Fatigue in Cardiac Disease

One of the most common causes of fatigue in cardiac disease is seen in association with myocardial infarction (MI). An unusual feature of the presentation of fatigue after acute MI is that it is much more common in women than in men. In a study of acute coronary syndromes, fatigue was a presenting complaint in 18% of women and 9% of men. The post-infarct fatigue syndrome was also associated with more severe fatigue when present in women compared with that in men. The causes of this gender difference are not clear. Still, it is important to recognize that fatigue and “tiredness” are atypical symptoms that are more common in women who are having an acute myocardial event, and if unexplained by other causes, they should make the practitioner consider evaluation for cardiac disease in individuals at risk. Possible speculation on mechanisms includes depression and anxiety and effects of hormonal changes, but these have not yet been elucidated.

Chronically, after an acute myocardial event, fatigue is even more commonly seen than that during the acute onset of infarction. The hypothesized causes of this increase in fatigue are multifactorial and are still unknown in many cases. Likewise, fatigue is also more common in individuals with congestive heart failure (CHF) and is often a primary feature of the condition. Interestingly, the symptom of fatigue is often present even without overt cardiac dysfunction or evidence of either systolic or diastolic dysfunction in both patients with post-MI syndromes and in patients with CHF. This has led investigators to try to elucidate the possible causes of CHF-related fatigue but with little clear success. Since the symptoms of fatigue are often vague and can overlap with any other aspects of advanced cardiac disease, there is often a great deal of difficulty in distinguishing between physiologic effects of decreased cardiac output, deconditioning, aging, and underlying mood disorders in specific cases. Highlighting the central role of fatigue in CHF, several studies have defined CHF syndromes based on inclusion of at least 2 of the following: dyspnea, fatigue, orthopnea, paroxysmal nocturnal dyspnea, third heart sound, jugular venous distention, rales, and leg edema. The biological mechanisms of fatigue that may be a part of heart failure include the following possible areas.

A large component of fatigue in cardiac disease can come from depression, which is commonly seen in both CHF and after MI. As a correlation of psychological state and fatigue, for any patient with cardiac disease, the presence of depression greatly increases the likelihood of fatigue. Additionally, the presence of depression increases mortality among all cardiac patients. It has been hypothesized that the mechanism for fatigue in depression and in cardiac disease may actually share several mechanisms. Some of the commonly shared abnormalities between patients with fatigue in cardiac disease (without depression) and patients with pure depression (without cardiac disease) include sympathoadrenal dysregulation, decreased heart rate variability, platelet dysfunction, and negative health behaviors. In addition to these changes, there also may be an attenuation of baroreflex control of heart rate and a contribution from immune system dysfunction. Attenuation of the baroreceptor reflex and loss of heart rate variability are associated with premature death in patients with cardiac disease, highlighting the importance of treatment of the fatigue if at all possible, since this may be a treatable risk factor in cardiac disease. These studies also correlated the autonomic dysfunction seen in the depressed population with an increase in cardiovascular mortality, further strengthening the importance of efforts to improve the autonomic function.

Additionally, hypothalamic-pituitary-adrenal (HPA) axis abnormalities in purely cardiac and purely depressed patients can share similarities in the alterations seen in stress responses. To have a normal stress response, there needs to be a synthesis of corticotropin-releasing hormone (CRH) in the hypothalamus, which then causes an increase in adrenocorticotropic (ACTH) hormone via the hypothalamo-hypophyseal portal system. The ACTH in turn causes an increase in secretion of catecholamines and cortisol from the adrenal glands, which then regulate the HPA axis via a feedback mechanism. Depression and cardiac disease both cause an excess of cortisol secretion and alterations in CRH and ACTH concentrations—in a pattern that mimics stress. This leads to an excess of sympathetic tone, which in turn leads to a reflex increase in heart rate in the “stress mode,” consistent with levels that are observed in untreated CHF and post-MI patients. In tandem with these findings is a decrease in heart rate variability in both depressed patients and in individuals with cardiac disease, which is known to be associated with increased risk of sudden death after MI. Similar findings of alteration in baroreflex responses are also present in patients with cardiac disease and depression, most of whom also have symptoms of fatigue.

Immune system dysfunction is also seen to have a role in fatigue in patients with cardiac disease. There is a role of alteration in cytokines and in the regulation of immune function that happens in both depression and with cardiac disease. Specifically, there is an association of excess of tumor necrosis factor alpha (TNF-α) and interleukin 1-beta (IL-1-β) and the symptoms of fatigue. A similar pattern of increased cytokines is also seen in patients after coronary surgery, after MI, and with heart failure. This alteration of cytokines and increased TNF-α may play a role in post-surgical or post-MI fatigue, which is seen in a great number of patients. The final mechanism that the immune dysregulation may have on the control of fatigue in cardiac patients may be through the effects that dysregulation of immune function can have on the HPA axis with alteration of catecholamines and subsequent increased circulating cortisol. It has been hypothesized that myocardial disease, specifically infarction, can lead to immune activation with the cascade or increased TNF-α and IL-1-β, leading to deregulation of the prefrontal cortex and producing limbic dysfunction with subsequent mood changes (depression) and direct increase in the humoral factors, which can lead to increased fatigue. A side effect of this is also an increase in cardiac events, including arrhythmias and increased MI. Reversal of the fatigue has not been clearly shown to improve the cardiac events but has been associated with an improvement in the humoral markers discussed previously.

Another consideration in the relationship of fatigue and cardiac disease is the role that fatigue has as a risk factor for further cardiac events. In the Copenhagen Heart study, vital exhaustion—a marker of fatigue with associated depressive symptoms—was found to be an independent risk factor for ischemic heart disease. Patients with depression were nearly twice as likely to develop subsequent cardiac events and had an increased overall mortality even for noncardiac events. The increased incidence of events and death was thought to be possibly mediated by the mechanisms mentioned already, including autonomic dysfunction, immune dysregulation, and altered platelet function. The same increase in events was found for patients who underwent percutaneous transluminal coronary angioplasty with an increased incidence in new cardiac events in patients who reported vital exhaustion.

Fatigue in Pulmonary Disease

Just as in patients with cardiac disease, patients with chronic obstructive pulmonary disease (COPD), interstitial lung disease (ILD), and other lung conditions often present with fatigue as a prominent symptom. In patients with COPD, fatigue is second only to breathlessness in incidence as a major symptom, being present in 68% to 80% of patients. Fatigue is also commonly seen in ILD, and assessment for the presence of fatigue is an integral part of the assessment of quality of life in lung disease. Although the exact cause of fatigue in these patients with chronic lung disease is not clearly understood, there are some aspects that overlap with other chronic diseases and some that are unique to lung disease.

The features of fatigue with COPD and ILD that are shared with other chronic diseases include muscle weakness, early fatigue (exhaustion with exercise), muscle wasting, and decreased muscle function. This is seen in the same way as in cardiac disease. There are thought to be several contributing factors to this constellation of fatigue symptoms, including semistarvation (both cardiac and pulmonary cachexia), reduced physical activity, and aging, along with the effects of lung failure. Additionally, patients with chronic lung disease often exist in a chronic catabolic state and have muscle changes that can resemble those seen in patients with anorexia and starvation. Another factor that can further increase this catabolic state is the effects of medications and the effects of immobility imposed by frequent hospitalizations and the limitations on activity from the lung disease itself. Patients with lung disease will often enter a spiral of decreasing weight after a series of hospitalizations with intubations and periods of decreased nutrition, high-dose steroids, and courses of broad-spectrum antibiotics.

Another cause of the fatigue that is so often present in COPD may be related to dyspnea and the effort of breathing. Patients with severe COPD may have no relief from the effort of breathing and develop anxiety and depression, which compound their fatigue. The mechanism of a large component of respiratory fatigue is related to the effort of breathing itself. The work of breathing is increased in COPD, because all aspects of the ventilatory cycle are active, since exhalation no longer is a passive activity due to air trapping. This increase in the work of breathing can increase resting metabolic demand up to twice the normal level. To further complicate this fatigue from increased work, there is a chronic increase in metabolic demand, which, coupled with the altered nutrition seen in patients with severe COPD, can lead to muscle wasting and malnourishment discussed previously. This leads to muscular weakness and increased perception of work, and a deadly downward spiral can ensue.

In addition to the increased metabolic demand, there are also limitations with appetite and changes in the ability to maintain lean body mass. The limitations to maintaining adequate dietary intake are multifactorial. Mechanical difficulty with eating comes from a combination of pressure on the diaphragm from a large meal, decreasing ventilatory reserve, and the increased metabolic demand of digestion, causing the patient to have more dyspnea. Decreased appetite from medications and the effects of glucocorticoids increasing fat percentage with a loss of lean body mass also contribute. The result is a pulmonary cachexia, which cycles with progressively more lean body mass loss into a chronic and potentially lethal spiral. This progressive cachexia and loss of lean body mass also lead to weakness of the muscles of respiration (diaphragm and accessory muscles of ventilation, which are extensively used for patients with COPD), leading to a loss of ventilatory capacity, which in turn leads to increased symptoms of dyspnea and chronic fatigue. Finally, it is hypothesized that there may also be biochemical pathways contributing to this chronic weight loss, but these are not clearly understood at this point.

Another factor in the development of fatigue in COPD is the possible presence of obstructive sleep apnea (OSA) along with lung disease. This is a relatively common concurrence of conditions, and one of the most prominent effects of sleep deprivation from OSA is an increase in fatigue, above and beyond the effects of COPD itself. The most effective intervention for a patient who presents with both conditions is to treat both COPD and OSA simultaneously and aggressively. Nocturnal, noninvasive, bilevel ventilation is a hallmark of this treatment and will help with OSA directly and may provide nocturnal rest for the ventilatory muscles fatigued by the increased effort of ventilation with obstructive lung disease. As evidence of the relationship of the conditions, when appropriately treated, most patients experience a marked improvement in fatigue. An additional interesting finding in individuals with both OSA and COPD is that fatigue is increased in direct proportion to decreased activity and fatigue is not directly related to the severity of OSA.

There is also an elevated incidence of depression in patients with OSA and COPD. This depression may be difficult to tease out from the physiologic effects of apnea. Another common factor with both OSA and COPD is the effects of hypercarbia and hypoxemia on the individual, with both abnormalities causing fatigue.

For patients with ILD, the mechanism of fatigue may be due to depression, muscle wasting, medications, and associated collagen, vascular, or autoimmune diseases, along with the effects of immobility. Medications that are most often associated with fatigue include corticosteroids and chemotherapeutic agents, such as azathioprine (Imuran), cyclophosphamide (Cytoxan), and interferon. Just as in COPD, added to these effects is the extra effort of breathing, possible presence of hypoxemia, and the development of pulmonary hypertension with subsequent right heart failure. The constellation of problems can all be seen in a single patient as the disease progresses, and, in part, this is why aggressive treatment with oxygen may help. However, no matter what treatments are offered, the onset of fatigue is likely. Just as in COPD, the extra work of breathing, combined with weakened musculature, can contribute to the onset of fatigue. Unlike in COPD, the increased work of breathing in ILD is not due to the loss of elasticity and subsequent active exhalation but rather due to the loss of compliance of the lungs. As the disease progresses, the lungs become very stiff and excessive force is needed to ventilate them, leading to smaller tidal volumes with increased inefficiency of breathing.

The effects of autoimmune conditions and collagen vascular diseases on fatigue are due to many mechanisms similar to those discussed in cardiac disease with increased cytokines and subsequent dysregulation of the immune system. High doses of glucocorticoid medications are also often used to treat concomitant collagen vascular disease, and these medications also have a role in causing fatigue. The underlying autoimmune disease can also directly damage muscles, causing direct muscle weakness and associated fatigue. An example of this is connective tissue disease-associated pulmonary fibrosis, which is seen in up to 89% of patients with mixed connective tissue disease, whereas up to 69% of patients have pulmonary function test abnormalities. The histopathology of lung involvement is similar to usual interstitial pneumonitis or nonspecific interstitial pneumonitis in most cases. In some rarer cases, ILD may be due to the treatment for the disease, most commonly when patients receive methotrexate as a part of the treatment of their autoimmune disorder.

Just as in patients with cardiac disease, patients with pulmonary disease can develop fatigue after surgery. Additionally, there is the possibility of fatigue in the setting of lung cancer and after the treatments that are instituted for cancer—surgery, chemotherapy, and radiation therapy. These treatments are all known to contribute to fatigue but will not be discussed in detail here. Other sources are available to review the serious consequences of cancer on lung function and the effects of medications, and interested readers can find the details in specific texts that relate to these disorders. The usual effect is one of ILD and the associated abnormalities discussed earlier.