Demands on the heart vary from moment to moment and from day to day. In moving from rest toexercise the cardiac output may be increased tenfold. Other increases in demand are seen when the heart must pump blood against a high pressure such as that seen in hypertensive heart disease. Each of these stresses requires special adjustments. Short-term increases in demand on the heart (e.g., exercise) are met by increases in the force and frequency of contraction. These changes are mediated by increases in sympathetic nervous system activity, an increase in the frequency of contraction, and changes in muscle length. The response to long-term stress (hypertension, thyrotoxicosis) results in an increase in the mass of the heart (hypertrophy) providing more heart muscle to pump the blood, which helps meet the increase in demand. In addition, subtle intracellular changes affect the performance of the muscle cells. In the pressure overload type hypertrophy (hypertensive heart disease) the pumping system of the sarcoplasmic reticulum responsible for calcium removal is slowed while the contractile protein myosin shifts toward slower cross-bridge cycling. The outcome is a slower, more economical heart that can meet the demand for pumping against an increase in pressure. At the molecular level the slowing of calcium uptake is caused by a reduction in the number of calciumpumps in the sarcoplasmic reticulum. The change in Vmax and economy of force development occur because each myosin cross-bridge head cycles more slowly and remains in the attached force-producing state for a longer period of time. In the thyrotoxic type of hypertrophy, calcium is removed more quickly while there is a shift in myosin. At the molecular level there are more sarcoplasmic reticular calcium pumps, while the myosin cross-bridge head cycles more rapidly and remains attached in the force-producing state for a shorter period of time. The result is a heart that contracts much faster but less economically than normal and can meet the peripheralneed for large volumes of blood at normal pressures.