Nitrates and Left Ventricular Remodeling

Nitrates and Left Ventricular Remodeling Bodh I. Jugdutt,

MD, MSc

Left ventricular remodeling is the major mechanism leading to cardiac enlargement, failure, and death after myocardial infarction. It is associated with early disruption of collagen matrix and expansion of the infarct zone (IZ) followed by progressive global ventricular dilation, hypertrophy of the noninfarct zone (NIZ), and further global dysfunction. In parallel, it is associated with healing which repairs the IZ with collagenous scar. Mechanical deformation forces, including ventricular diastolic and systolic loads, mediate structural remodeling during healing, and beyond. Experimental and clinical evi-

dence indicate that early and prolonged impedance reduction and diastolic unloading with nitric oxide donors like nitrates can effectively limit remodeling. Other benefits are mediated by limitation of infarct size and transmurality, improvement of left ventricular hemodynamics and collateral flow, decreased reperfusion injury, and antithrombotic effects. In addition to these benefits, nitrates have nonhemodynamic, antigrowth and cellular actions that limit progressive remodeling after infarction. Q1998 by Excerpta Medica, Inc. Am J Cardiol 1998;81(1A):57A– 67A

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infarction27 and postinfarct healing,7 and extends beyond.31,32 Second, it begins very early, with infarct zone (IZ) expansion involving a stretching, thinning, and bulging of the IZ present in diastole. This early regional dilation sets the stage for further remodeling of the noninfarct zone (NIZ), global dilation and shape change through a continuous process involving remodeling of shape and structure on a beat-to-beat basis (Figure 2).2,33 Third, the structural changes are associated with changes in the collagen matrix framework and collagen content, composition, and structure.23 Thus, a disruption of the supporting extracellular collagen matrix allows side-to-side myocyte slippage during acute regional IZ expansion34,35 as well as subsequent expansion of the NIZ during progressive global dilation.36 In addition, healing repairs the IZ by a process of organized new collagen deposition and remodeling to form a firm collagenous scar.37–39 Furthermore, ventricular enlargement triggers myocyte hypertrophy (via a sequence of ventricular dilation, increased wall stress, upregulation of contractile, and noncontractile protein gene expression40) as well as fibroblast hyperplasia and deposition of interstitial collagen protein in the NIZ.41 This hypertrophy and interstitial fibrosis of the NIZ contributes to impairment of diastolic function.42 Fourth, it is possible to limit ventricular remodeling, preserve shape and function, and improve outcome.11,32 In this effort, pathophysiologic staging (Table II) can guide timing and duration of therapy.2 Early and prolonged therapy is likely to produce the greatest benefits. Fifth, a specific therapy targeted at one mechanism might have unexpected effects6,11,12,14,19,20 so that the final outcome of therapeutic interventions represents the balance of effects. This principle is well illustrated in studies with nitrates,6,11,19 angiotensin-converting enzyme (ACE) inhibitors,19,20 and anti-inflammatory agents.12,14 The question of how the heart changes shape and structure by the remodeling process after myocardial damage is under active investigation in the investigator’s and other laboratories. To date, 4 mechanisms have been proposed: (1) cell necrosis, healing, collagen deposition, and collagen and scar remodeling22; (2) collagen matrix disruption, collagenase activation,

yocardial infarction and the consequent cardiac enlargement and heart failure are major causes of death and disability worldwide. During the past decade, left ventricular remodeling after myocardial infarction (Table I) has become recognized as the major mechanism for these sequelae.1,2 As a result of improved postinfarction therapies, the population of early survivors at risk for late remodeling and its consequences is expected to increase. For nearly two decades, the author’s laboratory has been dedicated to experimental and clinical research on the characterization, mechanisms, quantitation, and modification of left ventricular remodeling during healing postinfarction using various therapeutic strategies including nitrates.3–22 The determinants of ventricular remodeling postinfarction and their modification by vasodilator therapy have been reviewed.22–24 The hypothesis that left ventricular unloading produced by nitrates might attenuate ventricular remodeling after infarction was tested in experimental animal models6,12,17–19,25 and mechanistic studies in humans.10,11,13,16,21 This article provides an update on advances in our understanding of the pathophysiology of ventricular remodeling and the potential value of nitrates.

PATHOPHYSIOLOGY OF VENTRICULAR REMODELING Ventricular remodeling refers to the changes in structure and shape associated with myocardial damage. Left ventricular remodeling after myocardial infarction is a complex and dynamic process. It involves progressive changes in shape, volume, and mass, which frequently aggravate dysfunction, especially after large anterior transmural or Q-wave infarction.11,14,15,26 –30 Evidence from several laboratories1,2,22 underscores 5 important points about ventricular remodeling. First, it is a progressive, timedependent process (Figure 1) that spans phases of From the Cardiology Division of the Department of Medicine, University of Alberta, Edmonton, Alberta, Canada. Address for reprints: Bodh I. Jugdutt, MD, 2C2.43 Walter Mackenzie Health Sciences Centre, Division of Cardiology, Department of Medicine, University of Alberta, Edmonton, Alberta, Canada T6G 2R7. ©1998 by Excerpta Medica, Inc. All rights reserved.

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TABLE I The Cascade of Ventricular Remodeling Acute myocardial infarction Early infarct expansion Ventricular rupture: free wall, septum Scar remodeling Chronic aneurysm formation Progressive global dilation Progressive dysfunction Congestive heart failure Volume overload Hypertrophy Arrhythmias Increased morbidity and mortality

and myocyte slippage22; (3) myocyte hypertrophy and cell elongation22; and (4) cellular apoptosis43,44 or “cell drop-out” as distinct from cell death due to stress, injury, and necrosis. Apoptosis is an active, genetically regulated, energy-dependent process that has been studied in hypertrophied hearts45 and failing hearts.46,47

LIMITATION OF VENTRICULAR REMODELING The major determinants of ventricular remodeling (Table III) include infarct size, loading conditions (mechanical deformation forces and wall stress), integrity of the supporting collagen framework, and adequacy of the healing process. Several potential therapies (Table IV) can be directed at the determinants (Figure 2) .1,2,9 Appropriate timing and choice of the therapies according to the stage of progression2,22 can potentially interrupt, prevent, or reverse the vicious cycle of remodeling. Six primary aims of therapy to limit ventricular remodeling or antiremodeling therapy have been identified2,22,48: (1) to decrease infarct size and transmural extension of infarction; (2) to promote healing and provide nutrient flow for the process; (3) to protect the supporting, extracellular collagen matrix, to promote collagen deposition in the IZ, and to preserve the thickness of the infarct wall; (4) to reduce mechanical deformation or remodeling forces (such as high preload, high afterload, high heart rate, and increased contractility), to reduce ventricular dilation and high wall stress; (5) to prevent progressive dilation, hypertrophy, and necrosis; and (6) to prevent ventricular dysfunction from reperfusion, and oxygen free radical and oxidation injury.

An effective algorithm for therapeutic interventions in remodeling is as follows: salvage of ischemic myocardium B preserve structure and shape B improve systolic squeeze and diastolic function B improve outcome and survival. Several potential antiremodeling therapies have been proposed.2,22,48 These include coronary reperfusion, ACE inhibitors, nitrates, b-adrenergic blockers, new generation calcium antagonists, angiogenic agents, collagen promoters, superoxide dismutase, antioxidants, selective angiotensin II type 1 (AT1) receptor antagonists, and endothelin-A (ETA) receptor antagonists. Quantitative 2-dimensional echocardiography (with 3-dimensional reconstruction) is an effective, widely used technique for the noninvasive assessment of the effects of therapy on left ventricular remodeling and function in vivo.11,14,15,32 Efforts for reducing cardiovascular deaths between the mid-1970s and mid-1980s were directed to limiting infarct size. This was a logical strategy because deaths from pump failure, infarct expansion, left ventricular dilation, and left ventricular dysfunction were directly related to infarct size.26,49,50 There is general agreement that during the early infarction and early remodeling phases, early coronary artery reperfusion is most effective for limiting infarct size, transmural infarct extension, and ventricular dysfunction. Evidence from several clinical trials51–54 supports this consensus. Widespread use of reperfusion (by pharmacologic and mechanical means) in combination with b-adrenergic blockers and nitrates,55 over the last decade has resulted in a dramatic decrease in early postinfarction deaths from about 35% to nearly 7%.56 –59 Although the paradigm limit infarct size B reduce remodeling B improve function holds true for very early reperfusion, late reperfusion (that is, beyond 2 hours) results in a mismatch between limitation of early remodeling (that is infarct stretching, thinning, and dilation) and improvement in regional function. This phenomenon, which is due to stunning and reperfusion injury,60 – 65 supports the use of adjunctive therapies to prevent persistent postischemic ventricular dysfunction. Reperfusion also accelerates healing of the IZ66 and is associated with additional disruption of the extracellular collagen matrix.67,68 However, the negative effects of reperfusion are outweighed by the delayed march to necrosis and limitation of infarct size with reperfusion,69 the limitation of

TABLE II Stages in Healing and Remodeling Processes Timing After Infarction* Very early: #24 h Early: day 2–14 Late: 3–6 weeks Very late: 1.5–12 mo

Healing Process

Remodeling Process

Acute inflammation, march to necrosis in IZ, collagen matrix disruption and cell slippage in IZ. Chronic inflammation; fibroblast proliferation and collagen deposition in IZ; matrix disruption and stretching of NIZ. More collagen deposition after the collagen plateau in the IZ and collagen remodeling with crosslinking and myofibroblast formation Further scar remodeling with contraction, maturation and myofibroblast formation. Other growth: angiogenesis.

*Based on canine and human data. IZ 5 infarct zone; LV 5 left ventricular; NIZ 5 noninfarct zone.

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Infarct expansion Early LV dilation, aneurysm formation, LV rupture More LV dilation, LV hypertrophy Progressive LV dilation, LV hypertrophy

FIGURE 1. Histopathologic and topographic changes during infarct healing. Upper: The dynamic nature of histopathologic changes in the infarct substrate from 194 canine hearts studied at 10 time intervals after permanent coronary artery ligation. Lower: Topographic changes from maps of transmural and nontransmural infarcts among those hearts for 5 selected time intervals. (Adapted with permission from Can J Cardiol.2)

FIGURE 2. Schematic of approaches for limiting left ventricular remodeling after myocardial infarction. Short-axis section of the left ventricle showing the diastolic bulge in the infarct segment (darkened). IRA 5 infarct-related artery; IZ 5 infarct zone; LV 5 left ventricle; NIRA 5 noninfarct-related artery; NIZ 5 noninfarct zone. A SYMPOSIUM: NITRATE TOLERANCE

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TABLE III Major Determinants of Ventricular Remodeling IZ characteristics • Size, transmurality, location, type, age Mechanical deformation forces on IZ • Intracavitary distending forces (PUSH & STRETCH) • Preload, afterload, wall stress Efficacy of healing of IZ • Inflammatory response; collagen deposition • Collateral circulation; reperfusion Progressive dilation • Nutrient flow to NIZ • Remodeling of supporting collagen matrix • Hypertrophy of NIZ • Remodeling of LV shape • Remodeling of vascular structures IZ 5 infarct zone; LV 5 left ventricular; NIZ 5 noninfarct zone.

acute IZ expansion even in the absence of myocardial salvage,64,70 the provision of nutrient flow during IZ healing,64,66 and the limitation of late ventricular remodeling and dysfunction.71 Vasodilator therapy provides another potentially powerful strategy for limiting remodeling by a hemodynamic mechanism. However, its role in the acute infarction phase is mainly adjunctive, in combination with reperfusion therapy or as an alternative to reperfusion therapy.55 Vasodilators have the potential for: (1) unloading the left ventricle (that is, decreasing ventricular preload, afterload, and impedance to ejection) and thereby reducing wall stress, chamber size, and IZ expansion; (2) limiting left ventricular hypertrophy (via the reverse algorithm of less ventricular enlargement B less wall stress B less wall stretch B less protein gene expression B less hypertrophy); and (3) improving myocardial energetics and coronary artery reactivity.2,22 However, vasodilators can produce benefits via nonhemodynamic mechanisms at the tissue level. This is true for both nitrates and ACE inhibitors. However, unlike nitrates, ACE inhibitors produce va-

sodilation by blocking ACE and reducing vasoconstrictor actions of angiotensin II as well as by blocking bradykininase, which results in increased bradykinin levels.72 The latter leads to release of prostacyclin and nitric oxide,73 which contributes to ventricular unloading and antitrophic actions.74 –77 Vasodilator therapy of acute infarction with nitrates has been applied to effectively improve hemodynamics and limit infarction size, remodeling, and dysfunction.11,23,24 Early ACE inhibitor therapy of acute infarction with captopril78 and ramipril79 effectively reduced ventricular dilation, although enalapril produced excessive hypotension that was associated with excess mortality.80 Powerful vasodilators, such as nitrates and ACE inhibitors, clearly have the potential for causing excessive hypotension, the paradoxical J-curve effect, and extension of necrosis in higher doses during acute infarction.4,11,23,80 – 83 Such vasodilators should be used with caution in the acute infarction setting as more necrosis could potentially enhance remodeling.2 Vasodilator therapy plays a primary role in antiremodeling therapy after the early infarction phase. Several studies have shown that prolonged ACE inhibitors are highly effective in limiting left ventricular remodeling and reducing mortality in patients with anterior Q-wave infarction.32,84 – 89 When the vasodilator efficacy of prolonged nitrates is enhanced by the use of an eccentric dosage schedule with a nitrate-free interval16,17,90 or the newer formulation isosorbide mononitrate,18,25 beneficial antiremodeling effects are produced. Moreover, ACE inhibitor therapy during healing after infarction is associated with an inhibition of collagen deposition in the IZ and NIZ of rat hearts91–95 and the IZ of dog hearts.19,20,96 Although ACE inhibitor-induced limitation of myocyte hypertrophy18,19 and the interstitial fibrosis in the NIZ likely contributes to the improvement of diastolic function,42 recent studies suggest that a linkage exists between decreased IZ collagen and more IZ remodeling.20,39,96 Taken together, the negative results of the CONSEN-

TABLE IV Approaches for Limiting Ventricular Remodeling Postinfarction Target Infarction

Healing

Deformation forces Progressive dilation

Strategy

Avoid

Prevent infarction Limit infarction size Limit transmural extension Limit reperfusion injury LV unloading during infarction Promote normal healing Maintain infarct related artery patency Maintain non-infarct related artery patency Increase collateral flow Preserve collagen matrix Preserve architectural framework LV unloading during infarction, healing and beyond Limit chamber dilation Prevent inappropriate hypertrophy Protect architectural framework Preserve shape; prevent sphericity Preserve perfusion to non-infarct zones

IZ 5 infarct zone; LV 5 left ventricular; NIZ 5 non infarct zone.

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Paradoxical J-curve effect

Excessive anti-inflammatory drugs Excessive contractile pull with inotropes Excessive scar thinning Excessive exercise and loading Excessive inhibition of IZ collagen Collagen matrix disruption Excessive contractile pull with inotropes Excessive exercise and loading Reinfarction Excessive NIZ hypertrophy Excessive inhibition of IZ collagen

SUS II trial,80 the lack of an early separation of survival curves in other ACE inhibitor megatrials,58,59 and the finding of persistent ventricular dysfunction after early captopril in rats92 might have been related to early inhibition of collagen and collagen matrix in the IZ and NIZ.20,97–99 The decrease in heart rate and contractility produced by b-adrenergic blockers100,101 and calcium antagonists100,102 have also been suggested to decrease infarction expansion and limit left ventricular dilation postinfarction. The North American registry55 published in 1994, showed that patients treated with thrombolytic therapy also received adjunctive therapies such as intravenous nitroglycerin (76%), oral b blockers (30%), intravenous b blockers (17%), calcium antagonists (30%), intravenous heparin (97%), and aspirin (84%).

NITRATES FOR LIMITATION OF EARLY VENTRICULAR REMODELING The mechanisms for the cardioprotective effects of nitrates have been reviewed elsewhere.23,24,103 Briefly, nitrate-induced vasodilation of venous, arterial, and coronary beds results in decreased preload, afterload, and impedance, and enhanced myocardial perfusion that leads to improved ventricular geometry and myocardial energetics in acute infarction. Nitrate-induced increase in prostacyclin and decrease in platelet adhesiveness contribute in improving perfusion. Several experimental3,4,104 and small randomized clinical5,105–115 studies established that intravenous nitroglycerin in acute infarction decreases left ventricular systolic and diastolic loads, improves regional and global systolic function, and relieves pulmonary edema. These studies also indicate that nitrate-induced improvement in collateral blood flow is associated with decrease in ischemic injury and infarct size provided the dose is titrated to avoid excessive hypotension.3–5,104 –115 The nitrate-induced decrease in infarct size and transmurality,3,5,6,11,113,114 decrease in ventricular loading,23 and limitation of factors that favor early IZ expansion,8 regional diastolic bulging,13 myocyte slippage,34,35 collagen matrix disruption in the IZ,30,67,68 and regional distensibility34,35 contribute in limiting early IZ expansion. Nitrate-induced sparing of an epicardial rim of myocardium with preserved integrity of the collagen matrix30 contributes in resisting regional bulging. Although nitrates are now used as an adjunct to thrombolytic therapy in acute infarction,55 there is solid evidence from one large randomized and placebo-controlled study that intravenous nitroglycerin infusion during acute infarction limits early left ventricular remodeling (Figure 3) and improves function (Figure 4), in addition to several other beneficial effects.11 Unlike other long-acting vasodilators, nitroglycerin allows easy upward titration of the dose to achieve the optimal blood pressure lowering11,116 and “backing off” if hypotension develops. Individual analysis of the hemodynamic recordings in the 310 randomized patients11 revealed only partial tolerance in 24% of the patients.13 Although blood pressure in the nitroglycerin and placebo groups was similar be-

tween 12 and 48 hours of the infusion, the left ventricular volume and filling pressure were lower in the nitrate group.13 Furthermore, 1 hour after stopping the infusion, the blood pressure and left ventricular filling pressure showed partial reversal but the diastolic left ventricular dimensions and volumes did not return to baseline values despite the upward trend. Importantly, the beneficial effects on left ventricular function and topography were not blunted in the 24% of patients with partial tolerance. Although the decrease in infarct size was slightly less in patients who developed hypotension despite the titration (mostly those with inferior infarction), these patients still showed less early remodeling, less IZ expansion, less global ventricular dilation, and better left ventricular function compared with the placebo group.11 The treated patients demonstrated marked decrease in morbidity parameters (Figure 5) and other infarct-related complications. Not only did the strong positive effects on remodeling persist up to 1 year, but they correlated with decreased in-hospital mortality (Figure 6) and morbidity at 1 year in that study.11 The overall results of that study were the first to suggest that vasodilator-induced decrease in ventricular loading and wall stress could result in limitation of infarct size and early ventricular remodeling, and have long-term beneficial effects on morbidity and mortality. A subsequent meta-analysis of pooled data from these studies from the prethrombolytic era suggested a 49% decrease in mortality with intravenous nitroglycerin and a 35% decrease in mortality with all nitrate (and 3 nitroprusside) studies.117 In patients who had already developed marked infarct expansion during acute infarction in the prethrombolytic era, aggressive left ventricular unloading with intravenous nitroglycerin combined with intraaortic balloon counterpulsation for 4 –5 days was highly effective in preventing progressive NIZ stretching and global left ventricular dilation.118 A beneficial effect of nitroglycerin infusion in attenuating IZ dilation was also suggested in patients who received antiinflammatory agents (that delay IZ healing and block the inflammatory response in the first 2 weeks causing excessive IZ thinning and dilation119 –121) for pericarditis after large Q-wave infarctions.14 Recent evidence suggests that nitroglycerin can be safely combined with thrombolytic agents.16,21,55,122,123 The antiplatelet and antithrombotic properties of nitrates124 may enhance thrombolytic effects. Between 1990 and 1993, a registry of patients receiving thrombolytic therapy in the United States revealed that 76% were also treated with concomitant intravenous nitroglycerin. In a study of adjunctive intravenous nitroglycerin in patients with reperfusion achieved after 4 hours (with angioplasty or intracoronary streptokinase), nitroglycerin produced earlier and greater recovery of left ventricular function in addition to attenuation of remodeling.21 In another study of patients with nonreperfused infarction, adjunctive intravenous isosorbide dinitrate and streptokinase reduced creatine kinase infarct size.122 Recently, combined administration of N-acetylcysteine with intravenous streptokinase in patients with early myocardial A SYMPOSIUM: NITRATE TOLERANCE

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FIGURE 3. Changes in expansion index (left) and thinning ratio (right) for control and nitroglycerin groups. Expansion index is shown separately for anterior and inferior infarct subgroups. Values are mean 6 SD. *p <0.05, significance of difference comparing values at 2–3 days (2) and 10 days (3) with baseline. (Adapted with permission from Can J Physiol Pharmacol.11)

FIGURE 4. Changes in left ventricular (LV) asynergy and LV ejection fraction. Values as mean 6 SD. *p <0.001, significance of difference comparing values at 6 hours (2), 24 hours (3), and 48 hours (4), and 10 days (5) with the baseline (1). (Adapted with permission from Can J Physiol Pharmacol.11)

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FIGURE 5. Changes in Killip class score in control and nitroglycerin groups. Values (mean 6 SD) on admission (initial), at 24 and 48 hours and the maximum between 2 and 10 days are shown. *p <0.05, significance of difference between baseline and subsequent values in all controls and control subgroups. **p <0.05, significance of difference between baseline and subsequent values in the nitroglycerin group and subgroups. (Adapted with permission from Can J Physiol Pharmacol.11)

FIGURE 6. Actuarial survival curves for nitroglycerin and control groups. Data over the 43 months or 186 weeks of the long-term follow-up are shown. Left: All patients. Middle: Anterior subgroups. Right: Inferior subgroups. (Adapted with permission from Can J Physiol Pharmacol.11)

infarction was shown to reduce oxidative stress, accelerate reperfusion, and improve left ventricular function.123 Despite its antithrombotic effects,124 recent reports have suggested that intravenous nitroglycerin might decrease sensitivity to heparin and require an increase in the dose of heparin to maintain the anticoagulation endpoint.125–127 The 1996 American College of Cardiology/ American Heart Association (ACC/AHA) guidelines for the management of patients with acute infarction supports the use of intravenous nitroglycerin for the first 24 – 48 hours in acute infarction but does not comment on its role in limiting early ventricular remodeling.128

NITRATES FOR LIMITATION OF LATE VENTRICULAR REMODELING Although prolonged vasodilator therapy is a logical approach for preventing progressive ventricular remodeling after myocardial infarction, the development of tolerance with chronic application of nitrates is a major limitation. However, tolerance can be minimized by intermittent or eccentric administration of nitrates, or use of less tolerance-prone preparations such as isosorbide-5-mononitrate.129,130 Using these approaches, cardioprotection and antiremodeling effects were achieved during postinfarct healing, with16,18,21 or without10,17 reperfusion, and in the presence of concomitant therapies.11,19 Although combiA SYMPOSIUM: NITRATE TOLERANCE

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nation with oral hydralazine prevents tolerance in heart failure patients,131 the effect of the combination on remodeling remains to be assessed. Apart from recognized antianginal and flow promoting effects of nitrates, recent evidence indicates that, unlike ACE inhibitors, nitrates limit myocyte hypertrophy but do not inhibit collagen deposition in the IZ during healing.19 In addition, nitrate-induced increase in collateral flow and decrease in wall stress during healing have been postulated to protect against disruption of intermyocyte collagen struts in the NIZ, and thereby contribute to the limitation of progressive ventricular enlargement.103 Whether such a protective effect of nitrates on the collagen matrix and IZ collagen deposition might prove beneficial during ACE inhibitor therapy remains to be tested. Experimentally, several nitrate preparations were studied during healing after anterior infarction in a reproducible dog model.17 The nitrates effectively limited remodeling and the increase in left ventricular mass, but the antiremodeling efficacy was greater with prolonged therapy for 6 weeks than just for the first 2 weeks. In another study, isosorbide-5-mononitrate therapy was tested for 6 weeks after late coronary artery reperfusion in the dog model.18 The nitrate group showed earlier and greater recovery of function and less remodeling than late reperfusion alone. In a dog model of myocardial necrosis produced by direct current shock,25 prolonged therapy with isosorbide-5mononitrate limited the increase in left ventricular mass. In one randomized study of 56 patients with anterior Q-wave infarction in the prethrombolytic era,10 treatment with intravenous nitroglycerin for 48 hours was followed by placebo or buccal nitroglycerin in an eccentric dose schedule (8 AM, 1 PM and 6 PM with an 8-hour nitrate-free interval) for 6 weeks. Quantitative 2-dimensional echocardiograms demonstrated less remodeling with preservation of left ventricular size and shape, and improvement in systolic function in the nitrate group. Radionuclide scans showed smaller left ventricular volumes that correlated with clinical benefits up to 8.5 months after stopping therapy in the nitrate group.10 In another randomized study of 80 patients with anterior Q-wave infarction in the thrombolytic era,16 treatment with thrombolysis and intravenous nitroglycerin over 48 hours was followed by 4 treatment regimens using a factorial design: oral captopril (6.25–12.5 mg, 3 times daily), buccal nitrate (1–3 mg daily at 8 AM, 1 PM and 6 PM with an 8-hour nitrate-free interval), oral captopril plus buccal nitrate, or matching placebo. The preliminary data indicated that the nitrate and captopril groups produced similar beneficial effects on left ventricular remodeling and function. In a pilot study of the Fourth International Study of Infarct Survival (ISIS-4) trial,132 regular doses of isosorbide-5mononitrate (20 mg, 3 times daily) or captopril (12.5 mg, 3 times daily) for 1 month in patients with suspected myocardial infarction, were associated with attenuation of hemodynamic effects in the 64A THE AMERICAN JOURNAL OF CARDIOLOGYT

nitrate group compared with captopril. In a randomized study of 316 patients with acute infarction,133 (of whom 97% received thrombolysis, 17% had previous infarction and 42–56% had anterior infarction), treatment with intravenous isosorbide dinitrate or placebo was followed in some 160 patients with isosorbide-5-mononitrate (25–50 mg slow release, once daily; between 3 days and 6 weeks). The results showed heterogeneity of effect among the subgroups and no net benefit with nitrates. Two multicenter mortality megatrials involving 77,000 patients with suspected acute myocardial infarction in the thrombolytic era tested the hypothesis that addition of nitrates or ACE inhibitors to existing therapy for 6 weeks will reduce mortality. The Gruppo Italiano per lo Studio della Streptochinasi nell’ Infarcto Miocardico (GISSI)-3 trial58 used acute intravenous nitroglycerin followed by transdermal nitroglycerin for 6 weeks (10 mg daily with a 10-hour nitrate-free interval) and showed an insignificant mortality reduction with nitrate compared with the control group (6.52% vs 6.92%). The ISIS-4 trial59 used extended-release isosorbide-5mononitrate acutely and for 5 weeks and showed an insignificant mortality reduction compared with the control group (7.34% vs 7.54%). In both GISSI-3 and ISIS-4 trials, the fact that nearly 60% of patients received open-label nitrate reduced the power of the studies to detect the potential benefit of nitrates. However, in the ISIS-4 trial, mortality in the nitrate group over the first 2 days was reduced (1.77% vs 2.16%, p ,0.001). In the GISSI-3 trial, the combination of nitrate and lisinopril reduced total mortality by 17% (p 5 0.02). The same combination reduced the combined endpoint of mortality and ventricular dysfunction in the elderly by 21% (p 5 0.0004) and in women by 21% (p 5 0.0005). The nitrate group in the GISSI-3 trial also showed less postinfarction angina (p 5 0.03) and cardiogenic shock (p 5 0.009). The GISSI-3, ISIS-4, and subsequent trials134 –136 showed a small significant decrease in mortality with the ACE inhibitors. The combined results of all randomized and placebo-controlled nitrate trials showed a small significant reduction in mortality.59 Recent evidence suggests that nitrates may exert a beneficial effect on cardiac rupture, a major complication of ventricular remodeling postinfarction. Prethrombolytic studies suggested a lower frequency of septal or free wall rupture with nitrate therapy.11,14,15 Since the advent of thrombolysis, the frequency of free wall rupture appeared to increase alarmingly,137 although recombinant tissue-type plasminogen activator (rt-PA) was suggested to accelerate rupture events rather than increase the risk of rupture.138 In a clinicopathologic case-controlled study of 91 patients with free wall rupture complicating acute myocardial infarction, nitrates reduced the risk of rupture by approximately 30%.139 The 1996 ACC/AHA guidelines128 do not comment on the role of prolonged nitrate therapy for prevention of late remodeling postinfarction.

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CONCLUSIONS The prevention or limitation of left ventricular remodeling and preservation of left ventricular function are primary goals of antiremodeling therapy. During acute myocardial infarction, nitrates, alone or as an adjunct to thrombolytic therapy, can effectively limit early left ventricular remodeling. Prolonged vasodilator therapy after myocardial infarction can prevent late remodeling. However, the effectiveness of prolonged nitrate administration for preventing late ventricular remodeling is limited by the development of tolerance. Although benefits can be achieved by allowing a daily nitrate-free interval during long-term administration, future research should be directed to finding ways to reduce tolerance and the development of nitric oxide donors and ways to increase biologic nitric oxide activity.140 Acknowledgment: I thank Catherine Graham for typing and Will Ford for generating the figures. 1. Pfeffer MA, Braunwald E. Ventricular remodeling after myocardial infarction. Experimental observations and clinical implications. Circulation 1990;81:1161– 1172. 2. Jugdutt BI. Prevention of ventricular remodelling post myocardial infarction: timing and duration of therapy. Can J Cardiol 1993;9:103–114. 3. Jugdutt BI, Becker LC, Hutchins GM, Bulkley BH, Reid PR, Kallman CH. Effect of intravenous nitroglycerin on collateral blood flow and infarct size in the conscious dog. Circulation 1981;63:17–28. 4. Jugdutt BI. Myocardial salvage by intravenous nitroglycerin in conscious dogs: loss of beneficial effect with marked nitroglycerin-induced hypotension. Circulation 1983;68:673– 684. 5. Jugdutt BI, Sussex BA, Warnica JW, Rossall RE. Persistent reduction in left ventricular asynergy in patients with acute myocardial infarction by intravenous infusion of nitroglycerin. Circulation 1983;68:1264 –1273. 6. Jugdutt BI. Delayed effects of early infarct-limiting therapies on healing after myocardial infarction. Circulation 1985;72:907–914. 7. Jugdutt BI, Amy RWM. Healing after myocardial infarction in the dog: changes in infarct hydroxyproline and topography. J Am Coll Cardiol 1986;7: 91–102. 8. Michorowski BL, Senaratne MRJ, Jugdutt BI. Myocardial infarct expansion. Cardiovasc Rev Rep 1987;8:42– 47. 9. Michorowski BL, Senaratne MRJ, Jugdutt BI. Deterring myocardial infarct expansion. Cardiovasc Rev Rep 1987;8:55– 62. 10. Michorowski BL, Tymchak WJ, Jugdutt BI. Improved left ventricular function and topography by prolonged nitroglycerin therapy after acute myocardial infarction. (Abstr.) Circulation 1987;76(Suppl IV):IV–128. 11. Jugdutt BI, Warnica JW. Intravenous nitroglycerin therapy to limit myocardial infarct size, expansion and complications. Effect of timing, dosage and infarct location. Circulation 1988;78:906 –919. 12. Jugdutt BI. Effect of nitroglycerin and ibuprofen on left ventricular topography and rupture threshold during healing after myocardial infarction in the dog. Can J Physiol Pharmacol 1988;66:385–395. 13. Jugdutt BI, Warnica JW. Tolerance with low dose intravenous nitroglycerin therapy in acute myocardial infarction. Am J Cardiol 1989;64:581–587. 14. Jugdutt BI, Basualdo CA. Myocardial infarct expansion during indomethacin or ibuprofen therapy for symptomatic post-infarction pericarditis. Influence of other pharmacologic agents during early remodeling. Can J Cardiol 1989;5:211– 221. 15. Jugdutt BI. Identification of patients prone to infarct expansion by the degree of regional shape distortion on an early two-dimensional echocardiogram after myocardial infarction. Clin Cardiol 1990;13:28 – 40. 16. Jugdutt BI, Tymchak WJ, Humen DP, Gulamhusein S, Tang SB. Effect of thrombolysis and prolonged captopril and nitroglycerin on infarct size and remodeling in transmural myocardial infarction. (Abstr.) J Am Coll Cardiol 1992;19:205A. 17. Jugdutt BI, Khan MI. Effect of prolonged nitrate therapy on left ventricular remodeling after canine acute myocardial infarction. Circulation 1994;89:2297– 2307. 18. Jugdutt BI, Khan MI, Jugdutt SJ, Blinston GE. Impact of left ventricular unloading after late reperfusion of canine anterior myocardial infarction on remodeling and function using isosorbide-5-mononitrate. Circulation 1995;92: 926 –934. 19. Jugdutt BI, Khan MI, Jugdutt SJ, Blinston GE. Combined captopril and isosorbide dinitrate during healing after myocardial infarction. Effect on ventricular remodeling, function, mass and collagen. J Am Coll Cardiol 1995;25:1089 – 1096.

20. Jugdutt BI, Khan MI, Jugdutt SJ, Blinston GE. Effect of enalapril on

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