Functional significance of the Frank-Starling mechanism under physiological and pathophysiological conditions

Abstract

The functional significance of the Frank-Starling mechanism under physiological and pathophysiological conditions is discussed, based mainly on animal experiment results (in the dog, pig and rat). The dependence of individual stroke volume on end-diastolic volume can be described adequately using Frank's diagram. This can be illustrated by varying filling pressure (respiratory cycle, vascular tone in the capacitance system, body position, circulating blood volume) and by alterations in the duration of the filling period (heart rate and rhythm, rate of relaxation) and in ventricular compliance (wall thickness, fibrosis; contracture, rigor). The functional importance of the Frank-Starling mechanism lies mainly in adapting left to right ventricular output. During upright physical exercise an increase in end-diastolic volume due to the action of the peripheral muscle pump and increased venous tone can assist in enhancing stroke volume. Reduced contractility leads to a shift of the operating point to the right in the pressure-volume diagram, thus tending to prevent a decrease in stroke volume. However, the consequences of increased circulating blood volume in chronic heart failure are, as a rule, mainly detrimental (congestive symptoms; myocardial component of coronary resistance; cardiac energetics). Reduced contractility results in a flattening of the relation between stroke volume (or stroke work) and end-diastolic volume. Furthermore, the Starling mechanism is prevented from becoming effective if the sarcomere-length reserve is exhausted, or in the presence of inadequate sarcomere extension due to impaired relaxation or reduced distensibility of the ventricular wall. The latter is illustrated using the example of a dilated fibrotic left ventricle from a rat with experimental supravalvular aortic stenosis.

Disulfide-activated protein kinase G Iα regulates cardiac diastolic relaxation and fine-tunes the Frank–Starling response

“…Ca 2+ binding to titin is known to increase passive tension of the myocardium, making the ventricle stiffer and thus harder to fill12. Furthermore, because impaired relaxation results in inadequate extension of the sarcomeres, the myofilament Ca 2+ sensitivity—which is dependent on sarcomere length111229—will be reduced in the KI cardiomyocytes and also contribute to the decreased contractility observed in the KI hearts111236.…”

Origin of Cardiac Fibroblasts and the Role of Periostin

“…Balanced synthesis2 and degradation3–5 of this ECM is key to normal cardiovascular development, physiological growth of cardiac muscle (exercise), pathological responses to injury (myocardial infarction, hypertrophy, hypertension and ischemia-reperfusion)6–8, and for optimal heart function9. CFs themselves are a source of paracrine growth factors10, but can also respond to hormones, growth factors, cytokines and mechanical forces.…”

Enhanced Ca2+ binding of cardiac troponin reduces sarcomere length dependence of contractile activation independently of strong crossbridges

“…Thus SL-dependent changes in Ca 2ϩ -sensitivity of force generation result from the intrinsic properties of the thin filament (8, 42) as well as from complex interactions between thin and thick filament proteins. This is especially important to understand in cardiac muscle, since free intracellular [Ca 2ϩ ] during activation is known to be submaximal (17, 35) and loss of SL dependence of contraction can occur during heart failure (22,24,39).Under normal conditions, contractile activation is initiated by Ca 2ϩ -binding to the cTn complex on cardiac thin filaments, allowing tropomyosin movement that exposes myosin binding sites on actin. Myosin initially forms crossbridges with actin in a weak electrostatic conformation, then transitions to a strong hydrophobic conformation that generates force (15).…”

“…Thus SL-dependent changes in Ca 2ϩ -sensitivity of force generation result from the intrinsic properties of the thin filament (8,42) as well as from complex interactions between thin and thick filament proteins. This is especially important to understand in cardiac muscle, since free intracellular [Ca 2ϩ ] during activation is known to be submaximal (17,35) and loss of SL dependence of contraction can occur during heart failure (22,24,39).…”