**3. Anatomic and physiologic influences on venous and lymphatic return**

When ventricular function is preserved, the critical factor regulating CO is end-diastolic volume, which, through the Frank-Starling mechanism provides a non-neural, non-humorally mediated, regulation of stroke volume. End-diastolic volume is a function of venous and lymphatic return to the heart, which correspondingly, are dependent on circulatory system volume and venous/lymphatic system pressure. The importance of lymphatic return is not widely appreciated in the context of maintenance of circulatory volume, and venous pressure is often considered only in the context of high venous pressure being an indicator of heart failure. However, to fully understand extrinsic heart failure it is necessary to consider the profound influence of upright posture on venous and lymphatic return.

In supine posture, fluid pressures in the arterial system are approximately 100 mmHg, and pressures in the venous system range from 15-20 mmHg in the smallest vessels to approxi‐ mately 5 mmHg at the right atrium. The driving pressure to return venous blood back to the heart is therefore only 10-15 mmHg, or approximately 13-20 cm of water. Nonetheless, in the supine position this pressure is typically adequate to return venous blood from the lowest part of the body (typically the buttocks) back to the heart. In the upright position, however, hydrostatic forces (i.e. gravitational forces operating on the venous fluid column) add signif‐ icantly to arterial, venous, and capillary pressures. At the right atrium, fluid pressure drops to zero. Above the atrium, venous pressures become negative, venous blood readily flows back to the heart and the veins collapse. At the same time, hydrostatic forces serve to reduce arterial pressures by 40mmHg at the top of the head, and if this reduces arterial pressure below 60 mmHg, regulation of cerebral perfusion can be significantly affected [7].

Below the heart, venous pressure increases progressively with distance below the heart such that at the level of the feet venous pressure can exceed 100 mmHg; yet the driving return pressure (i.e. capillary pressure) remains at approximately 20 mmHg. Moreover, blood return to the heart must take place through the highly distensible venous system so that the volume of the venous system has the potential to increase significantly in upright posture. Hydrostatic effects also increase pressures in the arterial system below the heart, though the thick walled structure of arteries prevents significant dilation. However, the increased pressures in the capillaries result in increased extravasation, resulting in significant pooling of interstitial fluid until interstitial fluid pressures increase to match capillary pressures (Figure 2) [8].

tially no effect on interstitial fluid pooling nor on venous and lymphatic return pressures. Further, during locomotion it is well recognized that skeletal muscle pumping serves to drive venous blood back to the heart; however, for most people, for the vast majority of the time they are in upright posture, they are either standing or sitting quietly, not in ambulation. Correspondingly, the essential features of human physiology which permits long-term upright posture are the second heart (soleus muscle) combined with competent venous and lymphatic valves. In upright posture (sitting or standing) venous pressure alone is sufficient to pump blood only one-third of the distance up the lower leg. This blood then collects in the venous sinuses of the soleus muscle. These sinuses are large, thin-walled veins which have the capacity to hold large volumes of blood and the soleus muscle can have up to 18 such sinuses [11]. While the sinuses themselves are valveless, the indirect perforating veins feeding the sinuses are valved, as well as the posterior tibial and peroneal veins into which the soleus sinuses drain. These valves play a crucial role in the effectiveness of the calf muscle pump (CMP), providing an opportunity for the pump to incrementally force venous blood back to the heart. Impor‐ tantly, the soleus is a deep postural muscle, and correspondingly is composed of more than 70% slow-twitch muscle fibers [12]. Moreover, the soleus originates on the posterior tibia and fibula such that when either standing or seated the muscle is able to be active, producing slow, continuous rhythmic, involuntary contractions. During contraction, the soleus can generate venous driving forces exceeding 200 mmHg, more than sufficient to force the blood in the

Cardiomyopathy in Women: Second Heart Failure

http://dx.doi.org/10.5772/55433

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The soleus also plays an essential role in ensuring lymphatic drainage back to the heart. Collecting lymphatics, which appear downstream in the lymphatic system, contain smooth muscle cells in the media and therefore the ability for spontaneous contractions sufficiently large to pump lymph fluid back to the heart (fluid pressures in the collecting lymphatics is relatively low as the fluid column is not continuous) [14]. However, the initial lymphatics, which are the site of interstitial fluid absorption, are non-muscular, and so require an extrinsic force in the surrounding tissue to create a periodic driving pressure gradient. This force can arise from arterial pressure pulsations and arteriolar vasomotion, and muscle contraction. In the lower limbs, the involuntary contractile activity of the soleus, which typically is the sole active muscle in the lower leg during quiet sitting or standing, therefore provides a critical extrinsic periodic compression of these lymphatics, driving the lymph fluid in the initial lymphatics upward toward the collecting lymphatics, relying on endothelial microvalves to

The essential role of non-locomotory based calf muscle pumping (i.e. second heart activity) in maintaining CO when individuals are in quiet upright posture, raises the question of the extent to which second heart activity varies within the population. Recent studies in our laboratory have focused on identifying the extent of second heart insufficiency in adults, with a particular focus on the prevalence of second heart failure in women. The predictive ability of resting heart rate in identifying women at greatest risk of experiencing coronary events suggests that

sinuses back to the heart [13].

ensure unidirectional flow.

**5. Second heart failure in women**

**Figure 2.** Fractional blood volume changes associated with postural shifts in young adult men. *After Hagan, et al., (1978) J. Appl. Physiol. 45:414-417*

The net effect of these various processes is that 500-600 ml of blood pools into the lower limb veins within 2-3 minutes after attaining upright posture, while increased filtration from the capillaries reduces blood fluid volume by an additional 750 ml over the following 30-40 minutes, resulting in well over 1L decrease in effective circulatory system volume. The upright human therefore is confronted with three significant challenges with respect to maintaining adequate CO. First, fluid pooling into the lower limb veins and dependent tissues rapidly reduces effective blood fluid volume. Second, the fluid pressure available to return blood to the heart from the lower extremities remains at little more than 20 mmHg, which is incapable of overcoming the 80 mmHg of hydrostatic pressure created by the venous fluid column. Third, the high compliance of human skin allows these conditions to become exacerbated over the course of the day through interstitial fluid build up. This stress of upright posture is particu‐ larly challenging for women in that they have both more compliant veins [9], and somewhat more compliant skin [10].

#### **4. Soleus muscle anatomy/physiology**

The cardiovascular challenges of upright posture are, in part, overcome by neuro-humorally mediated venoconstriction which limits venous pooling, though vasoconstriction has essen‐ tially no effect on interstitial fluid pooling nor on venous and lymphatic return pressures. Further, during locomotion it is well recognized that skeletal muscle pumping serves to drive venous blood back to the heart; however, for most people, for the vast majority of the time they are in upright posture, they are either standing or sitting quietly, not in ambulation. Correspondingly, the essential features of human physiology which permits long-term upright posture are the second heart (soleus muscle) combined with competent venous and lymphatic valves. In upright posture (sitting or standing) venous pressure alone is sufficient to pump blood only one-third of the distance up the lower leg. This blood then collects in the venous sinuses of the soleus muscle. These sinuses are large, thin-walled veins which have the capacity to hold large volumes of blood and the soleus muscle can have up to 18 such sinuses [11]. While the sinuses themselves are valveless, the indirect perforating veins feeding the sinuses are valved, as well as the posterior tibial and peroneal veins into which the soleus sinuses drain. These valves play a crucial role in the effectiveness of the calf muscle pump (CMP), providing an opportunity for the pump to incrementally force venous blood back to the heart. Impor‐ tantly, the soleus is a deep postural muscle, and correspondingly is composed of more than 70% slow-twitch muscle fibers [12]. Moreover, the soleus originates on the posterior tibia and fibula such that when either standing or seated the muscle is able to be active, producing slow, continuous rhythmic, involuntary contractions. During contraction, the soleus can generate venous driving forces exceeding 200 mmHg, more than sufficient to force the blood in the sinuses back to the heart [13].

The soleus also plays an essential role in ensuring lymphatic drainage back to the heart. Collecting lymphatics, which appear downstream in the lymphatic system, contain smooth muscle cells in the media and therefore the ability for spontaneous contractions sufficiently large to pump lymph fluid back to the heart (fluid pressures in the collecting lymphatics is relatively low as the fluid column is not continuous) [14]. However, the initial lymphatics, which are the site of interstitial fluid absorption, are non-muscular, and so require an extrinsic force in the surrounding tissue to create a periodic driving pressure gradient. This force can arise from arterial pressure pulsations and arteriolar vasomotion, and muscle contraction. In the lower limbs, the involuntary contractile activity of the soleus, which typically is the sole active muscle in the lower leg during quiet sitting or standing, therefore provides a critical extrinsic periodic compression of these lymphatics, driving the lymph fluid in the initial lymphatics upward toward the collecting lymphatics, relying on endothelial microvalves to ensure unidirectional flow.
