Viabilidade miocárdica na prática clínica / Assessing myocardial viability in clinical practice

Embora a avaliação da viabilidade miocárdica seja comum na prática do cardiologista, muitos médicos têm dúvidas a respeito dos resultados dos métodos diagnósticos. A medicina nuclear tem papel importante nos estudos de viabilidade, mas os laudos precisam ser interpretados num contexto clínico e fisiopatológico. Este artigo teve o objetivo de revisar a origem e a evolução do conceito da viabilidade miocárdica. São expostos os métodos diagnósticos com ênfase na medicina nuclear com uma explicação funcional sobre cada tipo de exame. A partir disso, são mostradas imagens como exemplos e é proposta uma maneira de atuar nesses casos baseada na clínica, na porcentagem de miocárdio acometido e na topografia das lesões coronarianas (proximais ou distais). (AU)

Although assessing myocardial viability is a common cardiology practice, many physicians question the results of diagnostic methods. Nuclear medicine plays an important role in viability studies, but the reports require interpretation in a clinical and pathophysiological context. this article was aimed at reviewing the origin and evolution of myocardial viability. Here we present diagnostic methods by emphasizing nuclear medicine and provide a functional explanation of each test type using example images. We also propose how to act in these cases based on clinic examination findings, the percentage of affected myocardium, and coronary lesion topography (proximal or distal).(AU)

The mKATP Channels and protein-kinase C Are Involved in the Cardioprotective Effects of Genistein on Estrogen-Deficient Rat Hearts Exposed to Ischemia/Reperfusion: Energetic Study.

Estrogenic deficiency is considered a risk of coronary disease in women. The phytoestrogen genistein could be a safe preventive strategy. The first aim of this work was to validate a model of cardiac stunning in which natural estrogenic deficiency rats, ie, adult young male (YM) and aged female (AgF), are compared with young female rats (YF). The second aim was to study whether the in vivo administration of genistein prevents the stunning in estrogenic deficiency rats. The third aim was to evaluate whether in our estrogenic deficiency model exists a synergy between genistein and estradiol. The fourth aim was to characterize the underlying mechanisms of genistein. Stunning was induced by ischemia/reperfusion (I/R) in isolated hearts inside a calorimeter. The left ventricular pressure (P) and total heat rate (Ht) were simultaneously measured, while diastolic contracture and muscle economy (P/Ht) were calculated. During R, P/Ht and P recovered less in AgF and YM than in YF rat hearts. Genistein through i.p. (GST-ip) improved P and P/Ht in AgF and YM, but not in YF. In YM, the cardioprotections of GST-ip and estradiol were synergistic. After ischemia, GST-ip increased SR Ca leak causing diastolic contracture. The GST-ip cardioprotection neither was affected by blockade of PI3K-Akt, NO synthases, or phosphatases, but it was sensitive to blockade of protein-kinase C and mKATP channels. Results suggest that (1) estrogenic deficiency worsens cardiac stunning, (2) GST-ip was more cardioprotective in estrogenic deficiency and synergistic with estradiol, and (3) cardioprotection of GST-ip depends on the protein-kinase C and mKATP channel pathway activation.

Predictors of left atrial appendage stunning after electrical cardioversion in patients with atrial fibrillation.

The transient left atrial appendage (LAA) dysfunction after electrical cardioversion (CV), which is called as LAA-stunning, was found to be an important etiology of thrombus formation. The aim of the present study was to investigate the risk factors of LAA-stunning. This study included 134 patients who underwent catheter ablation for non-paroxysmal, non-valvular, and symptomatic atrial fibrillation (AF). Internal-CV was performed, and LAA emptying fraction (LAA-EF) was assessed using LAA-angiogram before and just after CV. LAA-stunning (defined as 10% reduction of LAA-EF after CV) was observed in 45/134 patients (34%). Patients in LAA-stunning group had longer duration of AF prior to CV, higher brain natriuretic peptide (BNP), higher prevalence of patients taking calcium blocker, larger left atrial (LA) diameter, elevated E wave, and larger LA volume than those in non LAA-stunning group. Multivariate analysis showed that longer duration of AF prior to CV (p = 0.015, OR 1.033 for 1 month extend, 95% CI 1.006-1.073) and elevated BNP (p = 0.038, OR 1.041 for each 10 pg/mL increase, 95% CI 1.001-1.009) were associated with LAA-stunning. In addition, all patients were divided into four groups based on the combination between duration of AF prior to CV and BNP; group 1 (low BNP/short-lasting AF), group 2 (high BNP/short-lasting AF), group 3 (low BNP/long-lasting AF), and group 4 (high BNP/long-lasting AF). The rate of LAA-stunning was the highest in the group 4 (55.6%). Elevated BNP and long duration of AF were associated with LAA stunning after electrical cardioversion.

[New thoughts in mechanism research of acupuncture for myocardial stunning from κ-opioid receptor signaling pathway].

By reviewing the literature regarding the development mechanism of myocardial stunning, effects of acupuncture on myocardial ischemic injury, and correlation between acupuncture and κ-opioid receptor, it was suggested that acupuncture was highly likely to act on κ-opioid receptor in myocardial cells, and directly treated myocardial malfunction induced by myocardial stunning through κ-opioid receptor and its signaling pathway. In addition, acupuncture could inhabit the signaling pathway of adrenoceptor ß1, one of the main functional receptors, to indirectly improve myocardial ischemic injury. From κ-opioid receptor signaling pathway, the action mechanism of acupuncture for prevention and treatment of myocardial stunning was discussed in this paper, hoping to provide new ideas for possible mechanism of acupuncture for myocardial ischemic injury.

Cardiovascular Abnormalities in Carbon Monoxide Poisoning.

Acute carbon monoxide (CO) poisoning is the most common cause of poisoning and poisoning-related death in the United States. It manifests as broad spectrum of symptoms ranging from mild headache, nausea, and fatigue to dizziness, syncope, coma, seizures resulting in cardiovascular collapse, respiratory failure, and death. Cardiovascular complications of CO poisoning has been well reported and include myocardial stunning, left ventricular dysfunction, pulmonary edema, and arrhythmias. Acute myocardial ischemia has also been reported from increased thrombogenicity due to CO poisoning. Myocardial toxicity from CO exposure is associated with increased short-term and long-term mortality. Carboxyhemoglobin (COHb) levels do not correlate well with the clinical severity of CO poisoning. Supplemental oxygen remains the cornerstone of therapy for CO poisoning. Hyperbaric oxygen therapy increases CO elimination and has been used with wide variability in patients with evidence of neurological and myocardial injury from CO poisoning, but its benefit in limiting or reversing cardiac injury is unknown. We present a comprehensive review of literature on cardiovascular manifestations of CO poisoning and propose a diagnostic algorithm for managing patients with CO poisoning.

Mitochondrial Bioenergetics During Ischemia and Reperfusion.

During ischemia and reperfusion (I/R) mitochondria suffer a deficiency to supply the cardiomyocyte with chemical energy, but also contribute to the cytosolic ionic alterations especially of Ca2+. Their free calcium concentration ([Ca2+]m) mainly depends on mitochondrial entrance through the uniporter (UCam) and extrusion in exchange with Na+ (mNCX) driven by the electrochemical gradient (ΔΨm). Cardiac energetic is frequently estimated by the oxygen consumption, which determines metabolism coupled to ATP production and to the maintaining of ΔΨm. Nevertheless, a better estimation of heart energy consumption is the total heat release associated to ATP hydrolysis, metabolism, and binding reactions, which is measurable either in the presence or the absence of oxygenation or perfusion. Consequently, a mechano-calorimetrical approach on isolated hearts gives a tool to evaluate muscle economy. The mitochondrial role during I/R depends on the injury degree. We investigated the role of the mitochondrial Ca2+ transporters in the energetic of hearts stunned by a model of no-flow I/R in rat hearts. This chapter explores an integrated view of previous and new results which give evidences to the mitochondrial role in cardiac stunning by ischemia o hypoxia, and the influence of thyroid alterations and cardioprotective strategies, such as cardioplegic solutions (high K-low Ca, pyruvate) and the phytoestrogen genistein in both sex. Rat ventricles were perfused in a flow-calorimeter at either 30 °C or 37 °C to continuously measure the left ventricular pressure (LVP) and total heat rate (Ht). A pharmacological treatment was done before exposing to no-flow I and R. The post-ischemic contractile (PICR as %) and energetical (Ht) recovery and muscle economy (Eco: P/Ht) were determined during stunning. The functional interaction between mitochondria (Mit) and sarcoplasmic reticulum (SR) was evaluated with selective mitochondrial inhibitors in hearts reperfused with Krebs-10 mM caffeine-36 mM Na+. The caffeine induced contracture (CIC) was due to SR Ca2+ release, while relaxation mainly depends on mitochondrial Ca2+ uptake since neither SL-NCX nor SERCA are functional under this media. The ratio of area-under-curves over ischemic values (AUC-ΔHt/AUC-ΔLVP) estimates the energetical consumption (EC) to maintain CIC. Relaxation of CIC was accelerated by inhibition of mNCX or by adding the aerobic substrate pyruvate, while both increased EC. Contrarily, relaxation was slowed by cardioplegia (high K-low Ca Krebs) and by inhibition of UCam. Thus, Mit regulate the cytosolic [Ca2+] and SR Ca2+ content. Both, hyperthyroidism (HpT) and hypothyroidism (HypoT) reduced the peak of CIC but increased EC, in spite of improving PICR. Both, CIC and PICR in HpT were also sensitive to inhibition of mNCX or UCam, suggesting that Mit contribute to regulate the SR store and Ca2+ release. The interaction between mitochondria and SR and the energetic consequences were also analyzed for the effects of genistein in hearts exposed to I/R, and for the hypoxia/reoxygenation process. Our results give evidence about the mitochondrial regulation of both PICR and energetic consumption during stunning, through the Ca2+ movement.

Cardiac Strain in a Swine Model of Regional Hibernating Myocardium: Effects of CoQ10 on Contractile Reserve Following Bypass Surgery.

There is conflicting clinical evidence whether administration of coenzyme Q10 (CoQ10) improves function following coronary artery bypass graft surgery (CABG). Using a swine model of hibernating myocardium, we tested whether daily CoQ10 would improve contractile function by MRI at 4-week post-CABG. Twelve pigs underwent a thoracotomy and had a constrictor placed on the left anterior descending (LAD). At 12 weeks, they underwent off-pump bypass and received daily dietary supplements of either CoQ10 (10 mg/kg/day) or placebo. At 4-week post-CABG, circumferential strain measurements in the hibernating LAD region from placebo and CoQ10 groups were not different and increased to a similar extent with dobutamine (-14.7 ± 0.6 versus -14.8 ± 0.1, respectively (NS)). Post-sacrifice, oxidant stress markers were obtained in the mitochondrial isolates and protein carbonyl in the placebo, and CoQ10 groups were 6.14 ± 0.36 and 5.05 ± 0.32 nmol/mg, respectively (NS). In summary, CoQ10 did not improve contractile reserve or reduce oxidant stress at 4-week post-CABG.

A Stunning Left Atrial Appendage Thrombus.

BACKGROUND: Left atrial appendage thrombus formation is a known major complication of atrial fibrillation and atrial flutter which increases the risk of embolism and stroke. This risk of thrombosis is greatly increased with a lack of anticoagulation. After conversion to a normal sinus rhythm in these arrhythmias, the risk of thrombus formation in the left atrium persists through a phenomenon termed atrial myocardial stunning. CASE: We present the case of a patient who previously underwent successful pulmonary vein isolation and was found to be in typical isthmus-dependent atrial flutter with a questionable recurrence of atrial fibrillation. The decision was made to return for atrial flutter ablation and for evaluation of prior pulmonary vein isolation. Initially, a transesophageal echocardiogram showed a normal ejection fraction, biatrial enlargement and no left atrial appendage thrombus. Ablation of the cavotricuspid isthmus was successfully accomplished with documented bidirectional block. A transesophageal echocardiogram probe was still in place prior to planned transseptal puncture for the evaluation of pulmonary veins. A large thrombus was now observed filling the left atrial appendage. Conclusion and Objective: Atrial stunning is a transient atrial contractile dysfunction that occurs whether sinus rhythm is restored spontaneously, electrically, pharmacologically or by ablation. We know after conversion that there is higher propensity to increased spontaneous echogenic contrast and decreased velocities; however, we do not have documented knowledge of exactly how soon after the conversion to a sinus rhythm a thrombus may be seen. We demonstrate a case of acute left atrial appendage thrombus formation immediately following the successful ablation of isthmus-dependent atrial flutter. Our report validates the belief that strategies of not interrupting anticoagulation prior to the conversion of these arrhythmias should be implemented.

[Clinical research of safflower injection on hibernating myocardial revascularization].

Coronary artery disease (CAD) is one of the leading causes of death. Safflower attracts great attention owing to its anti-ischemia/reperfusion injury effect. Ninety-three patients with CAD were included and randomized into safflower treatment group, PCI group and control group. Low-dose dobutamine stress echocardiography (DSE) was performed to measure end-systolic volume (ESV), end-diastolic volume (EDV), left ventricular ejection fraction (LVEF) and wall motion score index (WMSI) to determine the recovery of hibernating myocardium and cardiac function in all patients before treatment and after 3-month follow-up. The study was to investigate the effects of safflower on hibernating myocardial revascularization and cardiac function. It was found that LVEF was significantly improved, while the ESV and WMSI were significantly reduced after 2-week treatment in safflower and PCI treatment groups. No significant differences were found between safflower and PCI treatment groups in ESV, EDV, WMSI and LVEF after treatment Safflower injection effectively improved hibernating myocardial function.

Clinical research of safflower injection on hibernating myocardial revascularization / 中国中药杂志

Coronary artery disease (CAD) is one of the leading causes of death. Safflower attracts great attention owing to its anti-ischemia/reperfusion injury effect. Ninety-three patients with CAD were included and randomized into safflower treatment group, PCI group and control group. Low-dose dobutamine stress echocardiography (DSE) was performed to measure end-systolic volume (ESV), end-diastolic volume (EDV), left ventricular ejection fraction (LVEF) and wall motion score index (WMSI) to determine the recovery of hibernating myocardium and cardiac function in all patients before treatment and after 3-month follow-up. The study was to investigate the effects of safflower on hibernating myocardial revascularization and cardiac function. It was found that LVEF was significantly improved, while the ESV and WMSI were significantly reduced after 2-week treatment in safflower and PCI treatment groups. No significant differences were found between safflower and PCI treatment groups in ESV, EDV, WMSI and LVEF after treatment Safflower injection effectively improved hibernating myocardial function.

Direct protective effects of dexmedetomidine against myocardial ischemia-reperfusion injury in anesthetized pigs.

Systemic administration of α2-adrenergic agonists has been shown to protect ischemic myocardium, but the direct effects on ischemia-reperfused myocardium have not yet been clarified. This study was carried out to determine the effects of intracoronary dexmedetomidine (DEX) on the myocardial ischemia-reperfusion injury in anesthetized pigs. In open-chest pigs, the left anterior descending coronary artery was perfused through an extracorporeal circuit from the carotid artery. They received intracoronary infusion of DEX at a rate of 1 ng · mL(-1) (group LD, n = 9), 10 ng · mL(-1) (group MD, n = 9), or 100 ng · mL(-1) (group HD, n = 9) of coronary blood flow or vehicle (group C, n = 12) for 30 min before ischemia. Myocardial stunning was produced by 12-min ischemia of the perfused area of left anterior descending coronary artery and 90-min reperfusion. The effect on reperfusion-induced arrhythmias was evaluated using the incidence of ventricular tachycardia or fibrillation after reperfusion. Regional myocardial contractility was evaluated with segment shortening (%SS). Dexmedetomidine significantly reduced the incidence of reperfusion-induced ventricular arrhythmias. Dexmedetomidine significantly improved the recovery of percentage segment shortening at 90 min after reperfusion (32.6% ± 3.1% in group C, 58.2% ± 2.1% in group LD, 61.1% ± 1.8% in group MD, and 72.0% ± 2.0% in group HD). Dexmedetomidine suppressed the increase in plasma norepinephrine concentration after reperfusion. The results indicate that DEX would exert the protective effect against ischemia-reperfusion injury by the direct action on the myocardium, which is not mediated through the central nervous system.

Effects of chronic omega-3 polyunsaturated fatty acid supplementation on human atrial mechanical function after reversion of atrial arrhythmias to sinus rhythm: reversal of tachycardia-mediated atrial cardiomyopathy with fish oils.

BACKGROUND: Atrial mechanical stunning is a form of tachycardia-mediated atrial cardiomyopathy that manifests after reversion of persistent atrial arrhythmias to sinus rhythm. OBJECTIVES: This study sought to examine whether chronic omega-3 polyunsaturated fatty acid supplementation with fish oils can reverse atrial mechanical stunning. METHODS: Patients undergoing reversion of persistent atrial fibrillation (AF) or atrial flutter (AFL) to sinus rhythm were randomized to a control group (n = 26) or an omega-3 group (n = 23). The latter were prescribed 6 g/day of fish oil for ≥1 month prior to the procedure. Parameters of left atrial appendage function were compared immediately before and immediately after reversion. RESULTS: After fish oil intake for a mean of 70 days, the following were noted favoring the omega-3 group among both AF and AFL patients: (1) 2-fold higher serum omega-3 levels (P < .001), (2) less mean decrease in emptying velocity (e.g., AF: 8% vs. 32%, P = .02), (3) less mean decrease in appendage emptying fraction (e.g., AFL: 7% vs. 60%, P = .002), (4) lower incidence of new or increased spontaneous echocardiographic contrast (e.g., AF: 11% vs. 62.5%, P = .003), and (5) lower incidence of atrial mechanical stunning (e.g., AFL: 20% vs. 100%, P = .001). Omega-3 intake conferred protection against stunning in a multivariable analysis (odds ratio 0.18, P = .02). CONCLUSION: Chronic fish oil ingestion in humans attenuates atrial mechanical stunning after reversion of atrial arrhythmias to sinus rhythm. This suggests that fish oils may target or even reverse underlying cellular and/or structural remodeling that occurs in response to persistent atrial arrhythmias.

Postischemic infusion of sivelestat sodium hydrate, a selective neutrophil elastase inhibitor, protects against myocardial stunning in swine.

PURPOSE: It seems controversial whether or not neutrophil elastase inhibitors are effective in attenuating myocardial ischemia/reperfusion injury. We thus investigated possible protective effects of sivelestat, a neutrophil elastase inhibitor, against myocardial stunning i.e., prolonged myocardial dysfunction following a brief episode of ischemia. METHODS: Swine were divided into control group (group C), low-dose sivelestat group (group L), and high-dose sivelestat group (group H) (n = 7 for each group). All the swine were subjected to myocardial ischemia through ligation of the left anterior descending (LAD) coronary artery for 12-min, followed by 90-min reperfusion. Sivelestat was infused intracoronally at concentrations of 6 and 60 mg/ml throughout the reperfusion period in groups L and H, respectively, while saline was infused in the group C. Heart rate (HR), left ventricular developed pressure (LVdP), maximum rate of LVdP (LVdP/dt (max)), LV end-diastolic pressure (LVEDP), percentage of segment shortening (%SS, an index of regional myocardial contractility), and coronary venous interleukin-6 concentration in the LAD perfusion area were measured before ischemic induction and during reperfusion. RESULTS: The ischemia/reperfusion insult did not cause any significant changes in HR, LVdP, LVdP/dt (max), and LVEDP in all groups. However, it significantly reduced %SS in the LAD perfusion area and increased the interleukin-6 concentration in group C. Those changes in %SS and the interleukin-6 concentration were both greatly attenuated, but not prevented, in groups L and H. CONCLUSION: Sivelestat presumably attenuates myocardial contractile dysfunction due to myocardial stunning by inhibiting neutrophil-derived elastase, thereby suppressing the production of interleukin-6 in activated neutrophils.

Neurogenic stunned myocardium after acute hydrocephalus.

Neurogenic stunned myocardium (NSM) is a syndrome of cardiac stunning after a neurological insult. It is commonly observed after aneurysmal subarachnoid hemorrhage but is increasingly being reported after other neurological events. The underlying mechanism of NSM is believed to be a hypothalamic-mediated sympathetic surge causing weakened cardiac contractility and even direct cardiac myocyte damage. The authors report 2 cases of NSM in pediatric patients after acute hydrocephalus. Both patients experienced severe cardiac dysfunction in the acute phase but ultimately had a good neurological outcome and a full cardiac recovery. The identification, treatment, and outcome in 2 rare pediatric cases of NSM are discussed, and the history of the brain-cardiac connection is reviewed.

Intravenous administration of adenosine triphosphate disodium during primary percutaneous coronary intervention attenuates the transient rapid improvement of myocardial wall motion, not myocardial stunning, shortly after recanalization in acute anterior myocardial infarction.

BACKGROUND AND PURPOSE: Administration of adenosine attenuates myocardial stunning after reperfusion in a canine experimental ischemic model. However, it is unknown whether administration of adenosine triphosphate disodium (ATP) during reperfusion can attenuate myocardial stunning after coronary recanalization in patients with acute myocardial infarction (MI). Therefore, we sought to elucidate the effects of ATP administration on serial changes of left ventricular systolic function before and after coronary recanalization. METHODS: In 27 patients with first ST-elevation acute anterior MI, in whom primary percutaneous coronary intervention (PCI) was completed within 10 h after symptom onset, ATP at a mean rate of 103 microg/kg/min (n=16) or normal saline (n=11) was intravenously administered for 1 h during reperfusion. Left ventricular regional wall motion within the initially severely ischemic region was serially analyzed using the standard wall motion score index (WMSI) by transthoracic echocardiography. RESULTS: Means of WMSIs were similar shortly before primary PCI in both groups (2.79 in ATP group and 2.69 in controls). They changed to 2.56 and 2.22 shortly after PCI, 2.49 and 2.39 on day 2, 2.34 and 2.30 on day 3, 2.19 and 2.25 on day 10, and 1.85 and 2.02, 6 months later, respectively. Transient improved regional wall motion within the initially severely ischemic region was observed shortly after PCI in controls (10.3% of observed segments); however, it was significantly suppressed in the ATP group (2.55%). The percent recovery of WMSI on day 10, which was defined as WMSI on day 10 normalized by improvement of WMSI for 6 months, was 63.8% in ATP group and 65.7% in controls, implying ATP administration could not reduce myocardial stunning by day 10 after primary PCI. CONCLUSIONS: The high-dose administration of ATP during primary PCI prevented transient improved wall motion shortly after coronary recanalization rather than preventing left ventricular stunning. These results suggest that ATP can prevent reperfusion injury during primary PCI.

Hibernating myocardium: pathophysiology, diagnosis, and treatment.

Comprehensive management of patients with chronic ischemic disease is a critically important component of clinical practice. Cardiac myocytes have the potential to adapt to limited flow conditions by adjusting contractile function, reducing metabolism, conserving resources, and preserving myocardial integrity to cope with an oxygen and (or) nutrition shortage. A prime metabolic feature of cardiac myocytes affected by chronic ischemia is the return to a fetal gene pattern with predominance of carbohydrates as the substrate for energy. Structural adaptation with multiple intracellular changes is part of the remodeling process in hibernating myocardium. Transmural heterogeneity, which defines the pattern of injury in ventricular cardiomyocytes and the response to chronic ischemia, is a multifactorial process originating from functional, metabolic, and flow differences in subendocardial and subepicardial regions. Autophagy is typically activated in hibernating myocardium and has been identified as a prosurvival mechanism. Chronic ischemia is associated with changes in the number, size, and distribution of gap junctions and may give rise to conduction disturbances and arrhythmogenesis. Differentiation between viable and nonviable myocardium by assessing sensitivity of inotropic reserve is a crucial diagnostic tool that is correlated with the prognosis and outcome for improved contractility after restoration of blood perfusion in afflicted myocardium.Reliable and accurate diagnosis of ischemic, scar, and viable tissues is critical for recover strategies. Although early surgical reinstitution of blood flow is most effective in restoring physiologic function of the hibernating myocardium, several new approaches offer promising alternatives. Among others, vascular endothelial growth factor and fibroblast growth factor-2 (FGF-2), especially its lo-FGF-2 isoform, have been shown to be effective in rapid neovascularization. Substances such as statins, resveratrol, some hormones, and omega-3 fatty acids can improve recovery effect in chronically underperfused hearts. For patients with drug-refractory ischemia, intramyocardial transplantation of stem cells into predefined areas of the heart can enhance vascularization and have beneficial effects on cardiac function. This review of ischemic injury, its heterogeneity, accurate diagnosis, and newer methods of treatment, shows there is much information and tremendous hope for better management of patients with coronary heart disease.

Hypoxia inducible factor-1 improves the actions of positive inotropic agents in stunned cardiac myocytes.

1. In the present study, we tested hypothesis that upregulation of hypoxia-inducible factor-1 (HIF-1) would improve the actions of positive inotropic agents in cardiac myocytes after simulated ischaemia-reperfusion (I/R). 2. Hypoxia-inducible factor-1α was upregulated with deferoxamine (150 mg/kg per day for 2 days). Rabbit cardiac myocytes were subjected to simulated ischaemia (15 min, 95% N(2)-5% CO2) and reperfusion (re-oxygenation) and compared with control myocytes. Cell contraction and calcium transients were measured at baseline and after forskolin (10(-7) and 10(-6) mol/L) or ouabain (10(-5) and 10(-4) mol/L). 3. Under control conditions, high-dose forskolin and ouabain increased percentage shortening by 20 and 18%, respectively. Deferoxamine-treated control myocytes responded similarly. In stunned myocytes, forskolin and ouabain did not significantly increase shortening (increases of 8% and 9%, respectively). Deferoxamine restored the effects of forskolin (+26%) and ouabain (+28%) in stunning. The results for maximum shortening and relaxation rates were similar. The increased calcium transients caused by forskolin and ouabain were also depressed in stunned myocytes, but were maintained by HIF-1 upregulation. 4. These results suggest that simulated I/R impaired the functional and calcium transient effects of positive inotropic agents. Upregulation of HIF-1 protects cardiac myocyte function after I/R by maintaining calcium release.

Coronary vasospasm with myocardial stunning in a patient with colon cancer receiving adjuvant chemotherapy with FOLFOX regimen.

Colorectal cancer (CRC) represents a major public health problem accounting for > 1 million cases of new cancers and about half a million deaths worldwide. The risk of recurrence remains high despite curative surgery in early disease stages. The incremental benefit in absolute recurrence-free survival from 5-fluorouracil (5-FU)-based regimens in young patients with high-risk colon cancer is not insignificant. We present a case of a 57-year-old otherwise healthy white man who was treated with adjuvant chemotherapy consisting of modified 5-FU/leucovorin/oxaliplatin (FOLFOX6) regimen for stage III colon cancer. He experienced significant cardiotoxicity related to infusional 5-FU. Because of his young age and high-risk cancer, the patient opted to continue with adjuvant bolus 5-FU-containing chemotherapy after a lengthy discussion. With close cardiac monitoring and treatment with calcium channel blocker to prevent coronary vasospasm, he was able to successfully complete adjuvant chemotherapy. Currently, there are no guidelines for predicting a patient's risk for 5-FU-induced cardiotoxicity. Similarly, there is no uniform management of this 5-FU-related induced cardiotoxicity. We believe that our case report, with a brief review of related literature, might help fill some of this vacuum.

Ca2+ sensitizer superior to catecholamine during myocardial stunning?

BACKGROUND: After open-chest cardiac surgery, ventricular function remains depressed (myocardial stunning). Catecholamines (epinephrine) improve ventricular function by increasing the intracellular Ca(2+) concentration. In parallel, the oxygen consumption is increased, so that the hitherto intact myocardium can be jeopardized. In the very insufficient ventricle, epinephrine can even become ineffective. Since Ca(2+) sensitizers provide another therapeutic avenue, the effects of epinephrine and levosimendan on postischemic hemodynamics were investigated. METHODS: After hemodynamic steady state, isolated, blood (erythrocyte-enriched Krebs-Henseleit solution)-perfused rabbit hearts were subjected to 25 min normothermic, no-flow ischemia and 20 min reperfusion. Heart rate (HR), cardiac output (CO), left ventricular pressure (LVP), coronary blood flow (CBF), and arterio-venous oxygen difference (AVDO(2)) were recorded during reperfusion and after administration of either epinephrine (n=16; 0.03 micromol), or levosimendan (n=11; 0.75 micromol) or epinephrine plus levosimendan (n=5). RESULTS: Epinephrine increased HR (19%, p=0.01) and improved hemodynamics in terms of CO (62%, p=0.0006), stroke volume SV (46%, p=0.02), stroke work W (158%, p=0.01), LVP(max) (58%, p=0.0001), maximal pressure increase dP/dt(max)(140%, p=0.0004), minimal pressure increase dP/dt(min) (104%, p=0.0002), LVP(ed) (-26%, p=0.02), and increased coronary resistance CR (31%, p=0.05). Epinephrine impaired hemodynamics in terms of AVDO(2) (+63%, p=0.003), myocardial oxygen consumption MVO(2) (+67%, p=0.0003) and MVO(2)/beat (+36%, p=0.01). External efficiency eta was increased by 92% (p=0.02). Levosimendan in postischemic hearts increased HR (32%, p=0.009) and improved hemodynamics in terms of CO (85%, p=0.01), SV (44%, p=0.03), W (115%, p=0.04), LVP(max) (95%, p=0.04), dP/dt(max) (133%, p=0.009), dP/dt(min) (121%, p=0.007), LVP(ed) (-63%, p=0.0006), and CR (-17%; n.s., p=0.1). It altered hemodynamics in terms of AVDO(2) (+7.0%; n.s., p=0.3) and MVO(2) (+32%, p=0.007) and MVO(2)/beat (+2.3%; n.s., p=0.4). External efficiency was increased by 307% (p=0.04). In five additional extremely dysfunctional rabbit hearts, epinephrine was ineffective. Additional levosimendan increased hemodynamics in terms of HR (56%; n.s., p=0.1), CO (159%, p=0.04), SV (89%, p=0.03), W (588%, p=0.02), LVP(max) (168%, p=0.03), dP/dt(max) (102%, p=0.005), dP/dt(min) (78%, p=0.006), LVP(ed) (-98%, p=0.0006), and CR (-50%, p=0.02). It altered hemodynamics in terms of AVDO(2) (-11%; n.s., p=0.05), MVO(2) (+131%, p=0.04) and MVO(2)/beat (+171%, p=0.03). External efficiency was increased by 212% (p=0.04). CONCLUSION: In contrast to epinephrine, levosimendan improves ventricular function without increasing oxygen demand, thereby considerably improving external efficiency. Even during epinephrine resistance in extremely dysfunctional hearts, levosimendan successfully improves ventricular function.