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W M Vogel

Publications and source records attributed to W M Vogel.

At least 19 recordsLinked to original sources
PubMed1997

Considerations for toxicology studies of respiratory drug products.

The standard approaches for the preclinical development of chronically administered drugs also apply to most respiratory drugs. Modifications from the standard preclinical development plan, however, may be necessary if the drug is administered intranasally or by inhalation. Administration by these routes may result in airway toxicity and the intended patient population is often particularly susceptible. Current and former representatives of the Division of Pulmonary Drug Products (CDER, U.S. FDA) present this article to describe general principles of preclinical development for respiratory drug indications. The article addresses drugs intended for administration by the intranasal or inhalation routes. The article describes the types of studies recommended, considers the initial human dose, and discusses dose-escalation strategies in clinical trials. Other areas of special concern with intranasal or inhalation administration include immunotoxicity, reproductive toxicity, types of dosing apparatus, excipients and extractables, and formulation changes. The approaches described in this article are intended as general information and should be adapted to the scientific considerations and circumstances of a particular drug under development.

Humans↗
PubMed1994

Inhibition of long-chain acylcarnitine accumulation during coronary artery occlusion does not alter infarct size in dogs.

We tested whether inhibition of carnitine acyl-transferase-1 (CAT-1) during coronary artery occlusion can limit infarct size (IS) by suppressing accumulation of long-chain acylcarnitines (LCAs), potentially cytotoxic intermediates of fatty acid metabolism. The CAT-1 inhibitor 2-[5-(4-chlorophenyl)-pentyl]-oxirane-2-carboxylate (POCA) was administered to dogs before 90-min occlusion and 4-h reperfusion of the left anterior descending or left circumflex coronary artery (LAD, LCX). Dogs in the LAD occlusion series received 7.5 (n = 5) or 15 (n = 2) mg/kg POCA intravenously (i.v.); dogs in the LCX occlusion series received 15 mg/kg i.v. (n = 7); an equal number were treated with drug vehicle. Biopsies were obtained for determination of myocardial LCAs. The region at risk and IS were delineated by dye injection and tetrazolium staining. In vehicle-treated dogs, myocardial LCAs (in picomoles per milligram of wet weight +/- SEM) increased from 11 +/- 3 to a peak of 75 +/- 24 during LAD occlusion and from 32 +/- 10 to 192 +/- 55 during LCX occlusion. In POCA-treated dogs LCAs increased from 12 +/- 2 to only 33 +/- 13 pmol/mg wet weight during LAD occlusion (p < 0.05 vs. vehicle) and did not increase significantly during LCX occlusion; 22 +/- 8 to 27 +/- 5 pmol/mg wet weight (p < 0.005 vs. vehicle). LCX occlusion resulted in larger areas at risk and larger infarcts (as a percentage of left ventricle) than did LAD occlusion. IS as a percentage of the region at risk did not differ significantly among the experimental groups.(ABSTRACT TRUNCATED AT 250 WORDS)

Acetylcarnitine↗
PubMed1991

Coronary sinus occlusion: effect on ischemic left ventricular dysfunction and reactive hyperemia.

Pressure-controlled intermittent coronary sinus occlusion (PICSO) has been shown to reduce experimental infarct size. To examine the role of PICSO in limiting the consequences of brief ischemia on left ventricular function, we studied the effect of PICSO in nine open-chest anesthetized dogs. PICSO was performed using a pump-inflated, balloon-tipped catheter in the coronary sinus until coronary sinus occlusion pressure reached a plateau (10 +/- 3 seconds). The balloon was then rapidly deflated (2 seconds) and the cycle was repeated. Regional left ventricular function in the ischemic zone was assessed by sonomicrometry. Coronary blood flow was measured with a flow probe around the left anterior descending artery (LAD) proximal to an occluding suture. Measurements were obtained at baseline, during a 3-minute LAD occlusion, and for 10 minutes of reperfusion. In an additional five dogs, this sequence was repeated during an infusion of adenosine at a dose that abolished reactive hyperemia following LAD occlusion. The addition of PICSO beginning 15 minutes prior to ischemia and continuing throughout LAD occlusion and reperfusion did not prevent, reduce, or shorten ischemic left ventricular dysfunction. PICSO uniformly blunted reactive hyperemia during reperfusion. However, PICSO also reduced coronary blood flow during maximal vasodilatation achieved by adenosine infusion prior to LAD occlusion. Therefore, it is likely that PICSO decreases reactive hyperemia due to mechanical factors arising from venous engorgement rather than by reducing the ischemic stimulus causing vasodilation.

Animals↗
PubMed1991

Reversible and irreversible elongation of ischemic, infarcted, and healed myocardium in response to increases in preload and afterload.

BACKGROUND: Left ventricular aneurysm formation after myocardial infarction (MI) has been associated with elongation of infarcted tissue in response to wall stress. Such elongation most commonly occurs in acutely infarcted or partially healed regions during the early post-MI period; however, recent reports have indicated that mature (15-week-old) healed infarct regions also undergo elongation after stress. METHODS AND RESULTS: To assess factors contributing to post-MI left ventricular aneurysm formation, we subjected isolated strips (n = 50) of rabbit myocardial tissue from acutely ischemic (noninfarcted left ventricular), acutely infarcted (24 hours after MI), and healed infarct (3 and 15 weeks after MI) regions to a range of loading conditions and measured the reversible and irreversible length changes that occurred. The isolated strips were repetitively stretched for 1 hour at 4 Hz to impose cyclical physiological peak and resting stresses of 2.0 and 0.2 g/mm2. During a second hour, either peak stress ("afterload") or resting stress ("preload") was tripled, and the increase in strip length (strain) was measured. During a third hour, peak and resting stresses were returned to the initial values to assess the reversibility of length changes occurring during increased load. Elongation was expressed as the increase in natural strain from the first hour. Increasing afterload caused similar irreversible length increases of 4-5%/hr in acutely infarcted and 3- and 15-week-old healed infarct strips; acutely ischemic tissue length increased by 7.4%/hr (p less than 0.05 versus acutely infarcted tissue and scars). Increasing preload in acutely ischemic and acutely infarcted tissue caused a reversible length increase of less than 1%/hr. (Scar strips were not tested for the effect of preload.) CONCLUSIONS: Since an irreversible length increase may represent an early event in aneurysm formation, our results suggest that 1) afterload increases are more likely to lead to aneurysm development than preload increases, 2) acutely ischemic tissue is the most vulnerable to increased afterload, and 3) for a given wall stress level, healing scar tissue is as susceptible to irreversible length changes as is acutely infarcted tissue. The observation that even mature post-MI scar elongated in response to increases in afterload implies that long-term pharmacological management of afterload in post-MI patients may be beneficial in preventing tissue elongation and aneurysm formation and that factors that increase wall stress (e.g., hypertension and exercise stress) have the potential to promote aneurysm formation in healed infarct scars.

Animals↗
PubMed1990

Influence of glucose and insulin on the exaggerated diastolic and systolic dysfunction of hypertrophied rat hearts during hypoxia.

Myocardial hypertrophy can result in increased sensitivity toward the development of mechanical dysfunction during hypoxia. Alterations in glycolytic metabolism may contribute to this. We studied the response to 15 minutes of hypoxia in hypertrophied (deoxycorticosterone-salt hypertension model) and nonhypertrophied rat hearts and examined the influence of a high glucose (27.5 mM) and insulin (100 mU/ml) concentration. In response to hypoxia in the presence of a normal glucose concentration (5.5 mM), left ventricular end-diastolic pressure was higher in hypertrophied than in nonhypertrophied hearts (65 +/- 6 vs. 44 +/- 4 mm Hg; p less than 0.05). Perfusion with high glucose and insulin blunted the rise in left ventricular end-diastolic pressure in both hypertrophied and nonhypertrophied hearts and abolished the difference in diastolic dysfunction between groups during hypoxia (26 +/- 2 vs. 32 +/- 4 mm Hg, respectively; p = NS). At end hypoxia in the presence of a normal glucose concentration, developed pressure was more depressed in hypertrophied than in nonhypertrophied hearts (11 +/- 1 vs. 18 +/- 1% of baseline, respectively; p less than 0.05). Perfusion with high glucose and insulin resulted in improved function in both groups during hypoxia such that a greater impairment of developed pressure was no longer present in the hypertrophied versus nonhypertrophied hearts (21 +/- 1 vs. 24 +/- 2% of baseline, respectively; p = NS). At the end of hypoxic perfusion in the presence of a normal glucose concentration, hypertrophied hearts were producing 38% less lactate than nonhypertrophied hearts. Perfusion with high glucose and insulin increased lactate production in both groups and equalized lactate production between groups. Thus, the greater deterioration in hemodynamic function in hypertrophied hearts compared with nonhypertrophied hearts during hypoxia is associated with lower lactate production. Both the exaggerated hemodynamic dysfunction and deficient lactate production can be ameliorated by perfusion with a high glucose concentration and insulin.

Animals↗
PubMed1989

Effect of coronary occlusion and reperfusion on myocardial blood flow during infarct healing.

Coronary occlusion (CO) of 1 h or longer causes transmural myocardial infarction (MI) in the rabbit. We studied how reperfusion of an infarct affected myocardial blood flow (MBF) acutely and after 3 wk of healing. CO was performed in rabbits for 60 or 180 min (n = 22) followed by reperfusion, and MBF to normal and infarcted zones was determined by radioactive microspheres. In a separate series (n = 23), MBF was measured at 21-25 days post-CO in three groups that had either permanent CO or reperfusion after 60 or 180 min of CO. MBF to the infarct was approximately 8 +/- 3% (+/-SE) of normal MBF (3.8 +/- 0.5 ml.min-1.g-1) during 60-180 min of CO but 3 wk later had increased to 33 +/- 6% of normal MBF (P less than 0.005). Reperfusion after 60 or 180 min of CO resulted in 74 +/- 6% and 41 +/- 5% return of normal MBF, respectively, but 3 wk later, MBF had decreased to 25 +/- 5% (P less than 0.001) and 24 +/- 4% (P less than 0.025) of normal MBF, respectively. Thus after 3 wk of postinfarction healing, MBF to the permanently occluded infarcts increased fourfold, whereas MBF decreased by 50% in the reperfused infarcts so that MBF to the scar tissue was comparable among the three groups and was not influenced by acute post-MI reperfusion.

Animals↗
PubMed1989

Studies of the mechanism of the vasoconstrictor activity of stroma-free hemoglobin in the isolated perfused rat kidney and rabbit heart.

We have found that DBBF-Hb and Hb Ao have significantly less vasoconstrictor activity than unmodified Hb in the rabbit heart. In striking contrast to these findings, DBBF-Hb and unmodified Hb have comparable hemodynamic effects in the isolated kidney. We have demonstrated that lipophilic contamination of fraction V BSA causes vasoconstriction in the coronary vasculature and speculate that similar contaminants may contribute to the vasoconstrictor activity of SFH solutions. Finally, we have shown that renal vasoconstriction induced by DBBF-Hb is reversed by acetylcholine as well as nitroprusside. These studies suggest that renal vasoconstriction induced by DBBF-Hb is not related to inhibition of EDRF. These studies make it clear that SFH solutions have different effects on the heart and kidney vasculature. The use of both heart and kidney models should provide important information on the mechanisms by which SFH causes vasoconstriction in these two organs.

Acetylcholine↗
PubMed1988

Effects of alloxan-induced diabetes on ischemia-reperfusion injury in rabbit hearts.

Hearts from rabbits with 8-16 weeks of alloxan-diabetes were compared with hearts from normal rabbits to determine whether diabetic myocardium is more sensitive to ischemic injury. In isolated buffer-perfused hearts, left ventricular developed pressure, diastolic pressure, time to peak pressure (TTPP), time to half-maximal relaxation (RT1/2), and positive and negative dP/dt were measured during generation of left ventricular filling curves before and after 90 minutes of low-flow ischemia. Hearts from diabetic rabbits (blood glucose, 384 +/- 28 mg/dl, mean +/- 95% confidence limits) had left ventricular developed and diastolic pressures similar to normal hearts but exhibited significant increases in TTPP and RT1/2 with decreased positive and negative dP/dt. Left ventricular chamber volume relative to heart mass was greater in diabetic than in normal hearts. Recovery of developed pressure after ischemia was similar in normal (41 +/- 16%) and diabetic hearts (47 +/- 13%). In diabetic hearts during recovery from ischemia, TTPP and R1/2 remained increased compared with normal hearts, with positive and negative dP/dt decreased compared with normal hearts, in proportion to the preischemic differences. After ischemia, high-energy phosphates were depleted to the same extent in normal and diabetic rabbits. In coronary ligation experiments, histochemically determined infarct size in diabetic rabbits after 30 minutes occlusion and 24 hours reperfusion was similar to that in normal rabbits when adjusted for a significantly smaller heart weight and a correspondingly smaller anatomic risk region in the diabetic animals. Thus, despite characteristic abnormalities of mechanical function in diabetic hearts, the severity of injury after ischemia with reperfusion was normal for diabetic hearts.

Animals↗
PubMed1988

Effects of stroma-free hemoglobin solutions on isolated perfused rabbit hearts and isolated perfused rat kidneys.

"Stroma-free" hemoglobin solutions (SFH) cause hemodynamic alterations indicative of vasoconstriction. We studied vasoconstrictor activity in isolated rabbit hearts and rat kidneys of unmodified SFH and of SFH modified by pyridoxylation or glyoxylation, with or without glutaraldehyde cross-linking. The purity and chemical composition of the solutions, all prepared by other laboratories, were not characterized by us. In isolated hearts SFH prepared by conventional methods had potent vasoconstrictor activity. Pyridoxylation or purification by ion exchange chromatography did not alter the constrictor activity. Decreased constrictor activity was observed with human SFH cross-linked by glutaraldehyde treatment, or purified by affinity chromatography, and with bovine SFH purified by ultrafiltration and preparative HPLC. In isolated kidneys modified and unmodified SFH increased renal vascular resistance and decreased glomerular filtration rate with no morphologic evidence of tubular damage.

Animals↗
PubMed1987

Reduced coronary vasoconstrictor activity of hemoglobin solutions purified by ATP-agarose affinity chromatography.

Stroma-free hemoglobin (Hb) solutions are being developed as blood substitutes. We previously described coronary vasoconstrictor activity of Hb solutions prepared by conventional methods. In the present study we assessed the constrictor activity of unmodified and covalently modified Hb solutions purified by ATP-agarose affinity chromatography. The starting material was a red cell lysate, partially purified by ultrafiltration. Coronary constrictor activity was measured as increased perfusion pressure in isolated rabbit hearts perfused at constant coronary flow rate with buffer containing various concentrations of added Hb. The starting material increased perfusion pressure by 35 +/- 7 mmHg at 50 mg/dl. Purified Hb, retained by the affinity column, increased perfusion pressure by only 18 +/- 2 mmHg at 50 mg/dl. Hemoglobin covalently linked to ATP or pyridoxal phosphate, then purified by affinity chromatography, also had less constrictor activity than the starting material. Thus, a substance, removed by affinity chromatography but not by conventional purification, contributes to the vasoconstrictor activity of Hb solutions.

Adenosine Triphosphate↗
PubMed1986

Post-ischemic cardiac chamber stiffness and coronary vasomotion: the role of edema and effects of dextran.

Contributions of edema to left ventricular (LV) chamber stiffness and coronary resistance after ischemia were studied in isolated buffer-perfused rabbit hearts, with constant LV chamber volume, subjected to 30 min global ischemia and 60 min reperfusion. During reperfusion hearts were perfused with standard buffer or with 3% dextran to increase oncotic pressure and decrease water content. LV chamber volume was adjusted to an initial diastolic pressure (LVEDP) of 10 mmHg. In nonischemic hearts (n = 6) LVEDP was 11 +/- 0.3 mmHg and water content was 5.0 +/- 0.1 ml/g dry weight after 90 min of perfusion. In untreated ischemic hearts (n = 8) LVEDP was 51 +/- 4 mmHg and water content was 6.0 +/- 0.1 ml/g dry weight after 60 min reperfusion (P less than 0.001 v. nonischemic). In dextran-treated ischemic hearts (n = 8) LVEDP was 38 +/- 3 mmHg (P less than 0.05 v. untreated ischemic) and water content was 5.2 +/- 0.1 ml/g dry weight (P less than 0.001 v. untreated ischemic). Coronary resistance in untreated ischemic hearts increased by 26% from 2.0 +/- 0.06 to 2.6 +/- 0.06 mmHg/ml/min after 60 min reperfusion. In treated hearts coronary resistance increased by 16% from 1.9 +/- 0.09 to 2.2 +/- 0.09 mm/Hg/ml/min (P less than 0.01 v. untreated ischemic). To determine whether the decrease in coronary resistance with dextran could be ascribed to active vasodilation, dilator responses to 2 min hypoxia or 10(-4)M adenosine were tested in nonischemic and reperfused ischemic hearts. Dilator responses were stable in nonischemic hearts or hearts reperfused after 15 min ischemia but after 30 min ischemia the dilator response to hypoxia was reduced by 72% (P less than 0.025) and the dilator response to adenosine was eliminated (P less than 0.02). Thus the response to dextran was unlike that of a direct vasodilator. These data suggest that myocardial edema plays a significant role in maintaining increased ventricular chamber stiffness and coronary resistance during reperfusion after ischemia.

Adenosine↗
PubMed1986

Coronary constrictor effect of stroma-free hemoglobin solutions.

A coronary vasoconstrictor effect of human stroma-free hemoglobin (SFH) was identified in isolated rabbit hearts perfused with Krebs-Henseleit buffer or whole rabbit blood at a constant coronary flow rate. In buffer-perfused hearts, SFH in concentrations of 5 to 200 mg/dl produced dose-related increases of coronary perfusion pressure. At a concentration of 150 mg/dl, SFH, equilibrated with CO to form carboxyhemoglobin, caused an increase in perfusion pressure (55 +/- 7 mmHg), similar to that observed with oxyhemoglobin (57 +/- 6 mmHg); addition of potassium ferricyanide to form methemoglobin reduced the increase of perfusion pressure to 34 +/- 5 mmHg (P less than 0.05). The vasoconstrictor activity could not be eliminated by dialyzing against the perfusion buffer. Human SFH prepared by different methods had similar vasoconstrictor activity. Rabbit SFH and human SFH were equi-effective in the rabbit heart. Less constrictor activity of SFH was evident in rat and guinea pig heart. Polymerized, pyridoxalated SFH had greatly reduced constrictor effect compared with unmodified or pyridoxalated tetramer SFH. In blood-perfused hearts, increasing plasma hemoglobin to 1.6 +/- 0.1 g/dl, without changing total hemoglobin or arterial O2 content, increased coronary perfusion pressure by 36 +/- 13 mmHg (P less than 0.05). We conclude that stroma-free hemoglobin solutions exert a coronary vasoconstrictor effect that is unrelated to O2 delivery.

Animals↗
PubMed1985

Separation of inherent diastolic myocardial fiber tension and coronary vascular erectile contributions to wall stiffness of rabbit hearts damaged by ischemia, hypoxia, calcium paradox and reperfusion.

Ischemic myocardial contracture is exacerbated by reperfusion. This study examines the extent to which intensification of contracture by reperfusion is due to metabolic reoxygenation phenomena or hydraulic erectile contributions of coronary perfusion to left ventricular (LV) stiffness. Isolated rabbit hearts, with fluid-filled LV intraventricular baloons, were subjected either to: control aerobic perfusion; 30 or 60 min of global ischemia; 60 min of hypoxia with constant coronary flow; or 10 min of calcium-free perfusion to cause calcium paradox injury. During reperfusion with control perfusate isovolumic LV end diastolic pressure (LVEDP) was measured with constant coronary flow and during transient, 1 min, total global ischemia to measure the contribution of the coronary perfusion to LVEDP. In all injured groups LVEDP was increased compared to control hearts. The decrease in LVEDP during transient ischemia was greater in damaged hearts than in controls, demonstrating a greater contribution of coronary perfusion to LVEDP after injury. Only in the hypoxic hearts did diastolic fiber tension increase upon reperfusion. Inherent diastolic fiber tension decreased during 15 to 60 min of reperfusion in the ischemic and hypoxic injury groups, a trend which was masked by an increasing effect of coronary perfusion on LV chamber stiffness. During the reperfusion period enhancement of the erectile effect was more pronounced at higher preloads. Thus, reperfusion contracture was maintained both by changes in inherent fiber stiffness and by changes in the erectile effect. These contributions changed over time and varied with the type and severity of injury, but after all types of injury the erectile vascular effect made a greater contribution to diastolic chamber stiffness than inherent fiber tension.

Animals↗
PubMed1985

Effect of erythrocyte storage and oxyhemoglobin affinity changes on cardiac function.

Storage of blood can depress erythrocyte 2,3-diphosphoglycerate (DPG) levels and thereby increase oxyhemoglobin affinity and potentially decrease capillary-to-tissue oxygen transport. We measured myocardial function and metabolism in isolated rabbit hearts with fixed coronary flow under basal conditions and during isoproterenol stress at 37 and 30 degrees C, comparing high and low oxyhemoglobin affinity (OHA) erythrocytes. The high OHA state resulted from standard storage conditions, which caused depressed values of DPG and P50 (the oxygen tension at which hemoglobin is 50% saturated). The low OHA erythrocytes were initially stored and then underwent biochemical treatment to restore the DPG and P50 values to normal. The low OHA cells released more oxygen, and myocardial oxygen consumption and contractile function were increased relative to the high OHA cells during both the basal and stress states at both 37 and 30 degrees C. These observations may be relevant for patients with limited coronary flow when such patients receive large transfusions of stored blood.

Animals↗
PubMed1985

Effects of reperfusion after coronary artery occlusion on post-infarction scar tissue.

Early reperfusion after a coronary occlusion may reduce myocardial infarct size, but late reperfusion into necrotic myocardium may alter post-infarction healing. In rabbits, we compared 1- or 3-week-old scars resulting from permanent coronary occlusion to those resulting from a 1- or 3-hour occlusion followed by reperfusion. Reperfusion at 1 hour post-occlusion did not affect scar mechanical properties assessed at 1 week post-infarction, but at 3 weeks post-infarction, these scars had a tensile strength significantly lower than those not reperfused (78 +/- 11 vs. 158 +/- 15 g/mm2, P less than 0.001). They also were composed of a mixture of fibrous tissue (58 +/- 8%) and myocytes (43 +/- 8%) with a hydroxyproline content of 23 +/- 2.5 mg/g dry weight. The nonreperfused scars had a higher proportion of fibrous tissue (73 +/- 3%) by histological evaluation and a 35% higher hydroxyproline content (31 +/- 2 mg/g dry weight, P less than 0.001) than the scars reperfused after 1 hour. In contrast, 3-week-old scars resulting from "late" reperfusion at 3 hours post-occlusion were similar to nonreperfused scars in fibrous tissue composition and hydroxyproline content. Nonetheless, the tensile strength of these scars reperfused 3 hours post-occlusion was significantly less than that of the nonreperfused scars (72 +/- 5 vs. 158 +/- 15 g/mm2, P less than 0.001). The lower tensile strength was associated with a lower collagen cross-link density in this reperfused group of scars. At physiological stress levels (approximately 3 g/mm2), all groups of reperfused and nonreperfused scars had similar mechanical properties in terms of natural strain, stiffness, creep, and stress relaxation. Thus, although the reperfused scars ruptured more easily at high stresses, when assessed at physiological stresses their mechanical properties were not significantly different from those of nonreperfused scars.

Animals↗
PubMed1983

Myocardial healing and repair after experimental infarction in the rabbit.

Adequacy of healing after acute myocardial infarction may determine the incidence of postmyocardial infarction rupture and ventricular aneurysm. Accordingly, in 36 rabbits, from 1 to 8 days after coronary ligation, and in 18 shams, we measured collagen formation and mechanical resistance of the infarcted left ventricle to stretch and rupture. Prolyl hydroxylase, an intracellular enzyme of collagen synthesis, increased from control activity of 3970 +/- 431 to 9224 +/- 643 counts/min per mg (cpm/mg) extractable protein (P less than 0.01) at 48 hours and was nearly maximal at 3 days postmyocardial infarction (14,518 +/- 2,030 cpm/mg, P less than 0.01). Lysyl oxidase, an extracellular collagen cross-linkage enzyme, increased from control activity of 29.6 +/- 4.8 to 74.7 +/- 18.8 cpm/mg extractable protein (P less than 0.01) at 72 hours and peaked at 121.5 +/- 7.3 (P less than 0.01) 4-6 days postmyocardial infarction. Hydroxyproline, a measure of collagen content, increased from control of 2.8 +/- 0.2 to 5.3 +/- 0.6 mg/g dry weight (P less than 0.05) at 72 hours and continued to increase at 8 days postmyocardial infarction (14.5 +/- 1.7 mg/g dry weight; P less than 0.01). When enzyme activities and hydroxyproline content were expressed relative to other reference bases, including DNA, tissue protein, dry weight, and total left ventricle, similar results were obtained. The mechanical properties of the infarcted left ventricle were determined by filling a balloon in the excised left ventricle until rupture. The rupture threshold in the normal left ventricle, [664 +/- 43 mm Hg (n = 16)], was not significantly different from that of the infarcted left ventricle on days 1-8 postmyocardial infarction. However, left ventricular rupture occurred more often through the myocardial infarction on days 1-4 postmyocardial infarction (59%) than on days 6 and 8 (18%; P = 0.03) when collagen content had significantly increased. Wall stress at the point of rupture in left ventricles from shams and normals was 30 +/- 2 g/mm2; tensile strength in isolated left ventricle muscle strips was 25 +/- 4 g/mm2 and in isolated scar strips at 7 days postmyocardial infarction was 59 +/- 7 g/mm2. The passive stiffness of the infarcted left ventricle increased from control of 61 +/- 5 to 94 +/- 6 mm Hg/100 microliters (P less than 0.05) at 4 days and 100 +/- 7 mm Hg/100 microliters (P less than 0.01) at 6 days postmyocardial infarction. Stiffness correlated with hydroxyproline content over the 8 days postmyocardial infarction (r = 0.599; P less than 0.001). Thus, the acutely infarcted ventricle was highly resistant to rupture during the initial 48 hours postmyocardial infarction, before any increase in collagen occurred. This result suggests that the preinfarction collagen content has an important role in preventing rupture. After 72 hours postmyocardial infarction, collagen synthesis appeared to be a determinant of infarct stiffness and resistance of the infarcted ventricle to rupture.

Animals↗