♦Statistical significance (p < 0.05).

Table 2

Normalized Changes in Cardiac Performance Associated With Pericardiotomy and Explantation In Vitro

Statistical significance of % A attributed with each stage Explantation Pericardiotomy

Table 2

Normalized Changes 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

Similarly, for group 2, in situ baseline data, the effects of explantation in vitro in the presence of the pericardium, and in vitro pericardiotomy effects are shown.

The percentage change of cardiac performance associated with explantation and pericardiotomy was compared with statistical analysis; data are provided in Tables 2 and 3. With explantation, significant differences were observed with the intact pericardium only in left ventricular +dP/dt; no other parameters were affected. Conversely, pericardiotomy affected right ventricular +dP/dt and -dP/dt and left ventricular -dP/dt, depending on whether the pericardiotomy occurred prior to or following explantation. No significant difference in final in vitro cardiac output was observed, though it was observed during the experiment that, in all cases of in vitro pericardiotomy (group 2), cardiac output increased on removal of the pericardium.

The significantly smaller difference in percentage change of left ventricular +dP/dt associated with explantation with an intact pericardium vs without the pericardium suggests that, during orthotopic transplantation, the pericardium may help to preserve left contractile function (Table 2). Changes in right ventricular +dP/dt and -dP/dt were also noticed. During the same process, no difference was observed in right ventricular +dP/dt, suggesting that the left and right ventricles are affected differently by the pericardium.

Table 3

_Effects of Pericardiotomy Preceding vs Following Explantation

Statistical difference with sequence of pericardiotomy and explantation in vitro Final in vitro performance

Left ventricular +dP/dt (group 1 vs group 2) p < 0.01; significant

Left ventricular -dP/dt (group 1 vs group 2) p < 0.01; significant

Right ventricular +dP/dt (group 1 vs group 2) p > 0.05; not significant

Right ventricular -dP/dt (group 1 vs group 2) p > 0.05; not significant


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 sterno-pericardial 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 mm; 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.


With recent advances in minimally invasive cardiac surgical 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 peri-cardial 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 an-giogenic agents and various growth factors into the intraperi-cardial 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 collateral vessel development, regional myocardial blood flow, myo-cardial function in the ischemic region, and myocardial vascularity

6.1. Pericardial Pharmacokinetics

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 myocardium, 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 pericar-dial 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 biotransformation process. This is likely to occur with certain labile peptides and small molecules such as nitric oxide.

Unfortunately, there is very little known today about peri-cardial 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 biotransformation 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 halflife 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 pericar-dial 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, pro-cainamide 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 pro-cainamide 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 pericar-dial 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 ^g/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 of1.6 ± 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 dosing 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 pharmacoki-netic 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 surprisingly, it was reported that atrial and epicardial ventricular tissue had the highest amiodarone tissue concentration; ventricular endocardial amiodarone tissue concentrations were approx 10fold lower. However, importantly, the amiodarone levels were likely still within a therapeutic range. This was supported by the fact that pericardial amiodarone delivery prolonged endocar-dial ventricular refractory periods by up to 13%, which was equivalent to epicardial ventricular refractory period measurements and the magnitude of atrial refractory period prolongation. 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-

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, bringing 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. Several unique biomedical devices or tools have been and continue 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.

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