Lactate Extraction Ratio Research Articles

Dynamic Shift Towards Increased O2 Consumption and Reduced Lactate Uptake During Acute Volume Expansion in Sprague Dawley (SD) Rats

Rationale: In a recent study (PMID: 37575482), we established a method to assess alterations in O2 and substance metabolism in the kidneys in conscious free moving rat. This involved the repeated collection of renal arteriovenous blood and urine, alongside continuous measurements (24/7) of renal blood flow (RBF) and blood pressure (BP). Our previous studies demonstrated that in SD rats, there is an augmentation in RBF and GFR following chronic salt loading. Additionally, total renal O2 consumption (VO2) increases while there is a decrease in the net consumption of lactate with a tendency for its increased production. We hypothesize that these changes are not exclusive to the chronic phase of salt-loading but can also manifest during rapid increases of RBF and GFR. The primary aim of this study was to establish an experimental model reflecting these dynamics. Methods: SD rat (male, 10 wk age fed 0.4 NaCl (LS) diet, n=8) were studied. The jugular vein and femoral vein and artery were catheterized together with the renal vein. FITC-inulin (2 mg/mL) dissolved in 2%BSA saline was infused at 1.0 mL/100 g body wt/h from jugular vein. RBF was measured with an ultrasonic flow probe (Transonic, Inc) on the left renal artery and BP was measured through an arterial catheter. Whole blood, collected from donor rats, was diluted by 20% with saline, and a 6 mL volume expansion was performed with this solution over 1 hour. Blood was collected from both the renal venous and arterial catheters and urine from a ureteral catheter before and after volume expansion. O2 content was measured by radiometer and plasma lactate measured with a high sensitivity L-lactate fluorescent assay kit (ab169557, abcam). The same experiment was performed without volume expansion (i.e., sham study). O2 and lactate delivery and consumption were calculated as follows: Delivery = arterial content (A) x RBF; Consumption = (A − renal venous content (RV)) x RBF; Extraction = (A-RV) / A. Results: BP increased from 101 ± 3 to 111 ± 4 mmHg (p<0.05), RBF increased from 5.4 ± 0.5 to 7.9 to 0.6 mL/min/g kidney weight (gkw) (p<0.05) by volume expansion. GFR increased from 0.94 ± 0.06 to 1.19 ± 0.08 mL/min/gkw (p<0.05). O2 delivery increased from 1.06 ± 0.09 to 1.61 ± 0.12 mL/min/gkw (p<0.05). O2 consumption (VO2) increased from 0.06 ± 0.01 to 0.08 ± 0.01 mL/min/gkw (p<0.05). The O2 extraction ratio remained unchanged. Both lactate consumption (0.94 ± 0.11 to 0.47 ± 0.11 mM/gkw, p<0.05) and extraction ratio (0.18 ± 0.01 to 0.11 ± 0.02, p<0.05) were reduced by volume expansion. Conclusion: The increase of O2 consumption and reduction of lactate consumption with acute volume expansion model appear to be similar to those that we observed when SD rats were subjected to a chronic step increase of salt intake (from 0.4 to 4.0% NaCl). In contrast, however, an increase in O2 extraction was not observed with acute volume expansion as was the case with a high salt diet in which our studies have indicated that a prolonged tubular reabsorptive workload leads to enhanced oxidative stress with an uncoupling of oxidative phosphorylation. R01 HL151587, AHA 23POST1008714. This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Measurement of Myocardial Lactate Production for Diagnosis of Coronary Microvascular Spasm.

In about a quarter of patients with angina and non-obstructive coronary arteries, no epicardial spasm is noted on coronary arteriography during an angina attack. Since the pressure-rate product is almost identical at rest and the onset of attack in those patients, the decrease in coronary blood flow rather than increased myocardial oxygen consumption is likely to explain myocardial ischemia, indicating a substantial involvement with coronary microvascular spasm (MVS). Myocardial lactate production, which could be defined as a negative myocardial lactate extraction ratio (ratio of the coronary arterial-venous difference in lactate concentration to arterial concentration), is considered indicative of objective evidence to support the emerging myocardial ischemia. Thus, monitoring of the myocardial lactate production and the emergence of chest pain and ischemic electrocardiographic changes during acetylcholine (ACh) provocation testing is of significant value for detecting the entity of MVS. Practically, 1 min after incremental doses of ACh (20, 50, and 100 μg) are administered into the left coronary artery (LCA), paired samples of 1 mL of blood are collected from the LCA ostium and coronary sinus for measurement of lactate concentration by a calibrated automatic lactate analyzer. Then, the development of MVS could be confirmed by negative myocardial lactate extraction ratio despite the absence of angiographically demonstrable epicardial coronary spasm or before its occurrence throughout ACh provocation testing. In conclusion, assessment of myocardial lactate production is essential and valuable for the diagnosis of MVS.

Clinical implications of coronary artery morphology of patients with ischemia and non-obstructive coronary artery disease (INOCA) -An intracoronary OCT study-

Abstract Introduction Ischemia and non-obstructive coronary artery disease (INOCA), including microvascular spasm (MVS) and epicardial spasm, has recently attracted much attention, for which in vivo imaging evaluation for coronary artery morphology is warranted for better understanding of this disorder. Besides the improved diagnostic accuracy of optical coherence tomography (OCT) for coronary plaques, we have recently demonstrated its capability for in vivo visualization of coronary adventitial vasa vasorum (VV) and the enhanced VV formation in patients with epicardial spasm. Purpose We aimed to examine OCT-delineated morphological characteristics in patients with INOCA in vivo. Methods A total of 335 consecutive INOCA patients, who underwent pharmacological spasm provocation tests, lactate sampling, and OCT imaging over the entire length of the left anterior descending (LAD) coronary arteries, were enrolled at our institute over 68 months from April 2013. They were classified into 4 groups; control with non-cardiac chest pain, MVS, diffuse spasm (DS), or focal spasm (FS) (Fig. 1A). MVS was diagnosed when negative lactate extraction ratio (coronary orifice < coronary sinus) was detected despite the absence of epicardial spasm during the spasm provocation test. DS was defined as epicardial spasm induced in more than 2 coronary segments in LAD, and FS as epicardial spasm in one segment. Quantitative analyses for adventitial inflammation and atherosclerotic changes were performed by calculating VV density and %area stenosis (AS) on OCT (Fig. 1B, E). Furthermore, index of microcirculatory resistance (IMR), a marker of microvascular disorder with a cut-off value of ≥25, was measured during intravenous infusion of adenosine, which was then correlated with VV densities in the MVS and DS groups. Coronary plaque with a necrotic core was classified as fibroatheroma (FA), and the number of OCT frames with internal VV (IVV) in the atheroma was counted. Results VV density was significantly higher in MVS as compared with the controls (Fig. 1B). DS was most prevalent in INOCA (Fig. 1A) with highest VV density (Fig. 1B). Patients with IMR≥25 were predominantly distributed with a gradual increase in the MVS, DS, and FS groups, but none in the controls (Fig. 1C). Importantly, there was a significant positive correlation between VV densities and IMR in the MVS and DS groups (Fig. 1D). In addition, FS had the largest plaque size and showed the highest prevalence of FA and IVV (Fig. 1E–G). Conclusions These results indicate that MVS and DS are characterized by vasomotion abnormalities associated with adventitial inflammation and microvascular disorder, while FS by vulnerable atherosclerotic phenotype, suggesting that OCT may be useful for screening high-risk populations in INOCA. Figure 1 Funding Acknowledgement Type of funding source: None

Late gadolinium enhancement on cardiac magnetic resonance imaging is associated with coronary endothelial dysfunction in patients with dilated cardiomyopathy.

Myocardial fibrosis and coronary endothelial dysfunction are important determinants of outcome in patients with heart failure. However, the relationship of these factors in patients with dilated cardiomyopathy (DCM) is not fully understood. This study aimed to investigate the relationship between endothelium-dependent coronary vasomotor abnormality and late gadolinium enhancement (LGE) on cardiac magnetic resonance imaging (CMR) in patients with DCM. We examined 38 consecutive patients with DCM. All patients underwent CMR and the acetylcholine (ACh) provocation test using cardiac catheterization. During the ACh provocation test, we sampled blood simultaneously from the coronary sinus and aortic root to compare lactate concentrations, and quantified coronary blood flow volume using an intracoronary Doppler-tipped guidewire. LGE was detected in 17 (44.7%) patients. The lactate extraction ratio (LER) in the ACh provocation test was significantly decreased in the LGE-positive group (before vs after ACh, 18.6±13.6 vs -13.3±24.8%; p<0.001) and in the LGE-negative group (before vs after ACh, 14.2±19.5 vs 3.3±16.2%; p=0.02). The rate of patients with an LER<0% (indicating myocardial lactate production due to myocardial ischemia) was significantly higher in the LGE-positive group than in the LGE-negative group [12 (70.6%) vs 7 (33.3%); p=0.02]. Multivariable logistic regression analysis showed that a post-ACh LER<0% was a significant predictor of LGE positivity (odds ratio 7.75; 95% confidence interval 1.37-43.68; p=0.02). In conclusion, ACh-provoked coronary vasomotor abnormality is associated with myocardial fibrosis in patients with DCM. These results suggest that coronary endothelial dysfunction is involved in myocardial fibrosis and worsening heart failure concomitant with DCM.

Late gadolinium enhancement on cardiac magnetic resonance predicts coronary vasomotor abnormality and myocardial lactate production in patients with chronic heart failure.

Myocardial fibrosis and microvascular dysfunction are key determinants of outcome in heart failure (HF); we examined their relationship in patients with HF. Our study included 61 consecutive patients with HF but without coronary stenosis. All underwent gadolinium-enhanced cardiac magnetic resonance to evaluate late gadolinium enhancement (LGE) and an acetylcholine (ACh) provocation test to evaluate microvascular dysfunction. During the ACh provocation test, we sampled blood simultaneously from the coronary sinus and aortic root to compare lactate concentrations. We quantified coronary blood flow volume using an intracoronary Doppler-tipped guidewire. We detected LGE in 34 patients (LGE-positive); 27 were LGE-negative. Coronary blood flow volume increased significantly after the ACh provocation test only in LGE-negative patients (before vs. after ACh, 47.5 ± 36.8 vs. 69.2 ± 48.0 ml/min, respectively; p = 0.004). The myocardial lactate extraction ratio (LER) significantly decreased after the ACh test in both groups (LGE-negative, p = 0.001; LGE-positive, p < 0.001), significantly more so in the LGE-positive group (p = 0.017). Multivariate logistic regression analysis showed that a post-ACh LER < 0 (indicating myocardial lactate production) was a significant predictor of LGE-positivity (odds ratio 4.54; 95 % confidence interval 1.38–14.93; p = 0.013). In the LGE-positive group, an LGE volume greater than the median significantly predicted a post-ACh LER of <0 (p = 0.042; odds ratio 6.02; 95 % confidence interval 1.07–33.86). ACh-provoked coronary vasomotor abnormality is closely correlated with myocardial fibrosis in patients with HF but without organic coronary stenosis. Coronary vasomotor abnormalities in fibrotic myocardium may worsen HF.

Use of continuous retrograde gaseous oxygen persufflation for myocardial protection during open heart surgery

The infusion of a cardioplegic solution is the standard method of myocardial protection during open heart surgery. However, this method interrupts the surgical procedure and it is difficult to ensure a bloodless surgical field. To address these problems, the effect of continuous retrograde gaseous oxygen persufflation (ROP) on myocardial protection was assessed in comparison to St. Thomas' solution (STS). Eighteen adult mongrel dogs were divided into three groups of six. Group G received continuous ROP, Group C received STS every 30 min, and Group N received hypothermia alone during the 120 min hypothermic ischemia. The myocardial metabolism was assessed by measuring the coronary sinus lactate concentration, lactate extraction ratio (LER), coronary sinus lipid peroxidation (LPO) concentration, left ventricular myocardial adenosine triphosphate (ATP) concentration, and water content. Cardiac function was assessed by the percent recovery relative to the baseline. In Group G, the lactate, LPO, and water content were significantly lower (P = 0.0062, P = 0.03, and P = 0.0065, respectively), and ATP was significantly higher (P = 0.028) than in Group C. The LER was only positive in Group G. In addition, the cardiac functions in Groups G and C were not significantly different. Retrograde gaseous oxygen persufflation was not inferior to STS in regard to myocardial protection. This technique could therefore represent a potentially promising cardioplegic method.

Haemodynamic and metabolic effects of timolol (Blocadren) on ischaemic myocardium.

The effects of timolol (2.5 mg i.v.) on coronary haemodynamics and myocardial metabolism were studied in 26 patients with angina pectoris. Cardiac venous flow (CVF) was measured by thermodilution technique. Blood was sampled for metabolic studies. Angina pectoris was induced by atrial pacing and the same heart rate was regained after timolol. Metabolic ischaemia was defined as reduction in myocardial lactate extraction ratio (MLE) by at least 50% and to a ratio below 0.15. The study was completed in 22 patients, 9 of whom fulfilled the metabolic criteria for ischaemia. This subgroup did not differ from the total group in any other respect than in lactate metabolism. Beta-adrenergic blockade reduced myocardial oxygen consumption (MVO2) and CVF significantly at rest, but MVO2, CVF, myocardial glucose uptake and MLE were unchanged during pacing despite a decrease in systolic aortic pressure, ejection time and reduced myocardial free fatty acid uptake. Conclusively, timolol did not reduce MVO2 and metabolic ischaemia during pacing-induced angina.

Assessment of hepatosplanchnic pathophysiology during thoracoabdominal aortic aneurysm repair using visceral perfusion and shunt☆

Despite the recognition of importance to avoid visceral ischemia during thoracoabdominal aortic aneurysm (TAAA) repair, the methodology of visceral perfusion seems still controversial and its pathophysiology has not been clearly understood. We investigated hepatosplanchnic metabolism during visceral perfusion/shunt in TAAA repair. Seventeen patients (10 male, 64+/-15 years old) who underwent elective TAAA repair using visceral perfusion/shunt under mild hypothermic distal aortic perfusion were retrospectively enrolled. Their aneurysm extension was type I and II in eight patients. In seven patients, four visceral arteries were perfused through a side-arm of distal aortic perfusion, while they were perfused by an independent pump in another five patients. In four of these 12 (two in each technique), visceral perfusion was converted into selective shunt after completion of aortic anastomosis. In the remaining five patients, four branches were initially perfused through a side-arm of distal aortic perfusion, and aortic perfusion was subsequently stopped after completion of aortic anastomosis. Hepatic venous oxygen saturation (ShO(2)), oxygen and lactate extraction ratio (OER, LER), and arterial ketone body ratio (AKBR) were measured at six time points. There was no mortality, liver/renal dysfunction, or spinal cord injury. Two patients required re-exploration for bleeding. Fourteen patients were extubated within 24h postoperatively. Mean intensive care unit stay was 2.3+/-1.7 days. During visceral perfusion, OER raised (31+/-13% to 68+/-21%, p=0.0012) and ShO(2) decreased (67+/-12% to 34+/-24%, p=0.0026) significantly. They recovered to baseline at skin closure. During the same period, LER (41+/-22% to -1+/-34%, p=0.0035) and AKBR (0.47+/-0.13 to 0.20+/-0.08, p=0.0012) significantly decreased. AKBR recovered to baseline at skin closure, but LER did not. ShO(2) (R(2)=0.483, p=0.0257) and LER (R(2)=0.774, p=0.0018) at skin closure and LER after initiation of partial cardiopulmonary bypass (R(2)=0.427, p=0.0211) had significant correlation with postoperative peak serum bilirubin level. AKBR after initiation of partial cardiopulmonary bypass had significant correlation with postoperative peak serum alanine aminotransferase level (R(2)=0.289, p=0.0476). Visceral perfusion/shunt in TAAA repair may avoid critical irreversible hepatosplanchnic ischemia but provide unphysiological blood flow to the liver and thus should be shortened.

Norepinephrine to increase blood pressure in endotoxaemic pigs is associated with improved hepatic mitochondrial respiration

IntroductionLow blood pressure, inadequate tissue oxygen delivery and mitochondrial dysfunction have all been implicated in the development of sepsis-induced organ failure. This study evaluated the effect on liver mitochondrial function of using norepinephrine to increase blood pressure in experimental sepsis.MethodsThirteen anaesthetized pigs received endotoxin (Escherichia coli lipopolysaccharide B0111:B4; 0.4 μg/kg per hour) and were subsequently randomly assigned to norepinephrine treatment or placebo for 10 hours. Norepinephrine dose was adjusted at 2-hour intervals to achieve 15 mmHg increases in mean arterial blood pressure up to 95 mmHg. Systemic (thermodilution) and hepatosplanchnic (ultrasound Doppler) blood flow were measured at each step. At the end of the experiment, hepatic mitochondrial oxygen consumption (high-resolution respirometry) and citrate synthase activity (spectrophotometry) were assessed.ResultsMean arterial pressure (mmHg) increased only in norepinephrine-treated animals (from 73 [median; range 69 to 81] to 63 [60 to 68] in controls [P = 0.09] and from 83 [69 to 93] to 96 [86 to 108] in norepinephrine-treated animals [P = 0.019]). Cardiac index and systemic oxygen delivery (DO2) increased in both groups, but significantly more in the norepinephrine group (P < 0.03 for both). Cardiac index (ml/min per·kg) increased from 99 (range: 72 to 112) to 117 (110 to 232) in controls (P = 0.002), and from 107 (84 to 132) to 161 (147 to 340) in norepinephrine-treated animals (P = 0.001). DO2 (ml/min per·kg) increased from 13 (range: 11 to 15) to 16 (15 to 24) in controls (P = 0.028), and from 16 (12 to 19) to 29 (25 to 52) in norepinephrine-treated animals (P = 0.018). Systemic oxygen consumption (systemic VO2) increased in both groups (P < 0.05), whereas hepatosplanchnic flows, DO2 and VO2 remained stable. The hepatic lactate extraction ratio decreased in both groups (P = 0.05). Liver mitochondria complex I-dependent and II-dependent respiratory control ratios were increased in the norepinephrine group (complex I: 3.5 [range: 2.1 to 5.7] in controls versus 5.8 [4.8 to 6.4] in norepinephrine-treated animals [P = 0.015]; complex II: 3.1 [2.3 to 3.8] in controls versus 3.7 [3.3 to 4.6] in norepinephrine-treated animals [P = 0.09]). No differences were observed in citrate synthase activity.ConclusionNorepinephrine treatment during endotoxaemia does not increase hepatosplanchnic flow, oxygen delivery or consumption, and does not improve the hepatic lactate extraction ratio. However, norepinephrine increases the liver mitochondria complex I-dependent and II-dependent respiratory control ratios. This effect was probably mediated by a direct effect of norepinephrine on liver cells.

Metabolic relevance during isolation technique in total arch repair for patients at high risk with embolic stroke

In patients undergoing total arch replacement with protruding or mobile atheroma in the proximal aorta, we isolate cerebral circulation from systemic one by starting selective cerebral perfusion (SCP) before systemic arterial perfusion to prevent aortogenic embolic stroke. We disclose the safety of this isolation technique by measuring cerebral oxygenation and metabolism. Sixty-six patients underwent total arch replacement using SCP since 1998. The isolation technique was applied in sixteen patients. Jugular venous oxygen saturation (SjO(2)) was monitored in nine patients undergoing isolation technique (isolation-group) and in thirteen patients of the rest (conventional-group). Oxygen, glucose, and lactate extraction ratio (OER, GER, and LER) were measured at seven time points peri-operatively. The isolation-group had significantly longer SCP time (isolation: 185+/-52 min vs. conventional: 140+/-43 min, P<0.01). During cooling, SjO(2) was kept comparable between groups. OER was minimum at the end of cooling and comparable between groups (isolation: 3.8+/-7.7% vs. conventional: 11.7+/-13.8%, P=0.37). There were no significant differences in GER and LER between groups. There were neither in-hospital death nor stroke. Temporary neurological dysfunction was observed only in conventional-group (n=3, 23%, P=0.12). Isolation technique for total arch replacement could be performed safely and may provide acceptable results in patients at high risk for embolic stroke.

S-nitrosylated and pegylated hemoglobin, a newly developed artificial oxygen carrier, exerts cardioprotection against ischemic hearts

Cell-free hemoglobin (Hb) derivatives that have been developed as Hb-based artificial oxygen carrier cause both coronary vasoconstriction and platelet aggregation due to the scavenging actions of nitric oxide (NO). Recently, native Hb is found to undergo S-nitrosylation, which regulates blood flow, whereas artificial oxygen carriers are lacking of S-nitrosylation. Therefore, S-nitrosylated and pegylated hemoglobin (SNO-PEG-Hb) was prepared to overcome the above defects, where pegylation was included to avoid extravasation and to prolong the circulatory half-live. Since SNO-PEG-Hb possesses SNO property, we tested whether SNO-PEG-Hb increases coronary blood flow (CBF) and improves the severity of myocardial ischemia. In 19 open chest dogs, the left anterior descending coronary artery was perfused with blood from the carotid artery via the bypass tube, and then CBF and coronary perfusion pressure (CPP) were measured. After hemodynamic stabilization, CPP was reduced so that CBF decreased to 33% of the baseline and thereafter CPP was maintained constant. Ten minutes after the onset of coronary hypoperfusion, we infused 10% SNO-PEG-Hb into the coronary artery (2.5 ml/min). SNO-PEG-Hb increased CBF (28.1 ± 3.3 to 43.3 ± 3.9 ml/100 g/min, p < 0.05), fractional shortening (4.6 ± 1.2 to 16.6 ± 2.4%, p < 0.01) and lactate extraction ratio (− 38.5 ± 8.6 to 25.5 ± 1.3%, p < 0.01). Thus, we conclude that SNO-PEG-Hb increases coronary blood flow and improves the contractile and metabolic dysfunction of the ischemic myocardium. SNO-PEG-Hb, a newly developed artificial oxygen carrier, may mediate a cardioprotection in ischemic heart diseases in addition to blood supplementation.

A −786T&gt;C polymorphism in the endothelial nitric oxide synthase gene reduces serum nitrite/nitrate levels from the heart due to an intracoronary injection of acetylcholine

We identified a -786T>C polymorphism in the eNOS gene, and this polymorphism was strongly associated with coronary spasm. The present study aimed to elucidate whether the -786T>C polymorphism or acetylcholine (ACh)-induced coronary spasm affects serum nitrite/nitrate (NOx) levels. The study population comprised three groups: (i) 26 patients without coronary spasm in the left anterior descending coronary artery (LAD) with the T/T genotype (group A); (ii) 20 patients with coronary spasm in the LAD with the T/T genotype (group B); and (iii) 16 patients with coronary spasm in the LAD with the C/T genotype (group C). Paired blood samples were obtained from the coronary sinus (CS) and the aortic tract (Ao) before and after an intracoronary injection of ACh. Serum NOx and plasma lactate levels were measured. The delta NOx level was calculated as the serum concentration of NOx in the CS minus that in the Ao. We compared lactate extraction ratios (LERs) and delta NOx levels between the three groups. The LERs after the provocation test in groups A, B and C were 18.9+/-2.4%, -0.5+/-3.9% and -13.5+/-4.2%, respectively. The LER in group C was significantly lower than in group B. The delta NOx levels after the provocation test in groups A, B and C were 11.5+/-1.7 micromol/l, 10.4+/-3.5 micromol/l and -2.1+/-4.8 micromol/l, respectively. The delta NOx levels in group C were significantly lower (P<0.05). Although the NOx level was significantly increased after the provocation test in group A (P<0.05), the NOx level was significantly decreased after the provocation test in group C (P=0.001). In group B, the provocation test did not significantly change the delta NOx level. In conclusion, the -786T>C polymorphism reduces the NOx level from the heart due to an intracoronary injection of ACh, and thereby predisposes the patients to severe coronary spasm.

Blockade of histamine H2 receptors protects the heart against ischemia and reperfusion injury in dogs

We have previously reported that histamine H(2) blockers may be cardioprotective in patients with chronic heart failure. Since both endogenous histamine and histamine H(2) receptors are present in heart tissue, we tested the hypothesis that the blockade of histamine H(2) receptors mediates protection against reversible or irreversible ischemia and reperfusion injury. In open-chest dogs, the left anterior descending coronary artery was occluded for 90 minutes, followed by reperfusion for 6 hours. Administration of famotidine and cimetidine from 10 minutes before occlusion until after 1 hour of reperfusion reduced infarct size (17.0 +/- 4.1% and 17.8 +/- 2.9% vs. 36.9 +/- 5.9% of the solvent group, respectively) Famotidine administration only during the reperfusion period for 1 hour also attenuated infarct size (22.5 +/- 3.5%). There were no differences in either area at risk or collateral flow among the groups. In another set of experiments, we decreased coronary perfusion pressure in dogs so that the coronary blood flow decreased to 50% of the non-ischemic level. In such conditions, we observed the increases in histamine release compared with non-ischemic conditions (0.04 +/- 0.03 to 0.28 +/- 0.13 ng/ml, p < 0.05). Famotidine improved anaerobic myocardial metabolism gauged by both lactate extraction ratio and myocardial oxygen consumption. We conclude that the blockade of histamine H(2) receptors mediates improvements in the anaerobic myocardial metabolism, and thus protects against ischemia and reperfusion injury.

Tachycardia-induced myocardial ischemia and diastolic dysfunction potentiate secretion of ANP, not BNP, in hypertrophic cardiomyopathy

The aim of this study was to investigate what factor determines tachycardia-induced secretion of atrial and brain natriuretic peptides (ANP and BNP, respectively) in patients with hypertrophic cardiomyopathy (HCM). HCM patients with normal left ventricular (LV) systolic function and intact coronary artery (n = 22) underwent rapid atrial pacing test. The cardiac secretion of ANP and BNP and the lactate extraction ratio (LER) were evaluated by using blood samples from the coronary sinus and aorta. LV end-diastolic pressure (LVEDP) and the time constant of LV relaxation of tau were measured by a catheter-tip transducer. These parameters were compared with normal controls (n = 8). HCM patients were divided into obstructive (HOCM) and nonobstructive (HNCM) groups. The cardiac secretion of ANP was significantly increased by rapid pacing in HOCM from 384 +/- 101 to 1,268 +/- 334 pg/ml (P < 0.05); however, it was not significant in control and HNCM groups. In contrast, the cardiac secretion of BNP was fairly constant and rather significantly decreased in HCM (P < 0.01). The cardiac ANP secretion was significantly correlated with changes in LER (r = -0.57, P < 0.01) and tau (r = 0.73, P < 0.001) in HCM patients. Tachycardia potentiates the cardiac secretion of ANP, not BNP, in patients with HCM, particularly when it induces myocardial ischemia and LV diastolic dysfunction.

Negative inotropic action of propofol is enhanced in the acute ischemic myocardium of dogs

We investigated the effects of propofol on contractility and oxygen balance in acute ischemic myocardium and compared them with those of normal myocardium using a coronary microembolization model in dogs. In open-chest dogs, the left anterior descending coronary artery (LAD) was perfused through an extracorporeal bypass from the carotid artery. Regional myocardial contractility and myocardial oxygen balance were evaluated along with segment shortening (%SS), regional myocardial oxygen consumption (MVO2), and lactate extraction ratio (LER) of the area perfused by the LAD. Acute ischemia was produced by repeated injection of microspheres into the LAD-perfused area until %SS decreased by 50% of baseline. In normal myocardium, intracoronary infusion of propofol at doses of 1.2 and 2.4 mg x kg(-1) x h(-1) caused slight decreases in %SS to 83% +/- 8% and 80% +/- 10%, respectively. In ischemic myocardium, propofol caused greater decreases in %SS (59% +/- 18% and 35% +/- 20%, respectively). The changes in MVO2 after propofol infusion generally paralleled the changes in %SS, but LER was not changed in either ischemic or normal myocardium. Propofol causes a greater decrease in the contractility of acute ischemic myocardium as compared with normal myocardium in which myocardial oxygen imbalance is not involved as a mechanism.

Effect of Low Dose Norepinephrine Infusion on Myocardial Oxygen Consumption and Lactate Metabolism

Background: Norepinephrine infusion has been reported to be associated with adverse events in ischemic heart disease due to elevation of afterload and cardiac oxygen consumption. During coronary artery bypass graft, we observed changes of hemodynamic and laboratory parameters in low dose norepinephrine infusion. Also, we investigated effects of norepinephrine on cardiac oxygen metabolism by calculating oxygen consumption and lactate extraction ratio. Methods: Fifteen patients, ASA PS class IV-V, scheduled for elective coronary artery bypass graft were enrolled in this study. All of the operations were performed under general anesthesia. During harvesting of graft vessels, norepinephrine was infused at the rate of 0.02/kg/min, and then at the rate of 0.05/kg/min. We measured various hemodynamic and laboratory parameters in three periods (baseline, NE 0.02/kg/min, NE 0.05/kg/min). Also we calculated oxygen consumption and lactate extraction ratio of myocardium. Results: In the baseline period(no norepinephrine infusion), oxygen consumption () is 159.278.6 ml/min, lactate extraction ratio (LER) is 33.1 13.0%. After norepinephrine infusion at the rate of 0.02/kg/min, is 157.6 55.7 ml/min, LER is 29.9 10.7%. After norepinephrine infusion at the rate of 0.05/kg/min, is 212.5 134.5 ml/min, LER is 27.9 13.4%. Although and LER are changed in relation to the rate of norepinephrine infusion, there was no statistical significance. Conclusions: In conclusion, infusion of low dose norepinephrine during coronary artery bypass graft did not produce significant differences in myocardial oxygen consumption and lactate extraction ratio associated with myocardial oxygen balance.

Effects of volume resuscitation on splanchnic perfusion in canine model of severe sepsis induced by live Escherichia coli infusion.

IntroductionWe conducted the present study to investigate whether early large-volume crystalloid infusion can restore gut mucosal blood flow and mesenteric oxygen metabolism in severe sepsis.MethodsAnesthetized and mechanically ventilated male mongrel dogs were challenged with intravenous injection of live Escherichia coli (6 × 109 colony-forming units/ml per kg over 15 min). After 90 min they were randomly assigned to one of two groups – control (no fluids; n = 13) or lactated Ringer's solution (32 ml/kg per hour; n = 14) – and followed for 60 min. Cardiac index, mesenteric blood flow, mean arterial pressure, systemic and mesenteric oxygen-derived variables, blood lactate and gastric carbon dioxide tension (PCO2; by gas tonometry) were assessed throughout the study.ResultsE. coli infusion significantly decreased arterial pressure, cardiac index, mesenteric blood flow, and systemic and mesenteric oxygen delivery, and increased arterial and portal lactate, intramucosal PCO2, PCO2 gap (the difference between gastric mucosal and arterial PCO2), and systemic and mesenteric oxygen extraction ratio in both groups. The Ringer's solution group had significantly higher cardiac index and systemic oxygen delivery, and lower oxygen extraction ratio and PCO2 gap at 165 min as compared with control animals. However, infusion of lactated Ringer's solution was unable to restore the PCO2 gap. There were no significant differences between groups in mesenteric oxygen delivery, oxygen extraction ratio, or portal lactate at the end of study.ConclusionSignificant disturbances occur in the systemic and mesenteric beds during bacteremic severe sepsis. Although large-volume infusion of lactated Ringer's solution restored systemic hemodynamic parameters, it was unable to correct gut mucosal PCO2 gap.

Celiprolol increases coronary blood flow and reduces severity of myocardial ischemia via nitric oxide release.

Celiprolol is a selective beta(1)-adrenoceptor antagonist with antihypertensive actions, which causes renal vasodilation by increasing tissue nitric oxide (NO) levels. The authors tested whether celiprolol increases coronary blood flow (CBF) by increasing cardiac NO release in the ischemic heart in vivo. In open-chest dogs, coronary perfusion pressure of the left anterior descending coronary artery was reduced so that CBF decreased to 60% of control levels, and thereafter, coronary perfusion pressure was maintained constant. Ten minutes after the reduction of coronary perfusion pressure, we infused celiprolol into the left anterior descending coronary artery and measured fractional shortening and lactate extraction ratio as indices of regional myocardial contractility and metabolism. CBF significantly increased from 51.5 mL/100 g/min +/- 1.9 to 67.0 mL/100 g/min +/- 5.1 20 minutes after celiprolol infusion without changes in coronary perfusion pressure, while fractional shortening and lactate extraction ratio increased. Celiprolol also increased cardiac NO release. The L omega-nitroarginine methyl ester, the inhibitor of NO synthase, attenuated the increases in CBF, fractional shortening, lactate extraction ratio, and cardiac NO release due to celiprolol. ICI 118551, a beta(2)-adrenoceptor antagonist, did not blunt the effects of celiprolol and a nonselective beta-adrenoceptor antagonist, propranolol, increased neither CBF nor cardiac NO release, indicating that the effect of celiprolol is independent of beta-adrenoceptor blockade. It was concluded that celiprolol mediates coronary vasodilation and improves myocardial ischemia through NO-dependent mechanisms.

Impairment of myocardial protection in type 2 diabetic patients.

Diabetic patients are more prone to develop postinfarction complications. It remained unclear whether diabetes mellitus- or sulfonylureas-associated changes of ATP-sensitive potassium (K(ATP)) channels, an integral player in ischemic preconditioning, are responsible for the increased mortality. The purpose of this study was to determine the impact of diabetes mellitus per se and different sulfonylurea administration on cardioprotective effects in diabetic patients undergoing coronary angioplasty. Myocardial ischemia after coronary angioplasty was evaluated in 20 nondiabetic and 23 diabetic patients chronically taking either glibenclamide or glimepiride. Nondiabetic patients treated with glimepiride significantly lowered the ischemic burden assessed by an ST-segment shift, chest pain score, and myocardial lactate extraction ratios compared with the glibenclamide-treated patients, implying that acute administration of glimepiride did not abolish cardioprotection. In the diabetic glibenclamide-treated group, the reduction in the ST-segment shift afforded by nicorandil in the first inflation (-58% vs. the first inflation in the glibenclamide group alone) was similar to that afforded by preconditioning (-59% during the second vs. the first inflation). In glimepiride-treated groups, the magnitude of attenuated lactate production was less in diabetes than that in nondiabetes at the second inflation, suggesting that diabetes mellitus per se plays a role in determining lactate production. Our results show that both diabetes mellitus and sulfonylureas can act in synergism to inhibit activation of K(ATP) channels in patients undergoing coronary angioplasty. The degree of inhibition assessed by metabolic and electrocardiographic parameters is less severe during treatment with glimepiride than with glibenclamide. Restitution of a preconditioning response in glimepiride-treated patients may be the potential beneficial mechanism.

Correlation of lactate, pHi and oxygen extraction ratio with cardiac index in ICU patients after aortic surgery

Investigation of the relationship among Lac acid, pHi and O2ER with cardiac index (CI) and determination of the early indicator of hemodynamic compromise in patients undergoing aortic surgery during the first 24 hours of their stay in a multidisciplinary ICU.