Favorable Effects of Hyaluronidase on Electrocardiographic Evidence of Necrosis in Patients with Acute Myocardial Infarction

Maroko, Peter R.; Hillis, L. David; Muller, James E.; Tavazzi, Luigi; Heyndrickx, Guy R.; Ray, Maria; Chiariello, Massimo; Distante, A.; Askenazi, Joseph; Salerno, J. A.; Carpentier, J.-P.; Reshetnaya, N. I.; Radvany, Paulo; Libby, Peter; Raabe, Daniel S.; Чазов, Е. И.; Bobba, P; Braunwald, Eugene

doi:10.1056/nejm197704212961603

Cited by 161 publications

(45 citation statements)

References 34 publications

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“…24 h when it is administered before or up to 6 h after coronary artery occlusion in the dog (10,13). It also appears to be beneficial for at least 1 wk in patients with acute myocardial infarction when administered within 8 h of the onset of chest pain (12). The mechanism by which this agent protects the acutely ischemic heart is uncertain.…”

Section: Methodsmentioning

confidence: 99%

“…Of the various interventions tested in this study, the administration of H or CVF early after the occlusive event offers the greatest promise for further stuidy. The results of the preliminary clinical studies with H have been encouiraginig (11,12), but the definitive role of this agent in clinical practice needs to be determined in a much larger number of patients. CVF has not so far been giveni to patients; its role in clinlical practice is still to be determiined.…”

Section: Methodsmentioning

confidence: 99%

“…To achieve these goals four interventions that have previously been shown by indirect techniques to limit myocardial necrosis, hyaluronidase (5,6,(10)(11)(12)(13)(14), cobra venom factor (15), hydrocortisone (16), and methylprednisolone (17), and one other (reserpine) thought likely to be favorable because of its catecholaminedepleting action (18) were administered, and their effects on myocardial preservation compared.…”

Section: Introductionmentioning

confidence: 99%

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Long-Term Preservation of Ischemic Myocardium after Experimental Coronary Artery Occlusion

Maclean¹,

Fishbein²,

Braunwald³

et al. 1978

J. Clin. Invest.

170

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A B S T R A C T The results of experiments with indirect methods have suggested that various interventions reduce infarct size after coronary artery occlusion. To determine and quantify directly both the shortand long-term effects of several interventions on myocardial salvage without relying on indirect methods, the left coronary artery was occluded in 880 rats; they were then given either no treatment or one of the following interventions: (a) hyaluronidase, an enzyme that hydrolyzes interstitial glycoproteins, 1,500 National Formulary (NF) U/kg i.v. 5 min and 24 h after occlusion; (b) cobra venom factor, a protein that depletes the third component of complement, 20 U/kg i.v. 5 min after occlusion; (c) a glucocorticoid: hydrocortisone, 50 mg/kg i.v. 5 min after occlusion; or the fivefold more potent methylprednisolone (MP): (i) 50 mg/kg i.v. 5 min after occlusion or (ii) 50 mg/kg i.v. 5 min after occlusion followed by 50 mg/kg i.m. 3, 6, and 24 h after occlusion; or (d) reserpine, an agent that depletes the heart of catecholamines, 0.5 mg/kg i.m. once on each of the 3 days before occlusion. The animals were sacrificed either 2 days after occlusion, i.e., at the time of peak necrosis, or after 3 wk, i.e., after the infarct was completely healed. The amount of preserved myocardium was then assessed by two independent techniques: planimetric measurement of serial histologic sections and creatine kinase activity of the whole left ventricle. The amount of normal myocardium preserved at 21 days postocclusion was significantly increased, by 22.3±7.8% (P < 0.025) after the administration of hyaluronidase, by 25.3 ±5.8% (P < 0.005) after cobra venom factor, by 14.5 ±6.9% (P < 0.05) after hydrocortisone, by 20.8±8.2% (P < 0.025) after the single dose of MP, by 20.9±3.9% (P < 0

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Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Long-Term Preservation of Ischemic Myocardium after Experimental Coronary Artery Occlusion

Maclean¹,

Fishbein²,

Braunwald³

et al. 1978

J. Clin. Invest.

170

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“…Methods Sixty-eight mongrel dogs that weighed [17][18][19][20][21][22] kg were anesthetized with sodium thiamylal, endotracheally intubated, and ventilated with room air using a Harvard respirator. ECGs (lead aVF) and systemic arterial pressures through a polyethylene cannula in the left carotid artery (Statham P23Db pressure transducer) were recorded continuously throughout the experiments (Gould Instruments).…”

mentioning

confidence: 99%

Influence of the extent of the zone at risk on the effectiveness of drugs in reducing infarct size.

Ribeiro¹,

Cheung²,

Maroko³

1982

Circulation

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SUMMARY The goal of this study was to examine whether the effectiveness of a drug in protecting ischemic myocardium depends on the size of the hypoperfused zone (the area at risk) measured immediately after coronary artery occlusion (CAO). Methoxy-verapamil (D600), a potent calcium antagonist, was used to test this hypothesis. In 68 dogs, 1 minute after CAO, 8 mCi of technetium-99m-labeled albumin microspheres were injected into the left atrium for later assessment of the hypoperfused zone by autoradiography. Eighteen dogs were treated with D600 (0.8 mg/kg as a bolus 15 minutes after CAO and 0.2 mg/kg/ hour as a continuous infusion for 6 hours). After 6 hours, the hearts were excised and the left ventricles cut into 3-mm-thick slices and stained with triphenyltetrazolium chloride. The extent of myocardial damage was measured by planimetry of the unstained areas. Thereafter, the same slices were autoradiographed and the extent of the hypoperfused zones measured by planimetry of the "cold spots."Both the treated and control dogs were classified according to the amount of the left ventricle that was hypoperfused: small (< 25%), medium (25-30%), and large (> 30%). In control dogs with small, medium and large hypoperfused zones, the percentages of the hypoperfused zone that evolved to infarction were 95.9 + 3.5% (mean ± SEM), 90.8 3.5%, and 93.1 ± 2.6%, respectively; in the D600-treated dogs, 31.9 ± 8.3%, 53.8 ± 3.0%, and 61.3 9.2%, respectively. Thus, the dogs with the smallest areas at risk had the most extensive reduction in damage (67%); the effectiveness of treatment was intermediate in those with medium areas at risk (41%) and treatment had the least effect in those with the largest area at risk (34%). Thus, the size of the area at risk, determined in vivo immediately after CAO, is an important factor in determining the effectiveness of a drug in reducing myocardial damage.NUMEROUS INTERVENTIONS are effective in reducing the extent of myocardial damage after experimental coronary artery occlusion.'-5 However, it is not known whether, besides the beneficial properties of the intervention, the degree of effectiveness depends upon the initial size of the area at risk of infarction, i.e., the hypoperfused zone (HZ). The goal of this investigation was to determine whether methoxy-verapamil (D600), a potent calcium antagonist,6"'reduces myocardial damage to the same extent in areas of hypoperfusion of different magnitudes. To assess the zone of hypoperfusion, 2 x 106 highly radioactive (8 mCi) albumin microspheres, 20 u in diameter (3M Company), were injected into the left atrium 1 minute after coronary artery occlusion.8 9Fifteen minutes after occlusion, the dogs were randomized into two groups, 50 to a control group and 18 to a D600-treated group. In the latter, D600 was administered intravenously: 0.8 mg/kg as a bolus, followed by a continuous infusion of 0.2 mg/kg/hour until 6 hours after coronary artery occlusion.Six hours after coronary artery occlusion, the dogs were killed and the left ventricle (LV) was diss...

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“…ejection fraction. Of 11 group 1 patients with ad sion ejection fraction B45%, 10 (NS). This failure to demonstrate improved preservation of R waves in patients with anterior infarctions would appear to correlate with the high incidence of nonresponders among patients with anterior transmural infarctions.…”

Section: Resultsmentioning

confidence: 99%

A randomized prospective trial of intravenous nitroglycerin in patients with acute myocardial infarction.

et al. 1983

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A prospective randomized study of intravenous nitroglycerin (TNG) administered for 48 hr after acute infarction was undertaken to determine whether clinical improvement and/or evidence of preservation of ischemic myocardium could be demonstrated. One hundred four patients were randomly assigned to TNG (n = 56) and placebo groups (n = 48). TNG was infused at a rate sufficient to lower mean arterial pressure 10%, monitored noninvasively. When all TNG-and placebo-treated patients were compared, no significant differences in clinical or laboratory outcomes could be demonstrated. TNG-and placebo-treated patients were retrospectively subdivided into early and late treatment groups (treatment begun <10 hr vs 3 10 hr after onset of symptoms). Early TNG treatment was associated with a lower incidence of infarct complications within the first 10 days, defined by new congestive heart failure, infarct extension, or cardiac death (15% in early TNG compared with a mean of 39% in the other three subgroups; p = .003). Mortality at 3 months was lower in the group treated early with TNG (15%) compared with a mean of 25% in the other three subgroups (p = NS). No significant differences were found in peak creatine kinase (CK) blood levels, creatine kinase infarct size, or preservation of precordial R waves by serial electrocardiographic mapping. Among 49 patients with pretreatment and day 7 to 14 posttreatment left ventricular ejection fraction measurements, improvement of 3 10% occurred in 35% of TNG patients treated early compared with 6% of those treated late with TNG, 11% of those treated early with placebo, and 0% of those treated late with placebo (p = .004). Similarly, in 68 patients in whom paired thallium scintigrams were taken, a decrease of B75% in the computer-determined thallium defect score was seen in 48% of TNG patients treated early, compared with 14% of TNG patients treated late, 33% of placebo patients treated early and 0% of placebo patients treated late (p = .039). Patients demonstrating significant scintigraphic improvement were treated earlier, tended to have less severe initial scintigraphic abnormalities, inferior rather than anterior infarctions, a longer history of angina, and no prior history of heart failure. Thus intravenous TNG could not be shown to result in significant improvement in clinical or scintigraphic outcomes when the patient population was analyzed as a whole. After retrospective subgroup analysis, intravenous TNG could be shown to protect ischemic myocardium in the subset of patients with smallto-moderate sized myocardial infarctions when treatment was begun within 10 hr of the onset of symptoms. The results of this trial also suggest that future clinical trials designed to show a reduction in infarct size might limit patient entry to those admitted early after symptom onset and those with significant abnormalities in their admission scintigraphic studies. Larger-scale studies are needed to determine whether TNG therapy can significantly reduce mortality and to further define the...

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Favorable Effects of Hyaluronidase on Electrocardiographic Evidence of Necrosis in Patients with Acute Myocardial Infarction

Cited by 161 publications

References 34 publications

Long-Term Preservation of Ischemic Myocardium after Experimental Coronary Artery Occlusion

Long-Term Preservation of Ischemic Myocardium after Experimental Coronary Artery Occlusion

Influence of the extent of the zone at risk on the effectiveness of drugs in reducing infarct size.

A randomized prospective trial of intravenous nitroglycerin in patients with acute myocardial infarction.

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