2. Pathophysiology of CVD in Aged Adults
Functional changes in aging adults hearts have been characterized, which include reports of diastolic and systolic dysfunction, and also electrical dysfunction, including the development of arrhythmias [9]. Collectively, both functional and electrical defects result in a high prevalence of heart failure, atrial fibrillation, and other CVDs, in aging patients [9]. The high prevalence of CVD in this population (Figure 1) has been linked to a number of factors, including increased oxidative stress, inflammation, apoptosis and overall myocardial deterioration, and degeneration [1]. An increase in the production of reactive oxygen species (ROS) is known to occur with the onset of advanced age [1,2], and is linked to persistent inflammation and progression to chronic disease status, as in CVD [1]. Increased production of proinflammatory markers is a hallmark of aged hearts, including high levels of interleukin-6 (IL-6), tumor necrosis factor-α (TNFα), and CRP (C-reactive protein) [1]. Production of inflammatory factors and other mediators contribute to cardiac remodeling, including significant extracellular matrix (ECM) remodeling, which is caused by impaired ECM turnover [1,10]. Dysregulation in matrix metalloproteinase (MMP) and tissue inhibitor of metalloproteinase (TIMP) expression levels are frequently linked to increased collagen deposition and the development of cardiac hypertrophy and fibrosis in aged hearts [10]. Fibrosis and hypertrophy are both significant structural changes that lead to eventual cardiac dysfunction in aging patients [11]. Fibrosis, due to impaired ECM turnover, has been shown to develop in the atria of aging patients, which also results in atrial fibrillation in many of these patients [12].
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Oxidative stress, including the production of excess ROS that occurs with cardiac aging, will also lead to mitochondrial dysfunction [9]. Cardiac aerobic metabolism is greatly dependent on mitochondrial production of ATP; thus, the loss of mitochondrial function plays a major role in the development of cardiac dysfunction in aging adults [13]. It has been reported that mitochondrial DNA is particularly susceptible to oxidative damage, since it lacks protective histones, and is in close proximity to ROS production during electron transport [14]. ROS production has also been shown to impair the efficiency of mitochondrial respiration, which also contributes to the cardiac aging process via augmented ROS production [14]. Mitochondrial oxidative stress has also been shown to result in impaired calcium signaling via dysregulation in the type 2 ryanodine receptor (RyR2) [15]. RyR2, a calcium ion channel, is primarily responsible for the release of calcium from the sarcoplasmic reticulum, allowing for muscle contraction [15]. Decreased activity of sarcoplasmic reticulum Ca2+ ATPase pump (SERCA) has also been observed with age [16]. Generation of biologically active lipid mediators may also result in response to age-related inflammation. Mitochondrial dysfunction due to increased ROS has been reported to result in production of lipid oxidation, which has been linked to the development of atherosclerosis [17]. Although impaired lipid metabolism via mitochondrial dysfunction is known to occur with age, however, this process is still not completely understood. One experimental study in mice reported that diets enriched with omega-6 in older aged mice leads to chronic low-grade inflammation and impaired oxidative-redox balance, resulting in electrocardiographic disturbances [18]. Collectively, age-related oxidative stress results in significant cellular and structural changes, and these eventually lead to impaired cardiac functionality and development of CVD.
