Cardiac fibrosis in the elderly, normotensive athlete: case report and review of the literature

Changes associated with aging are difficult to separate from those due to diseases prevalent in the elderly, most notably hypertension. Histological changes seen in the non hypertensive aging heart include increased myocyte necrosis and apoptosis [4] and an altered deposition of types I and III collagen [1]. An autopsy study of 230 noncardiac patients demonstrated increased fibrosis and fat within the cardiac conduction system of elderly patients [2]. An age-related increase in right atrial fibrosis and decrease in nerve plexus population has also been demonstrated [3]. Burns [5] reported increased cardiac fibrosis, significantly more prominent in the posterior left ventricle, with aging. Klima [5] reported increased interstitial fibrosis related to aging that was independent of other cardiac diseases. A comparison of endomyocardial biopsies from elderly and young patients found increased cell diameter and nuclear area (a sign of increased protein production) and an increased deposition of lipid and lipofuscin with age [6].

While hypertensive patients show increased deposition of collagen, nonhypertensive aging patients develop increased interstitial collage levels due to decreased degradation [7, 8]. Antihypertensive therapy prevents left ventricular fibrosis, which is secondary to pressure overload, but is ineffective in preventing right ventricular fibrosis [9], supporting the concept of disease-independent cardiac fibrosis in elderly patients.

Hypertensive cardiac fibrosis is related to the direct effects of pressure overload and to circulating hormones. Perivascular fibrosis and cardiac fibroblast activation correlate with increased activity of the renin-angiotensin-aldosterone system (RAAS) and elevated serum mineralocorticoids; this fibrosis is preventable with angiotensin-converting enzyme (ACE) inhibitors or spironolactone [10, 11]. In heart failure, elevations in aldosterone and angiotensin II result from ischemia of the kidney and adrenal gland, as well as increased salt intake. Weber [12] reported local production of angiotensin II within the myocardium, suggesting a role for intrinsic myocardial activation of ACE secondary to ischemia.

The molecular activity of angiotensin II and adrenergic stimulation involve the extracellular-signal-related kinases (ERK1/2), p38 and Jun N-terminal kinase (JNK) [13, 14], leading to fibroblast activation. Inflammation is also involved in hypertensive collagen deposition; Nicoletti [14] emphasized the role of inflammation in the development of cardiac fibrosis. Angiotensin II activates monocytes [15]. Infiltration of inflammatory cells has been documented in animal models of the hypertensive heart [14, 16, 17]. The inflammatory infiltrate is initially perivascular and later spreads interstitially, following the same pattern as that of collagen deposition [16]. Myocardial remodeling in the development of congestive heart failure has also been attributed to reactive oxygen species (ROS) production by the mitochondrial, xanthine oxidase, nitric oxide synthetase and NADPH oxidase pathways [18, 19].

Myocardial fibrosis that occurs with normal aging should not be dependent upon the RAAS or inflammatory mediators, as neither of these systems are activated in the healthy elderly patient. Even in the absence of overt hypertension, arterial vascular walls loose compliance with age, resulting in some degree of pressure overload with normal aging. Whether this age-related pressure overload is severe enough to cause cardiac ischemia and fibrosis is unknown. Aging rats show increased left ventricular weight, extracellular collagen and collagen cross-linking, and decreased mRNA collagen expression [20]. This supports the theory that an age-related increase in cardiac fibrosis is not secondary to increased production, but instead is due to decreased destruction of existing collagen.

It is well documented that athletes frequently develop left ventricular hypertrophy [21], but this is not thought to be associated with fibrosis, as it regresses upon cessation of physical activity [22]. Lindsay and Dunn [23] questioned the validity of the common theory that exercise-induced hypertrophy is entirely physiological, based on the fact that veteran athletes often do not experience complete resolution of ventricular hypertrophy [24, 25], suggesting a mechanism other than pure myocyte hypertrophy. Athletes are prone to the development of EKG abnormalities [25]. Following endurance exercises, athletes have elevations in serum markers of myocyte damage and reduction in diastolic and systolic function [26], although these changes return to baseline within 24 hours. In the evaluation of 45 veteran endurance athletes [23], echocardiographic evidence of left ventricular hypertrophy and elevations in serum markers of collagen synthesis, degradation and inhibition of degradation were documented, suggesting the presence of cardiac fibrosis related to long-term athletic activity. Whyte et al. [27] reported the case of a 57 year old athlete who died suddenly while running a marathon. Autopsy revealed biventricular fibrosis, left ventricular hypertrophy and reduction of left ventricular chamber volume.