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Dr. Evangelia Kranias Lab

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Research Topics

Heart Failure

Cardiac Function

The Sarcoplasmic Reticulum

Phospholamban

SERCA

Calsequestrin

HRC

Junctin

HAX-1

Heat Shock Proteins

Protein Phosphate 1 Inhibitor-1

Human SR Genetic Variations



Director

Cardiac Function: A Simple View

As outlined above, the primary function of the heart is to pump blood throughout the body. The regular and continuous contracting of heart muscle, myocardium, generates and sustains an arterial blood pressure necessary to provide adequate perfusion of organs. The valves, coronary arteries and the conduction system also contribute to normal heart function.

The cardiac myocyte is composed of bundles of myofibrils that contain myofilaments (Figure 1a). The myofibrils have distinct, repeating microanatomical units, termed sarcomeres, which represent the basic contractile units of the myocyte. The sarcomere is composed of thick and thin filaments. Contraction occurs when the myosin head in the thick filament interacts with actin in the thin filament, causing the two filaments to slide past each other. The troponin complex in the thin filament regulates the actin-myosin interaction regulated by the intracellular free Ca 2+ concentration ([Ca2+] i ) (Figure 1b).

Figure 1a: Myofibrils in cardiac myocyte, which contains myofilaments. Sarcomere lies between two Z lines. Figure 1b: Cardiac myofilaments. Myosin (thick filaments) contains two heads with APTase activity. Thin filaments are made of actin, tropomyosin and troponin (TN). TN-C binds to Ca2+ released from sarcoplasmic reticulum (SR). TN-I inhibits the binding of actin-myosin binding until Ca2+ binds to TN-C.

Figure 2: Frank-Starling Law.

The heart has an intrinsic capability to increase its force of contraction and therefore stroke volume (SV) in response to an increase in venous return. This is called the Frank-Starling law (Fig 2). The raise of venous return increases the ventricular filling (end-diastolic volume) and therefore preload, which extends the myocyte sarcomere length, causing an increase in force generation. The underlying mechanism is found in the length-tension and force-velocity relationships for cardiac myocytes. Briefly, increase of sarcomere length enhances troponin C calcium sensitivity, which upregualtes the rate of myosin-actin attachment and detachment, and the amount of tension developed by the muscle fiber.
Pressure-volume (PV) loops provide a highly useful way of describing the activity of the left ventricle. PV loops are generated by plotting simultaneous points of the left ventricular volume curve and the left ventricular pressure curve (Fig 3).


Figure 3: Left ventricular (LV) pressure-volume loop. Figure shows the cardiac cycle phases of ventricular filling (4?1), isovolumetric contraction (1?2), ejection (2?3) and isovolumetric relaxation (3? 4). The end-diastolic volume (EDV) is the maximal volume achieved at the end of filling, and end-systolic volume (ESV) is the minimal volume (i.e., residual volume) of the ventricle found at the end of ejection. The width of the loop, therefore, represents the difference between EDV and ESV, which is by definition the stroke volume (SV). The filling phase moves along the end-diastolic pressure-volume relationship (EDPVR), or passive filling curve for the ventricle. The slope of the EDPVR is the reciprocal of ventricular compliance. The maximal pressure that can be developed by the ventricle at any given left ventricular volume is the end-systolic pressure-volume relationship (ESPVR), which represents the inotropic state of the ventricle.