Determinants of Ventricular Function

Determinants of Ventricular Function

• Ventricular function, a key aspect of cardiovascular physiology, refers to the mechanical performance of the heart’s ventricles. While discussions of ventricular function often focus on the left ventricle, the same principles apply to the right ventricle. The ventricles don’t function independently; they are interdependent.
• Ventricular function can be divided into two main parts:
  • Systolic function refers to the ventricle’s ability to eject blood.
  • Diastolic function refers to the ventricle’s ability to fill with blood.¹
• A central measure of ventricular function is cardiac output (CO), which is the total volume of blood the heart pumps per minute. It is expressed as the product of SV and heart rate (HR).

HR

• When SV is constant, CO is directly proportional to HR.
• The sinoatrial (SA) node sets the intrinsic HR through spontaneous depolarization, but this rate can be modified by autonomic, humoral, and local factors.
• The normal intrinsic rate of the SA node in young adults is about 90 to 100 beats per minute, but this rate decreases with age based on the following formula:

• Vagal activity: Enhanced vagal activity slows HR by stimulating M2 cholinergic receptors.
• Sympathetic activity: Enhanced sympathetic activity increases HR. It primarily works by activating β1-adrenergic receptors and, to a lesser extent, β2-adrenergic receptors.¹

SV

• SV is the amount of blood pumped out of the left ventricle with each heartbeat. The three major factors that generally determine SV are:
  • Preload: The degree of myocardial stretch at the end of diastole
  • Afterload: The resistance the ventricle must overcome to eject blood
  • Contractility: The inherent strength of the myocardial contraction
• The heart is a three-dimensional, multichambered pump; both ventricular geometric form (regional wall motion abnormalities) and valvular dysfunction can also affect SV.

Preload

Definition

• Ventricular preload is defined as the end-diastolic volume, which is the volume of blood in the ventricle at the end of its relaxation phase (diastole). This is primarily determined by how effectively the ventricle fills with blood.
• Clinically, preload is difficult to measure directly.²
  • Central venous pressure is an indicator of right ventricular preload
  • Pulmonary capillary wedge pressure is an indicator of left ventricular preload.

Frank-Starling Law²

• This fundamental principle describes the relationship between CO and preload.
• The Frank-Starling law states that the strength of a ventricular contraction is directly dependent on the initial length of its resting muscle fibers.
• An increase in left ventricular preload (end-diastolic volume) leads to an increase in SV without needing external neural or hormonal mechanisms.
• Since left ventricular end-diastolic volume (LVEDV) is difficult to measure, left ventricular end-diastolic pressure (LVEDP) is often used as a surrogate marker.
• This holds true as long as the HR and contractility remain constant.

Mechanism of Frank-Starling Law

• The mechanism of the Frank-Starling law is traditionally attributed to the degree of overlap between actin and myosin myofilaments in diastole, which determines the number of cross-bridges that form during contraction. This is known as the length-tension relationship.
• The maximal force of contraction occurs when the sarcomere is stretched to approximately 2.2 μm. This length is optimal for forming actin and myosin cross-bridges without the thin filaments overlapping (Figure 1b). In a normal heart, this optimal length corresponds to an LVEDP of about 10–12 mmHg.
• When the sarcomere is shorter than 2.2 μm, the overlapping of thin filaments reduces the tension that can be generated (Figure 1a). This leads to a loss of contractile energy due to work against friction and distortion of the sarcomere.
• When the sarcomere is stretched beyond 2.2 μm, fewer actin-myosin cross-bridges form, resulting in a reduction in the force of contraction (Figure 1c). This occurs in ventricular failure, not in a normal heart.
• At 3.6 μm, there is no overlap of actin and myosin myofilaments, resulting in no active tension (Figure 1d).

The Frank-Starling Curve

• The left ventricular performance curve relates preload, as measured by LVEDV or LVEDP, to cardiac performance, as measured by SV.
  • I. Normal Heart: In a normally functioning heart, cardiac performance increases continuously with increasing preload (Figure 2).
  • II. Positive Inotropy: During states of increased myocardial contractility (inotropy), such as with norepinephrine infusion, the curve shifts upward. The heart achieves greater cardiac performance for a given preload.
  • III. Negative Inotropy: During states of decreased contractility, such as in systolic heart failure, the curve shifts downward. The heart exhibits decreased cardiac performance for a given preload.

Clinical Significance of the Frank-Starling Law³

• The Frank-Starling mechanism also plays a crucial role in compensating for systolic heart failure. Heart failure caused by impaired contractility results in a downward shift of the ventricular performance curve, leading to a decrease in SV for any given preload.
• This leads to incomplete ventricular emptying and an increased residual volume, which stretches the myocardial fibers and induces a greater SV on the next contraction via the Frank-Starling mechanism. This compensatory effect allows for better emptying of the enlarged ventricle and helps preserve CO.
• However, the benefit of this compensation is limited. In severe heart failure, the ventricular performance curve may be nearly flat at higher diastolic volumes, meaning increased chamber filling no longer significantly increases CO. In this situation, a severe elevation in LVEDV and LVEDP can lead to pulmonary congestion.
• In the treatment of systolic heart failure, clinicians use inotropic drugs such as digitalis and dopamine to increase intracellular calcium, which enhances the interaction between actin and myosin. This results in a hemodynamic effect of shifting a depressed Frank-Starling curve upward, leading to an increased SV and CO.

Afterload

• Afterload is the force or resistance the heart must overcome to eject blood during systole.
• It is commonly understood as either the resistance from the arterial system to blood ejection (aortic compliance) or the ventricular wall tension during contraction.
• Aortic compliance refers to the ability of the aorta to stretch and accommodate blood from the ventricles.⁴
  • Conditions that increase afterload by decreasing aortic compliance include aortic stenosis and chronic hypertension.
• Ventricular wall tension is explained by Laplace’s Law1, which states:
  • The wall stress (ventricular wall tension) is directly proportional to the pressure inside the chamber and its radius, and inversely proportional to the wall thickness.

• • Wall stress (or wall tension): It represents the force the myocardial (heart muscle) cells must generate to withstand the pressure inside the ventricle.
  • Higher wall stress means the heart muscle has to work harder.
  • Pressure (P): This refers to the intraventricular pressure—the pressure exerted by the blood inside the chamber. This is the force pushing outwards against the walls.
  • Radius (R): This is the radius of the chamber (e.g., the ventricular radius). It represents the size of the chamber.
  • Wall Thickness (h): This refers to the thickness of the wall of the chamber. In the heart, this is the thickness of the myocardial muscle.

Implications of Laplace’s Law

• Ventricular dilation and heart failure: When a ventricle dilates (e.g., dilated cardiomyopathy), its radius increases. According to Laplace’s law, this requires the heart muscle to generate significantly more force (wall tension) to maintain the same pressure. This increased workload can lead to a vicious cycle where the heart muscle is overworked, becomes less efficient, and dilates further, ultimately contributing to heart failure.
• Hypertension and ventricular hypertrophy: In conditions like chronic hypertension, the heart must pump against a consistently higher pressure. To maintain adequate CO, the heart muscle thickens (hypertrophies). This increase in wall thickness acts as a compensatory mechanism, as a thicker wall reduces the wall stress required to overcome the higher pressure, as shown by the inverse relationship between wall thickness and wall stress in the equation. While this initially helps the heart cope, prolonged hypertrophy can eventually lead to stiffness and impaired diastolic function.
• Myocardial oxygen consumption: Wall stress is a major determinant of the heart’s oxygen consumption. A higher wall stress, whether due to increased pressure or ventricular dilation, demands more energy and oxygen from the heart muscle. This explains why conditions that increase afterload or cause ventricular dilation can lead to myocardial ischemia in individuals with underlying coronary artery disease.

Myocardial Contractility

• Myocardial contractility, or inotropy, is the heart’s intrinsic ability to pump without being affected by changes in preload or afterload.
• This function is directly related to the rate of myocardial muscle shortening, which, in turn, depends on the amount of calcium (Ca2+) inside the cells during systole.
• Factors increasing contractility (positive inotropy)
  • The sympathetic nervous system is the most significant factor influencing contractility. Sympathetic nerve fibers release norepinephrine, which enhances contractility by activating β1-receptors.
  • Similarly, sympathetic drugs and epinephrine released from the adrenal glands also increase contractility through β1-receptor activation.
• Factors decreasing contractility (negative inotropy)
  • Hypoxia, acidosis, and catecholamine depletion
  • Loss of muscle mass: Damage to the heart muscle from conditions like ischemia can permanently reduce its pumping ability.
  • Medications: Many anesthetics and anti-arrhythmic drugs, when administered in large doses, can act as negative inotropes, directly decreasing the heart’s contractility.

Regional Wall Motion Abnormalities¹

• Regional wall motion abnormalities impair the heart’s ability to pump blood effectively, leading to a breakdown in the symmetrical contraction of the ventricles.
• This can be caused by conditions such as ischemia, scarring, or altered electrical conduction.
• The severity of the abnormality ranges from:
  • Hypokinesis: weakened contractions
  • Akinesis: No contractions at all
  • Dyskinesia: A paradoxical bulging during contractions

Valvular Dysfunction¹

• Valvular dysfunction, which can include stenosis or regurgitation, or both, can affect any of the heart’s four valves.
• This dysfunction impacts SV, but the mechanism differs depending on which valve is affected.
  • Stenosis of an atrioventricular (AV) valve: A narrowed AV valve (tricuspid or mitral) makes it difficult for blood to flow from the atrium to the ventricle. This primarily reduces SV by decreasing ventricular preload (the volume of blood in the ventricle at the end of diastole).
  • Stenosis of a semilunar valve: A narrowed semilunar valve (pulmonary or aortic) makes it harder for the ventricle to eject blood into the major arteries. This primarily reduces SV by increasing ventricular afterload (the resistance the ventricle must overcome).
  • In contrast to stenosis, valvular regurgitation reduces SV by allowing blood to flow backward with each contraction. A significant portion of the blood that should be pumped forward leaks backward into the preceding chamber (e.g., from the ventricle back into the atrium through an incompetent AV valve). This backward flow, known as the regurgitant volume, directly reduces the effective SV that is pumped out to the body, even if preload, afterload, and contractility are unchanged.

Conclusions

• Understanding ventricular function involves grasping the interplay between HR and SV, as well as the three factors that define it: preload, afterload, and contractility.
• The Frank-Starling law explains how the heart’s pumping force increases with greater preload, while Laplace’s Law details the critical relationship between wall stress, pressure, radius, and wall thickness.
• When these mechanisms are strained—such as in heart failure or valvular dysfunction—the heart’s ability to supply the body with blood is compromised.
• A deeper understanding of these concepts is crucial for recognizing how the heart compensates for stress and how medical interventions can help restore balance.