7 The Pericardium

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7 The Pericardium

EDWARD CHINCHOY, PhD, MICHAEL R. UJHELYI, PharmD, FCCP~

ALEXANDER J. HILL, PhD, NICHOLAS D. SKADSBERG, PhD, AND PAUL A. IAIZZO, PhD

CONTENTS INTRODUCTION ANATOMY

MECHANICAL EFFECTS OF THE PERICARDIUM

ISOLATED PERICARDIAL HEMODYNAMIC EFFECTS AND TRANSPLANTATION ANATOMICAL ANIMAL COMPARISONS OF THE PERICARDIUM

INTRAPERICARDIAL THERAPEUTICS AND DIAGNOSTICS SUMMARY

COMPANION C O MATERIAL REFERENCES

1. INTRODUCTION

The pericardium is a fibroserous conical sac structure encompassing the heart and roots of the great cardiac vessels.

In humans, it is located within the mediastinal cavity posterior to the sternum and cartilages of the third, fourth, fifth, sixth, and seventh ribs of the left thorax and is separated from the anterior wall of the thorax. It is encompassed from the posterior resting against the bronchi, the esophagus, the descending thoracic aorta, and the posterior regions of the mediastinal surface of each lung. Laterally, the pericardium is covered by the pleurae and lies along the mediastinal surfaces of the lung.

It can come in direct contact with the chest wall near the ventricular apical region, but varies with the dimensions of the long axes of the heart or with various disease states. Under normal circumstances, the pericardium separates and isolates the heart from contact of the surrounding tissues, allowing freedom of cardiac movement within the confines of the pericardial space (Fig. 1).

2. A N A T O M Y

In humans, the 1 - to 3-mm thick fibrous pericardium forms a flask-shaped bag. The neck of the pericardium (superior From: Handbook of Cardiac Anatomy, Physiology, and Devices Edited by: P. A. Iaizzo © Humana Press Inc., Totowa, NJ

aspect) is closed by its extensions surrounding the great cardiac vessels; the base is attached to the central tendon and to the muscular fibers of the left side of the diaphragm. Much of the diaphragmatic attachment of the pericardium consists of loose fibrous tissue that can be readily separated and/or isolated, but there is a small area over the central tendon where the diaphragm and the pericardium are completely fused.

Examination of the pericardium reveals that it is comprised of two interconnected different and separate structures. The outer sac is known as thefibrous pericardium and consists of fibrous tissue. The inner sac is known as the serouspericardium and is a delicate membrane composed of a single layer of flat- tened cells resting on loose connective tissue that lies within the fibrous pericardium, lining its inner walls. The heart enters the wall of the serous sac from above and behind, creating an infold encompassing nearly the entire pericardial cavity space. (See also Chapter 4, Fig. 4.)

The surrounding great vessels that receive fibrous prolonga- tions from this serous pericardium include the aorta, the superior vena cava, the right and left pulmonary arteries, and the four pulmonary veins. The inferior vena cava enters the pericardium through the central tendon of the diaphragm, in which there exists a small area of fusion between the pericardium and the central tendon, but receives no covering from this fibrous layer.

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Fig. 1. A posterior view of the pericardial sac, with the anterior surface and heart cut away. It can be seen that the great vessels of the heart penetrate through the pericardium, which extends up these vessels for several centimeters.

Between the left pulmonary artery and subjacent pulmonary vein is a triangular fold of the serous pericardium known as the ligament of the left vena cava (vestigial fold of Marshall). It is formed by a serous layer over the remnant of the lower part of the left superior vena cava (duct of Cuvier), which regresses during fetal life, but remains as a fibrous band stretching from the highest left intercostal vein to the left atrium, where it aligns with a small vein known as the vein of the left atrium (oblique vein of Marshall), eventually opening into the coronary sinus.

The pericardium is also attached to the posterior-sternal surface by superior and inferior sternopericardial ligaments, which securely ~inchor the pericardium and act to maintain the orien- tation of the heart inside the thorax.

As mentioned, the serous pericardium is a closed sac that lines the fibrous pericardium and consists of visceral and parietal portions. The visceral portion, which covers the heart and the great vessels, is commonly referred to as the epicardium and is continuous with the parietal layer that lines the fibrous pericardium. The parietal portion, which covers the remaining vessels, i s arranged in the form of two tubes. The aorta and pulmonary artery are enclosed in one tube (the arterial meso- cardium); the superior and inferior venae cavae and the four pulmohary veins are enclosed in the second tube (the venous mesocardium). There is an attachment to the parietal layer between the two branches, behind the left atrium, commonly referred to as the oblique sinus. There is also a passage between the venous and arterial mesocardia (i.e., between the aorta and

pulmonary artery in front and the atria behind) that is termed the transverse sinus. The superior sinus or superior aortic recess extends upward along the right side of the ascending aorta to the origination point of the innominate artery. The superior sinus also joins the transverse sinus behind the aorta, and they are both continually fused until they reach the aortic root.

The arteries of the pericardium are derived from the internal mammary and its musculophrenic branch and from the descending thoracic aorta. The nerves innervating the pericardium are derived from the vagus and phrenic nerves and the sympathetic trunks.

3. MECHANiCAt EFFECTS OF THE PERICARDIUM

The degree to which the pericardium alters wall movement varies depending on the ratio of cardiac to pericardial size, loading conditions, and the degree of active and passive filling.

Closure of the pericardial sac following open heart surgery has been proposed to (1) avoid possible postoperative complica- tions, (2) reduce the frequency of ventricular hypertrophy, and (3) facilitate future potential reoperations by reducing fibrosis (I). Differences in ventricular performance dependent on the presence of the pericardium have been reported following cardiac surgery (2,3).

The presence of the pericardium physically constrains the heart, often resulting in a depressive hemodynamic influence that limits cardiac output by restraining diastolic ventricular filling (4,5). The physical constraint by the pericardium is trans- lated into direct external mechanical forces that alter patterns in myocardial and systemic blood flow (5,6). Direct primary and indirect secondary effects are observed as additional forces through the free wall. Because both the left- and right-side atria and ventricles are bound by a common septum, geometrical changes from chamber interactions are dynamic, depending on the different filling rates and ejection rates of each of the four chambers (7,8). Thus, it is important to note that chamber-to- chamber interactions through the interventricular septum and by the pericardium further promote direct mechanical chamber interactions (9-11).

The effects of the pericardium on mechanical measures of cardiac performance are generally not evident until ventricular and atrial filling limitations are reached, i.e., changing geometrical and mechanical :properties through factors such as maximum chamber vo!umes and elasticity. These effects become more evident as these pericardial limitations become extended (12,13). W i t b t h e known force-length dependence of cardiac muscle, variation Of chamber volumes through removal of the pericardium will influence isometric tension and therefore has a direct impact on systolic ejection. On the other hand, in specific cases when the restrictive role of the pericardium greatly increases, such as during cardiac tamponade, an increased intrapericardial fluid volume may result in critical restriction by the pericardium, which then clinically reduces cardiac performance (14).

It should also be noted that intrathoracic pressure creates an additional interaction between the ventricles, as well as between the heart and lungs in a closed chest. Thus, studying cardiac function in situ (with an opened chest) or in vitro allows elimination of the influences of intrathoracic pressures

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CHAPTER 7 / THE PERICARDIUM 103 for identifying and quantifying pericardial influences on car-

diac performance and ejection (15). Such isolation of pericardial effects from diastolic filling is necessary because normal ventricular output is dependent on diastolic pressure independent of the presence of the pericardium (16).

4. ISOLATED PERICARDIAL H E M O D Y N A M I C EFFECTS A N D T R A N S P L A N T A T I O N

Previous experiments have suggested that, in a normal intact heart at normal levels of right ventricular diastolic filling, the pericardium does not exert constraining effects on ventricular function (3,8). However, with increasing levels of right ventricular preload pressure, pericardial constraint increases, significantly influencing right ventricular function (17). By restricting atrial filling, the pericardium causes reductions in atrial systolic contributions to ventricular filling (18), mediated by atrioventricular interaction in addition to the direct ventricular interaction (8). In the left ventricle, at normal or only mod- erately elevated pressures, the pericardium has been reported to have a significant constraining effect on diastolic filling (19), often occurring without detectable changes in pericardial pressure (20,21). This suggests that, when normal cardiac limitations may be near maximum duress or capacity, such as during and following transplantation, the role of the pericardium may become more evident or prominent.

4.1. Four-Chamber Working In Vitro Model

With cardiac output physiologically dependent on diastolic pressure, in vitro, diastolic pressure and cardiac output can be controlled more without systemic influences. The sensitivity of the left ventricle to pericardial pressure is more evident given the differences in left ventricular performance with no significant difference in right ventricular performance associated with the effects of the pericardium. However, given the pericardial and chamber interactions, no attempt to separate or isolate the primary vs secondary pericardium effects on each chamber can be independently done.

In a study by our laboratory, we modeled pericardial effects during transplantation using swine hearts because of their anatomical and histological similarities to those of humans. The role of the pericardium hemodynamic function was investigated during and following simulated human orthotopic transplantation by use of an in vitro apparatus. This apparatus, capable of sustaining physiological cardiac function, was used to separate the pericardial influences from systemic effects and to simulate transplantation.

As detailed and documented in a previous study, the hemodynamic effects of explantation into the apparatus resulted in stability of ejecting parameters while working all four chambers (22). This is consistent with previous reports in which considerations of metabolic and contractile differences were observed between nonejecting and ejecting models; further, the role of the pericardium was noted with consideration to recov- ery of both left and right ventricular performance following an ischemic period (23,24).

Modified Krebs Henseleit buffer was used as perfusate with various additions to aid in maintenance of cardiac performance:

ethylenediaminetetraacetic acid (EDTA) (0.32 mmol/L) to che-

G r o u p 1 ( n = 1 2 )

o.O, s.o.o, '

G r o u p 2 ( n = 1 2 )

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Fig. 2. Experimental protocols for groups 1 and 2. In group l, a pericardiotomy was performed previous to explantation into the apparatus. In group 2, explantation preceded pericardiotomy. During all phases, the heart was allowed to stabilize until hemodynamic parameters were measured. DC, data collection.

late toxic metal ions and free calcium concentration titration;

insulin (10 U/L) to aid in glucose utilization; sodium pyruvate (2.27 mmol/L) as an additional energy substrate; and mannitol (16.0 mmol/L) to increase osmolarity and reduce cardiac edema.

The in vitro approach was employed because, in vivo, ventricular output is coupled to the pulmonary system and flows through the coronary vessels, limiting chamber ejection rates (i.e., right ventricle output cannot be steadily greater than left atrial output). Decoupling these flows in vitro allowed intrinsic output of the left and right side to operate independently with controlled atrial preload.

In one group of animals (n = 12), cardiac hemodynamic parameters were measured in situ following pericardiotomy and explantation into an in vitro apparatus. In a second group (n = 12), cardiac hemodynamic parameters were measured in situ following explantation in vitro and pericardiotomy (Fig. 2;

see also MPEG 1 on the Companion CD.). Mean postmortem heart weights were statistically similar at 327 _+ 3 g (group 1) and 346 - 2 g (group 2). (See JPEG 1 on the Companion CD.) Comparison of baseline cardiac parameters following medial sternotomy revealed no statistical difference between the two groups (p > 0.05 for both right and left _+dP/dt). Per- formance was dependent on the order of pericardiotomy and explantation. Differences existed between the two groups with final in vitro left ventricular +dP/dt (p < 0.001); no difference was observed in final in vitro right ventricular +dP/dt (p > 0.05).

With in situ pericardiotomy, left and right ventricular +dP/dt changes of 5.1 + 16.5% and 27.7 _+ 31.4%, respectively, were observed vs 21.1 _+ 11.8% and 21.6 -+ 28.9%, respectively, with in vitro pericardiotomy. Concordantly, changes o f - 2 . 7 _+ 18.6%

and 5.1 + 20.1%, respectively, were observed in left ventricular +dP/dt associated with explantation following in situ pericardiotomy, compared to -2.0 _+ 7.5% and 5.5 -+ 24.5%, respectively, following in vitro pericardiotomy.

Several significant differences were associated with final in vitro cardiac performance with and without the pericardium in values of left ventricular +dP/dt (1126.1 __. 110.1 vs 925.3 -+

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Fig. 3. Results detailing the effects of transplantation in vitro with and without the pericardium (n = 12 per set). In situ baseline control, pericardiotomy, and explantation in vitro maximum ±dP/dt performance characteristics as indicators of ventricular contractility and relaxation are shown.

117.7, respectively; p < 0.05) and -dP/dt (1116.4 _+ 159.9 vs 859.2 _+ 174.5, respectively) and in right ventricular -dP/dt (192.6 _+ 33.6 vs 221 +_ 39.8, respectively). No differences in right ventricular +dP/dt were observed between removing the pericardium in situ vs in vitro.

These findings indicated that an intact pericardium has a depressive influence on normal left ventricular performance and may help preserve left ventricular systolic function as measured by left ventricular +dP/dt following transplantation, but that these relative effects were not equivalent for both ventricles. The nonsymmetrical results between the left and right ventricles under constant filling preload and afterload resistance supported the notion that chamber reaction of one ventricle oppositely affects the other chamber because of interactions across the free wall. Yet, previous studies including both human and animal models have assumed similar in situ and in vitro function independent of the pericardium. Based on these findings, care should be taken when interpreting hemodynamic

results with respect to the absence or presence of the pericardium, especially when the ratio of forces because of pericardial constraint affecting diastolic filling is unknown.

In group 1 (in situ pericardiotomy and explantation in vitro), a medial sternotomy was performed, and the rib cage was retracted, preserving the integrity of the pericardial sac, which was freed from the surrounding interthoracic tissues. In situ data were recorded to measure myocardial performance with rib cage pressure relieved. Following pericardiotomy, including all connective tissue and fat, hemodynamic measurements were then repeated as outlined above.

The hemodynamic effects were normalized with respect to the previous stage by calculating percentage of change associated with each procedure. In addition, the percentage change between initial in situ values and final in vitro values were determined. Group 1 in situ baseline data, the effects of in situ pericardiotomy, and the effects of explantation in vitro in the absence of the pericardium are shown in Fig. 3 and Table 1.

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CHAPTER 7 / THE PERICARDIUM 105

Mean ,+ SD (n = 12)

Table 1

Effects of Order of Pericardiotomy and In Vitro Transplantation

Baseline (in situ) Postpericardiotomy (in situ) Postexplantation (in vitro) Group 1

Heart rate (beats/min) 97.6 ± 18.5 91.3 _+ 13.4 87.9 ± 11.9

Cardiac output 3.4 .+ 0.6 3.5 ± 0.7 2.2 ± 0.3

Left ventricular +dP/dt (mmHg/s) 967.7 +- 174.0 890.2 .+ 181.4 925.3 -+ 147.7 *

(% A from previous stage) (-7.5 ,+ 9.6) (5.1 -+ 16.5)

(% A from in situ baseline) (-2.7 ± 18.6)

Left ventricular -dP/dt (mmHg/s) 1364.7 ,+ 175.3 1210.6 .+ 187.2 859.2 ± 174.5 * (% A from previous stage) (-10.7 ± 12.8) (-27.3 ± 19.2)

(% A from in situ baseline) (-35.5 --. 19.1)

Right ventricular +dp/dt (mmHg/s) 246.5 ,+ 38.7 204.9 .+ 31.9 257.4 ± 55.7

(% A from previous stage) (-15.2 ± 16.7) (27.7 _+ 31.4)

(% A from in situ baseline) (5.1 .+ 20.1 )

Right ventricular -dp/dt (mmHg/s) 282.0 -+ 21.9 265.0 _+ 29.9 192.6 ± 33.6

(% A from previous stage) (-6.0 .+ 8.2) (-25.1 ± 14.5)

(% A from in situ baseline) (-29.9 .+ 13.5)

Mean ± SD (n = 12) Baseline (in situ) Postexplantation (in vitro) Postpericardiotomy (in vitro) Group 2

Heart rate (beats/min) 93.8 - 13.6 96.2 -+ 21.1 93.2 _+ 21.5

Cardiac output 3.5 -+ 0.7 2.2 -+ 0.3 2.4 _+ 0.2

Left ventricular +dp/dt (mmHg/s) 935.3 + 119.9 1152.5 -+ 142.3 1126.1 _+ 110.1 *

(% A from previous stage) (23.7 _+ 9.4) (-2.0 -+ 7.5)

(% A from in situ baseline) (21.1 _+ 11.8)

LV -dp/dt (mmHg/s) 1284 _+ 115.7 1076.8 -+ 143.5 1116.4 _+ 159.9 *

(% A from previous stage) (-18.6 -+ 15.1) (3.2 ± 6.5)

(% A from in situ baseline) (-12.5 +- 14.9)

Right ventricular +dp/dt (mmHg/s) 221.8 -+ 29.1 255.8 -+ 43.6 266.1 ± 58.9

(% A from previous stage) (16.2 -+ 19.4) (5.5 -+ 24.5)

(% A from in situ baseline) (21.6 ± 28.9)

Right ventricular-dp/dt (mmHg/s) 261.5 -+ 33.4 198.8 _+ 33.4 221.9 ,+ 39.8

(% A from previous stage) (-19.8 ,+ 17.2) (12.1 ± 12.8)

(% A from in situ baseline) (11.1 ± 16.0)

*Statistical significance (p < 0.05).

Table 2

Normalized Chan~es in Cardiac Performance Associated With Pericardiotomy and Explantation In Vitro Statistical significance of % A attributed with each stage Explantation Pericardiotomy Left ventricular +dP/dt (group 1 vs group 2)

Left ventricular -dP/dt (group 1 vs group 2) Right ventricular +dP/dt (group 1 vs group 2) Right ventricular -dP/dt (group 1 vs group 2)

p < 0.01; significant p > 0.05; not significant p > 0.05; not significant p > 0.05; not significant

p > 0.05; not significant p < 0.01; significant p < 0.05; significant p < 0.01; significant

S i m i l a r l y , for group 2, in situ b a s e l i n e data, the effects o f e x p l a n t a t i o n in vitro in the p r e s e n c e o f the p e r i c a r d i u m , and in vitro p e r i c a r d i o t o m y effects are shown.

The percentage change o f cardiac p e r f o r m a n c e associated with explantation and p e r i c a r d i o t o m y was c o m p a r e d with statistical analysis; data are p r o v i d e d in T a b l e s 2 and 3. W i t h explantation, significant differences were o b s e r v e d with the intact p e r i c a r d i u m o n l y in left v e n t r i c u l a r +dP/dt; no other parameters were affected. C o n v e r s e l y , p e r i c a r d i o t o m y affected right ventricular +dP/dt and - d P / d t and left ventricular - d P / d t , d e p e n d i n g on whether the p e r i c a r d i o t o m y occurred prior to or following explantation. No significant difference in final in vitro

cardiac output was observed, though it was o b s e r v e d during the e x p e r i m e n t that, in all cases o f in vitro p e r i c a r d i o t o m y (group 2), cardiac output increased on r e m o v a l o f the pericardium.

The significantly smaller difference in percentage change o f left ventricular +dP/dt a s s o c i a t e d with e x p l a n t a t i o n with an intact p e r i c a r d i u m vs without the p e r i c a r d i u m suggests that, during orthotopic transplantation, the p e r i c a r d i u m m a y help to preserve left contractile function (Table 2). Changes in right ventricular +dP/dt and - d P / d t were also noticed. During the same process, no difference was o b s e r v e d in right ventricular +dP/dt, suggesting that the left and right ventricles are affected differently by the pericardium.

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Table 3

Effects of Pericardiotomy Precedin~ vs Followinlg Explantation Statistical difference with sequence

of pericardiotomy and explantation in vitro Final in vitro performance Left ventricular +dP/dt (group 1 vs group 2)

Left ventricular -dP/dt (group 1 vs group 2) Right ventricular +dP/dt (group 1 vs group 2) Right ventricular -dP/dt (group 1 vs group 2)

p < 0.01; significant p < 0.01; significant p > 0.05; not significant p > 0.05; not significant

5. ANATOMICAL ANIMAL

COMPARISONS O F T H E PERICARDIUM

The pericardium is fixed to the great arteries at the base of the heart and is attached to the sternum and diaphragm in all mammals, although the degree of these attachments to the diaphragm varies between and within species (25,26). Specifically, the attachment to the central tendinous aponeurosis of the diaphragm is firm and broad in humans and pigs, the phrenoperi- cardial ligament is the only attachment in dogs, and the caudal portion of the pericardium is attached via the strong sternopericardial ligament in sheep (25,26).

Although the basic structure of the pericardium is the same, differences exist between various species with respect to both geometry and structure (27-29). Generally, pericardial wall thickness usually increases with increasing heart and cavity size between the various species (27). However, humans are a notable exception to this rule, having a much thicker pericardium than animals with similar heart sizes (27). Specifically, the pericardium of human hearts varies in thickness between 1 and 3.5 mm (30); the average pericardial thickness of various animal species was found to be considerably thinner (ovine hearts 0.32 _+ 0.01 mm, porcine hearts 0.20 + 0.01 mm, and canine hearts 0.19 _+ 0.01 ram; 28). Differences in the volume of pericardial fluid also exist. Holt (27) reported that most dogs have between 0.5 and 2.5 mL of pericardial fluid, with some dogs having up to 15 mL, compared to 20-60 mL in adult human cadaver hearts.

6. I N T R A P E R I C A R D I A L

T H E R A P E U T I C S AND DIAGNOSTICS

With recent advances in minimally invasive cardiac surgi- cal procedures, it is likely that instances and abilities in preserving the integrity of the pericardium during cardiac surgery will increase. The diminished ability of cardiac cells to regenerate under adverse loading conditions impairs the ability to regenerate lost myocardial function, making procedures that reduce myocardial trauma of particular interest. In addition, access into the pericardial space provides a new route for numerous novel treatments and therapies that can be applied directly to the epicardial surface and/or the coronary arteries.

For quite some time, nonsurgical intrapericardial therapy has been employed in patients with sufficient fluid in the pericardial space, allowing a needle to be safely placed within the space (31). This methodology has been used for patients with such clinical indications as, but not limited to, malignancies, recurrent effusions, uremic pericarditis, and/or connective tis-

sue disease. Instrumenting the pericardium has been made possible by numerous techniques that allow for the study of intraperi-cardial therapeutics and diagnostics by clinicians and investigators alike. More specifically, the endoluminal delivery of various agents has been clinically limited because of short residence time, highly variable deposited agent concentration, inconsistency in delivery concentrations, and relatively rapid washout of agent from the target vessel (32). A desired example of targeted application includes infusion of concentrated nitric oxide donors; which could present undesirable effects if systemically delivered. Further, one is allowed increased site specificity and the delivery of label-specific therapeutic agents to target cells, receptors, and channels.

A great deal of interest has been focused on delivery of angiogenic agents and various growth factors into the intrapericardial space (33-35). In particular, research has concentrated on administration in patients with ischemic heart disease (36,37). Early results indicated several benefits associated with the delivery of angiogenic agents, including increased collat- eral vessel development, regional myocardial blood flow, myocardial function in the ischemic region, and myocardial vascularity

6.1. Pericardial P h a r m a c o k i n e t i c s

In the healthy human, the pericardium is generally believed to contain 20-25 mL of physiologic fluid (0.25 __. 15 mL/kg) situated within the cavity space (38). Yet, dye studies suggested that pericardial fluid is not uniformly distributed over the myo- cardium, with the majority of pericardial fluid residing within the atriaventricular and interventricular grooves as well as the superior-transverse sinuses. Although the pericardial fluid is not uniformly distributed, pharmacokinetic studies suggested that there is complete mixing of the fluid so that pericardial fluid content is spatially uniform (39-41). Hence, sampling pericardial fluid content should not vary by sampling location (40).

Tissue distribution and drug clearance clearly affect all drug response. Because specific pericardial pharmacokinetic data remain unknown for the majority of compounds, pericardial drug disposition must be gleaned from physical chemical properties based on a few select studies. Pericardial fluid is cleared via lymphatics and epicardial vasculature, with the former being a very slow process (42). In addition to these passive clearance mechanisms, the epicardial tissues contain metabolic enzymes that may clear compounds via a biotransforma- tion process. This is likely to occur with certain labile peptides and small molecules such as nitric oxide.

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Unfortunately, there is very little known today about pericardial drug metabolism. In general, it is considered that whether or not a compound residing in the pericardial space is cleared via lymphatic drainage, passive diffusion or biotrans- formation will depend on its molecular size, tissue affinity, water solubility, and enzymatic stability. Thus, compounds such as large proteins do not rapidly diffuse into the vascular space and are slowly cleared from the pericardial space, perhaps via lymphatics, unless of course they are biotransformed (40,43).

This yields a pericardial fluid clearance and residence time longer than the corresponding plasma half-life. For example, administering atrial natriuretic peptide into the pericardial fluid space had a fivefold longer clearance and residence time within the pericardial fluid space compared to plasma clearance of an intravenous dose (43). Similarly, small water-insoluble compounds may also have very prolonged pericardial fluid residual times.

One case report documented that the pericardial fluid half- life of 5-fluorouracil was approx 10-fold longer than plasma half-life (16 vs 160 min); it should be noted that the patient in this investigation had metastatic breast carcinoma with pericardial involvement (39). The patient had received a relatively large pericardial 5-fluorouracil dose (200 mg) to manage recurrent pericardial effusion. This large dose, however, was associated with nearly undetectable plasma levels, indicating minimal spillover from pericardial fluid into the systemic circulation.

Although it was expected that 5-fluorouracil would have a longer pericardial residual time because it is water insoluble, it is unknown if these findings would occur in a healthy pericardial fluid space.

On the other hand, small water-soluble compounds have up to five- to eightfold shorter pericardial fluid clearance and residence times compared to plasma (41). For example, procainamide is a water-soluble compound that has a pericardial fluid half-life ranging from 30 to 41 _+ 2 min compared to the 180-min plasma half-life; it has been reported that the procainamide rapidly diffused out of the pericardial space with a terminal elimination half-life approximately five to seven times shorter than plasma (44). However, procainamide spillover from pericardial fluid into plasma was not considered to produce measurable plasma concentrations because of the relatively low pericardial doses (0.5 to 2 mg/kg). Similarly, it is not surprising that the converse was also true, that intravenously administered procainamide rapidly diffused into the pericardial space, across a plasma-to-pericardial fluid concentration gradient, such that pericardial fluid procainamide concentrations were similar to plasma approx 20-30 min following an intravenous injection. The likely explanation for these findings is that the vast ventricular epicardial blood supply served as a clearing system (pericardial administration) or a delivery system (intravenous administration) according to drug concentration diffusion gradient. Importantly, the diffusion of pericardial-administered procainamide into the vascular space will likely prevent drug accumulation in ventricular tissue and a global pharmacological response.

In addition to pericardial drug residence and clearance times, the determination of distribution volume may be considerably important, particularly to achieve desired peak drug concentra-

tions. There is a direct and inverse relationship between peak drug concentrations and drug distribution volumes, such that a low drug distribution volume achieves higher peak concentrations.

Perhaps of clinical importance, with the very small pericardial fluid volume, it is obvious that pericardial drug doses can be substantially reduced to achieve therapeutic concentrations.

This was evident when sequential pericardial procainamide doses of 0.5, 1, and 2 mg/kg produced peak pericardial fluid concentrations that ranged from 250 to 900 ~tg/mL; these concentrations were nearly 1000-fold greater than peak plasma concentrations of procainamide following the administration of a 2-mg/kg intravenous dose. In a follow-up study, in which a single procainamide dose was employed, similar findings were documented; it was also reported that a pericardial fluid volume of distribution of 1.6 + 0.2 mL/kg was observed, which is approx 1000-fold smaller than plasma procainamide volume of distribution of 2000 mL/kg. Although pericardial procainamide dos- ing produced very large pericardial fluid concentrations, procainamide could not be detected in the plasma given the very small doses.

With such a powerful diffusion gradient, it is likely that pericardial procainamide delivery can achieve very high atrial tissue concentrations. Indirect evidence of tissue distribution is a procainamide distribution volume that is larger (40-50 mL) than the estimated pericardial fluid volume of 20-30 mL.

Because the procainamide pericardial volume of distribution exceeded the expected pericardial volume, there was some tissue distribution. These pharmacodynamic data suggest that tissue distribution mainly occurs in the atrium, likely because the atrium is a very thin structure with a low blood supply. Thus, this tissue architecture is ideal for specialized therapeutic drug diffusion and therefore differs from that of the ventricles.

Unfortunately, most pericardial procainamide pharmacokinetic studies performed to date have not directly measured tissue concentrations following infusion. However, in one study that evaluated the pharmacodynamic effects of pericardial amiodarone delivery, the amiodarone tissue distribution was quantified at several myocardial locations (45). Not surpris- ingly, it was reported that atrial and epicardial ventricular tissue had the highest amiodarone tissue concentration; ventricular endocardial amiodarone tissue concentrations were approx 10- fold lower. However, importantly, the amiodarone levels were likely still within a therapeutic range. This was supported by the fact that pericardial amiodarone delivery prolonged endocardial ventricular refractory periods by up to 13%, which was equivalent to epicardial ventricular refractory period measurements and the magnitude of atrial refractory period prolonga- tion. The similar refractory response between epicardial and endocardial measurements, with very large differences in amiodarone tissue concentrations, indicates that amiodarone effects are maximal at low tissue concentrations.

Unlike pericardial amiodarone administration, pericardial procainamide had no effect on endocardial ventricular refractory periods (41). It is likely that such a beneficial ventricular tissue distribution does not occur with more water-soluble compounds such as procainamide. On the other hand, it is not surprising that amiodarone, when administered into the peri-

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... ~t

Fig. 4. The PerDUCER instrument uses a sheathed needle with a suction tip designed for grasping the pericardium to access the pericardial space using a transthoracic approach, thus minimizing the risk of myocardial puncture.

cardial space, could penetrate ventricular tissue and affect global ventricular electrophysiology because it is highly lipo- philic and has a huge tissue distribution, including the intra- cellular space (45).

Last, perhaps it is possible to modify molecules to achieve an optimal pericardial fluid residence time and thus their therapeutic outcomes (benefits). More specifically, for some agents, it may be desirable to have a short residence time. For example, pericardial drug delivery to cardiovert atrial fibrillation may require very high drug concentrations for only a brief duration, given the acute nature of the therapy. On the other hand, the ability to manage chronic conditions such as ischemic heart disease or heart failure may necessitate longer pericardial residual times. In this regard, Baek et al. (46) showed that a derivitized nitric oxide donor molecule, dia- zeniumdiolate, with bovine serum albumin resulted in a fivefold increase in pericardial fluid clearance and residence time vs a small molecule nitric oxide donor (diethylene-triamine/

nitric oxide). This group went on to show that it may be possible that a single pericardial dose of the nitric oxide donor could inhibit in-stent restenosis. Unlike patients with any type of effusion, the normal pericardium is a very thin layer, bring- ing it closer to the heart and subsequently increasing the risk of harm to the patient.

6.2. Clinical Pericardial Access

Until recently, safely entering the normal pericardium or pericardial sac with minimal effusion was not realizable. Sev- eral unique biomedical devices or tools have been and con- tinue to be developed to aid in accessing pericardial space using novel catheter designs, allowing controlled myocardial penetration during fluoroscopic visualization. Specifically, a technology has been developed that uses a sheathed needle with a suction tip designed for grasping the pericardium and accessing the pericardial space using a transthoracic approach and at the same time minimizing the risk of myocardial puncture; the PerDUCER ® instrument (Comedicus, Inc., Columbia Heights, MN) is placed using subxiphoid access into the

mediastinum under fluoroscopic guidance, and the apparatus is positioned onto the anterior surface of the pericardial sac (Fig. 4). Manual suction is applied to the side port resulting in a bleb of pericardium being captured. The needle is advanced to puncture the bleb and a guidewire is pushed through the needle into the pericardium. The PerDUCER ® is removed and a standard delivery catheter is placed into position.

The ability to access the pericardial space as such has created new opportunities to understand further the role of the pericardium under normal cardiac function and following cardiac disease. Despite the growing literature establishing the feasibility of intrapericardial therapeutics and diagnostics, the results of clinical trials employing pericardially delivered agents directed toward angiogenesis, restenosis, and/or other coronary and myocardial indications are currently lacking.

7. S U M M A R Y

The pericardium is a unique structure that surrounds the heart and serves several important physiological functional roles. Removal of the pericardium or the buildup of fluids within this space will alter hemodynamic performance. Yet, often following open heart surgery, the pericardium is not repaired or closed; the rationale for this is under evaluation. Therapeutic approaches have been directed to exploit the access space that exists between the pericardium and the epicardial surface of the heart. Nevertheless, an important consideration when utilizing animal models to study such biomedical devices is that the pericardium in humans is much thicker than that of most commonly employed animal models.

C O M P A N I O N C D M A T E R I A L

JPEG 1. Posterior portion of the pericardial sac in a swine from which the heart was removed.

MPEG 1. The effect of removing the pericardium from an isolated swine heart.

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