Cardioplegia and Calcium Antagonists: A Review

COLLECTIVE REVIEW

Cardioplegia and Calcium Antagonists: A Review Jan W. de Jong, Ph.D. ABSTRACT During open-heart operations, periods occur during which the blood supply to the heart is stopped. Myocardial damage can be limited by cooling and induction of electromechanical arrest (cardioplegia). Many animal studies and some clinical trials provide strong evidence for the use of calcium antagonists, such as nifedipine, verapamil hydrochloride, diltiazem hydrochloride, and lidoflazine, as adjuncts to cardioplegia to optimize the protection. Salutary effects of calcium antagonists are discussed in regard to possible mechanism of action, application time, and efficacy during hypothermia. A major conclusion is that virtually no negative effects on cardiac protection have as yet been described in experimental or clinical studies, apart from short-term negative inotropic responses, while there is an increasing body of positive evidence for their efficacy. A new development is the use of these drugs for regional cardioplegia during dilation of coronary arteries (transluminal angioplasty). One of the breakthroughs in the area of cardiovascular surgery over the last thirty years concerns myocardial preservation. With adequate measures, including hypothermia, early mortality after aorta-coronary artery bypass grafting operations is low; it approaches 1%for first operations. However, mortality after reoperation by bypass grafting and after certain other cardiovascular operations, such as valve replacement, is (much) higher. Evidently, better methods are needed to protect the myocardium during such operations. Morbidity should and can be improved as well. In myocardium moderately impaired by ischemia, function recovers but only after prolonged intervals [l].Full restoration of myocardial function can take months after bypass grafting. Protection of the myocardium has been t i e d in many ways. Induction of electromechanical arrest (cardioplegia) combined with hypothermia is widely used to limit the initial insult, thereby improving recovery after cardiac operations. However, certain types of cardioplegia fail to protect the heart adequately from ischemic damage. In the last few years, a substantial amount of research has been carried out on interventions involving calcium metabolism. From the following, it will become clear that (additional) protection of the heart by calcium antagonists has been demonstrated in many animal studies and that the time has come for more extensive clinical work.

From the Cardiochemical Laboratory, Thoraxcenter, Erasmus University Rotterdam, PO Box 1738, 3000 DR Rotterdam, The Netherlands. Address reprint requests to Dr. de Jong.

593 Ann Thorac Surg 42593-598, Nov 1986

Calcium The myocardium of mammals contains about 2 mmol of Ca2+ per kilogram of body weight, the largest part of which resides in internal stores near the endoplastic reticulum. During diastole, the Ca2+ concentration of the cytosol is presumably lower than 0.0001 mmoVL; however, for active tension development, a Ca2+ concentration of about 0.01 mmoYL is necessary. Therefore, calcium from subcellular organelles or from outside the cell has to be transported to the cytosol to accomplish the change from resting to active status. In the blood, the ionized Ca2+ level is about 2.5 mmoVL. Four pathways exist for calcium ions to enter the cell: passive diffusion, exchange with sodium, voltageactivated transport, and possibly also exchange with potassium (Fig 1).Per beat, only little calcium is pumped (reversibly) inside. If there is a lack of oxygen, however, the cardiac cell membrane becomes more permeable for Ca2+ ions from the extracellular space, thereby causing an increased influx into the ischemic tissue during reperfusion [2]. Excessive accumulation leads to ischemic contracture, the ”stone heart” syndrome, which is a lifethreatening event. It is therefore imperative to prevent calcium accumulation, whatever the route. The phenomenon of the calcium paradox illustrates the importance of calcium homeostasis for the myocyte.

Calcium Paradox The calcium paradox occurs when hearts are perfused for some time with a solution containing less than 0.05 mmoVL of calcium, followed by reperfusion with a solution containing a normal concentration of calcium. Then tissue disruption ensues, with enzyme release and contracture. Abrupt massive calcium influx to intracellular compartments seems responsible for the process [l].The clinical relevance of this discovery did not become clear until later: in a number of surgical procedures, calcium supply to the heart is stopped, possibly instigating the calcium paradox during reperfusion. Some of the damage, which occurs because of the influx of calcium, can be prevented with calcium antagonists [3].

Calcium Antagonists The term calcium antagonist has been used since 1969 for drugs with negative inotropic properties that can be counteracted by calcium. In the definition of Fleckenstein [4], a calcium antagonist specifically blocks excitation-contraction coupling by mitigating the effects of Ca2+. Drugs like verapamil hydrochloride, nifedipine, diltiazem hydrochloride, and possibly also lidoflazine are calcium antagonists that are used clinically to treat angina pectoris and hypertension. They inhibit the slow, inward calcium flux, which is responsible for the plateau

594 The Annals of Thoracic Surgery Vol 42 No 5 November 1986

passive diffusion

Ca2+

Ca**INa+ exchange

Ca2*

voltageactivated transport

Ca2+

Ca2+lKf exchange

Ca2+

Fig 1 . Routes of calcium entry into mammalian heart muscle. (out = external side of plasma membrane; in = internal side.)

phase of the action potential. Hence they are also called "slow-channel inhibitors" or "calcium channel inhibitors." The negative inotropic effect of these compounds can be ascribed to this decreased, slow calcium influx. On the other hand, beta-adrenergic agents exert their positive inotropic action by increasing the Ca2+ influx through slow calcium channels. From Table 1, it is clear that calcium antagonists form a heterogenous group of drugs. Nifedipine, a 1,4dihydropyridine, is the "mother" compound of a series of drugs such as nisoldipine, niludipine, nimodipine, and nitrendipine. These belong to the most potent vasodilators on the market. Verapamil, a compound with a structural resemblance to papaverine hydrochloride, has as its "congeners" gallopamil, tiapamil, and anipamil. Energy-rich phosphates are broken down relatively quickly by the heart when there is a lack of oxygen. Then adenosine triphosphate (ATP) is catabolized to the level of the purines adenosine, inosine, hypoxanthine, xanthine, and urate, metabolites that are washed out. Resuscitation of an anoxic or ischemic heart is impossible if more than 75% of the adenine nucleotide pool has been broken down to purines [5]. Inhibition of ATP catabolism by verapamil in ischemic and reperfused heart has been documented extensively [4, 61. In addition, energy conservation by calcium antagonists has been described for nifedipine, diltiazem, and recently also for bepridil and nisoldipine [q. Although many studies demonstrate the salutary ef-

fect of calcium antagonists on myocardial energy metabolism during transient ischemia, their mechanism of action is not fully clear. Figure 2 depicts in a speculative way how a reduction of Ca2+influx with calcium antagonists could prevent ATP catabolism. Protection due to a reduction of work, to vasodilatation, or to interference with subcellular organelles, rather than to any specific direct action on Ca2+ fluxes across the heart cell membrane, cannot be excluded.

Why Calcium Antagonists during Open-Heart Operations? With the application of cold chemical cardioplegia during routine heart operations, the tolerable duration of ischemia can be extended from less than 1 hour to 3 hours; in experimental studies, reversible ischemia of up to 24 hours appears possible [8]. Three facets necessary for effective protection play a role: (1)energy sparing by induction of instantaneous electromechanical arrest (cardioplegia) with compounds such as potassium; (2) slowing down of energy-consuming and degradative reactions by hypothermia; and (3) combating harmful changes caused by ischemia and reperfusion with protective agents [8]. Analysis of the principles that underlie these three components and the mechanism of action of the specific interventions reveals the control of calcium movement to be one of the most critical factors in effective protection of the heart. In this setting, calcium antagonists could be beneficial. From the available literature, it is clear that many experiments with animals and a few clinical trials demonstrate calcium antagonists to have a protective effect on the heart. Animal Studies

Table 2 indicates that nifedipine, diltiazem, verapamil, and lidoflazine have been given as adjuncts to potassium cardioplegia in the anesthetized dog and in the isolated perfused heart of several species. In all studies carried out in myocardium at 37"C, calcium antagonists protected against damage caused by ischemia. Somewhat less clear is the effect of these drugs on the hypothermic heart. Many investigators reported additional

Table 1. Some Calcium Antagonists Used for Protection of the Heart Generic Name

Trade Name

Basic Chemical Structure

DL-Bepridil DL-Diltiazem . HCI"

ORG 5730, CERM-1978, Vascor, Cordium CRD 401, Tildiem, Dilzem, Cardizem, Herbesser D 600, Procurum, methoxyverapamil . HCl R 7904, Clinium Bay a 1040, Adalat, Procardia Bay a 5552 D 365, Isoptin, iproveratril

Benzylphenylamine pyrrolidine Benzothiazepine

Gallopamil Lidoflazineb Nifedipine Niso1dipine DL-Verapamil . HCI'

isomer has greater potency. lacks calcium antagonistic specificity according to Fleckenstein [4] 'Both enantiomers exert purely calcium antagonistic actions. 'D-&

%s

Phenylalkylamine Diphenylalkyl piperazine 1,4-Dihydropyridine 1,4-Dihydropyridine Phenylalkylamine

595

Collective Review: de Jong: Cardioplegia and Calcium Antagonists

out cell membrane

rn

in

rn

Ca2' overload

C a 2 + homeostasis

reduced mi tochondrial

excessive A T P consumptim

El adequate A T P synthesis

ATP consumption

\-.----adequate energy-rich phosphates

+

energy-rich

1

necrosis

A

t cardioprotection

I

B

Fig 2 . How blockade of Ca2+ entry could lead to maintenance of myocardial structure and function: (A)development of necrosis caused by intracellular Ca2+ overloading and (B)prevention of necrosis by calcium antagonist. (ATP = adenosine triphosphate.)

protection by calcium antagonists. In some studies, however, the drugs did not significantly ameliorate ischemia-induced damage during hypothermia (see Table 2). Most of the negative studies were reported by Hearse and co-workers [14, 19,251, who also found that at lower temperatures, calcium antagonists failed to prevent damage caused by the calcium paradox. Nayler [29], on the other hand, showed that the protective effects of hypothermia and nifedipine are additive. However, when the hearts were arrested with potassium, this additive effect could not be shown at temperatures lower than 28°C [2]. If the ischemic damage is virtually nil or the protection by hypothermia alone already adequate, calcium antagonist administration may be redundant. However, even if the specific cardioplegic effect is diminished, the calcium antagonist may be useful by lowering the preischemic energy demand [30]. Also, reperfusion conditions may be improved. It is important to note that negative effects of the use of calcium antagonists as adjuncts to potassium cardioplegia have not been reported. Moreover, studies in which the heart was arrested by means other than potassium cardioplegia also pointed at the protection afforded by verapamil, diltiazem, nifedipine, and lidoflazine [29]. One has to keep in mind, however, that a (reversible)negative inotropic effect can persist for some time, which could cause problems in the hospital setting. Clinical Trials Only a few clinical studies of calcium antagonists used during cardiac operations have been published in detail.

Clark and co-workers [31] reported the effectiveness of nifedipine in a multicenter trial. From an open-heart population of 4,777 patients, 205 highest-risk patients were selected for the study in which cold potassium cardioplegia was used. Hemodynamics were influenced in a positive sense by the drug, but the authors provided no statistical details. Myocardial levels of ATP also seemed to be preserved by nifedipine in this study. However, no significant reduction in myocardial creatine kinase release was observed. Flameng and associates [32] found that the addition of nifedipine to the cardioplegic solution could prevent the ischemia-induced degradation of nucleotides, as it occurred when myocardial cooling was inadequate. This effect, however, was not associated with an improved clinical outcome. In an earlier trial, Flameng and coworkers [33] showed that lidoflazine protects in a dosedependent way against breakdown of high-energy phosphates and glycogen. In addition, ultrastructure and left ventricular stroke work index were better maintained by lidoflazine. In this investigation, patients were pretreated with the drug. Operation was done with intermittent aortic clamping and hypothermic conditions. Hicks and colleagues [34] studied the effect of verapamil added to the cardioplegic solution and nifedipine instituted postoperatively. This regimen, for which the rationale remained unexplained, resulted in a reduction in postoperative levels of serum creatine kinase. From a more recent study, which was conducted without suitable controls, Hicks and DeWeese [35] concluded that verapamil potassium cardioplegia is associated with excellent protection against postoperative abnormalities in cardiac conduction. Kaplan and associates [36], however, did not advocate the addition of verapamil to potassium cardioplegia. In their small group of patients, they observed that it increased the need for pacing and inotropic drugs.

596 The Annals of Thoracic Surgery Vol 42 No 5 November 1986

Table 2. Efficacy of Calcium Antagonists Administered as Adjuncts to Potassium Cardioplegia to Prevent Damage due to Myocardial Ischemia Drug

Preparation

Temperature of Heart ("C)

Variables Tested

Nifedipine

Dog, CPB Dog, CPB Dog, CPB Dog, CPB Dog, CPB Isolated rabbit heart Isolated rat heart Isolated rat heart Dog, CX lig. Isolated rabbit heart Isolated rat heart

10 10 10,37 24 12, 21 15-37 20 vs 37 15 30 14 20-37

Hernodynamics, edema Hernodynamics Hernodynamics Ca2 homeostasis Plhernody namics Hernodynamics Hemodynamics, enzymes P/hemodynamics Hernodynamics Hemod ynamics Hernodynamics, enzymes

Isolated rat heart Dog, CPB Isolated rat heart

20 vs 37 7 10

Hernodynamics, enzymes Plhemody narnics Plarrhythrnias

Dog, CPB Isolated dog heart Isolated rabbit heart Dog, CPB Isolated rat heart Dog, CPB Dog, CX lig.

37? 4 14 377 20-37 37 18

Mitoch.ihemodynarnics Hemodynamics Hemodynamics Cerebral flow Hernodynamics, enzymes Plhemod y namics Mitoch.

Dog, CX lig. Dog, CPB, CX lig. Dog, CPB

30 20 37?

Hemod ynamics Hernodynamics Cerebral flow

Diltiazern hydrochloride

Veraparnil hydrochloride

Resulta

+

+ + + + NS

+, a28"c * vs + + + + +, 231" C

NSvs

+

t

+

+ + + +

+, 334" c + +

Reference Magovern et a1 [9] Christlieb et a1 [lo] Clark et a1 [ l l ] Boe et a1 [12] Johnson et a1 [13] Nayler [2] Yarnamato et a1 [14] Menasche et a1 [15] Guyton et a1 1161 Katsurnoto and Inoue [17] Fukunarni and Hearse [18] Yarnamoto et a1 [19] Standeven et a1 [20] Van Gilst et a1 [21] Pinsky et a1 [22] Morishita et a1 [23] Katsurnoto and Inoue [17] White et a1 [24] Hearse et a1 [25] Lupinetti et a1 [26] Yoon et a1 [27]

Lidoflazin e

"A

+ indicates protection

NS

+ +

Guyton et a1 [16] Kates et a1 [28] White et a1 [24]

additive to potassium cardioplegia, and NS means protection not additive to cardioplegia.

CPB = cardiopulmonary bypass; P function

=

myocardial high-energy phosphates; CX lig.

Vouh6 and co-workers [37] studied the effects of diltiazem in conjunction with profound hypothermia during aortic cross-clamping. They found it safe; the drug reduced the release of myocardial enzyme and probably improved hemodynamic function immediately after bypass. From these trials and from preliminary data from other studies [8], the overall picture emerges that calcium antagonists, such as nifedipine, verapamil, lidoflazine, and diltiazem, can contribute to protection during open-heart operations.

Calcium Antagonists for Regional Cardioplegia In the last six years, percutaneous transluminal coronary angioplasty (PTCA) has established itself in the armamentarium of the cardiologist. In this technique, a catheter is introduced through a systemic artery under local anesthesia to dilate a stenotic artery by controlled

=

circumflex coronary artery ligation; mitoch.

=

mitochondria1

inflation of a distensible balloon. After a period in which only a proximal stenosis in a single vessel was treated (provided the patient had stable angina and normal ventricular function), today treatment is less conservative. Serruys and colleagues [38] reported that PTCA is also used for patients with unstable angina and diminished ventricular function. Various obstructed vessels can be dilated; the total period of occlusion can exceed ten minutes. After PTCA, substantial amounts of lactate and ATP catabolites can be demonstrated in the myocardial efflux [39]. It is therefore obvious that protection of the heart during such an intervention may be useful. Local cardioplegia with calcium antagonists is currently being tested. Calcium antagonists have been used to prevent arterial spasm during coronary angioplasty. It seems as if the time necessary for dilation can be prolonged safely by intracoronary application of nifedipine [38]. However, protection of the heart with calcium antagonists during angioplasty is only in the initial research phase.

597 Collective Review: de Jong: Cardioplegia and Calcium Antagonists

Calcium Antagonists as Insurance Policy Hearse and co-workers [8] stressed that a good and uniform degree of hypothermia in the heart can be well maintained in the laboratory, but that is certainly not always possible in the clinical setting, where one observes warm spots. Also, problems exist because of a varying degree of cooling. Calcium antagonists could then act as an insurance policy against regional areas of poor perfusion or unexpected warming [8], when administered in addition to the usual measures of highvolume cardioplegia and topical cooling. Furthermore, some of these drugs protect against vasoconstriction by microscopically small particles in unfiltered cardioplegic solutions [40], which is the reason Henry [8] called them “particle antagonists.” This author [8] made it clear that the action of calcium antagonists goes beyond just another cardioplegic maneuver. It seems that these drugs play an important role in protecting the heart during the periods before and after cardiopulmonary bypass. During reperfusion, the cardioplegic protection by hypothermia and potassium is no longer effective and it becomes important to interfere pharmacologically with minimal disturbance of pump activity. Calcium antagonists could exert their salutary action partly by protecting the vessel wall. Finally, some of these drugs could be beneficial to inhibit rhythm disturbances during reperfusion [21, 351.

ischemia [2, 7, 301. Calcium antagonists have been given intravenously to animals before an ischemic period or as a component of hypothermic hyperkalemic cardioplegia, hypothermic normokalemic cardioplegia, and normothermic normokalemic cardioplegia. In most cases they show salutary effects on the heart. Preusse and associates [44] claimed that pretreatment with verapamil followed by calcium-free cardioplegic solution has a ”membrane-labilizing” effect. However, to avoid the risk of creating the calcium paradox, the use of calciumfree cardioplegia should be discouraged anyway. It seems essential that the calcium antagonist be present before reperfusion starts. It is debatable whether it makes sense to treat patients per 0 s for several weeks preoperatively. When asked, Magovern [8] explained that his group treats only high-risk surgical patients with these drugs. On the basis of their study with nifedipine, Casson and associates [45] suggested that the drug should be continued up to the time of operation. To create local cardioplegia, calcium antagonists can be used in an intracoronary way before transluminal angioplasty. This technique needs much more experimentation.

I am grateful to Mrs. M. J. Kanters-Stam for her secretarial assistance and to P. W. Achterberg, M.Sc., and R. W. Brower,

Ph.D., for their criticism.

Administration

Dose It seems sensible to give calcium antagonists in a moderate dose together with the cardioplegic solution before open-heart operation. For nifedipine, this is probably 200 to 300 pg/L if about 1.5 L of cardioplegic solution is used [31, 321. A high concentration of a calcium antagonist is strongly negatively inotropic, which could lead to problems during weaning from extracorporeal circulation or in the postoperative period. Difficulties could arise during the reperfusion phase if calcium antagonists are very slowly washed out. The biological half-life for intravenously administered verapamil and diltiazem is 4 to 5 hours; that of nifedipine, 1 to 2 hours [41]. Verapamil and bepridil accumulate in muscle cells [42]. The latter is known to bind very strongly to membranes. It will take approximately 1 hour to remove the drug from myocardial tissue [8]; in contrast, nifedipine and diltiazem permeate more slowly [42] and are displaced rapidly [8]. Bepridil and nisoldipine (an analogue of nifedipine) are very slowly washed from the tubing system used in a perfusion apparatus [43]. Therefore, it is important to check the affinity of calcium antagonists for the extracorporeal circuit to which they have access. When, How,and to Whom? When should calcium antagonists be given to minimize ischemic damage effectively? Nifedipine, nisoldipine, or diltiazem administered before flow reduction in the isolated heart act better than the drug applied during

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598 The Annals of Thoracic Surgery Vol 42 No 5 November 1986

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