Myocardial Lactate Research Articles

Abstract 11228: The Endothelial Nitric Oxide Synthase Gene -786T/C Polymorphism is a Significant Predictive Factor for Myocardial Lactate Production During Acetylcholine-Provoked Coronary Spasm

Myocardial lactate production (MLP) in the coronary circulation is a supporting diagnostic marker useful in the evaluation of coronary spasm-induced myocardial ischemia during acetylcholine (ACh)-provocation test. We previously found a -786T/C polymorphism in the 5’-flanking region of the endothelial nitric oxide synthase (eNOS) gene and reported that this polymorphism is strongly associated with coronary spasm. However, there is no report showing the relation between MLP induced by ACh-provocation test and eNOS gene -786T/C polymorphism in the large study population. We examined 712 consecutive patients who underwent myocardial lactate measurement during ACh-provocation test and agreed with genetic screening test of eNOS gene -786T/C polymorphism between January 1991 and December 2010. ACh-provoked MLP was observed in 252 out of 712 patients included in the present analysis [252 MLP-positive and 460 MLP-negative patients]. MLP-positive patients were more likely to be female, diabetic, non-smokers, had epicardial, multivessel and diffuse spasm pattern, with eNOS-786T/C polymorphism (60% vs. 44%, p<0.001, 25% vs. 19%, p=0.047, 61% vs. 46%, p<0.001, 83% vs. 36%, p<0.001, 37% vs. 11%, p<0.001, 39% vs. 12%, p<0.001, and 23% vs. 15%, p=0.011, respectively). Multiple logistic regression analysis identified female gender, epicardial spasm and -786T/C polymorphism to correlate with the MLP-positive finding (OR: 0.327; 95% CI: 0.226-0.475; p<0.001, OR: 10.137; 95% CI: 6.767-15.187; p<0.001, and OR: 1.621; 95% CI: 1.025-2.564; p= 0.039). In the analysis of patients with epicardial coronary spasm, Kaplan-Meier survival curve showed no difference in 5-year survival rates free from major adverse cardiac events between MLP-positive and MLP-negative patients with epicardial coronary spasm (p=NS). In conclusion, multiple predictors including female gender and eNOS gene -786T/C polymorphism were the significant predictors for the MLP induced by ACh-provocation test, highlighting the close relation between the genetic factors and ACh-induced myocardial ischemia in Japanese patients with coronary vasospastic angina.

Subnormothermic Preservation in Somah: A Novel Approach for Enhanced Functional Resuscitation of Donor Hearts for Transplant

Organ preservation at 4°C results in temporally irreversible injury to cellular structure and function. This study was designed to evaluate the possibility of storing hearts at ambient temperatures in novel organ preservation solution Somah to prevent damage and preserve optimum function by maintaining cellular energy over the temperature range of storage. Porcine hearts were stored in Celsior at 4°C and Somah at 4°C, 13°C and 21°C for 5 h thereafter reperfused and reanimated in vitro for 3 h. Heart weights, histopathology, ultrastructure and 2-dimensional echocardiography (2D-Echo) assessments showed preservation of structure in Somah groups. Tissue high-energy phosphate levels in Somah groups after storage were significantly greater than the Celsior hearts (p < 0.05) and highest in the 21°C Somah hearts. Upon reperfusion, myocardial O2 consumption and lactate levels quickly achieved steady state in 21°C hearts, but were delayed in Somah 4/13°C groups and severely depressed in the Celsior group. Inotrope and electroconversion requirements were inversely related to storage temperature. In vitro 2D Echo demonstrated a discordantly attenuated function in the Celsior group, moderate functionality in 4°C Somah group and superior reestablishment of performance in the Somah higher temperature groups. Hearts stored in Somah at 21°C were metabolically and functionally superior to any other groups.

Thyroid hormone and the stunned myocardium.

Acute critically ill patients experience a rapid decline in plasma free thyroid hormone levels (free triiodothyronine (FT3) and free levothyroxine (FT4)), with a marked elevation of reverse T3, recognized as the euthyroid sick syndrome (ESS) or low-T3 syndrome. The ESS is also often associated with depressed myocardial function, sometimes referred to as the 'stunned myocardium'. Its clinical effects may vary from minimal hemodynamic impairment to cardiogenic shock. Medical management may range from aspirin alone to placement of a left ventricular assist device. With adequate supportive therapy, recovery usually occurs within days or weeks. The effect of T3/T4 therapy has been studied in three conditions in which the ESS and myocardial functional depression have been documented - i) transient regional myocardial ischemia and reperfusion, ii) transient global myocardial ischemia in patients undergoing cardiac surgery on cardiopulmonary bypass, and iii) transient inadequate global myocardial perfusion in brain-dead potential organ donors. Under all three conditions, myocardial ischemia leads to rapid loss of high-energy phosphates, accumulation of myocardial tissue lactate, and probably loss of homeostasis of cytosolic calcium, which may further increase cell injury. There is an inability to generate ATP through the Krebs cycle, which reduces the high-energy phosphate pool essential for all cell ATPases. Under all three conditions, following administration of T3/T4, the myocardial dysfunction was rapidly reversed. We, therefore, cautiously advocate the use of thyroid hormonal therapy to any patient with the ESS and/or a stunned myocardium.

Ulinastatin protects cardiomyocytes against ischemia‑reperfusion injury by regulating autophagy through mTOR activation.

Autophagy is significant in myocardial ischemia-reperfusion (IR) injury. Ulinastatin has been demonstrated to protect cardiomyocytes against IR through inducing anti-inflammatory effects. However, whether ulinastatin has an anti‑autophagic effect is yet to be elucidated. The present study aimed to investigate the effect of ulinastatin on the regulation of autophagy during IR injury. Cardiomyocytes of neonatal rats were randomly divided into control, hypoxia-reoxygenation (HR) and ulinastatin groups. In order to investigate whether mammalian target of rapamycin (mTOR) is involved in mediating the protective effect of ulinastatin, cells were treated with the mTOR inhibitor, rapamycin 30 min prior to ulinastatin treatment. To demonstrate the anti-autophagic effect of ulinastatin in vivo, a rat IR model was established. Ulinastatin (1x104 U/kg body weight) was administered 30 min prior to the induction of IR via peritoneal injection. Light chain 3 (LC3), phosphorylated (p)‑mTOR, p‑protein kinase B (Akt) and p‑P70S6 kinase (p‑P70S6K) protein expression were assessed using western blot analysis. In addition, cell vitality, myocardial infarct size and lactate dehydrogenase (LDH) levels were measured. LC3‑Ⅱ protein expression was found to be downregulated, while p‑Akt, p‑mTOR and p‑P70S6K protein expression were observed to be upregulated by ulinastatin. In addition, cell vitality was found to increase and LDH was observed to decrease in the ulinastatin group compared with the HR group in vitro. Furthermore, rapamycin was found to attenuate the myocardial protective effect that is induced by ulinastatin. In vivo, ulinastatin was found to downregulate LC3‑Ⅱ protein expression, and reduce myocardium infarct size and LDH serum levels. These findings indicate that ulinastatin exhibits a myocardial protective effect against IR injury by regulating autophagy through mTOR activation.

The anti-apoptotic and cardioprotective effects of salvianolic acid a on rat cardiomyocytes following ischemia/reperfusion by DUSP-mediated regulation of the ERK1/2/JNK pathway.

The purpose of this study was to observe the effects of salvianolic acid A (SAA) pretreatment on the myocardium during ischemia/reperfusion (I/R) and to illuminate the interrelationships among dual specificity protein phosphatase (DUSP) 2/4/16, ERK1/2 and JNK pathways during myocardial I/R, with the ultimate goal of elucidating how SAA exerts cardioprotection against I/R injury (IRI). Wistar rats were divided into the following six groups: control group (CON), I/R group, SAA+I/R group, ERK1/2 inhibitor PD098059+I/R group (PD+I/R), PD+SAA+I/R group, and JNK inhibitor SP600125+I/R group (SP+I/R). The cardioprotective effects of SAA on the myocardium during I/R were investigated with a Langendorff device. Heart rate (HR), left ventricular systolic pressure (LVSP), left ventricular end-diastolic pressure (LVEDP), maximum rate of ventricular pressure rise and fall (±dp/dtmax), myocardial infarction areas (MIA), lactate dehydrogenase (LDH), and cardiomyocytes apoptosis were monitored. To determine the crosstalk betwee JNK and ERK1/2 via DUSP2/4/16 with SAA pretreatment, siRNA-DUSP2/4/16 were performed. The expression levels of Bcl-2, Bax, caspase 3, p-JNK, p-ERK1/2 and DUSP2/4/16 in cardiomyocytes were assayed by Western blot. Our results showed that LDH, MIA and cell apoptosis were decreased, and various parameters of heart function were improved by SAA pretreatment and SP application. In the I/R group, the expression levels of p-ERK1/2 and DUSP4/16 were not significantly different compared with the CON group, however, the protein expression levels of p-ERK1/2, Bcl-2 and DUSP4/16 were higher, while p-JNK, Bax, caspase 3 and DUSP2 levels were reduced among the SAA+I/R, PD+SAA+I/R and SP+I/R groups. The above indices were not significantly different between the SAA+I/R and SP+I/R groups. Compared with the SAA+I/R group, p-ERK1/2 was increased and p-JNK was decreased in the SAA+si-DUSP2+I/R, however, p-ERK was downregulated and p-JNK was upregulated in SAA+si-DUSP4+I/R group. SAA exerts an anti-apoptotic role against myocardial IRI by inhibiting DUSP2-mediated JNK dephosphorylation and activating DUSP4/16-mediated ERK1/2 phosphorylation.

Assessment of Myocardial Performance During Ex Vivo Heart Perfusion.

Objective: Ex vivo heart perfusion (EVHP) may facilitate resuscitation of non-utilized donor hearts and expand the donor pool. However, a reliable means of demonstrating organ viability prior to transplantation is required. We sought to identify metabolic and functional parameters that correlated with myocardial performance during EVHP. Methods: Six normal pig hearts and 8 donation after circulatory death hearts (238±10 grams) were procured and perfused ex vivo with a donor blood-STEEN solution (hemoglobin concentration of 45 g/L). Myocardial performance was determined by measuring the cardiac output indexed to heart weight (left atrial pressure = 8mmHg, diastolic pressure = 40mmHg). Myocardial function was assessed using a conductance catheter placed in the left ventricle (LV). Metabolic function was assessed by measuring myocardial oxygen consumption (MVO2) and lactate metabolism. Cardiac efficiency was calculated by the ratio of cardiac work and MVO2. Linear regression with stepwise selection analysis was used to determine which parameters best correlated with myocardial performance. Results: The minimum rate of pressure change in the LV (dP/dtmin; R2=0.92) was the best functional correlate of myocardial performance, while the isovolumic relaxation time (Tau; R2=0.78), maximum rate of pressure change (dP/dtmax; R2=0.62), preload recruitable stroke work (PRSW; R2=0.57), cardiac efficiency (R2=0.53), end-diastolic pressure volume relationship (EDPVR; R2=0.23), and end-systolic pressure volume relationship (ESPVR; R2=0.14) correlated to lesser degrees.Myocardial oxygen consumption (R2=0.75) was the best metabolic predictor of myocardial performance, while lactate metabolism failed to demonstrate any correlation (R2=0.004). The combination of the dP/dtmin and MVO2 was the most reliable predictor of myocardial performance (R2=0.94). Conclusions:Measurement of lactate metabolism is an insufficient means of determining organ viability during EVHP, while the combined evaluation of dP/dtmin and MVO2 produced the most reliable assessment of myocardial performance. Further studies are required to determine thresholds of these parameters that predict successful transplantation.

Sub-normothermic preservation of donor hearts for transplantation using a novel solution, Somah: A comparative pre-clinical study

Hearts preserved ex vivo at extreme hypothermia (4°C) undergo time-dependent irreversible injury. Our studies using a novel solution, Somah, suggest that hearts are viably preserved at 21°C. In this study we evaluate the relative efficacy of Somah for preservation of hearts at 21°C when compared with the clinically used Celsior and University of Wisconsin (UWS) solutions. Porcine hearts arrested by cardioplegia at 21°C using Somah, Celsior or UWS solution were stored in the respective solutions at 21°C (n = 5) for 5 hours and then reperfused ex vivo for functional assessment. We assessed development of edema, cardiac tissue high-energy phosphate (HEP; ATP + creatine phosphate) levels and release of cardiac enzymes. Alterations in left ventricular wall thicknesses and functional parameters were examined by 2-dimensional (2D) echocardiography. Changes in myocardial oxygen consumption (MVO2) and lactate utilization were assessed at reperfusion. Heart weights were unaltered during 5-hour storage in all groups. After storage, HEP levels were 28.33 ± 5.51, 10.20 ± 2.78 and 5.92 ± 1.46 nmol/liter per milligram protein (p < 0.001) in the Somah, Celsior and UWS group hearts, respectively. Upon reanimation, 2D echocardiography showed edema in the Celsior and UWS hearts; prompt attainment of physiologic function was associated with rapid establishment of aerobic metabolism not requiring stimulatory interventions in the Somah hearts, but not in the Celsior/UWS hearts. Percent fractional area change, ejection fraction and stroke volume were significantly higher (p < 0.001) in Somah hearts than in Celsior and UWS group hearts. Increased synthesis of HEP, rapid metabolic switch and optimal function together provide evidence that hearts procured for transplantation are preserved in a superior viable condition at 21°C with Somah, but not with other commonly used clinical preservation solutions.

Relationship of high sensitivity C-reactive protein with cardiac biomarkers in patients presenting with acute coronary syndrome.

To determine high sensitivity C-reactive protein (hsCRP) levels in patients with acute myocardial infarction (AMI) and its correlation with classical enzyme markers of myocardial damage. Observational study. Department of Emergency Medicine at King Khalid University Hospital, King Saud University, Riyadh and Department of Physiology, from August 2010 to December 2011. Consecutive eligible patients with either ST elevation myocardial infarction (STEMI) or non-ST elevation myocardial infarction (NSTEMI) who were admitted to the Emergency Department of King Khalid University Hospital were recruited. A total of 71 subjects were finally selected for the study. The hsCRP, Troponin I (Trop I), creatine kinase myocardial bound (CK-MB), aspartate aminotransferase (AST) and lactate dehydrogenase (LDH) concentrations of all patients with an acute myocardial infarction (AMI) were measured. Among all patients 34 (47.9%) patients had diabetes mellitus, 21 (29.6%) were hypertensive, and 16 (22.5%) had no associated illness. Patients with STEMI had significantly higher levels of CKMB (p=0.0348), LDH (p=0.0471) and hsCRP (p=0.0231) compared to NSTEMI patients. While the differences were non-significant for Trop I (p=0.7022), AST (p=0.9729) and Lp(a) (p=0.5985). Spearman's correlations revealed that CRP correlated significantly with Trop I, CK-MB and LDH. There was a significant predictive relationship of hsCRP with Trop I, LDH and CK-MB while with AST it was nonsignificant. High sensitivity CRP levels is a significant predictor of standard markers for myocardial damage and it may be a useful prognostic marker in acute coronary syndromes.

Postresuscitation Administration of Doxycycline Preserves Cardiac Contractile Function in Hypoxia-Reoxygenation Injury of Newborn Piglets*

Cardiac injury is common in asphyxiated neonates and is associated with matrix metalloproteinase-2 activation. Although studies have demonstrated the cardioprotective effects of matrix metalloproteinase inhibition, this has not been tested in clinically translatable models of hypoxia-reoxygenation injury. We aimed to elucidate the effect of doxycycline, a matrix metalloproteinase inhibitor, on cardiac injury and functional recovery in a swine model of neonatal hypoxia-reoxygenation. Thirty-three newborn piglets were acutely instrumented for continuous monitoring of cardiac output and systemic arterial pressure. After stabilization, normocapnic alveolar hypoxia (10-15% oxygen) was instituted for 2 hours followed by 4 hours of normoxic reoxygenation. Piglets were blindly, block randomized to receive IV boluses of normal saline (control) and doxycycline at 5 minutes of reoxygenation (n = 7/group). Sham-operated piglets (n = 5) received no hypoxia-reoxygenation. Markers of myocardial injury (plasma and myocardial tissue troponin I; myocardial lactate) and oxidative stress (lipid hydroperoxides) were measured by enzyme-linked immunosorbent assay and Western blot. Myocardial matrix metalloproteinase-2 activity was quantified by gelatin zymography and immunoprecipitation. University animal laboratory. Piglets (1-4 d old, weighing 1.4-2.5 kg). IV doxycycline (3, 10, or 30 mg/kg) given during resuscitation. Hypoxic piglets had cardiogenic shock (cardiac output 58% ± 1% of baseline), hypotension (systemic arterial pressure 31 ± 1 mm Hg), and acidosis (pH 7.02 ± 0.02). Doxycycline improved cardiac and stroke volume index with no chronotropic effect in doxycycline-treated piglets compared with controls. Systemic arterial pressure was higher and the pulmonary artery pressure/systemic arterial pressure ratio was lower in doxycycline groups, with reduced levels of markers of myocardial injury and oxidative stress in doxycycline-treated piglets compared with controls. Negative correlations were found between markers of myocardial injury (plasma troponin I, myocardial lactate) and functional recovery and between myocardial tissue and plasma troponin I. Doxycycline-treated piglets had lower myocardial matrix metalloproteinase-2 activity compared with controls. Postresuscitation administration of doxycycline attenuates cardiac injury and improves functional recovery in newborn piglets with hypoxia-reoxygenation.

Catecholamine induced cardiomyopathy in phaeochromocytoma.

Sir, In their article “Catecholamine induced cardiomyopathy” Varghese et al. have presented an interesting case of a patient with pheochromocytoma who presented with acute decompensated heart failure. They also highlighted the important point in the management of that patient with milrinone in a situation where further vasoconstriction with ionotrope would have been detrimental. One thing we would like to point out is that this patient developed the symptoms of heart failure only after the start of treatment with prazosin. Prazosin in a potent alpha presynaptic blocker and it decrease the levels of epinephrine and norepinephrine. However, in few patients with chronic heart failure it increases the level of epinephrine and norepinephrine leading to surge in the level of catecholamine. It has also been shown to increase myocardial lactate level indicating myocardial ischemia.[1] In our view, this mechanism of prazosin have probably precipitated heart failure. Since echocardiography was not previously done it is very difficult to say that the patient was not having pre-existing left ventricular dysfunction only on the basis of clinical examination. Patients of pheochromocytoma usually present with catecholamine induced cardiomyopathy after some stress like surgery or acute illness. In this patient prazosin must have precipitated heart failure by increasing the level of catecholamines.

Remote ischemic preconditioning with – but not without – metabolic support protects the neonatal porcine heart against ischemia-reperfusion injury

BackgroundWhile remote ischemic preconditioning (rIPC) protects the mature heart against ischemia-reperfusion (IR) injury, the effect on the neonatal heart is not known. The neonatal heart relies almost solely on carbohydrate metabolism, which is modified by rIPC in the mature heart. We hypothesized that rIPC combined with metabolic support with glucose-insulin (GI) infusion improves cardiac function and reduces infarct size after IR injury in neonatal piglets in-vivo. Methods and results32 newborn piglets were randomized into 4 groups: control, GI, GI+rIPC and rIPC. GI and GI+rIPC groups received GI infusion continuously from 40min prior to ischemia. rIPC and GI+rIPC groups underwent four cycles of 5min limb ischemia. Myocardial IR injury was induced by 40min occlusion of the left anterior descending artery followed by 2h reperfusion. Myocardial lactate concentrations were assessed in microdialysis samples analyzed by mass spectrometry. Infarct size was measured using triphenyltetrazolium chloride staining. Systolic recovery (dP/dtmax as % of baseline) after 2h reperfusion was 68.5±13.8% in control, 53.7±11.2% in rIPC (p<0.05), and improved in GI (83.6±18.8%, p<0.05) and GI+rIPC (87.0±15.7%, p<0.01). ConclusionrIPC+GI protects the neonatal porcine heart against IR injury in-vivo. rIPC alone has detrimental metabolic and functional effects that are abrogated by simultaneous GI infusion.

In-Hospital Arrhythmia Development and Outcomes in Pediatric Patients With Acute Myocarditis

Cardiac arrhythmias are a complication of myocarditis. There are no large studies of in-hospital arrhythmia development and outcomes in pediatric patients with acute myocarditis. This was a retrospective 2-center review of patients ≤21 years hospitalized with acute myocarditis from 1996 to 2012. Fulminant myocarditis was defined as the need for inotropic support within 24 hours of presentation. Acute arrhythmias occurred at presentation and subacute after admission. Eighty-five patients (59% men) presented at a median age of 10 years (1 day to 18 years). Arrhythmias occurred in 38 patients (45%): 16 acute, 12 subacute, and 9 acute and subacute (1 onset unknown). Arrhythmias were associated with low voltages on the electrocardiogram (14 of 34, 41% vs 6 of 47, 13%; odds ratio [OR] 4.78, 95% confidence interval [CI] 1.60 to 14.31) and worse outcome (mechanical support, orthotopic heart transplant, or death; OR 7.59, 95% CI 2.61 to 22.07) but were not statistically significantly associated with a fulminant course, ST changes, initial myocardial function, lactate, creatinine level, C-reactive protein and/or erythrocyte sedimentation rate, or troponin I level, after adjusting for multiple comparisons. Subacute arrhythmias were associated with preceding ST changes (10 of 15, 67% vs 15 of 59, 25%, OR 5.87, 95% CI 1.73 to 19.93). All patients surviving to discharge had arrhythmia resolution or control before discharge (10 on antiarrhythmic), with 1 exception (patient with complete heart block requiring a pacemaker). At 1-year follow-up, there were 3 recurrences of ventricular arrhythmias, but no arrhythmia-related mortality. In conclusion, arrhythmias are common in pediatric patients with myocarditis, occurring in nearly 1/2 of all hospitalized children and are associated with a worse outcome. Early identification of subacute arrhythmias using electrocardiographic changes may help management. A majority of patients do not require continued postdischarge arrhythmia treatment.

High-dose erythropoietin during cardiac resuscitation lessens postresuscitation myocardial stunning in swine

We investigated the metabolic and functional myocardial effects of erythropoietin (EPO) administered during resuscitation from cardiac arrest using an open-chest pig model of ventricular fibrillation and resuscitation by extracorporeal circulation, after having reported in rats a reversal of postresuscitation myocardial dysfunction associated with activation of mitochondrial protective pathways. Ventricular fibrillation was induced in 16 male domestic pigs and left untreated for 8 minutes, after which extracorporeal circulation was started and maintained for 10 additional minutes, adjusting the extracorporeal flow to provide a coronary perfusion pressure of 10 mmHg. Defibrillation was accomplished and the extracorporeal flow was adjusted to secure a mean aortic pressure of 40 mmHg or greater during spontaneous circulation for up to 120 minutes. Pigs were randomized 1:1 to receive EPO (1200 U/kg) or 0.9% NaCl before starting extracorporeal circulation. Severe postresuscitation myocardial dysfunction developed in both groups. However, recovery of myocardial function-comparing baseline with 120 minutes postresuscitation-was better in pigs treated with EPO than NaCl, as shown for left ventricular ejection fraction (from 45 ± 8% to 36 ± 9% in EPO, not significant; and from 46 ± 8% to 26 ± 8% in NaCl, P < 0.001) and for peak systolic pressure/end-systolic volume (from 2.7 ± 0.8 mmHg/mL to 2.4 ± 0.7 mmHg/mL in EPO, not significant; and from 3.0 ± 1.1 mmHg/mL to 1.8 ± 0.6 mmHg/mL, P < 0.001 in NaCl). The EPO effect was associated with significantly higher myocardial O2 consumption (12 ± 6 mL/min/unit of tissue vs 6 ± 2 mL/min/unit of tissue, P < 0.017) without effects on myocardial lactate consumption. Thus, EPO administered during resuscitation from ventricular fibrillation lessened postresuscitation myocardial stunning-an effect that could be useful clinically to help promote postresuscitation hemodynamic stability.

Doxycycline Attenuates Cardiac Injury and Improves Cardiac Function with Inhibition of Myocardial Matrix Metalloproteinase (MMP)‐2 in a Swine Model of Hypoxia‐ Reoxygenation (H‐R)

BackgroundCardiac dysfunction is common in asphyxiated neonates. Although small animal studies support attenuation of cardiac injury with the known MMP inhibitor doxycycline in H‐R, this effect has not been tested in a clinically relevant large animal model of H‐R. We hypothesized that doxycycline would improve the recovery of cardiac function in newborn piglets with H‐R.MethodsPiglets were instrumented for hemodynamic monitoring and subjected to 2 hr of hypoxia followed by 4 hr of normoxic reoxygenation. Piglets were blindly randomized to receive i.v. saline or doxycycline (3, 10, or 30 mg/kg) 5 min into reoxygenation (n=7/group). Sham piglets (n=5) received no H‐R. Markers of myocardial injury (serum and myocardial tissue troponin; myocardial lactate) and oxidative stress (lipid hydroperoxides) were measured by ELISA and Western blot. Myocardial MMP‐2 activity was quantified by gelatin zymography.ResultsDoxycycline dose‐dependently improved cardiac (CI) and stroke volume (SVI) index (30mg/kg: 84±3 (SEM)% and 78±5% of baseline vs. 65±3% and 50±5% in controls [p&lt;0.05]). Markers of myocardial injury, oxidative stress and MMP‐2 activity were improved in doxycycline groups vs. control [all p&lt;0.05]. Significant correlations were found between markers of myocardial injury and CI and SVI recovery (r =−0.5, p&lt;0.01), with a negative correlation also observed between myocardial tissue and serum troponins (r =−0.4, p=0.02).ConclusionsDoxycycline attenuates cardiac injury and improves functional recovery in newborn pigs with H‐R.Funded by: Canadian Institutes of Health Research and the Women and Children's Health Research Institute

The relationship between lactate production in the myocardium and the development of chest pain in patients with coronary artery disease (CAD)

Silent myocardial ischemia (SMI) was recognized as early as the beginning of the 20th century. The consequences of silent ischemia can be grave because lack of symptoms and lack of symptom recognition. Early detection of SMI may prevent many episodes of sudden cardiac death annually. However, the role and behavior of the factors determining the occurrence of silent myocardial ischemia have not been fully established. To detect if there is a relationship between the level of lactate production in the myocardium and the development of chest pain in patients with coronary artery disease (CAD). This study was carried out in cardiology and biochemistry departments, Zagazig University on 46 patients (38 males) with coronary artery significant disease (>70% stenosis) including left anterior descending artery disease. Cannulation of coronary sinus with Amplatz left catheter was done and a pigtail catheter was introduced into the mid LV cavity. Right atrial pacing was done and the heart rate was increased stepwise 10 bpm/1 min until a maximum of 150 bpm or chest pain occurs or significant S–T segment depression occurs. LV gram for assessment of systolic function and blood samples were withdrawn from the LV and coronary sinus before and after pacing induced ischemia and the patients were classified into two groups according to development of chest pain (angina group; 28 patients) during pacing induced tachycardia or not (silent group; 18 patients). 24-h Holter ECG monitoring was done to all patients. Myocardial lactate production was significantly very high in angina group than in silent ischemia group; 10 patients (35.7%) had lactate diminished extraction and 18 patients (64.3%) had lactate production in response to pacing induced tachycardia in group 1 (angina group). All 18 patients (100%) in group 2 (silent ischemia group) had lactate diminished extraction in response to pacing induced tachycardia (<0.001). LV systolic function reduction in response to pacing induced ischemia was non significant between the 2 groups. Silent ischemic attacks represented >80% of total ischemic episodes during 24 h Holter ECG study and it occurred at lower heart rate than angina attacks ( P = 0.03). The magnitude of S–T segment depression was non significant between the two groups. In patients with coronary artery disease, myocardial lactate production is significantly higher in patients with angina than in patients with silent ischemia and as lactate is known (with other metabolic agents) to cause chest pain and this is considered an explanation (mechanism) for the occurrence of silent myocardial ischemia.

Retrograde Machine Perfusion for Long-Term Preservation of Canine Hearts

Purpose Most machine perfusion preservation strategies utilize antegrade delivery of perfusate or blood through the ascending aorta but this technique is potentially limited by aortic valve incompetence. We hypothesize that retrograde machine perfusion preservation through the coronary sinus avoids this issue and allows for recovery of donor hearts after long-term storage. Methods and Materials Canine hearts were procured after cardioplegic arrest with 1 liter University of Wisconsin Machine Perfusion Solution (UWMPS) and preserved for 12 hours in UWMPS by either conventional static storage (Static group, n=4) at 0-4oC or retrograde machine perfusion through the coronary sinus (RP group, n=4) at 5oC. Myocardial oxygen consumption (MVO 2 ) and lactate accumulation were monitored in perfused hearts. Donor hearts were implanted into recipient animals and reperfused for six hours. The preload recruitable stroke work (PRSW) was determined hourly. Total CK was measured at the end of each experiment. Results RP hearts maintained stable MVO 2 over the 12 hour preservation interval. Lactate accumulation was low in RP hearts. All RP hearts separated from cardiopulmonary bypass (CPB). All static storage hearts either did not separate from CPB or required a return to CPB by the end of the six hour reperfusion interval (p Conclusions Retrograde machine perfusion can preserve donor hearts for long intervals. Cardiac function after implantation was not different from baseline function suggesting excellent myocardial protection. A retrograde machine perfusion strategy appears promising for safely extending the donor ischemic interval and improving results of heart transplantation. GroupTotal Ischemic Time (min)PRSW (mm Hg)CK (IU/mL)Static836±1017±1121439±5798Retrograde Perfusion840±1759±6*9123±716Data are mean±SEM; *-p

Low-flow Perfusion Preservation Versus Static Preservation for Isolated Rat Heart: Effects on Recovery of Myocardial Function

BackgroundClinically, donor hearts cannot be preserved for >6 hours between explantation and recipient implantation. A better approach is needed to preserve donor hearts for a longer time. We tested whether low-flow perfusion (LFP) could satisfactorily preserve isolated rat hearts with histidine-tryptophan-ketoglutarate (HTK) solution or Fuwai modified (FWM) solution. MethodsWe divided 32 male Sprague-Dawley rats randomly into 4 groups (n = 8): H1, H2, F1, and F2. The Langendorff heart model immersed isolated hearts in the H1 and F1 groups in HTK or FWM solution for 8 hours at 4°C. Isolated hearts in the H2 and F2 groups were low-flow perfused with HTK solution and FWM solution for 8 hours at a pressure of 10 cmH2O at 4°C. After 60 minutes reperfusion, we measured recovery of cardiac function, myocardial water content, and leakage of myocardial enzymes. ResultsAfter reperfusion, no cardiac rebeating was observed among F1 group hearts; in addition, they showed significantly higher myocardial water content and lactate dehydrogenase leakage compared with the other 3 groups (P < .05). The recovery rates of cardiac function among H2 hearts were better than the other 3 groups (P < .05); their myocardial water content and enzyme leakage were less than the other 3 groups (P < .05). ConclusionsHypothermic LFP was better than static storage to preserve isolated rat hearts. HTK solution afforded better myocardial protection than FWM.

Depletion of myocardial glucose is observed during endotoxemic but not hemorrhagic shock in a porcine model

IntroductionMetabolic dysfunction is one of the hallmarks of sepsis yet little is known about local changes in key organs such as the heart. The aim of this study was to compare myocardial metabolic changes by direct measurements of substrates, such as glucose, lactate and pyruvate, using microdialysis (MD) in in-vivo porcine endotoxemic and hemorrhagic shock. To assess whether these changes were specific to the heart, we simultaneously investigated substrate levels in skeletal muscle.MethodsTwenty-six female pigs were randomized to three groups: control (C) n = 8, endotoxemic shock (E) n = 9 and hemorrhagic shock (H) n = 9. Interstitial myocardial pyruvate, lactate and glucose were measured using MD. Skeletal muscle MD was also performed in all three groups.ResultsMarked decreases in myocardial glucose were observed in the E group but not in the H group compared to controls (mean difference (CI) in mmol/L: C versus E -1.5(-2.2 to -0.8), P <0.001; H versus E -1.1(-1.8 to -0.4), P = 0.004; C versus H -0.4(-1.1 to 0.3), P = 0.282). Up to four-fold increases in myocardial pyruvate and three-fold increases in lactate were seen in both shock groups with no differences between the two types of shock. There was no evidence of myocardial anaerobic metabolism, with normal lactate:pyruvate (L:P) ratios seen in all animals regardless of the type of shock.In skeletal muscle, decreases in glucose concentrations were observed in the E group only (mean difference: C versus E -0.8(-1.4 to -0.3), P = 0.007). Although skeletal muscle lactate increased in both shock groups, this was accompanied by increases in pyruvate in the E group only (mean difference: C versus E 121(46 to 195), P = 0.003; H versus E 77(7 to 147), P = 0.032; C versus H 43(-30 to 43), P = 0.229). The L:P ratio was increased in skeletal muscle in response to hemorrhagic, but not endotoxemic, shock.ConclusionsEndotoxemia, but not hemorrhage, induces a rapid decrease of myocardial glucose levels. Despite the decrease in glucose, myocardial lactate and pyruvate concentrations were elevated and not different than in hemorrhagic shock. In skeletal muscle, substrate patterns during endotoxemic shock mimicked those seen in myocardium. During hemorrhagic shock the skeletal muscle response was characterized by a lack of increase in pyruvate and higher L:P ratios.Hence, metabolic patterns in the myocardium during endotoxemic shock are different than those seen during hemorrhagic shock. Skeletal muscle and myocardium displayed similar substrate patterns during endotoxemic shock but differed during hemorrhagic shock.

Perspectives on the Value of Biomarkers in Acute Cardiac Care and Implications for Strategic Management

Biomarkers in acute cardiac care are gaining increasing interest given their clinical benefits. This study is a review of the major conditions in acute cardiac care, with a focus on biomarkers for diagnostic and prognostic assessment. Through a PubMed search, 110 relevant articles were selected. The most commonly used cardiac biomarkers (cardiac troponin, natriuretic peptides, and C-reactive protein) are presented first, followed by a description of variable acute cardiac conditions with their relevant biomarkers. In addition to the conventional use of natriuretic peptides, cardiac troponin, and C-reactive protein, other biomarkers are outlined in variable critical conditions that may be related to acute cardiac illness. These include ST2 and chromogranin A in acute dyspnea and acute heart failure, matrix metalloproteinase in acute chest pain, heart-type fatty acid binding protein in acute coronary syndrome, CD40 ligand and interleukin-6 in acute myocardial infarction, blood ammonia and lactate in cardiac arrest, as well as tumor necrosis factor-alpha in atrial fibrillation. Endothelial dysfunction, oxidative stress and inflammation are involved in the physiopathology of most cardiac diseases, whether acute or chronic. In summary, natriuretic peptides, cardiac troponin, C-reactive protein are currently the most relevant biomarkers in acute cardiac care. Point-of-care testing and multi-markers use are essential for prompt diagnostic approach and tailored strategic management.

Which Is the Better Option During Neonatal Cardiopulmonary Bypass

The optimal myocardial protection strategy for newborns/infants undergoing congenital heart surgery remains controversial. The purpose of this study was to compare myocardial protection using histidine-tryptophan-ketoglutarate (HTK) and cold blood cardioplegia in a neonatal piglet model. Twenty-one piglets were randomized to three groups: the control group (C group, n = 7), a single dose of HTK group (H group, n = 7), and multidose cold blood cardioplegia group (B group, n = 7). Animals in the two experimental groups were placed on hypothermic cardiopulmonary bypass, after which the ascending aorta was clamped for 2 hours. Immediately after declamping, both the difference between arterial and coronary sinus blood lactate concentrations and the oxygen extraction did not differ between the H group and the B group. At 3 hours after declamping, rise in serum troponin-T and creatine kinase isoenzyme MB levels showed no significant differences between the H group and the B group (p = 0.735 and p = 0.103, respectively). No significant differences were noted in the myocardial lactate content, ATP content, and histopathological score between the H group and the B group (p = 0.810, p = 0.158, and p = 0.399, respectively). Transfusion requirement in the B group was significantly more than that in the H group (p = 0.003). HTK solution provides equivalent myocardial protection to multidose cold blood cardioplegia for the neonatal heart with less transfusion requirement.