19.1 Arteriovenous Fistula

A typical adaptive response to the opening of a “mature” (3 weeks post-procedure) femoral AV fistula in a dog is marked by a 5% drop in mean arterial pressure (MAP) and an increase in SV (18%), HR (24%), and CO (37%) [1]. There is a partial transfer of the circulating blood volume from arterial to venous side of the circulation with increase in CVP. Similar changes occur in dogs lacking spinal and autonomic innervation [2]. Creation of a more proximal fistula, i.e., by placement of a 10 mm diameter graft between infra-renal aorta and vena cava in dogs results in an immediate doubling of HR (97–173 beats/min) and CO (250%) and concomitant increase in SV and EDV [3]. Ventricular (load-independent) contractility index (E_max) was maintained in the immediate period of fistula opening but became significantly depressed during a week-long experiment. In spite of the compensatory hypertrophy (an average increase in heart mass of 10%), the animals experienced signs of severe congestive heart failure (ascites, limb edema, high LVEDP, and pulmonary edema) [3]. Fujisawa et al., on the other hand, noted an immediate increase in contractility (E_max) in dogs after opening of a large aorto-caval fistula [4].

When the initially large fistula flows are “within the limits” of cardiovascular compensation, a chronic condition ensues, characterized by a gradual return of HR and MAP to control levels, with concomitant increase in heart mass (hypertrophy) and expansion in extracellular fluid and blood volumes, resulting in progressive hemodilution. Huang and coworkers showed that in rats with large fistula flows (equaling about 50–77% of baseline CO), there was a progressive increase in CO over a 5 week period, reaching values over three times of control; however, when adjusted for increase in weight (due to increased blood volume), the cardiac index (CI) was the same as in the control group. The mean arterial pressure and systemic flow (determined by subtracting fistula flow from CO) initially decreased but gradually returned to normal. The persistence of near normal HR in the face of greatly increased CO indicated a large increase in SV [5]. This observation has been confirmed by several other reports in which increases in SV of up to 80–90% were observed in acute and chronic AV fistulas. With time, the circulation through the fistula continues to increase with further expansion of arterial and venous collaterals, leading to a vicious cycle of escalating cardiac outputs and CHF [6, 7]. In terms of cardiac biochemical and energetic changes, Gibbs and coworkers found only a small increment (13%) in basal metabolic activity and no change in mechanical efficiency in the hearts of rabbits subjected to chronic volume overload (12 weeks of aorto-caval fistula flows). This was in contrast to chronic pressure overload studies in which partial obstruction of the aorta resulted in a marked depression of myocardial metabolic activity, leading the authors to conclude that, “It seems clear from both our pressure- and volume-overload studies that in vivo cardiac failure can occur regardless of whether many of the intrinsic contractile and biochemical processes of cardiac cells are relatively unimpaired” [8].

Conventional explanation of circulatory effects caused by AV fistulae is invariably based on the concept of a drop in peripheral resistance. For example, Guyton and Sagawa initially maintained that LV hypertrophy is a response to increased workload on account of increased venous return and filling pressures [2], whereas in a later study by Guyton’s group the authors submitted that the cause of LV hypertrophy is not completely understood. However, the fact that blood flow to individual organs is eventually normalized, in the face of decreased peripheral resistance, suggests that flows are dictated by the metabolic demands of the tissues [5].

In addition to the systemic effects listed above, a variety of peculiar local phenomena have been observed in connection with acquired or created AV fistulas, such as thickening of the intima and media (arterializations) of the vein proximal to the fistula, elongation and increased tortuosity of the proximal artery, flow reversal in the distal artery [9], peripheral ischemia due to “stolen” perfusion or increased limb growth (Fig. 19.1). (For review, see [10]). Some of these phenomena such as the retrograde flows in veins have eluded explanations based on the conventional circulation model.

High-output cardiac failure is a known complication of aorto-caval fistula in experimental animals [7] and in humans [11, 12] and is relatively common in renal patients on hemodialysis [13, 14]. Recent data moreover suggests that dialysis patients with high fistula flows develop pulmonary hypertension (PHT) [15, 16]. It is noteworthy that closure of the fistula in experimental animals [1] and end-stage renal disease (ESRD) patients, say, after receiving of a donor kidney, reverses the changes [17, 18]. Massive diuresis has been reported in a patient after closure of chronic aorto-caval fistula [19].

Several physiologists have remarked on a striking similarity between the acute circulatory response to exercise and the opening of a large AV fistula in the sense that a large decrease in peripheral resistance is met by increased CO (references quoted in [20]). However, as shown in Sect. 14.​1, numerically derived “peripheral resistance” from Poiseuille’s equation [20] or Ohmic relationship [10] reflects neither global nor local state of organ perfusion. As mentioned, a surge in CO seen in aerobic exertion is a physiologic stimulus to increased metabolic demands that calls for a parallel rise in pulmonary blood flow and differs markedly from the increased pulmonary flows due to AV fistula. The overall increase in volume flow in AV fistula comes from two sources, namely, from the shunt and from the expanded blood volume due to maldistribution of systemic perfusion, with concomitant increase in plasma levels of rennin and atrial natriuretic peptide (ANP) [5]. The real difference between the two conditions, however, becomes apparent during chronic cardiovascular adaptation to increased fistula flows which invariably lead to increased pulmonary resistance and pulmonary hypertension.

19.2 Eisenmenger Syndrome

In addition to AV fistulas, other congenital cardiac abnormalities exist which lead to pulmonary vascular disease due to increase in pulmonary flows. Eisenmenger syndrome (ES), the most advanced form of pulmonary hypertension, is typically associated with a large communication between the pulmonary and systemic circulations at the atrial, ventricular, or aorto-pulmonary levels. The current interpretation of hemodynamics in ES goes back to 1950 when Paul Wood characterized the underlying pathophysiology of the condition in his classical paper as “pulmonary hypertension due to high pulmonary vascular resistance with reversed or bidirectional shunt” under the collective eponym of the Eisenmenger syndrome [21].

As noted by Wood, the starting point for understanding of the ES should begin with the normal fetal circulation. Briefly, the oxygenated blood (SpO₂ ~ 85%) from the placenta reaches the fetus via the umbilical vein and flows into the RA via the IVC. Of the 69% of total cardiac output (TCA) that enters the RA via the inferior vena cava, 27% is shunted through the foramen ovale into the LA. The LA in addition receives deoxygenated blood returning from the lung (7% of TCA). The LV thus receives only 34% of TCA, which is ejected into the aorta to supply mainly the upper part of the body. The balance of blood entering the RA via the IVC (69% − 27% = 42%) and blood from the SVC (21% of TCA) and the coronary sinus (3%), totaling 66% of TCA passes through the tricuspid valve into the right ventricle and is ejected into the pulmonary artery. The vast majority of RV output (59%) is shunted via the widely opened ductus arteriosus into the descending aorta and only 7% continues to flow via the pulmonary artery to perfuse the lung [22] (Fig. 19.2).

Of note is the fact that a relatively hypoxic environment of the fetus is critical for the development of fetal lungs and pulmonary vasculogenesis. The near-term pulmonary vasculature actively responds to vasoactive agents and to changes in oxygen tension. Unlike the systemic vessels, which relax in response to hypoxia, the pulmonary vessels react with marked constriction. Hypoxic pulmonary vasoconstriction (HPV) is a physiological response by which the circulating blood is diverted away from hypoxic alveoli, in order to match perfusion with ventilation. The presence of low arterial PO₂ in utero increases, while maternal hyperoxia decreases, fetal PVR. Increasing evidence suggests that the fetal pulmonary circulation is actively maintained in a vasoconstricted state by HPV (For review, see [23, 24]).

Because of extensive communications between the left and right side of the heart, the pressures throughout the cardiac cycle are essentially equal. In terms of pressure generation, the ventricles can be considered a single functional unit; however, in respect of volume throughput, the RV receives 2/3, and the LV only 1/3 of the TCA. The two ventricles, moreover, differ in the quality of blood they receive, i.e., the blood in the LV is more oxygenated than the blood in the RV (SpO₂ 65% vs. 55%). Finally, the placenta, the fetal “respiratory organ” receives about 50% of TCA. Its efferent vessel, the umbilical vein, directs the oxygenated blood back to the fetus via ductus venosus (Botalli) directly into the inferior vena cava, bypassing the liver. It is significant that the PO₂ in fetal “oxygenated” blood is lower than the venous PO₂ during air respiration. (The placenta receives venous blood with a PO₂ of about 23 mmHg from the fetus and oxygenates it to levels of 30–35 mmHg—compared to PO₂ of 40 and 100 mmHg, for venous and arterial bloods, respectively, for lung respiration.) The fetus therefore thrives in a predominantly venous milieu (Fig. 19.3). The existence of communication between the atria (foramen ovale) and the pulmonary artery/aorta (ductus arteriosus) ensures equal systolic and diastolic pressures in the ventricles as well as in the aorta and the pulmonary artery (Fig. 19.4).

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