QJM Advance Access originally published online on February 16, 2008
QJM 2008 101(4):251-259; doi:10.1093/qjmed/hcm131
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Why traumatic leg amputees are at increased risk for cardiovascular diseases
From the 1Department of Internal Medicine A and 2Department of Rehabilitation, The Flieman Hospital and Rappaport Family Faculty of Medicine, Technion-Israel Institute of Technology, Haifa, Israel
Address correspondence to J.E. Naschitz, MD, Department of Internal Medicine A, Flieman Hospital, Haifa 31021, Ramot Remez, Zalman Shneur Street, P.O. Box 2263, Israel. email: naschitz{at}tx.technion.ac.il
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Summary |
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Background: Post-traumatic lower limb amputees have an increased morbidity and mortality from cardiovascular disease. Risk factors for this amplified morbidity and the involved pathophysiologic mechanisms have not been comprehensively studied.
Methods: The MEDLINE database was reviewed, with case–controlled studies and nested in cohort studies eligible for inclusion in this analysis.
Results: Insulin resistance, psychological stress and patients’ deviant behaviors are prevalent in traumatic lower limb amputees. Each of these factors may have systemic consequences on the arterial system and may contribute to the increased cardiovascular morbidity in traumatic amputees. Abnormalities of arterial flow proximal to the amputation site may hold the explanation for the linkage between the extent of leg amputation and the magnitude of the cardiovascular risk: proximal leg amputation is associated with greater risk than distal amputation and bilateral amputation with greater risk than unilateral amputation. This review focuses on hemodynamic culprits (shear stress, circumferential strain, reflected waves), hemodynamic consequences in proximity to the occluded femoral artery and hemodynamic consequences at a distance.
Conclusions: Coronary risk in lower limb amputees may be substantially greater than predicted by available algorithms, given that neither hemodynamic nor psychological factors concern the current prediction models. It seems reasonable to take early prophylactic measures in lower limb amputees by discouraging smoking, excessive alcohol consumption and adherence to a low fat diet. Studies are needed to evaluate the optimal intensity of physical exercise effects on reflected pulse waves and their possible long-term consequences. Guidelines for optimal blood pressure, blood glucose and lipid control in amputees need to be convened.
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Introduction |
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Post-traumatic lower limb amputees are subject to increased morbidity and mortality from cardiovascular disease, discussed in the literature over the past four decades.1–11 However, risk factors for this amplified morbidity and the involved pathophysiologic mechanisms have not been comprehensively studied.
The story begins when the Veterans Administration was charged with determining whether amputation was a causal factor in cardiovascular diseases with Congress passing the Veterans Disability, Compensation and Survivor Benefits Act of 1976. Two studies were mandated: a review of the medical literature and an epidemiologic survey of veterans who had amputations as a result of injuries. The literature review of cardiovascular disorders after post-traumatic amputation of the lower limb comprised studies from the United States, England, Germany and Finland.1–5 Only one study revealed an increased cardiovascular morbidity after amputation; none of these studies entailed comparison with appropriate controls.5
The epidemiological study ordered by the Congress was conducted by Hrubec and Ryder6 who determined the mortality rates among three groups of US male soldiers wounded during World War II: 3887 were proximal limb amputees (above knee or elbow), 3890 were injured with disfigurement but without amputation, and 2917 were distal limb amputees (loss of only part of the hand or foot). Their follow-up period extended to 1977. The relative risk for death by cardiac causes was 1.58 times as great in unilateral above-knee amputees and 3.5 times as great in bilateral above-knee amputees in comparison with disfigured veterans. This is the largest controlled study ever done on the impact of amputation on life expectancy. Subsequent controlled studies attested that traumatic above-knee amputation was associated with an increased cardiovascular morbidity or mortality on the long term. In a survey of a mixed group of 101 war veterans with unilateral above- or below-knee amputation who were re-examined an average 24 years later, the relative risk to die by cardiac causes was 2.2 vs. healthy controls.8 In another study of 26 war veterans examined an average 22 years after unilateral above-knee amputation, the relative risk to have overt ischemic heart disease was 3.3 vs. healthy subjects.7 Finally, among 329 war veterans examined an average 43 years after unilateral above-knee amputation, the relative risk of having an abdominal aortic aneurysms was 5.1 greater than among war veterans without amputation (Table 1).9
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The present review summarizes current understanding of risk factors and pathogenic mechanisms responsible for increased cardiovascular morbidity ensuing proximal limb amputation and potential applications in clinical research and patient care. Eligible were case–controlled studies and nested in cohort studies. We searched the MEDLINE and reference lists of obtained articles. We used terms related to traumatic leg amputees in combination with any of the following terms: myocardial infarction, myocardial ischemia, coronary heart disease, atherosclerosis, arterial hypertension, stroke, cerebrovascular disease, aortic aneurysm, energy expenditure, social conditions, post-traumatic stress disorder, psychosocial, drug abuse and depression.
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Pathophysiology |
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The causes for an excess in cardiovascular morbidity and mortality among traumatic lower limb amputees are not well understood. Systemic influences and regional hemodynamic effects may be involved in this process, though neither has been comprehensively investigated.7–14 Insulin resistance, psychological stress and patients’ deviant behaviors are factors with systemic consequences, purportedly involved in the increased cardiovascular morbidity in traumatic amputees. Abnormalities of arterial flow proximal to the amputation site may provide the explanation for the linkage between the extent of leg amputation and the magnitude of the cardiovascular risk (Figure 1).
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Systemic influences |
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A pathogenic role for insulin resistance in the excess cardiovascular morbidity among traumatic lower limb amputees was suggested by Rose et al.12 In their study of 19 bilateral above-knee amputees from the Vietnam war in comparison with 12 age-matched unilateral below-elbow amputees, Rose observed significantly more hypertension and obesity in above-knee amputees. Insulin responses to orally administered glucose were markedly increased (260 ± 60 µU/ml) in above-knee amputees compared with below-elbow amputees (101 ± 20 µU/ml), and the mean body fat content was elevated in above-knee amputees (37.2%) vs. below-elbow amputees (22.6%). Both insulin response and body fat content independently correlated with diastolic blood pressure (r = 0.55, P < 0.01, and r = 0.62, P < 0.01, respectively). The authors concluded that insulin may be a major factor in blood pressure regulation in maturity-onset obesity that develops following traumatic leg amputation in previously young, healthy men. Peles et al.14 looked at the plasma insulin response to oral glucose load and at the autonomic nervous activity in traumatic lower limb amputees (n = 52), aged 50–65 years, and healthy controls (n = 53). The subjects in both groups had similar body mass index, blood pressure and plasma lipid levels. Amputees were found to have higher fasting plasma insulin levels (18.4 mU/l ± 9.7 vs. controls 13.7 ± 5.1 mU/l, P = 0.005) and higher insulin response to oral glucose (1 h levels of 88.1 mU/l ± 45.3 vs. controls 62.1 mU/l ± 42.7, P = 0.016) with similar plasma glucose levels, indicating insulin resistance. Modan et al.8 studied possible risk factors involved in the excess cardiovascular morbidity in 101 traumatic leg amputees. Their work attested that insulin levels were increased in amputees compared with healthy controls. After adjustment for potential covariates (age, smoking, physical activity, body mass index, mean arterial blood pressure and cholesterol), insulin levels remained significantly higher in amputees.
Amputees also manifested higher blood coagulability indices compared to matched healthy subjects8: higher fibrinopeptide A levels (28.2 ± 35.8 in amputees vs. 16.2 ± 18.3 ng/ml in healthy controls, P = 0.0003), higher factor VII level (89.1 ± 28.6 U/dl vs. 81.3 ± 28.6 U/dl, P = 0.05) and lower antithrombin III (91.2 ± 10.5 U/dl vs. 93.3 ± 8.6 U/dl, P = 0.03).
Autonomic nervous functioning was assessed during an oral glucose tolerance test in amputees vs. healthy subjects.14 Amputees had larger increments in low-frequency power of heart rate variability with concomitant increase in plasma norepinephrine levels. The authors advanced the hypothesis that sustained psychic stress in amputees may be responsible for increased sympathetic nervous activity, increased blood coagulability and enhanced shear stress forces, which cause, conjointly, endothelial injury, atheroma formation and thrombosis.8
Involvement of psychosocial factors in the excess cardiovascular morbidity in traumatic lower limb amputees has been repeatedly suggested but remains unproven.6,8 In a variety of different settings, psychosocial factors were shown to be involved in the pathogenesis of coronary heart disease.15 The INTERHEART study16 strongly supports the role of psychological factors in the pathogenesis of coronary heart disease.
Post-traumatic stress disorder may be associated with increased cardiovascular morbidity and mortality.17,18 The role of depression in coronary heart disease events has been disputed among cardiologists and behavioral medicine specialists. The bulk of data supports the role of depression as a coronary risk factor.19 Progression of carotid atherosclerosis was accelerated in patients with high cynical distrust and high anger-control.20 Attention is turning increasingly to the investigation of possible effects of psychosocial factors on biological precursors of coronary artery disease.21 Inflammation may be a pathway linking psychosocial factors to ischemic heart disease21: higher levels of cynical distrust were associated with higher levels of inflammatory markers; higher levels of chronic stress were associated with higher concentrations of IL-6 and C-reactive protein; depression was positively associated with IL-6 levels. Results are compatible with a mediating role of obesity, behaviors and diabetes, i.e. psychosocial factors determining health behaviors (smoking, physical inactivity and alcohol intake) predictive of inflammation.
Furthermore, psychosocial factors are associated with obesity and insulin resistance, which are established correlates of systemic inflammation.22 Psychosocial factors may also be associated with proinflammatory changes in the autonomic nervous system and the hypothalamic–pituitary–adrenal axis. Cytokines and glucocorticoid hormones mediate the acute-phase response and experimental evidence suggests that, like cortisol, inflammatory markers respond to acute psychological stressors.23
The time-honored list of coronary risk factors does not include psychogenic risk factors, neither under the heading ‘traditional’ nor under ‘emerging’ risk factors.24,25 Yet, prospective studies consistently indicate that hostility, depression and anxiety bear an increased risk of coronary heart disease and cardiovascular death. Their role in the pathogenesis of atherothrombosis after limb amputation is reasonably probable, but remains to be purposely investigated in this particular patient population.
There is substantial epidemiological evidence to the effect that army veterans who suffered from post-traumatic stress disorder during their military service are at increased risk of cardiovascular morbidity, compared to those who did not.17–18 Unrelatedly, as noted above, army veterans with post-traumatic above-knee amputation are at increased risk of cardiovascular morbidity and mortality.6–9 There are no studies comparing cardiovascular morbidity in cohorts of veterans in general, veterans suffering from service related post-traumatic stress disorders, vs. amputee veterans with post-traumatic stress disorders. Psychological stress on its own appears inadequate to clarify why veterans with amputation have higher cardiovascular events rates than disfigured veterans. Thus psychological factors alone may not be the mechanism responsible for the increased rate of cardiovascular events in army veterans with post-traumatic above-knee amputation.
Social deprivation and environmental barriers are constant challenges for traumatic limb amputees and may promote lifestyle-mediated cardiovascular disease risk factors such as obesity, levels of physical activity and smoking.26–28 Indeed, studies have consistently shown that individuals living in deprived neighborhoods are at an increased risk for being smokers, obese and not engaging in physical activity.26,27 Amputees also encounter environmental barriers. In a study of 914 community-dwelling persons with limb loss, 87% of persons experienced barriers in one or more areas with 57% reporting barriers in four or more of the five categories: policies, physical/structural, work/school, attitudes/support and services/assistance subscales.28 It has been suggested that interventions focusing on contextual aspects of neighborhoods, in addition to changing individual behaviors, may have a greater impact on cardiovascular diseases than the sole focus on individuals.27
Alcohol consumption and substance abuse are quite common among patients with post-traumatic stress disorder as well as among amputees29,30 and thus lessons learned from the effects of these agents on cardiac health may bear on the increased morbidity and mortality of amputees. Alcohol abuse is associated with cardiomyopathy, hypertension and arrhythmia.31 Most reviews on the relation between alcohol and cardiovascular disease have examined the quantities imbibed per week or month but have not critically evaluated the pattern of drinking. These studies have consistently shown that moderate alcohol consumption has a cardioprotective effect. On the other hand, an increased risk of cardiovascular death has been observed among heavy binge drinkers to the extent that the association between binge drinking and cardiovascular death meets criteria for causality.32
The documented occurrence of myocardial infarction after cocaine use appears unrelated to the amount ingested.33 The mechanisms suggested for this cocaine-related myocardial ischemia or infarction may relate to increased myocardial oxygen demand in the setting of a limited or fixed oxygen supply; marked coronary arterial vasoconstriction; and enhanced platelet aggregation and thrombus formation. Amphetamines have many of the cardiovascular toxicities seen with cocaine, including acute and chronic cardiovascular diseases. Heroin and other opiates can cause arrhythmias and noncardiac pulmonary edema: they may reduce cardiac output.31 Though cardiovascular problems are less common with cannabis (marijuana) than with opiates, major cognitive disorders may be seen with its chronic use exacerbating other factors operating to increase cardiac mortality among amputees. It is still controversial whether caffeine can cause hypertension and coronary artery disease, and questions have been raised about its safety in patients with heart failure and arrhythmia.31
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Hemodynamic factors operating proximal to the amputation |
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Proximal leg amputation is associated with greater risk to develop cardiovascular diseases than distal amputation, and bilateral amputation with greater risk than unilateral amputation. Hemodynamic abnormalities, resulting from perturbed arterial flow proximal to the amputation site, are assumed to explain this incremental risk related to the site and extent of leg amputation. Few studies have addressed this issue specifically. In the following section, we focus on possible hemodynamic culprits (shear stress, circumferential strain, reflected waves), hemodynamic consequences in proximity (next to the occluded femoral artery—atherosclerosis, arterial remodeling, infrarenal aortic aneurysm), and hemodynamic consequences at a distance (systolic hypertension, left ventricular hypertrophy and accelerated ischemic heart disease) (Table 2).
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Shear stress and cyclic circumferential strain are the predominant forces that have been characterized in relation to vascular structural dynamics. Growing experimental evidence indicates that low antegrade or oscillatory shear conditions promote proliferative, thrombotic, adhesive and inflammation-mediated degenerative conditions throughout the vascular system.34 In vitro systems can re-create shear stress and cyclic circumferential strain and apply them directly on cultured vascular endothelial cells. Cultured endothelial cells subjected to shear forces undergo cytoskeletal reorganization, reorganization of their F-actin filament, alignment in the direction of the shear flow and cellular proliferation. Shear stress also affects the synthesis and secretion of macromolecules. Prostacyclin, a potent vasodilator and platelet antiaggregant, is produced at a greater rate within human endothelial cells subjected to pulsatile shear stress vs. static control cell cultures. The rate of secretion of tissue-type plasminogen activator is greater in endothelial cells subjected to shear. A potassium selective ionic current has been identified in vascular endothelial cells stimulated by shear stress and represents one of the earliest couplings of hemodynamic stimulus with the endothelial cell response. Extrapolating from these data, there may be implications for the increased atherogenicity of a low-shear environment.34
Cyclic circumferential strain refers to the repetitive, pulsatile, pressure distention on a vessel wall. In an experimental setting, cultured endothelial cells exposed to cyclic tensional deformation and relaxation, increase synthesis of DNA and increase their rate of proliferation.35
Reflections pulse waves: reflections occur at aortic bifurcations, small arteries, sites arising from spatially varying geometries and material properties, as well as sites with increased vascular stiffness.36 Extra-reflection waves are produced at arterial occlusion sites.36–38 Early return of reflected waves occurs in a variety of disorders, including femoral arterial occlusion (similar to the amputated limb). An early returned reflection wave generates a second-systolic peak, causing a substantial increase in aortic systolic pressure. In turn, increased aortic systolic pressure is associated with increased left ventricular afterload, causing left ventricular hypertrophy, coronary atherothrombosis and increased cardiovascular mortality.38
Pythoud's experiment in dogs demonstrated that intermittent occlusion of the aorta causes early wave reflections resulting in a second systolic pressure peak: the pressure in the ascending aorta is the sum of the incident and reflected waves.36 In human, the influence of arterial wave reflection was studied by external compression of femoral arteries.37,38 This acute experiment may reproduce hemodynamic conditions similar to those which occur after proximal limb amputation. Two groups of patients presenting a variety of heart diseases were studied: group I aged age <30 years and group II aged >40 years. While both femoral arteries were compressed, the reflected wave returned in early diastole in group I but in late systole in group II. The time constant of the left ventricular pressure decay was shortened during femoral artery compression in group 1, whereas it was prolonged in group II. Early return of wave reflection generated a late systolic peak, with a substantial increase in aortic systolic pressure. Reflection waves and their impact on the blood pressure in the ascending aorta can be assessed by noninvasive techniques, i.e. diagnostic applanation tonometry. Measurement of central blood pressure assessment and wave reflections may give new perspectives for the stratification of cardiovascular risk39 and could also be important for the understanding of the contribution of hemodynamic forces in the pathogenesis of atherothrombosis in lower limb amputees.
Localization of atherosclerosis has a nonrandom distribution.40 The coronary arteries, the major branches of the aortic arch, and the abdominal aorta and its visceral and major lower extremity branches are particularly susceptible sites. The modification of endothelial cell structure and function by shear stress and circumferential strain, are thought to be responsible for the nonrandom distribution of atherosclerosis.34
Arterial remodeling has been studied in animal experiments. A femoral artery cuff41 as well as unilateral ligation of the carotid artery in the mouse are two accepted models for the study of vascular remodeling.42 In response to partial ligation of the left carotid artery, the blood flow decreased by 90% in the left carotid and increased by 70% in the right carotid artery. Morphometry showed that both carotid arteries underwent outward remodeling. Remodeling was greater in the right carotid artery with predominantly increased lumen and very little increase in media or adventitia. In the left carotid artery there was a dramatic increase in media with adventitia growth and intima formation. Involved in this process were macrophage infiltration, upregulation of matrix metalloproteinase-9, reorganization of extracellular matrix and proliferation of vascular smooth muscle cells.42 Intima-media thickening in response to hemodynamic stress is a physiological process that requires coordinated signaling among endothelial, inflammatory and vascular smooth muscle cells. There were significant strain-dependent differences that suggest fundamental alterations in sensing or transducing hemodynamic signals among strains.43 A recent study demonstrated that Axl, a receptor tyrosine kinase that regulates cell migration, phagocytosis and apoptosis, has an important role in the flow-dependent remodeling of arteries by regulating vascular apoptosis and vascular inflammation.44 In a femoral artery cuff model in the atherosclerotic ApoE3 (Leiden) transgenic mouse, Tlr4 activation by LPS stimulated plaque formation and subsequent outward arterial remodeling. In Tlr4-deficient mice, however, no outward arterial remodeling was observed independent of neointima formation. These findings provide genetic evidence that Tlr4 is involved in outward arterial remodeling, probably through upregulation of Tlr4 and Tlr4 ligands.38 Intraaortic elastase infusion in mice and rats consistently produces abdominal aortic aneurysms. This animal model permits study of the effect of unilateral iliac artery ligation on aneurysm formation. Unilateral common iliac artery ligation in rodents decreased the aortic wall shear stress in proportion to diminished aortic flow, without affecting the blood pressure. Seven days later, larger abdominal aortic aneurysms resulted following ligation than after elastase infusion alone.45 Data obtained from these rodents models, as well as computational human aortic models and MR-derived in vivo human aortic flow data46 support the contention that increased abdominal aortic risk in amputees may be due to asymmetric infrarenal aortic blood flow and associated low antegrade or oscillatory shear conditions in the infrarenal aorta. The rodent data also suggests that elevated antegrade shear stress present during sustained high flow conditions (following arterial-venous fistula AVF creation in these experiments, or increased lower extremity activity in human subjects) may limit aneurysmal progression.46
The higher the level of amputation, the greater the hemodynamic changes observed.9 The blood flow in the terminal aorta is reduced by nearly a quarter, because of flow diversion in the renal and visceral arteries, while the blood flow in the suprarenal aorta remains constant after leg amputation.47 Unilateral flow reduction or interruption causes an asymmetric flow pattern at the aortic bifurcation. The changed hemodynamics with higher shear stress zones at the aortic convexity and low shear stress along the concavity are supposed to be the main cause for late damage to the aorto-iliac vessels.47 In the study of Vollmer et al., post-traumatic above-knee amputees were five times more likely to develop abdominal aortic aneurysms more than 40 years following injury than nonamputee subjects. Aneurysm morphology in the amputee patients was strongly influenced by amputation site.9 This data was not corroborated by another study, the frequency of abdominal aortic aneurysms being similar in traumatic above-knee amputees and nonamputees.10 A cross-sectional study assessed the diameters and flow indices in central and peripheral arteries in high-performance athletes, below-knee amputated athletes and untrained subjects. No significant differences were observed in the diameters of the abdominal aorta and in aortic flow between the groups.48 The inner femoral artery diameter was increased in able-bodied road cyclist athletes vs. controls. Similar increased diameters of the femoral artery were found in the intact limb of below-knee amputated athletes. The diameters of the femoral artery were lower in athletes with paraplegia and in below-knee amputated athletes proximal to the lesion. These data suggest that the size and blood flow volume of the proximal limb arteries are adjusted to the metabolic needs of the corresponding extremity musculature and underscore the impact of exercise training or disuse on the structure and the function of the arterial system.48
Aortic stiffness in traumatic above-knee amputees is enhanced not only in response to changes in local hemodynamics but may also be affected by insulin resistance. The metabolic syndrome, shown to be prevalent in traumatic leg amputees, adversely affects the large arteries resulting in increased arterial stiffness independently of other cardiovascular risk factors.34,40,42,43 High systolic and pulse pressures increase circumferential arterial wall stress, which likely causes breakdown of medial elastin, increases endothelial damage and favors development of atherosclerosis.49 In this vicious circle of pathophysiological events, arterial stiffness becomes an independent risk factor for cardiovascular morbidity and mortality.50–53
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Cardiovascular risk estimate in traumatic leg amputees |
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Currently, two algorithms for assessing cardiovascular risk are recommended in the National Cholesterol Education Program Adult Treatment Pannel III Guidelines.54 The first algorithm involves counting major risk factors based on an equation derived from the Framingham Heart Study. The second algorithm identifies the metabolic syndrome. These predictive models have a lower than desired accuracy in predicting coronary heart disease risk in an individual patient.24,25,55 The report from the Atherosclerosis Risk in Communities (ARIC) Study documents that the established major cardiovascular risk factors account for no more than 50% of cardiovascular events; and many people who experience cardiovascular events have no risk factors. Several novel risk markers were found to be associated with coronary heart disease risk, but few proved useful in improving the risk prediction model.24 We submit that the coronary risk in lower limb amputees may be substantially greater than predicted by available algorithms, given that neither hemodynamic nor psychological factors concern the current prediction models.
It seems reasonable to take early prophylactic measures in amputees6,8,9 so as to reduce their inherently elevated cardiac risk, by discouraging smoking, avoidance of excessive alcohol consumption, and adherence to a low fat diet. In a large prospective survey involving about 22 000 adults from Greece (the Greek cohort of the EPIC study), an inverse correlation between a greater adherence to a Mediterranean-style diet and reduction in coronary heart disease mortality was shown.56 Psychosocial stress is also a highly modifiable risk factor18–20 in this context, though it is disputed whether use of psychotropic medications may prevent coronary events.57 Optimal treatment of high blood pressure and its complications in this population should consider arterial stiffness, central aortic pressure and left ventricular wasted energy—all of which should be reduced to the lowest possible level. To this aim, preference should be given to vasodilator drugs that affect peripheral muscular arteries, reduce wave reflection amplitude and markedly lower systolic and pulse pressures as well as ventricular afterload.58
As the energy cost of ambulation is greater for amputees than for nonamputees, and ascending level of amputation appears to be associated with increasing metabolic demand, appropriate exercise may be essential for improved walking ability of these patients. To generate a safe and effective aerobic training program, exercise testing of amputees is recommended.59
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Future studies |
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An improved assessment of coronary risk in traumatic leg amputees, so as to guide prophylactic and therapeutic measures, is required. This aim may be advanced via large-scale studies where potential risk factors are linked to cardiovascular events. In addition to traditional and novel risk factors, assessment of psychological stress and psychological morbidity, as well as parameters of arterial stiffness might be profitable. Studies are needed to evaluate the optimal intensity of physical exercise on reflected pulse waves and their possible long-term consequences. Guidelines for optimal blood pressure, blood glucose and lipid control in amputees need to be convened.
Conflict of interest: None declared.
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References |
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