to increase cardiac output and mitochondrial O2 consumption during exercise to over five or six-fold, and in birds to more than twice as much as in mammals.