Use of nifedipine to decrease ischemic-reperfusion injury in the surgical setting

This report summarizes studies that provided a basis for a randomized clinical trial of nifedipine in cold hyperkalemic cardioplegic solution. Data from normothermic, isolated working rabbit heart studies demonstrated that presence of micromolar concentrations of nifedipine in the perfusate during continuous low flow or nifedipine used as bolus washouts during global ischemia prevented increases in systolic and diastolic stiffness, which could be related to dose and prevention of intracellular accumulation of calcium. Other studies in open-chest dogs in whom regional ischemia was produced showed that nifedipine was superior to sodium nitroprusside when infused during the ischemic and reperfusion intervals with respect to preservation of hemodynamic variables and reduction of myocardial injury. Further, data from cardiopulmonary bypass experiments in dogs conducted at myocardial temperatures of 37, 28, 18 and 12 degrees C with 1, 2 and 3 hours of global ischemia all demonstrated significant efficacy. To date, the randomized clinical trial has shown a small reduction in the incidence of low cardiac output syndrome in high-risk patients. Those receiving nifedipine had improved hemodynamic variables. No patient in the treated group had myocardial injury in the postoperative interval shown by radionuclide pyrophosphate scan. The conclusions from this trial are that nifedipine was efficacious when included in a cold hyperkalemic cardioplegic solution. The responses observed, however, appear to be dose-, vehicle- and species-dependent.     

Differential cardiovascular effects of calcium channel blocking agents: potential mechanisms

The three major calcium channel blocking agents, diltiazem, nifedipine and verapamil, inhibit calcium entry into excitable cells. Despite this apparent common action at the cell membrane, these drugs produce quantitative and frequently qualitative differences in cardiovascular variables (for example, heart rate, atrioventricular [A-V] conduction and myocardial inotropic state) when evaluated at equieffective vasodilator doses. All three drugs increase coronary blood flow in a dose-dependent fashion (nifedipine greater than diltiazem = verapamil), and produce a negative inotropic effect in vitro in isolated atria and ventricles, also in a dose-dependent manner (verapamil greater than nifedipine greater than diltiazem). However, in conscious dogs nifedipine increases, verapamil decreases and diltiazem has little effect on the inotropic state. A-V conduction is slowed by diltiazem and verapamil but not by nifedipine in anesthetized dogs and in conscious dogs as judged from the P-R interval in the electrocardiogram. Heart rate is slowed in pentobarbital-anesthetized animals but is accelerated in conscious dogs (nifedipine greater than verapamil greater than diltiazem). Nifedipine also appears to interfere significantly with the arterial baroreceptor reflex by an apparent vagolytic action that is less evident with diltiazem and verapamil. Diltiazem, and possibly verapamil and nifedipine as well, appears to retard myocardial damage that accompanies ischemia. The mechanisms and sites of action of these drugs are presumed to be at the cell membrane; however, intracellular sites may also be involved.     

Comparative echocardiographic study of recovery of diastolic versus systolic function after brief periods of coronary occlusion: differential effects of intravenous nifedipine administered before and during occlusion

The effect of intravenous nifedipine (5 micrograms/kg) on the recovery of myocardial function after occlusion of the left anterior descending coronary artery was studied in 18 closed chest dogs. Using computer-aided analysis of two-dimensional echocardiograms, systolic and diastolic function of ischemic segments in low papillary left ventricular cross sections were characterized, respectively, as holosystolic fractional area change and early diastolic velocity of luminal area change. The time required for systolic function to return to preocclusion values after a 1 minute untreated control occlusion (n = 12) was 5 to 10 minutes, and after a 2 minute occlusion (n = 6) it was 20 to 30 minutes. When nifedipine was administered during the occlusion, recovery after a 2 minute occlusion was accelerated slightly to 10 to 15 minutes. Recovery times of early diastolic function were substantially longer, and nifedipine effects were more pronounced. After a 1 or 2 minute control coronary occlusion, 60 to 75 minutes or 90 to 105 minutes were needed to return early diastolic function to normal levels. Nifedipine administered during a 1 or 2 minute coronary occlusion improved these recovery times to 10 to 15 minutes. When the dogs were treated with intravenous nifedipine before coronary occlusion, recovery after 1 or 2 minutes of acute ischemia was apparent as early as 2 minutes after reperfusion. Thus, intravenous nifedipine accelerates the recovery of myocardial function after brief periods of ischemia, and when administered before coronary occlusion, it assures very prompt recovery of function.     

Hemodynamic effects of sublingual nifedipine in acute myocardial infarction

Twenty-six patients with acute myocardial infarction (mean delay time 6 hours after onset of symptoms) were randomized to control or nifedipine treatment (10 mg sublingually, followed by 10 mg every 6 hours for a total of 24 hours). Nifedipine reduced arterial blood pressure from 127/78 to 115/70 mm Hg at 30 minutes (p < 0.001) and continued to reduce the blood pressure significantly for 12 to 18 hours. Nifedipine also reduced systemic vascular resistance and the rate-pressure product. Cardiac output increased from 4.9 liters/min before nifedipine to 5.4 liters/min at 60 minutes (p < 0.05 vs controls). In patients with high initial pulmonary wedge pressures, sublingual nifedipine decreased the wedge pressure (p < 0.001) more effectively than did 80 mg of furosemide given intravenously. Thus, nifedipine may be useful in patients with early myocardial infarction and left ventricular failure.     

Nifedipine administered after reperfusion ablates systolic contractile dysfunction of postischemic "stunned" myocardium

Recent evidence suggests that postischemic contractile dysfunction of viable myocardium salvaged by reperfusion ("stunned myocardium") may be a consequence of abnormal calcium flux within the previously ischemic cells. Calcium channel blocking agents have been shown to enhance contractile function of stunned postischemic tissue, but it is not certain whether these improvements in function are due to the profound hemodynamic and vasodilator effects of these agents or to a direct effect on calcium flux within the stunned myocytes. Therefore, the effects of 1) high doses of nifedipine, given intravenously at 30 min after reperfusion, and 2) minute doses of nifedipine, infused directly into the coronary circulation at 30 min after reflow, were assessed and compared in anesthetized open chest dogs subjected to 15 min of transient coronary artery occlusion. As anticipated, intravenous nifedipine significantly reduced arterial pressure and increased regional myocardial blood flow. In addition, intravenous nifedipine restored systolic contractile function of the stunned, previously ischemic tissue to essentially normal preocclusion values: segment shortening averaged 102 +/- 8% versus 26 +/- 11% of baseline at 2 h after treatment in treated versus control dogs, respectively (p less than 0.003). Low dose intracoronary infusion of nifedipine did not alter hemodynamic variables or myocardial blood flow, but did improve segment shortening (90 +/- 9% versus 37 +/- 10% of preocclusion values at 1 h after treatment versus 25 min after reperfusion [that is, pretreatment], respectively; p less than 0.03). These data indicate that the calcium channel blocking agent nifedipine, given 30 min after reperfusion, enhances systolic contractile function of postischemic stunned myocardium.(ABSTRACT TRUNCATED AT 250 WORDS)     

Prevention of ischemic injury and early reperfusion derangements by hypothermic retroperfusion

Hypothermic synchronized retroperfusion was applied during coronary artery occlusion to determine its ability to alleviate junctional derangements of reperfusion and to reduce infarct size. The proximal left anterior descending coronary artery was occluded in 25 closed chest dogs for 3 hours and then reperfused for 7 days. Thirteen dogs with no reperfusion pretreatment served as a control group (Group A). In 12 dogs, hypothermic retroperfusion was applied from 30 minutes up to 3 hours of the occlusion period (Group B). Sequential two-dimensional echocardiographic and hemodynamic as well as metabolic measurements were performed. Compared with untreated control dogs, dogs with hypothermic synchronized retroperfusion had significantly reduced heart rate and rate-pressure product, decreased left ventricular volumes and improved ejection fraction during the occlusion period. Two-dimensional echocardiographically-derived ischemic zone systolic fractional area change and systolic wall thickening indicated significantly improved function as a result of retroperfusion. During the reperfusion period, untreated control dogs (group A) had more severe derangements in hemodynamics and wall motion than dogs treated by hypothermic retroperfusion (group B). Mortality was 30.7% in group A, 16.7% in group B and 7th day infarct size as percent of the left ventricle was 12.0 +/- 6.5 (mean +/- standard deviation) and 4.2 +/- 5.9, respectively (p less than 0.02). It is concluded that hypothermic synchronized retroperfusion applied after coronary occlusion and before reperfusion significantly improves cardiac function during occlusion, minimizes complications of reperfusion and reduces the ultimate infarct size. Because this form of circulatory assistance helps maintain cardiac function and delays the evolution of myocardial necrosis, its application may be beneficial during an evolving acute myocardial infarction before achievement of surgical or nonsurgical reperfusion.     

Effects of nifedipine on myocardial perfusion and ischemic injury in dogs

To determine whether nifedipine, a calcium antagonist, protects ischemic myocardium, conscious dogs were subjected to coronary occlusion and given nifedipine by intravenous infusion beginning 30 minutes after the onset of ischemia and lasting for 24 hours while systemic arterial pressure, left atrial pressure, and cardiac output were monitored. Local myocardial perfusion at selected intervals after coronary occlusion was assessed with radioactive microspheres injected into the left atrium. In regions of myocardium exhibiting moderately depressed flow 29 minutes after occlusion in control dogs (n = 8), flow was significantly greater 3 and 23.5 hours later, reflecting increases in collateral perfusion. Corresponding zones of myocardium in treated dogs (n = 9) exhibited significantly greater increases in flow at each interval after occlusion (P less than 0.05). Furthermore, myocardial creatine kinase depletion (which correlated well with morphometric estimates of necrosis) in myocardium matched for ischemia prior to treatment was 1.5 to 3 times less in treated than in control dogs (P less than 0.05). Thus, nifedipine produced sustained increases in collateral flow and reduced myocardial ischemic injury.     

Nifedipine in the treatment of unstable angina,coronary spasm and myocardial ischemia

The effects of nifedipine, a potent calcium antagonist, were studied in patients with unstable angina, coronary spasm and myocardial ischemia. Data from two separate groups of patients studied in the cardiac catheterization laboratory indicate that intracoronary injection of nifedipine promptly reversed coronary spasm—whether provoked or spontaneous—in five of six patients. In other patients, direct intracoronary injection of the drug was compared with intravenous administration. After intracoronary injection, local mechanical cardiac action virtually ceased, and the ventricular wall became thinner during systole. Thus, a specific inhibitory action on contractile energy expenditure could be demonstrated in the presence of increased coronary flow. This “oxygen-sparing” effect was tested in a group of 31 patients with symptomatic unstable angina whose pain at rest, with ST-T changes, had not responded to 8 hours of treatment with maximal beta adrenergic blockade, nitrates and bed rest. The addition of 6 × 10 mg of nifedipine rendered 27 of these patients asymptomatic within 1.5 hours. In the four patients who did not respond, coronary arteriography demonstrated severely stenotic lesions. Two of the four patients subsequently responded to intraaortlc balloon pumping and bypass surgery; one patient had a myocardial infarction and one who had a 90 percent reduction in the diameter of the left main coronary artery, died.It is concluded that nifedipine should be added to beta adrenergic blockade therapy if the latter does not appear to be immediately effective. This combination has not been shown to cause any hemodynamlc deterioration, and only a minority of the patients treated sustained a myocardial infarction during the first 3 months of follow-up. The use of nifedipine in unstable angina deserves further clinical evaluation.     

Contrasting effects of nifedipine and verapamil on myocardium and vascular smooth muscle at two levels of coronary occlusion in the dog

The calcium flux inhibitors nifedipine and verapamill have recently been used in the setting of both classical Heberden's and variant angina. It has also been suggested that these agents may preserve function and viability of threatened myocardium. The effects of these agents on the relationship between myocardial blood flow and contraction in the setting of partial coronary occlusion is unknown. Thus 39 open-chest dogs underwent partial coronary occlusion to diastolic perfusion pressures of 25 or 40 mm Hg. The dogs then received intracoronary infusions of 10 μg nifedipine or 100 μg verapamil. Myocardial blood flow was measured with tracer microspheres and myocardial shortening was assessed with ultrasonic crystals. At 25 mm Hg nifedipine improved myocardial shortening while blood flow did not change. In contrast, verapamil caused shortening to be abolished but also did not change blood flow. At 40 mm Hg nifedipine, while not affecting shortening, caused a “redistribution” of blood flow from endocardium; in contrast, verapamil again caused shortening to be abolished, but only increased epicardial blood flow leaving endocardial flow intact. Thus verapamil and nifedipine have differing effects. Nifedipine is a potent vasodilator at doses having no negative inotropic effects. In addition, nifedipine can cause a transmural “redistribution” of blood flow from endocardium to epicardium. In contrast, verapamil is also a potent vasodilator, but has profound negative inotropic effects.     

Effect of nifedipine on the myocardial and vascular response to myocardial ischemia

Summary Nifedipine reduces reactive hyperemia following brief coronary artery occlusions. To determine whether this is related to improvement in collateral blood flow to ischemic myocardium or alterations in myocardial oxygen consumption, ten chloralose anesthetized dogs were instrumented with coronary sinus catheters, circumflex artery flowmeters, and ultrasonic microcrystals for measurement of myocardial segment shortening. Myocardial oxygen consumption and circumflex coronary artery flow were determined at rest and during incremental infusions of isoproterenol. Myocardial blood flow measured with microspheres and segmental function were assessed during and following 30- and 60-second coronary artery occlusions. Thirty minutes after the intravenous administration of nifedipine, 10 g/kg iv, all measurements were repeated. Nifedipine did not alter myocardial oxygen consumption or the relationship between oxygen consumption and circumflex coronary artery flow either at rest or during isoproterenol infusion. Following 60-second coronary occlusions, nifedipine reduced peak circumflex coronary artery flow (176±99 vs. 128±68 cc/min) and reactive hyperemia debt repayment (221±84 vs. 158±66%; p<0.01). Nifedipine did not alter flow to ischemic segments during coronary artery occlusions (0.16±0.10 vs. 0.19±0.13 ml/min/g mean transmural flow). Furthermore, nifedipine did not affect the severity of ischemic segment dysfunction, nor the rate of recovery of ischemic segment function following release of coronary artery occlusion. We conclude that the reduction in reactive hyperemia induced by nifedipine was not related to alterations in the severity of hypoperfusion in ischemic areas, or alterations in myocardial oxygen consumption. Reductions in reactive hyperemia produced by nifedipine did not impair recovery of mechanical function in postischemic myocardium.This study was supported in part by grants HL01162 and HL20598 from the National Heart, Lung and Blood Institute of the National Institutes of Health, Bethesda, Maryland; and by a grant-in-aid from the American Heart Association, Minnesota Affiliate, Inc. Dr. Homans was a fellow of the American Heart Association, Minnesota Affiliate, and recipient of National Research Service Award (HL06575) from the National Heart, Lung and Blood Institute of the National Institute of Health at the time that this work was performed.     

Efficacy of nifedipine therapy for refractory angina pectoris

Nifedipine is a calcium-channel blocking agent that has been effective for patients with angina pectoris when used as single-agent therapy and as part of a combination regimen with conventional antianginal therapy. However, the efficacy of nifedipine in patients with angina refractory to maximum tolerated conventional therapy has not been extensively studied. We present experience using nifedipine in the treatment of three distinct subsets of patients with refractory angina pectoris. One hundred twenty-seven patients with Prinzmetal's variant angina and documented coronary vasospasm were treated with nifedipine after experiencing an inadequate response to conventional therapy. Nifedipine, 40 to 160 mg daily, reduced the mean weekly rate of angina attacks from 16 to 2 (p < 0.001). In 63% of the patients complete control of angina attacks was achieved, and in 87% the frequency of angina was reduced by at least 50%. Nifedipine therapy was well tolerated, and the beneficial response persisted for the 9 months of follow-up. Nifedipine therapy was added to a second group of 11 consecutive patients with refractory episodes of recurrent rest ischemia following acute myocardial infarction. Prior to infarction all the patients had a history of exertional angina only; yet following the infarction, episodes of recurrent ischemia occurred at rest in spite of maximal medical management with beta blockers and/or nitrate preparations. With maximum tolerated conventional therapy the heart rate was lowered to a mean of 65 beats/min and the blood pressure to a mean of $\text{109}\text{70}\text{mm Hg}$. The episodes of rest ischemia were prevented in all but one patient by the addition of nifedipine (mean daily dose 60 mg, range 40 to 120 mg) without causing a change in heart rate or blood pressure. Two patients continued to have myocardial ischemia with minimal exertion, although resting pains were abolished, and they underwent coronary bypass surgery for rellef of exertional pain. Only one patient continued to have episodes of ischemia at rest, and bypass surgery was necessary for pain relief. The other eight patients have been managed medically for a mean of 5.4 months and have remained pain free on combined regimens of nifedipine, beta blockers, and/or nitrate preparations. The third group of patients treated with nifedipine is composed of 239 patients with severe classic exertional angina pectoris without a suspicion of superimposed coronary vasospasm. The anginal episodes in these patients were refractory to maximum tolerated conventional therapy; however, the addition of nifedipine (mean daily dose 60 mg, range 40 to 120 mg) reduced the mean weekly angina attack rate from 20.8 to 6.4 (p < 0.00001). Although only 11% of patients had complete prevention of angina during nifedipine therapy, a total of 70% experienced a reduction in angina frequency of at least 50%. We conclude that the addition of nifedipine therapy may provide further benefit for patients with angina pectoris refractory to maximum tolerated conventional therapy. Randomized, placebo-controlled studies are necessary to confirm the efficacy of nifedipine therapy in patients with refractory angina and to clarify the mechanism of the beneficial response.     

Calcium antagonists and myocardial infarction

In vitro and in vivo studies have demonstrated many similarities between the three calcium antagonists verapamil, nifedipine, and diltiazem in relation to protection of the myocardium during hypoxia. Important clinical differences exist between the three drugs when they are used during or after an acute myocardial infarction with the purpose of preventing death and reinfarction. The balance between the negative inotropic and the vasodilator properties and concomitant treatment with beta blockers may explain the results of clinical trials with the three calcium antagonists. Patients not treated with beta blockers. Nifedipine has been demonstrated to be no better than placebo both during and after an acute myocardial infarction. No placebo-controlled studies exist with diltiazem. Verapamil had no effect during the acute phase of a myocardial infarction. After a myocardial infarction, verapamil improved survival and reduced the reinfarction rate, an effect primarily found in patients without heart failure in the coronary care unit. Patients also treated with beta blockers. Nifedipine prevents the development of myocardial infarcts in patients with unstable angina. Diltiazem probably prevents reinfarction in the first two weeks after non-Q-wave infarction. Secondary prevention with diltiazem after an acute myocardial infarction had no overall effect on death or cardiac events (i.e., reinfarction or cardiac death). Subgroup analysis demonstrated in diltiazem-treated patients, compared with placebo-treated patients, a significant reduction of cardiac events in patients without and a significant increase of cardiac events in patients with heart failure. At present no indications exist for nifedipine during or after a myocardial infarction; further studies are needed with diltiazem, and verapamil may be used in secondary prevention of death and reinfarction.     

Myocardial revascularization after acute infarction

The purpose of this study was (1) to establish the maximal interval between the onset of ischemia and reperfusion that would permit a decrease in the size of infarction, and (2) to evaluate the relation between changes in infarct size and preservation of cardiac function. Studies were carried out in 19 dogs of which 13 had temporary (1 to 3 hours) occlusion of the left anterior descending coronary artery. The hospital course of 15 patients of whom 13 underwent myocardial revascularization within 8 hours of acute infarction was also reviewed. In dogs, the eventual pathologic infarct size was significantly reduced if reperfusion was performed within 2 hours of ischemia. After 2 hours of ischemia, the revascularized segment remained dyskinetic on angiographic assessment and cardiac function was depressed. After 3 hours of ischemia, in spite of a patent coronary artery, the extent of infarct and dykinesia was greater than during ligation of the left anterior descending coronary artery. In patients, small infarcts developed with revascularization performed more than 4 hours after infarction but with revascularization of the left anterior descending coronary artery the size of the dyskinetic area (as assessed with angiography) was similar to that in patients with a closed graft to the left anterior descending coronary artery but with a patent graft to its diagonal branch. In all patients after revascularization the extent of the left ventricular dyskinetic area was smaller and cardiac function was significantly better than in patients who did not receive revascularization for complete occlusion of the left anterior descending coronary artery. In spite of successful revascularization, electrocardiographic evidence of transmural infarction persisted postoperatively. It is concluded that reperfusion of an area of myocardium that has been ischemic for less than 2 hours in dogs or less than 4 hours in man may lead to a significant reduction in the extent of infarction as well as improvement in cardiac function. However, the revascularized area remains angiographically dyskinetic and electrocardiographically abnormal.     

Nifedipine in acute myocardial infarction

Preliminary experimental and clinical data suggest that nifedipine can abort early acute myocardial infarction (AMI) or decrease infarct size by reversal of coronary artery spasm, improved coronary flow to the ischemic zone, reduction in myocardial oxygen demand or protection of ischemic cells. The first large clinical trial testing the ability of nifedipine to reduce infarct size, the Nifedipine Angina Myocardial Infarction Study, was recently reported. Nifedipine treatment failed to prevent progression of threatened infarction to AMI or to reduce infarct size in patients with AMI. The study suggested an increased early mortality rate in patients with AMI treated with nifedipine, but this finding should be interpreted with caution pending the results of similar trials now in progress.     

Ischemic event characteristics determine the extent of myocardial stunning in conscious dogs

Both the severity and duration of postischemic myocardial dysfunction (stunned myocardium) are unpredictable and may vary considerably between subjects that underwent apparently similar ischemic insults. To explain this heterogeneous response of the heart to ischemia and reperfusion, we investigated the determinants of stunning in conscious dogs.Twenty-five dogs were chronically instrumented for measurement of global and regional myocardial performance (wall thickening) and myocardial perfusion (coloured microspheres). A hydraulic occluder was positioned around the LAD coronary artery. Conscious dogs were subjected to acute coronary artery occlusions of predetermined duration (2, 5 and 10 min), followed by complete reperfusion.Multiple regression analysis identified the following variables as determinants of postischemic contractile recovery: 1) the duration of ischemia (p<0.01), 2) the amount of collateral perfusion (p=0.01) and 3) left ventricular end-diastolic pressure during ischemia (p<0.01). Neither the severity of regional dyskinesia during ischemia nor indices of global systolic hemodynamic performance correlated with the rate of recovery.Our data confirm that myocardial stunning relates primarily to the intensity of preceding ischemia. Variations in the preexisting level of collateral perfusion may result in markedly different recovery profiles. Except for LV end-diastolic pressure during ischemia, indices of global and regional cardiac performance fail to predict the severity of postischemic contractile failure.Supported in part by the Nationaal Fonds voor Wetenschappelijk Onderzoek: grant #3.0071.90     

Nifedipine reduces the incidence of myocardial infarction and transient ischemia in patients undergoing coronary bypass grafting

A randomized study was performed on 104 patients undergoing elective coronary artery bypass grafting to examine whether the infusion of nifedipine (n = 53) reduces the incidence of perioperative myocardial ischemia and necrosis in the early postoperative period. Continuous hemodynamic and three-channel Holter monitoring was performed for 24 hours and serial assessment of serum enzymes and 12-lead electrocardiography were performed for 36 hours postoperatively. Nifedipine (minimum dose, 10 micrograms/kg/hr for 24 hours) was applied from the onset of extracorporal circulation. The control group (n = 51) received nitroglycerin (minimum dose, 1 micrograms/kg/min for 24 hours). Using the combined analyses of electrocardiography and Holter recordings, myocardial ischemia was defined as being either a transient ischemic event (TIE), transient coronary spasm (TCS), or myocardial infarction (MI). The two groups did not differ with respect to preoperative New York Heart Association classification, age, history of myocardial infarction, extracorporal circulation and aortic cross-clamp time, number of distal anastomoses, or systemic and pulmonary hemodynamics. The incidence of perioperative myocardial ischemia was substantially lower in the nifedipine than in the nitroglycerin group [TIE: three of 53 patients (6%) versus nine of 50 patients (18%), p less than 0.001; MI: two of 53 patients (4%) versus six of 50 patients (12%), p less than 0.001; and TCS: none of 53 patients (0%) versus two of 50 patients (4%), p = NS].(ABSTRACT TRUNCATED AT 250 WORDS)     

Treatment with diltiazem preoperatively in open heart surgery for myocardial protection: experimental studies in dogs with chronic healed myocardial infarction

Calcium antagonists have become important in open heart surgery because of their effects on myocardial protection and cardioplegia. We evaluated the effect of pretreatment with the calcium antagonist diltiazem for myocardial protection in dogs with experimentally induced, chronic, healed myocardial infarction in a double-blind randomized study. One group consisted of 5 dogs treated with diltiazem (10 mg/kg bodyweight) for 7 days preoperatively, while a second group of 4 dogs were treated with placebo. All animals then underwent hypothermic, ischemic cardiac arrest (90 min) with extracorporeal circulation (ECC), followed by 30 min of reperfusion. Hemodynamic parameters were measured before and after ECC. An EKG was recorded during the entire procedure. The myocardium was studied by light microscopy for fresh necroses. The old, experimentally induced infarction scars were quantified by a new method that was developed for planimetry of the histological specimens. The diltiazem group compared with the placebo group showed myocardial cell necroses to a smaller extent. The hemodynamic studies supported the contention that diltiazem given preoperatively has a myocardial protective effect. These results encourage further studies on the use of diltiazem preoperatively for myocardial protection.     

Relation between reversal of diastolic creep and recovery of systolic function after ischemic myocardial injury in conscious dogs

Although prolonged functional abnormalities after transient myocardial ischemia have been well described, the interrelationship between postischemic systolic and diastolic alterations remains controversial. Therefore, 24 chronically instrumented conscious dogs were studied with left ventricular and pleural micromanometers, ultrasonic dimension transducers in the left anterior descending (LAD) coronary distribution, and vena caval and coronary artery occluders. The LAD was occluded for 15 minutes and reperfused for 24 hours while vena caval occlusions were performed at intervals to measure myocardial segment length at 0 mm Hg transmural diastolic left ventricular pressure (L0). Coronary occlusion produced an immediate fall in systolic function as assessed by ejection shortening and stroke work and also induced a 16 +/- 4% increase in L0, which was termed diastolic creep. Throughout reperfusion, reversal of diastolic abnormalities correlated strongly with recovery of segmental shortening and stroke work (p less than 0.001). Correlation between systolic dysfunction and diastolic creep was also observed during alteration of inotropic state by dopamine, during initial reperfusion hyperfunction, and during pharmacologic manipulation of afterload. In 5 additional dog hearts fixed in diastole by rapid glutaraldehyde infusion after coronary occlusion, myocardial creep measured by the segment length transducers paralleled sarcomere elongation measured by electron microscopy. Thus, the direct correlation between diastolic creep and systolic dysfunction throughout reperfusion and during hemodynamic alterations suggests that diastolic properties of postischemic myocardium may not be entirely passive and that systolic and diastolic dysfunction induced by ischemia may have a common basis at the cellular level.     

Effects of nifedipine on triggered activity in 1-day-old myocardial infarction in dogs

Triggered activity arising from a delayed afterdepolarization occurs in canine subendocardial Purkinje fibers 1 day after myocardial infarction (MI). Standard microelectrode techniques were used to study small preparations (20 to 48 mm2) in vitro. Nifedipine, 1 mg/liter, reversibly suppressed triggered activity by reducing maximum diastolic potential, action potential amplitude and the rate of depolarization of the delayed afterdepolarization. Complete quiescence or exit block resulted. The effects of nifedipine were antagonized by elevating extracellular calcium ion concentration. These results suggest that spontaneous ectopic rhythms 1 day after MI that are the result of triggered activity are dependent on transmembrane calcium ion movement, which nifedipine can directly antagonize.     

Sustained limitation of myocardial necrosis 24 hours after coronary artery occlusion: Verapamil infusion in dogs with small myocardial infarcts

Studies were undertaken to ascertain whether verapamil infusion affords a sustained limitation of myocardial injury in the dog after a 24-hour period of coronary artery occlusion. Regional myocardial ischemia was induced by an embolization procedure which did not involve thoracotomy. Immediately after embolization radioactive microspheres were administered intraventricularly to define any area of myocardial underperfusion (zone at risk of infarction). Verapamil (0.005 mg/kg/min) was then administered and maintained for 24 hours during which time the dogs were allowed to recover from anesthesia. The control group received a corresponding infusion of saline solution. After 24 hours the dogs were killed and transverse myocardial sections (3 mm) were prepared. The resulting area of necrosis was visualized by tetrazolium staining, and risk zones were visualized by autoradiography. In the control heart, 62 ± 7% of the zone at risk deteriorated to necrotic tissue, whereas in the verapamil-treated group only 18 ± 4% of the tissue in the zone at risk became necrotic. Verapamil appeared to exert a significant (p < 0.001) tissue-sparing effect that was sustained for at least 24 hours after the onset of ischemia.