Microphysiology of the Pericardium:

Substrate for Intrapericardial Therapeutics

David H. Spodick
1
Abstract
Recent capability to enter the normal effusion-free pericardi-
um has expanded intrapericardial therapy which was formerly
restricted to patients with effusive pericardial disease, to intra-
pericardial treatment of cardiac diseases of all kinds. It is now
possible to deposit in the intact pericardium a variety of ther-
apeutic agents targeting the myocardium, valves, conduction
system and even the endocardium. In addition to such specific
agents, the unique microphysiology of the pericardial meso-
thelium provides investigators with 2 entirely new applica-
Mikrophysiologie des Perikards: Das Substrat fr intraperikardiale therapeutische Anwendungen
Zusammenfassung
Die intraperikardiale Therapie hat die Mglichkeit erffnet,
sich Zugang ins Perikard zu verschaffen, auch wenn kein
Perikarderguss vorliegt. Diese Mglichkeit stand frher nur
fr Patienten mit Perikarderguss zur Verfgung. Es ist heute
mglich, in das intakte Perikard eine Reihe von thera-
peutischen Substanzen einzubringen, deren Angriffspunkte
Myokard, Herzklappen, Reizleitungssystem und sogar das
Endokard sein knnen. Fr diese Therapie bietet die Mikro-
physiologie des Perikardbeutels, ein einzigartiges, weitgehend
abgeschlossenes System, ideale Voraussetzungen. Das Meso-
thel verfgt ber Enzyme und Rezeptoren, zum Beispiel ber
die Zyklooxigenase, Prostazyklinsynthase und Lipoxigenase,
tions of intrapericardial therapy: 1. supplementing substances
like prostanoids and a variety of immune factors, and 2. stimu-
lating pericardial production of such products of metabolism,
e. g., superfusion of the normal pericardium by non-steroidal
antiinflammatory agents to stimulate prostanoid production
with a variety of effects including possible inhibition of coro-
nary thrombosis. Continuing research and development
should determine the precise roles of these new applications
in human medicine.
das Endothelin, Sekretionsmechanismen fr Komplement-
faktoren und Rezeptoren fr Fibronolytika.
So ist in Zukunft gut vorstellbar, dass in intaktes oder
entzndetes Perikard Substanzen wie Prostanoide und
immunologische Faktoren (Zytokine und Antizytokine)
eingebracht werden, um Stimulatoren fr die Produktion
nicht steroidaler antiinflammatorischer Substanzen oder die
Prostanoidproduktion zu frdern oder um eine Koronar-
thrombose zu inhibieren. Dies ist nur ein Ausschnitt mg-
licher Angriffspunkte zur intraperikardialen Anwendung am
Menschen.
Key Words: Pericardium Pericardial microphysiology Intrapericardial therapeutics
Schlsselwrter: Perikard Perikardiale Mikrophysiologie Intraperikardiale Therapeutika
1
Worcester Medical Center/Saint Vincent Hospital, Medical School,
University of Massachusetts, Worcester, MA, USA.
Pericardial macroanatomy and microanatomy [1] are
uniquely configured to serve its macrophysiology and
microphysiology [2]. Traditionally, intrapericardial
therapy has been introduced when the macrophysiology
has been affected by excessive pericardial fluid, permit-
ting easy access not only for drainage but also to intro-
duce specific medications (Table 1). Intrapericardial
therapy in the absence of excessive fluid is aimed at di-
rect and semi-direct treatment of heart disease, provid-
ing at least 2 applications [1]: introduction into the nor-
mal pericardium of antiarrhythmic, antiinflammatory,
oxygen and NO-supplying agents and angiogenic and
other agents (Table 2) [2]. Pericardial microphysiology
extends the applications of intrapericardial therapy to
Urban & Vogel 2000 Herz
720 Herz 25 2000 Nr. 8 Urban & Vogel
Spodick DH, et al. Microphysiology of the Pericardium
721 Herz 25 2000 Nr. 8 Urban & Vogel
agents that will stimulate favorable products of pericar-
dial microphysiology and block or neutralize unfavor-
able products of pericardial microphysiology. Pericar-
dial microphysiology can be outlined as follows.
Outline of the Microphysiology
of the Normal Pericardium
2
Servomechanisms
Pericardial servomechanisms contribute to mechanical
and perhaps membranous functions of the pericardium.
1. Neuroreceptors in the epicardium and the fibrosa that
detect lung inflation and may operate via the vagus
nerves to alter blood pressure and heart rate.
2. Sympathetic efferents: these do the opposite of the va-
gal effects.
3. Mechanoreceptors sensitive to changes in ventricular
stretch determined by ventricular volume and trans-
mural pressure. Pericardial dysfunction is sensed by
mechanoreceptors with phrenic afferents that appear
to monitor beat-to-beat changes in cardiac volume.
Mechanoreceptors with unmyelinated fibers signal
myocardial tension and appear to reflexly match con-
traction strength with peripheral resistance, e. g., dur-
ing exercise. (Some of these receptors output can
contract the spleen and lower blood pressure.)
4. Chemoreceptors sensitive to substances in the peri-
cardial fluid. (These actually include hybrid mecha-
noreceptors responding to digitalis glycosides and
perhaps contributing to bradycardic effects.)
Normal Pericardial Fluid
Normally, there are 15 to 30 ml of serous fluid in the per-
icardial sac, mainly an ultrafiltrate of plasma that may
include some overflow of myocardial interstitial fluid as
well as myocardial lymph drainage.
1. Protein concentration: lower than in plasma but with
a relatively high albumin component.
2. Electrolyte concentration: as predicted for a plasma
ultrafiltrate.
Mesothelial Metabolic Activity
The mesothelium has cyclooxygenase, prostacyclin syn-
thethase and lipoxygenase activities:
1. Prostanoids: Prostaglandin E2, eicosanoids and pros-
tacyclin are continually released by the entire pericar-
dial mesothelium into the pericardial cavity in re-
sponse to pericardial stretching, to increases in
myocardial work and loading and to hypoxia [3, 4].
They are additionally stimulated by angiotensin II
and bradykinin. Pericardial prostacyclin may also
potentiate the chronotropic and algesic properties of
bradykinin, particularly during angina and perhaps
also the pain of pericardial inflammation. Prostacy-
clin is also a potent inhibitor of platelet aggregates
and may inhibit thrombosis in the major coronary
2
Modified from [14].
Therapy Targets
(pericardial disease)
Fibrinolytic Blood, hemopericardium
Streptokinase/streptodornase Pyopericardium, Hemopyopericardium
Antineoplastics Malignant tissue
Sclerotherapy Persistent effusions
Corticosteroids Inflammation: general, vasculitic,
immunopathic
Antibiotics (generally Specific infections
unnecessary)
Table 1
Established intrapericardial therapy via pericardial effusions (modi-
fied from [15]).
Tabelle 1
Etablierte intraperikardiale Therapie ber perikardiale Effusionen
(modifiziert nach [15]).
Therapy Targets
(cardiac disease)
Gene Vessels: mesothelium, conducting tissues
Angiogenic Vessels
Apolipoproitein A-Milano Vessels: intima, adventitia
Nitric oxide Vessels: lumen; walls
Donors/precursor (L-arginine) Platelets
Voltage sensitive Damaged (depolarized) cells
Hypothermic Damaged/ischemic myocardium
Oxygen Damaged/ischemic myocardium
Antiarrhythmic Myocardium/conducting tissues
Procainamide
Amiodarone
L-arginine (via nitric oxide)
Antiarrhythmic/antibody Myosin of damaged cells
Calcium-avid Increased cell calcium
Table 2
Intrapericardial therapy via normal peridardium (modified from [16]).
Tabelle 2
Intraperikardiale Therapie ber normales Perikard (modifiziert nach
[16]).
Spodick DH, et al. Microphysiology of the Pericardium
722 Herz 25 2000 Nr. 8 Urban & Vogel
vessels as well as clotting when there is blood in the per-
icardium. These prostanoids can alter pericardial sym-
pathetic neurotransmission and myocardial contractil-
ity and modulate the caliber and tone of the underlying
vessels (i. e., direct vasodilation by prostaglandin and in-
directly by opposing coronary spasm). Increased peri-
cardial prostaglandins also inhibit efferent sympathetic
effects acting as modulators of sympathetic neurotran-
smission with multiple effects on cardiac electrophysiol-
ogy [5], possibly including reduction of reperfusion-in-
duced arrhythmias.
2. Endothelin: Mesothelial synthesis and release, in-
creased by angiotensin II stimulation, may act as a
vasoconstrictor.
3. Defensive Immunologic Constituents: Small amounts
of complement (C3, C4, CH 50). Other immune fac-
tors, myocardial cellular enzymes and related compo-
nents are released into the pericardial fluid, neces-
sarily transiting the visceral pericardium (unless
damaged).
4. Fibrinolytic Activity: The intact mesothelial serosa
itself opposes both intrapericardial clotting and for-
mation of adhesions via its fibrinolytic activity. (Yet,
after any kind of pericardial injury, including physical
and chemical trauma, pericardial fibrinolytic activa-
tor activity decreases.)
Lubricant Function
Reducing friction during the cardiac cycle:
1. generation of normal pericardial fluid, and
2. phospholipid surfactants capable of reducing friction
between otherwise hydrophilic surfaces consistent
with the classical theory of boundary lubrication
[6],
3. cell-to-cell interaction between pericardial mesothe-
lial cells and ventricular myocytes (so far demonstrat-
ed in vitro) may have a role in the complex scheme of
pericardial microphysiology.
Intrapericardial Therapeutics and Pericardial
Microphysiology
To take advantage of pericardial microphysiology, intra-
pericardial therapeutics would be aimed at a) stimulat-
ing or supplementing the favorable effects of pericardial
metabolites (e. g. prostanoids, prostacyclin synthetase,
cyclooxygenase, lipoxygenase and antithrombotic sub-
stances) and b) blocking or neutralizing potentially
harmful substances like endothelin (unless vasocon-
striction were, for some reason, to be desirable).
The material in Tables 1 and 2 is self-explanatory.
Established therapies via the enlarged pericardial space
during pericardial effusion (more related to the macro-
physiology of the pericardium) targets pericardial dis-
eases. Intrapericardial therapy via the normal pericardi-
um, as yet experimental, targets cardiac diseases [710].
Intrapericardial therapy utilizing pericardial micro-
physiology (see outline) would target both pericardial
and cardiac disease based on 2 approaches: 1. stimulat-
ing the pericardial mesothelium to produce specific sub-
stances in larger than normal amounts, and 2. either
supplementing or blocking products of pericardial mi-
crophysiology. Presumably intrapericardial deposition
of therapeutic agents in large amounts would parallel
the results of the procedures in Table 2 in the sense that
systemic effects would be minimal or at least undetect-
able so that large concentrations of appropriate agents
could be delivered in preparations for long duration of
delivery according to indication. A great deal of investi-
gation will be necessary to bring these to practical clini-
cal usage, including meticulous determination of risk-
benefit ratios.
Prostanoids produced by the pericardial mesotheli-
um, for example, can alter pericardial sympathetic neu-
rotransmission and myocardial contractility. They may
modulate the caliber and tone of the underlying coro-
nary vessels (i. e., direct vasodilation by prostaglandin
and indirectly by opposing coronary spasm). Their pro-
duction by the pericardium may be stimulated by non-
steroidal antiinflammatory agents (NSAIDs), particu-
larly the cyclooxygenase inhibitors delivered directly
upon the epicardium [3, 11]. Inhibitors of efferent sym-
pathetic neurotransmission in addition to eicosanoids
affect cardiac electrophysiology and may reduce reper-
fusion-induced arrhythmias [12]. Prostacyclin is also a
potent inhibitor of platelet aggregates and may inhibit
thrombosis within the major coronary vessels as well as
clotting when there is blood in the pericardium. In the
latter case, increased prostacyclin production would
supplement the fibrinolytic activity of intact mesothelial
serosa [2].
Prostanoids are also stimulated by angiotensin II
and bradykinin. Since pericardial prostacyclin, generat-
Spodick DH, et al. Microphysiology of the Pericardium
723 Herz 25 2000 Nr. 8 Urban & Vogel
ed during hypoxia and work may potentiate the chrono-
tropic and algesic properties of bradykinin, particularly
during angina and perhaps also the pain of pericardial
inflammation, bradykinin would not appear to be a
practical clinical stimulant. On the other hand, angio-
tensin II, if devoid of unwanted systemic effects, may be
worth investigating as a stimulant; however, it also in-
creases mesothelial synthesis and release of endothelin.
During hemopericardium of any etiology there is a
strong potential for adhesions and ultimate constriction,
particularly when the fibrinolytic activity of the intact
mesothelial serosa is reduced by injury (physical and
chemical trauma as well as inflammation can decrease
pericardial fibrinolytic activator activity [2]). Here, sup-
plementation by antithrombotic agents, as already prac-
ticed under some circumstances, may be desirable after
drainage of blood and pericardial lavage.
Striking success in animals (Table 2) for example,
prevention of acute and chronic ischemia and of coro-
nary atherosclerosis by NO donors [13] urgently calls
for extensive and intensive investigative effects with
intrapericardial therapy in human beings.
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Address for Correspondence:
David H. Spodick, MD, DSc, FACC, Professor of Medicine,
Director of Cardiovascular Fellowship Training, Worcester
Medical Center/Saint Vincent Hospital, University of
Massachusetts Medical School, 20 Worcester Center Blvd.,
Worcester, MA 01608, USA,
Phone (+1/508) 363-6162, Fax -225,
e-mail: DHSPOD@WMC.com
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