The skeletal muscle pump is considered one of the most important factors that increase venous return mainly from the lower extremities acting as a “peripheral heart” [19
]. Although in accordance to the classic muscle pump hypothesis, increased venous pressure caused, for example, by a head upright tilt, would produce increased blood flow, different insights about skeletal muscles have been brilliantly elucidated [31
]. Laughlin et al. proved that the peak venous outflow is directly related to the total tension produced during skeletal muscle contraction [32
]. The authors also established the duration of muscle contraction as an important determinant of venous outflow dynamics. Both the amount of venous outflow per contraction and the time course of outflow during contraction are altered by changes in stimulation patterns.
Competent venous valves, that divide the hydrostatic column of blood into segments, assist the muscle pump to avoid gravitational venous reflux [30
]. It happens mainly during walking and dynamic exercise when the rhythmic contraction of the peripheral skeletal muscles increases and causes intramuscular veins to suffer greater compression [20
]. In turn, this compression increases the mean circulatory pressure about three times the normal value and expels large amounts of blood from the venous vasculature toward the heart. Thus, this muscle pump mechanism is one of the main factors that increases the cardiac output at the onset of muscular activity (in conformity to Frank-Starling mechanism), and it is mostly dependent upon muscle mass and pump activity intensity [32
The ability of the skeletal muscle pump to empty the venous vessels has been widely demonstrated in animal and human studies [20
]. The main skeletal muscles responsible for this pump function are the lower limb muscles including those of the feet, calves, and thighs. Among these, the most important is the calf muscle pump due to its large capacitance, and to the highest pressure generated [19
]. Studies have demonstrated that over 60% of the venous volume can be moved centrally with a single calf muscle contraction [19
]. At least two mechanisms are responsible for this circulatory pump role played by lower limb muscle contraction. First, during muscular compression of intramuscular venous vessels, a considerable amount of kinetic energy is transmitted to the venous blood that facilitates its return to the heart (assisted by the venous valves). Second, during muscular contraction, venous pressure is reduced to very low values or even negative values, which generates a greater arterial-venous gradient just after the end of muscle contraction that contributes to the venous flow. As a result, venous return is augmented, and it contributes to most of the increase in cardiac output during exercise [17
Whereas the practice of physical exercise positively associates venous return and cardiac output, the disuse is the main mechanism to a negative relationship. Indeed, in aging underlies the comprehension of the disuse and of the cellular/biochemistry processes involved in muscle atrophy [40
Other causes of skeletal muscle atrophy may include: alcohol associated myopathy, Amyotrophic Lateral Sclerosis (ALS or Lou Gehrig's disease), BurnsGuillainBarré syndrome, injury, long-term corticosteroid therapy, muscular dystrophy, and other diseases with immobilization, like osteoarthritis, polio, rheumatoid arthritis, spinal cord injury and stroke. Among chronic diseases related to skeletal muscle there are: diabetes, uremia, cancer, and congestive heart failure [41
]. A decrease in strength muscle will cause venous blood pooling which favors an increase in the unstressed volume and a decrease the stressed volume.
As a result, the mean circulatory filling pressure will decrease producing a reduction in right atrium filling (Figure 1).
Moreover, as consequence of muscle atrophy and extensive physical deconditioning, the demand of oxygen to the muscle is reduced leading to vascular atrophy [44
]. This compensatory mechanism will increase vascular resistance and contribute to a reduction in venous return [45
]. Thus, in the absence of skeletal muscle venous pumps, these hemodynamic changes promote an abnormal venous return that could compromise stroke volume and cardiac output [47
Indeed, some studies have reported cardiac output to be reduced after periods of inactivity induced by bed rest, spinal cord injury, and spaceflight [46
]. Further, after 2 weeks of bed rest, Levine et al. [53
] found decrease cardiac filling, which promoted a decrease in LV distensibility and impaired cardiac function. Despite some studies not reporting a decrease in cardiac diastolic and systolic function after spinal cord injury [45
], it has been discovered that left ventricle mass index and cardiac dimensions were reduced by prolonged inactivity and short-term spaceflight [45
Unquestionably, muscle atrophy caused by several conditions can impair cardiovascular hemodynamics and promote cardiac alterations.
Some important genetic muscle atrophy disorders, like Becker and Duchenne diseases [54
], show progressive cardiac dysfunction. Both are clinically characterized by progressive muscle weakness, whose implications are [56
] attributed as a cause or a consequence of cardiovascular complications and are thought to, directly or indirectly, affect the cardiac output and, consequently, the venous return. These dystrophies generally develop during the second decade of the patient's life [57
]. Although cardiac dysfunction originates due to specific myocardial loss of dystrophin, extrinsic hemodynamic parameters may impact the development, as well.
In Becker muscular dystrophy patients, there is no correlation between cardiac involvement [61
] and the severity of the cardiomyopathy. Cardiac involvement may manifest as electrocardiographic abnormalities, hypertrophic cardiomyopathy, dilation of the cardiac cavities with preserved systolic function, dilative cardiomyopathy, and cardiac arrest. On the other hand, taking [62
] the organ into account, myocardial damage increases with age through progressive reduction of left ventricular ejection fraction as observed in patients over 20. Patients under 20 years of age do not present altered cardiac parameters such as ventricular dimensions, wall thickness, fractional shortening, and ratio of early (E) to late (A) ventricular filling velocities (E/A ratio); however, these young patients present lower systolic and diastolic intramyocardial velocity gradients, indicating the possible myocardial disease [63
Ducceschi et al. [64
] showed that in patients with Becker muscular dystrophy there is a tendency towards a straight relationship between the entity of cardiac sympathetic activity and the degree of left ventricular systolic dysfunction. The authors reported evolution of systolic impairment appearing somehow to be associated with the development of autonomic imbalance, a condition that contributes to increase ventricular propensity to arrhythmias. Further investigations, nonetheless, demonstrate no autonomic nervous system involvement as a key finding in Becker muscular dystrophy [65
Lee et al. [60
] demonstrated a reduction in left ventricle mass, combined with a decrease in stroke volume and no alterations in cardiac output in patients with Duchenne muscular dystrophy. To maintain the cardiac output, their hearts are forced to increase beating frequency to compensate reductions in left ventricle size. Consequently, the cardiac muscle encounters two major threats, i.e. mass reduction and overwork, that could evoke chronic cardiac fatigue and alter cardiovascular hemodynamics. Further, independent from additional genetic alterations in cardiac tissue, the widespread dystrophic damage of skeletal muscle concurrent with postural adaptation may also result in hemodynamic adaptation, which has been established as a risk factor for the development of cardiomyopathy [66
]. Therefore, progressive skeletal muscle degeneration and weakness most likely contributes to progressive cardiac dysfunction.
Interestingly, animal studies with knockout mice have already demonstrated a potential causal link between skeletal muscle disease and cardiomyopathy. Normally, the mdx mice, a mouse model of Duchenne muscular dystrophy, do not show characteristic dystrophic cardiomyopathy until they reach 21 or more months of age [68
]. Nevertheless, the mdx:MyoD-/- mice lacking dystrophin and the skeletal muscle-specific bHLH transcription factor MyoD display pronounced myopathic phenotype caused by marked reduction in skeletal muscle regeneration due to impaired satellite cells activity [70
]. Using this mice model, Megeney et al. [70
] observed that accelerated skeletal muscle deterioration caused cardiac dilation and myocardial fibrosis in the 5-month-old mdx:MyoD-/- mice heart. As MyoD is not expressed in the heart and plays no role in heart development, any myocardial changes evident in mdx: MyoD2y2 mice would be directly attributable to the level of skeletal muscle damage. Hence, the author suggested the progression of skeletal muscle damage as a significant contributing factor leading to the development of cardiomyopathy.
Since in Becker and Duchenne muscular dystrophy cardiac impairment is not directly correlated with the severity of skeletal muscle involvement [71
], the venous return is not directly a subject, but it is indirectly involved in cardiac manifestations. Cardiac involvement has been confirmed in cases preceding the onset of skeletal muscle manifestation and in cases of wheelchair-bound patients who did not develop cardiac dysfunctions.