The natural process of aging has a profound and progressive effect on cardiac function, particularly on lusitropy, the active process of myocardial relaxation. Over time, the heart's ability to relax and fill with blood during diastole becomes less efficient, even in the absence of overt cardiovascular disease. This is a complex phenomenon driven by a cascade of molecular, cellular, and structural changes. The following sections explore the specific mechanisms through which aging impairs lusitropy.
The Role of Altered Calcium Homeostasis
Efficient myocardial relaxation is critically dependent on the rapid removal of calcium ($Ca^{2+}$) from the cardiac muscle cells (cardiomyocytes). This process is largely governed by the sarcoplasmic reticulum ($SR$), a network of internal membranes that stores and releases calcium. Age-related changes severely disrupt this delicate calcium handling system.
- Decreased SERCA Activity: A primary mechanism is the downregulation of the Sarco/endoplasmic Reticulum Calcium ATPase (SERCA2a) protein. SERCA2a is the primary calcium pump that re-sequesters calcium back into the SR after each heart contraction. With age, the expression and activity of SERCA2a diminish, slowing the rate of calcium reuptake and, consequently, prolonging myocyte relaxation. Studies have shown that restoring SERCA activity can mitigate age-related muscle weakness and atrophy.
- Altered Phospholamban (PLN) Regulation: Phospholamban is a protein that inhibits SERCA activity. Its inhibitory effect is typically counteracted by phosphorylation, a process enhanced by $\beta$-adrenergic stimulation. In the aging heart, there is a blunted $\beta$-adrenergic response, meaning the heart is less responsive to stress signals. This leads to a relative over-inhibition of SERCA by un-phosphorylated PLN, further contributing to slower relaxation.
- Reduced SR Calcium Content: The age-associated decrease in SERCA activity and altered PLN regulation lead to a lower overall calcium content within the SR. This reduces the amount of calcium available for release during contraction, potentially contributing to a weaker contraction, but also slows the overall cycle of relaxation and re-filling.
- Increased Sodium-Calcium Exchanger (NCX) Dependence: With less efficient calcium reuptake by the SERCA pump, the aged heart becomes more reliant on the sodium-calcium exchanger (NCX) to remove excess calcium from the cell. This compensatory mechanism is less efficient than SERCA, further slowing the relaxation process.
Myocardial Stiffness and Extracellular Matrix Changes
Beyond intracellular calcium handling, the physical structure of the heart muscle itself changes with age, contributing to stiffness and reduced distensibility.
- Increased Interstitial Fibrosis: As we age, there is a progressive increase in collagen deposition, or fibrosis, in the spaces between cardiomyocytes. This fibrotic tissue stiffens the ventricular walls, reducing myocardial compliance and impeding the heart's ability to stretch and relax during filling.
- Changes in Myocyte Structure and Size: While some studies suggest a decrease in myocyte number, the remaining cells often undergo compensatory hypertrophy (enlargement). This contributes to increased ventricular wall thickness, which, coupled with fibrosis, further stiffens the heart.
- Altered Myosin Cross-Bridge Cycling: Changes in the kinetics of the myosin-actin cross-bridge cycle have been implicated in age-associated muscle weakness and changes in contractile and relaxation properties. A prolonged attached state of cross-bridges can increase myocardial stiffness, slowing relaxation.
Impact on Diastolic Filling and Heart Function
These cellular and structural changes culminate in measurable alterations to the heart's diastolic function, often referred to as diastolic dysfunction.
- Prolonged Isovolumic Relaxation Time: The period between the closure of the aortic valve and the opening of the mitral valve (isovolumic relaxation) lengthens with age, indicating a slower initial phase of relaxation.
- Shifting Filling Pattern: In a young heart, the majority of ventricular filling occurs rapidly and passively in early diastole. In the aged heart, slowed early diastolic relaxation reduces this rapid filling phase. The heart becomes more dependent on a more forceful atrial contraction (the 'atrial kick') to complete ventricular filling later in diastole, increasing the heart's vulnerability to rhythm disturbances like atrial fibrillation.
Comparison of Lusitropy in Young vs. Aged Hearts
| Characteristic | Young Heart | Aged Heart |
|---|---|---|
| SERCA Activity | High, efficient re-uptake of calcium | Reduced, slowing calcium clearance |
| Myocardial Relaxation | Rapid and complete | Prolonged and less complete |
| Calcium Handling | Primarily SERCA-dependent | Increased reliance on NCX, less efficient |
| Myocardial Stiffness | Low, compliant ventricular walls | Increased due to fibrosis and hypertrophy |
| Diastolic Filling Pattern | High proportion of filling in early diastole | Shift toward late diastolic filling via atrial contraction |
| Response to Stress | Strong $\beta$-adrenergic response enhances relaxation | Blunted $\beta$-adrenergic response |
The Role of Exercise in Counteracting Age-Related Impairment
Regular physical activity has been shown to be one of the most effective interventions for attenuating age-related cardiovascular decline. Exercise can help maintain or even improve cardiac function in older individuals, suggesting that the changes associated with aging are not entirely irreversible.
- Improved Calcium Handling: Exercise training can increase SERCA protein levels and activity, which helps to improve calcium handling and accelerate myocardial relaxation.
- Reduced Fibrosis: Regular exercise can help modulate the balance of extracellular matrix proteins, potentially reducing age-related fibrosis and maintaining ventricular compliance.
- Enhanced $\beta$-Adrenergic Responsiveness: Physical training can improve the heart's sensitivity to $\beta$-adrenergic stimulation, enhancing its ability to respond to stress by improving both contractility and relaxation.
- Better Cardiovascular Reserve: By improving these underlying mechanisms, exercise helps to preserve the heart's functional reserve, enabling it to better meet the demands of physical activity and other stressors.
Conclusion
Aging impairs lusitropy through a multi-faceted process involving decreased SERCA activity, altered phospholamban regulation, and increased myocardial fibrosis. These changes progressively slow myocardial relaxation, alter diastolic filling patterns, and reduce the heart's reserve capacity. While this physiological decline is a normal part of aging, lifestyle interventions, particularly regular exercise, can effectively mitigate many of these age-related changes, preserving cardiac function and reducing the risk of conditions like heart failure with preserved ejection fraction (HFpEF) and atrial fibrillation. Understanding these intricate mechanisms is key to promoting healthy cardiovascular aging. For more details on the molecular mechanisms involved, see the review "Cardiac Aging: The Role of Changes in Cellular Calcium Handling" by Wei et al..
