Over 70% of 50 million Americans over 60 years of age have cardiovascular disease (CVD) [1, 2]. CVD prevalence increases with age, and outcomes in older patients with acute coronary syndromes are poor [1, 3]. It is important to note, however, that aging itself, even in the absence of CVD, alters LV structure and function and impairs the ability of the LV to respond to stress and injury. Thus, understanding the mechanisms of cardiac aging has significant clinical relevance.

While most studies focus on the myocyte contribution to cardiac systolic function, indices for systolic function, such as ejection fraction, systolic velocities, and systolic isovolumic acceleration rate, have been shown to have little relation with age in both clinical and animal studies [4, 5]. In contrast, echocardiographic indices of diastolic function including early (E) and late (Atrial-A) diastolic peak filling velocities and the E and A velocity ratio (E/A ratio), mitral deceleration time (the time from the peak to the end of the Doppler E-wave), isovolumic relaxation time (the time between the closing artifact of the aortic valve), and the earliest detection of trans-mitral blood flow have been demonstrated to decline with age in clinical studies [6–8]. With physiological aging, the LV undergoes monotonic structural changes that include increased wall thickness, chamber diameter, and mass [6–8].

We have shown diastolic dysfunction at the organ level in mice during cardiac aging [9], and diastolic dysfunction is caused by increased myocardial stiffness at the tissue level [10]. The myocardium is composed of myocytes (muscle) surrounded by the ECM environment. Accordingly, myocardial stiffness is determined by the volume ratio and the combined mechanical property of the myocytes and ECM. In the diastolic phase, myocytes are relaxed and ECM is a critical determinant to the change of LV wall stiffness. About 90% of cardiac ECM composition in the young LV is collagen I and III. We have shown that collagen content in senescent mouse hearts doubles compared to young hearts [9, 11]. Since collagen has a magnitude increase in stiffness over myocytes, the age-related increase of collagen content in the LV shifts myocardial mechanical properties from a myocyte-based stiffness to one influenced by collagen-based stiffness [12]. Therefore, the goal of this study was to evaluate the effects of ECM composition on LV remodeling with aging using a mathematical model developed by integrating cardiac mechanics and our experimental results in mice.

Different LV wall stress models, such as the Laplace law based thin-wall models, thick-wall shell models, and finite element models, have been established to describe LV mechanics and compute stress [13, 14]. Most current thin-wall and thick-wall models of LV remodeling were established assuming idealistic spherical, spheroidal, or ellipsoidal geometries. While finite element models allow some flexibility in the LV geometry, they require high computational power. Currently, these models focus on the stress calculation taken from a particular snapshot of the cardiac cycle or for the entire cycle. However, the interplay between LV stress and strain and between remodeling and geometric evolution on the life-time scale has not been established.

Phenomenological models on geometric remodeling with aging have been developed to apply on arteries under hypertensive conditions [15, 16]. The arterial wall is considered as a thick-wall vessel, and the remodeling equation on either inner or outer artery surface has been postulated as a function of strain and stress at the corresponding location. While these models do not consider the intrinsic relationships between phenomenological assumptions, they provide a possible methodology to model the temporal progression of tissue remodeling with aging.

There are very few computational models available to study LV geometric adaptation with aging. Recently, we established a computational model of LV aging that incorporates Laplace law based stress model [11]. This model captures the overall trend of LV radius change with age. However, this thin-wall model assumes a constant thickness and no stress variation across the wall, LV thickening with age was not addressed. Here, we improve this model by adopting a more sophisticated thick-wall theory and stretch-induced tissue growth theory for the model used in this study. The novelty of this model lies in the integration of both computational and experimental approaches. The wall radii remodeling model established in this study was subject to the temporal function of the total mass which was measured in our experiments. Additionally, the predictions of LV geometry and end diastolic pressure-volume relation from the mathematical model were compared with our experimental measurements to validate predictions of the mathematical model.