The Effect of Glycemic Control on Left Ventricular Function in Clinical and Experimental Diabetes.

Background: Glycemic control in diabetes mellitus (DM) has not improved cardiovascular outcomes with normal left ventricular (LV) function. We assessed the effect on LV dysfunction using a canine model of LV dysfunction and DM, and in patients with DM and LV dysfunction. Methods: Chronic LV dysfunction was produced by coronary microsphere embolization in 34 canines (15-25 kg). Following 8 weeks of stabilization, DM was induced in 24 canines and randomized to good or poor glycemic control for 3 months. Ten canines without DM were controls. Hemodynamic and Doppler echocardiographic data were obtained prior to and following pressure loading. We reviewed the Doppler-echocardiography at baseline and follow-up in 207 patients with DM with reduced ejection fraction (EF; median follow-up = 612 days) and 60 age- and sex-matched non-DM patients with normal EF. Laboratory results, medications, and incident adverse events from medical records were obtained. Results: EF = 43.8% ± 11.2% for all canines at 8 weeks. Canines with poor glycemic control (hemoglobin [Hb]A1c = 8.05% ± 3.02%) demonstrated reduced LV mass and rate-corrected velocity of circumferential fiber shortening, compared to those with LV dysfunction (1.36 ± 0.73 vs 0.88 ± 0.13 circumference per second, P < 0.01). Good glycemic control (HbA1c = 3.88% ± 0.89%) demonstrated similar LV parameters, compared to controls (HbA1c = 2.99% ± 0.44%). EF was similar among groups. Patients with vs without DM were followed for up to 3 years. Patients with DM and poor glycemic control had reduced EF, lower rate-corrected velocity of circumferential fiber shortening = 0.93 ± 0.26 vs 1.11 ± 0.26, P < 0.001), and greater incidence of heart failure. Conclusions: Poor glycemic control had an adverse effect on preexisting LV dysfunction experimentally and in patients with type 2 diabetes.

Contexte: Chez les personnes atteintes de diabète sucré (DS), la maîtrise glycémique n'a pas amélioré les résultats cardiovasculaires en présence d'une fonction ventriculaire gauche (VG) normale. Nous avons évalué l'effet d'une dysfonction VG au moyen d'un modèle canin de dysfonction VG et de DS, ainsi que chez des patients atteints de ces deux troubles. Méthodologie: Une dysfonction VG chronique a été produite chez 34 chiens (pesant de 15 à 25 kg) au moyen d'une embolisation coronarienne par microsphères. Après huit semaines de stabilisation, un DS a été provoqué chez 24 chiens, qui ont été répartis aléatoirement pour faire l'objet d'une bonne ou d'une mauvaise maîtrise glycémique pendant trois mois. Les 10 chiens sans DS ont servi de témoins. Des données hémodynamiques et échocardiographiques (Doppler) ont été obtenues avant et après la mise en charge. Nous avons aussi étudié l'échocardiogramme Doppler, au départ et lors du suivi, de 207 patients atteints de DS et présentant une fraction d'éjection (FE) réduite (suivi médian de 612 jours) et de 60 patients non atteints de DS qui ont été appariés en fonction de l'âge et du sexe et dont la FE était normale. Enfin, nous avons obtenu leurs dossiers médicaux : résultats des épreuves de laboratoire, listes de médicaments et manifestations indésirables découvertes fortuitement. Résultats: La FE était de 43,8 % ± 11,2 % pour l'ensemble des chiens après huit semaines. Chez les chiens dont la maîtrise glycémique était mauvaise (hémoglobine [Hb]A1c = 8,05 % ± 3,02 %), la masse VG et la vitesse de raccourcissement circonférentiel des fibres myocardiques corrigée en fonction de la fréquence cardiaque (VCFc) étaient toutes deux réduites comparativement à celles observées chez les chiens présentant une dysfonction VG (1,36 ± 0,73 vs 0,88 ± 0,13 circonférence par seconde [circ/s], p < 0,01). Chez les chiens avec une bonne maîtrise glycémique (HbA1c = 3,88 % ± 0,89 %), les paramètres VG étaient semblables à ceux observés chez les témoins (HbA1c = 2,99 % ± 0,44 %). La FE était également similaire dans tous les groupes. Les patients atteints de DS ont été suivis et comparés à des patients non atteints de DS pendant une durée allant jusqu'à trois ans. Les patients qui étaient atteints de DS et dont la glycémie était mal maîtrisée présentaient une FE réduite, une diminution de la VCFc (0,93 ± 0,26 vs 1,11 ± 0,26; p < 0,001) et une incidence accrue de cas d'insuffisance cardiaque. Conclusions: Une mauvaise maîtrise glycémique a eu un effet indésirable sur une dysfonction VG préexistante, tant dans le modèle animal que chez les patients atteints de diabète de type 2.

Intracoronary aqueous oxygen perfusion, performed 24 h after the onset of postinfarction reperfusion, experimentally reduces infarct size and improves left ventricular function.

BACKGROUND: Intracoronary aqueous oxygen (AO) hyperoxemic perfusion, initiated shortly (15-30 min) after the onset of postinfarction reperfusion, reduces infarct size and improves left ventricular function. Whether such therapy provides similar benefits when administered many hours after the onset of reperfusion is unknown. Accordingly, the hypothesis was tested that AO hyperbaric perfusion, performed 24 h after the onset of postinfarction reperfusion, reduces infarct size and improves left ventricular ejection fraction (LVEF) in swine. METHODS: Following a 1-h balloon occlusion of the left anterior descending coronary artery in air-ventilated juvenile domestic swine, reperfusion was allowed to proceed without adjunctive therapy overnight in all animals. The following day, half of the reanesthetized, air-ventilated swine were randomized to treatment with intracoronary AO hyperbaric perfusion for 90 min (n=6, mean arterial perfusate PO(2)=899+/-78 mm Hg), while the remainder served as controls (n=6). RESULTS: Infarct size by triphenyl tetrazolium chloride was reduced by 48% and the [area of necrosis]/[area at risk] ratio was reduced by 44% in the AO group compared to the control group (p<0.05). By serial ventriculography, mean LVEF improved by 21% during AO perfusion, relative to baseline and control group values (p<0.05), with no significant change 1 h after completion of treatment (p>0.05). CONCLUSION: AO hyperbaric perfusion, delayed 24 h after the onset of postinfarction reperfusion, reduces infarct size and improves LVEF in an experimental animal model.

Aqueous oxygen near the homogeneous nucleation limit of water: stabilization with submicron capillaries.

Previous studies have demonstrated that the metastability threshold of aqueous oxygen (AO) is inversely dependent on the internal diameter of capillary tubes used to deliver it into blood. The hypothesis was tested herein that significantly higher thresholds are attainable with capillaries having markedly smaller dimensions (submicron) than those previously studied. Water was equilibrated with oxygen over a 0.3- to 0.7-k bar range. Inert gases (argon, helium) facilitated studies at pressures to 2.5 k bar. An argon-ion laser was used to visualize fluorescein in the liquid effluent from silica capillaries that were tapered at the distal end to a submicron internal diameter (0.5 +/- 0.3 microns). During infusion of the fluorescent effluent into host water at 21 degrees C and atmospheric pressure, integrity of the effluent and lack of microbubbles were monitored by videomicroscopy. No microbubbles were noted at AO concentrations ranging from 7.5 to 12.8 ml O2/g (0.34 to 0.68 k bar, respectively) or in the aqueous argon effluent at concentrations to 14 ml Ar/g (0.75 k bar). For aqueous helium, effluent nucleation was not observed at a mean concentration of 13 +/- 3 ml He/g (2.0 +/- 0.5 k bar), with an upper value of 15.2 ml He/g (2.4 k bar). The data represent the highest values of the tensile strength of water ever observed and approximate its theoretical homogeneous nucleation limit. Thus, remarkably high metastable concentrations of AO and other gases are attainable with the use of submicron capillaries.

Aqueous oxygen attenuation of reperfusion microvascular ischemia in a canine model of myocardial infarction.

Uncorrected microvascular ischemia may contribute to left ventricular impairment during reperfusion after prolonged coronary artery occlusion. Attenuation of such ischemia in microvessels with impaired erythrocyte flow may require delivery of oxygen at high levels in plasma. Intraarterial infusion of aqueous oxygen (AO) can be used in a site specific manner to achieve hyperoxemic levels of oxygenation in the perfusate. With this new approach, the hypothesis was tested that reperfusion microvascular ischemia can be attenuated. After a 90 min coronary balloon occlusion in a canine model, AO hyperoxemic intracoronary perfusion was performed for 90 min after a 30 min period of autoreperfusion. Control groups consisted of normoxemic reperfusion, both passive (autoreperfusion) and active (roller pump). A significant improvement in left ventricular ejection fraction (p < 0.05) at 2 hr of reperfusion was noted only in the AO hyperoxemia group (17 +/- 6% by two dimensional echo), without a significant reduction in the improvement 1 hr after termination of treatment. During AO hyperoxemic perfusion, ECG ST segment isoelectric deviation normalized, and frequency of ventricular premature contractions was significantly reduced, in contrast to the autoreperfusion control group (p < 0.05). Microvascular blood flow, measured as the ischemic/normal left ventricular segment ratio by radiolabeled microspheres immediately after AO hyperoxemic perfusion, was double the value of the autoreperfusion control group at 2 hr of reperfusion (p < 0.05). We conclude that reperfusion microvascular ischemia is attenuated by intracoronary AO hyperoxemic perfusion and acutely improves left ventricular function in this model.

Aqueous oxygen hyperbaric reperfusion in a porcine model of myocardial infarction.

OBJECTIVES: The purpose of the study was to test the hypothesis that intracoronary aqueous oxygen (AO) hyperbaric reperfusion reduces myocardial injury after prolonged coronary occlusion. Background. Attenuation of ischemia/reperfusion injury by the use of hyperbaric oxygen (HBO) administered during reperfusion has been demonstrated for a wide variety of tissues, including myocardium. We have recently developed a more practical, catheter-based, site-specific method for delivery of oxygen at hyperbaric levels with aqueous oxygen infusion. METHODS: Following a 60-minute balloon occlusion of the left anterior descending coronary artery in swine, intracoronary AO hyperoxemic perfusion (50 mL blood/minute; 1.5 mL AO/minute; mean pO2 = 834 104 mmHg) was performed for 90 minutes after a 15-minute period of normoxemic autoreperfusion (physiologic reperfusion). Control groups consisted of autoreperfusion alone; active normoxemic perfusion (50 mL/minute) for 90 minutes; and hyperoxemic perfusion with a hollow fiber oxygenator (HFO) for 90 minutes. Results. A significant improvement in left ventricular ejection fraction was noted by ventriculography at 105 minutes of reperfusion (ANOVA, p < 0.05), compared to the 15-minute autoreperfusion period, only in the AO and HFO groups. Mean percent infarct size (area of necrosis)/(area at risk), quantitative post-mortem hemorrhage score, and myocardial myeloperoxidase levels at 3 hours of reperfusion were significantly less in the AO group (ANOVA, p < 0.05), but not in the HFO group, compared to normoxemic groups. Conclusions. The results demonstrate that intracoronary hyperbaric reperfusion with AO, but not with a membrane oxygenator, attenuates myocardial ischemia/reperfusion injury.