Management of catecholamine-induced stunned myocardium--a case report.

Hypertensive, hypervolumic, and hemodilution therapy (triple-H therapy) is administered to patients with symptomatic cerebral vasospasm after intracranial aneurysm clipping. This therapy can sometimes result in cardiac dysfunction because of pharmacologically induced hyperadrenergic state. The diagnosis may be missed if blood pressure alone is monitored to guide triple-H therapy. In this report, we describe one such patient who developed cardiac failure after triple-H therapy. This was diagnosed by using a bioreactance noninvasive cardiac output monitoring. Continuous cardiac output monitoring by this technique facilitated treatment of cardiac failure with milrinone and dobutamine. At discharge, the patient had no neurologic deficits.

Myocardial metabolism in toxin-induced heart failure and therapeutic implications.

BACKGROUND: Under normal conditions, myocardial metabolism is 60-80% reliant on the oxidation of fatty acids. This can be modified by conditions such as ischemia or poisoning with specific drugs, with the myocardium becoming more dependent on carbohydrate metabolism for energy. Acute poisoning with cardiotoxic drugs may be complicated by heart failure that is at present usually treated by inotropic drugs and vasopressors. However, changes in metabolic processes in poisoning may offer an opportunity for novel therapies. CURRENT EVIDENCE: The scientific evidence obtained from ischemia-reperfusion models and the preservation of myocardial metabolism when myocardial blood flow is restored after a brief coronary occlusion (a theory known as "myocardial stunning") support this concept. Generalized or localized myocardial stunning may develop in patients who do not present with acute myocardial ischemia secondary to coronary artery disease, a condition referred to as takotsubo cardiomyopathy. This is characterized by the preservation of myocardial blood flow, associated with a depressed myocardial contractility, lasting from hours to weeks. THERAPEUTIC IMPLICATIONS: Several factors have been associated with takotsubo cardiomyopathy:- excessive sympathetic stimulation, either from exogenous or endogenous origin; drug poisoning or drug withdrawal. The metabolism of both glucose and fatty acids appears to be reduced in the hypocontractile areas. One of the hypotheses is that the catecholamine-mediated myocardial insulin resistance may be responsible for reduced glucose uptake. Among the drugs taken in overdose, calcium channel blockers and beta-blockers have been shown to influence myocardial metabolism, with a shift from fatty acids to glucose utilization. This is the rationale for the administration of insulin in order to stimulate glucose myocardial uptake. In addition, insulin at high doses seems also to have inotropic effects, which are independent from its effects on myocardial substrate handling. CONCLUSION: Better understanding of the relationship between the receptor interactions of myocardial toxins and their effects on myocardial metabolism is likely to result in the development of new targeted therapies aimed specifically at optimising metabolic processes in poisoning.

Near-fatal tramadol cardiotoxicity in a CYP2D6 ultrarapid metabolizer.

BACKGROUND: Tramadol is a synthetic, centrally acting analgesic for the treatment of moderate to severe pain. The marketed tramadol is a racemic mixture containing 50% (+)tramadol and 50% (-)tramadol and is mainly metabolized to O-desmethyltramadol (M1) by the cytochrome P450 CYP2D6. Tramadol is generally considered to be devoid of any serious adverse effects of traditional opioid receptor agonists, such as respiratory depression and drug dependence. CASE REPORT: A 22-year-old Caucasian female patient was admitted to our ICU in refractory cardiac arrest requiring extracorporeal membrane oxygenation. This aggressive support allowed resolution of multi-organ dysfunction syndrome. Repeated blood analyses using liquid chromatography-tandem mass spectrometry confirmed high concentrations of both tramadol and its main metabolite O-desmethyltramadol. Genotyping of CYP2D6 revealed the patient to be heterozygous for a duplicated wild-type allele, predictive of a CYP2D6 ultrarapid metabolizer (UM) phenotype, confirmed by calculation of the tramadol/M1 (MR1) metabolic ratio at all time points. DISCUSSION: We here report a case of near-fatal isolated tramadol cardiotoxicity. Because of the inhibition of norepinephrine reuptake, excessive blood epinephrine levels in this CYP2D6R UM patient following excessive tramadol ingestion could explain the observed strong myocardial stunning. This patient admitted intermittent tramadol consumption to gain a "high" sensation. In patients with excessive morphinomimetic effects, levels of tramadol and its main metabolite M1could be measured, ideally combined with CYP2D6 genotyping, to identify individuals at risk of tramadol-related cardiotoxicity. Tramadol treatment could be optimized in these at-risk individuals, consequently improving patient outcome and safety.

Is stress cardiomyopathy the underlying cause of ventricular dysfunction associated with brain death?

Most deaths in the first 30 days after cardiac transplantation are due to failure of the donor heart, often with the clinical picture of right ventricular failure. Indeed, there is a significant reduction in contractility of the human donor heart and loss of contractile reserve before and soon after transplantation. This myocardial insult appears in association with brain death in the donor and follows a "catecholamine storm" associated with a rapidly rising intracranial pressure. Microscopy of the myocardium in organ donors shows a picture typical of catecholamine-induced injury and similar to changes found in endomyocardial specimens of stress cardiomyopathy (catecholamine-induced cardiomyopathy, or Takotsubo cardiomyopathy). There are 3 common features between stress cardiomyopathy and the heart of a brain-dead donor: exposure of the heart to unusually high catecholamine levels, ventricular dysfunction, and prompt recovery. Stress cardiomyopathy is a temporary myocardial dysfunction that has been described after sub-arachnoid hemorrhage, traumatic head injury, pheochromocytoma, acute emotional distress, exogenous administration of catecholamines, and non-related surgery. Given the common features of this catecholamine-mediated myocardial insult, we ask if brain-dead donor heart dysfunction is an extreme variant of stress cardiomyopathy? And, if so is it, like stress cardiomyopathy, reversible? Can we therefore expect recovery of the dysfunctional donor heart over time, thereby permitting increased use of hearts offered for transplantation?

Myocardial stunning following combined modality combretastatin-based chemotherapy: two case reports and review of the literature.

Myocardial stunning, known as stress cardiomyopathy, broken-heart syndrome, transient left ventricular apical ballooning, and Takotsubo cardiomyopathy, has been reported after many extracardiac stressors, but not following chemotherapy. We report 2 cases with characteristic electrocardiographic and echocardiographic features following combined modality therapy with combretastatin, a vascular-disrupting agent being studied for treatment of anaplastic thyroid cancer. In 1 patient, an ECG performed per protocol 18 hours after drug initiation showed deep, symmetric T-wave inversions in limb leads I and aVL and precordial leads V(2) through V(6). Echocardiography showed mildly reduced overall left ventricular systolic function with akinesis of the entire apex. The patient had mild elevations of troponin I. Coronary angiography revealed no epicardial coronary artery disease. The electrocardiographic and echocardiographic abnormalities resolved after several weeks. The patient remains stable from a cardiovascular standpoint and has not had a recurrence during follow-up. An electrocardiogram performed per protocol in a second patient showed deep, symmetric T-wave inversions throughout the precordial leads and a prolonged QT interval. Echocardiography showed mildly reduced left ventricular function with hypokinesis of the apical-septal wall. Acute coronary syndrome was ruled out, and both the electrocardiographic and echocardiographic changes resolved at follow-up. Although the patient remained pain-free without recurrence of anginal symptoms during long-term follow-up, the patient developed progressive malignancy and died.

CARDIAC role of the mitochondrial Ca2+ transporters in the high-[K+](o) cardioprotection of rat hearts under ischemia and reperfusion: a mechano-energetic study.

UNLABELLED: The role of mitochondrial transporters in the cardioprotection of rat hearts exposed to high [K+]-low [Ca2+]-cardioplegia (CPG) and ischemia and reperfusion (I/R) was studied through the mechano-energetic consequences of target drugs. The total heat rate (Ht) and the left intraventricular pressure (LVP) were simultaneously measured in isolated perfused hearts (30 degrees C and 1 Hz) inside a flow-calorimeter during 45 minutes of no-flow I and 45 minutes of R. After stabilization (C) they were pretreated with CPG and 100 microM 5-hydroxidecanoate (5HD, selective mKATP blocker) without and with 10 or 30 microM clonazepam (Clzp, mNCX inhibitor), 30 microM diazoxide (Dzx, selective mKATP opener), 1 microM Ru360 (selective Ca-uniporter blocker), and 0.2 microM cyclosporine-A, (mPTP inhibitor, before I and during R). Before I, 5-hydroxydecanoate in CPG increased the resting heat rate (17.83 +/- 3.55 mW/g) without changing the stunning. Clzp 30 microM + CPG + 5-hydroxydecanoate reduced the postischemic P with diastolic contracture and high Ht. Dzx protected C-hearts from stunning but increased it in CPG hearts with low economy (P/Ht) as well as Ru360. Cyclosporine-A did not modify the stunning of C or CPG ischemic hearts, suggesting that the mPTP was not opened. CONCLUSIONS: Mitochondria have a precise role for determining cardioprotection or stunning in high-K+ cardioplegic rat hearts under I/R. Known protective drugs, such as Dzx and Ru360, which reduce the mitochondrial Ca2+-uptake, increased the stunning of CPG-rat hearts and reduced muscle economy, whereas 5-hydroxydecanoate and Clzp together increased the stunning by inducing mitochondrial Ca2+ overload.

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.

Cardiogenic shock with stunned myocardium during triple-H therapy treated with intra-aortic balloon pump counterpulsation.

INTRODUCTION: Excessive use of adrenergic agents may result in stunned myocardium. CASES: We report the cases of two patients with subarachnoid hemorrhage (SAH) complicated by cardiogenic shock secondary to triple-H therapy for cerebral vasospasm. Both patients had normal cardiac function on admission and no signs of acute myocardial infarction at the onset of cardiogenic shock. Intra-aortic balloon pump (IABP) counterpulsation was used to maintain adequate cerebral perfusion while enabling the high doses of norepinephrine that were being administered to be reduced. Reversal of the myocardial dysfunction after vasopressors were discontinued supported a diagnosis of catecholamine-induced stunned myocardium. CONCLUSION: IABP counterpulsation may be one therapeutic option for patients with vasospasm after SAH when high doses of vasopressors can induce severe myocardial dysfunction. However, this invasive device may not be sufficient to maintain adequate cerebral perfusion and fatal embolic events can complicate the clinical course.

Effects of rosuvastatin and pitavastatin on ischemia-induced myocardial stunning in dogs.

Incomplete recovery of myocardial contraction after reperfusion following brief ischemia is called the "stunning phenomenon" in an animal experiment. A hydrophilic 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitor (statin) does not affect this phenomenon, but lipophilic statins further reduce the contraction during reperfusion. The effects of novel hydrophilic rosuvastatin and lipophilic pitavastatin on myocardial stunning in dogs were examined. In a preliminary experiment in vitro, pitavastatin reduced L6 cell viability at 10(-6) M and higher, whereas rosuvastatin and pravastatin up to 10(-5) M did not show such effects. An empty capsule or a capsule filled with rosuvastatin (2 mg/kg per day) or pitavastatin (0.4 mg/kg per day) was orally administered to dogs. After 3 weeks, both statins lowered the serum cholesterol level to the same extent. Under pentobarbital anesthesia, dogs were subjected to 15-min ischemia followed by 120-min reperfusion. Ischemia arrested the myocardial contraction in the ischemic area, and reperfusion recovered it but incompletely, showing the stunning phenomenon. Rosuvastatin did not modify the stunning phenomenon, while pitavastatin further deteriorated the myocardial contraction during reperfusion.

Glibenclamide action on myocardial function and arrhythmia incidence in the healthy and diabetic heart.

Myocardial sarcolemmal ATP-dependent potassium (KATP) channels, which are normally closed by high ATP concentration, open during ischemia when ATP generation decreases favoring K(+) efflux. This reduces action potential duration (APD) decreasing the time of Ca(2+) influx and Ca(2+) overload. This behavior suggested that they might be involved in the protection against stunning and arrhythmias and in the mechanism of ischemic preconditioning. Sulfonylureas, used as hypoglycemic agents for the treatment of type 2 diabetes also block myocardial KATP channels prolonging APD during ischemia, which by allowing Ca(2+) entry for a longer period of time, is potentially harmful to the heart. Controversial findings have been reported regarding the protective effect of sulfonylureas. Due to their importance in the clinical setting, their action on the heart of large conscious animal models is relevant. The effect of glibenclamide, a representative sulfonylurea, has been studied in a conscious sheep model submitted to regional 12 min ischemia. Glibenclamide (0.4 mg/kg) completely blocked KATP channels, as assessed by monophasic APD, producing a deleterious effect on reperfusion-induced arrhythmias and myocardial recovery from stunning in normal animals. This adverse effect was more noticeable in alloxan-induced diabetic sheep, where a lower dose (0.1 mg/kg) inhibited KATP channel opening worsening mechanical recovery and arrhythmia incidence. However, glibenclamide did not abolish ischemic late preconditioning against stunning and arrhythmias in normal animals. Because diabetic sheep do not develop this cardioprotective phenomenon, probably due to KATP channel dysfunction, it was not possible to assess glibenclamide effect on preconditioning in this pathological condition. In conclusion, in large conscious animals, glibenclamide interferes with the beneficial action of KATP channel opening during acute ischemia-reperfusion events both in normal and diabetic animals. Therefore, despite some studies claiming no added cardiovascular risk due to glibenclamide treatment, this pharmacological agent should be further investigated to ensure its safe administration in patients with concurrent heart disease.

[Case of bronchial asthma complicated with Takotsubo cardiomyopathy after frequent epinephrine medication].

A 62-year-old man with non-topic severe persistent asthma and chronic obstructive disease suffered severe asthma exacerbation. Epinephrine was repeatedly injected subcutaneously (0.3mg x 8 times in four hours) in addition to intravenous methylprednisolone for his severe asthma. Despite these treatments, his symptoms steadily deteriorated and thus he was transferred to our hospital. He did not have chest pain or a sensation of compression, while ECG on admission demonstrated ST elevation, loss of R-wave progression, negative T waves and QT interval prolongation, suggesting ischemic heart disease. Nonetheless creatine kinase and its MB isozyme were within normal range and myosin light chain I and troponin T were only mildly elevated. Echocardiography demonstrated apical dyskinesia and hypersystole in the basal region of the heart. Finally this case was diagnosed as Takotsubo cardiomyopathy, probably due to catecholamine-mediated myocardial stunning by overuse of epinephrine for acute severe asthma exacerbation. Abnormal findings of ECG and echocardiography became normal without any specific treatments for the heart.

Hyperkalemic cardioplegia-induced myocyte swelling and contractile dysfunction: prevention by diazoxide.

BACKGROUND: Hyperkalemic cardioplegia (9 degrees C) results in significant myocyte swelling and reduced contractility, representing a possible mechanism of myocardial stunning. Adenosine triphosphate-sensitive potassium channel (KATP) openers have been shown to ameliorate stunning. This study evaluated the hypothesis that a KATP opener would prevent hyperkalemic cardioplegia-induced myocyte swelling and reduced contractility. METHODS: Isolated rabbit myocytes were perfused with 37 degrees C Tyrode's solution for 20 minutes, followed by test solution (9 degrees C or 37 degrees C) including control Tyrode's, Tyrode's + 100 micromol/L diazoxide (KATP opener), St. Thomas's solution; or 9 degrees C St. Thomas's + 100 micromol/L diazoxide or St. Thomas's + 100 micromol/L diazoxide + 20 micromol/L HMR1098 or 50 micromol/L 5-hydroxydeconoate (KATP blockers) for 20 minutes (n = 8 per group). Myocytes were then reexposed to 37 degrees C Tyrode's solution for 20 minutes. Volume and contractility were measured by videomicroscopy and video-based edge detection, respectively. RESULTS: St. Thomas's solution (9 degrees C) caused significant myocyte swelling and associated reduced contractility (p < 0.05). The addition of diazoxide abolished myocyte swelling (p < 0.0001), and eliminated the associated reduced contractility (p < 0.05). Findings were unchanged by the addition of HMR 1098 and 5-hydroxydeconoate. CONCLUSIONS: Diazoxide prevented myocyte swelling and reduced contractility secondary to hyperkalemic cardioplegia, and this was unchanged by the addition of either KATP channel blocker. Prevention of myocyte swelling was associated with improved contractility, consistent with the hypothesis that myocyte swelling may be a mechanism of myocardial stunning. Diazoxide may play a role in myocyte volume homeostasis by means of a mechanism separate from opening the KATP channel.

Stunning of the left atrium after pharmacological cardioversion of atrial fibrillation.

INTRODUCTION: Stunning of the left atrium and atrial appendage is a well known but not fully clarified phenomenon observed during the cardioversion of atrial fibrillation regardless of the cardioversion method attempted. AIM: To assess the effects of propafenone and amiodarone on left atrium and left atrial appendage contractility. METHODS: Forty patients with paroxysmal atrial fibrillation (20 females, 20 males), aged 60-83 (mean 72.0+/-10.1) years, were enrolled into the study. Half of these patients had sinus rhythm restored by the administration of oral propafenone (150-300 mg) and the remaining 20 patients were treated with intravenous amiodarone (150-450 mg). The control group consisted of 20 patients (10 females, 10 males) aged 52-78 (mean 61.2+/-9.3) years with sinus rhythm and no history of atrial fibrillation. All the patients had a transthoracic (TTE) and transesophageal (TEE) echocardiography performed while still in the AF, before drug administration and 1 hour after sinus rhythm restoration. RESULTS: All haemodynamic parameters of the left atrium measured after the sinus rhythm restoration were significantly worse when compared with the control group. Left atrial fractional shortening and total atrial fraction were significantly lower after propafenone than amiodarone (8.6+/-3.6% vs 11.7+/-5.5%, p<0.05; and LA FC 16.2+/-5.3% vs 23.3 (+/-6.3)% respectively, p<0.05). Doppler echocardiographic parameters included in the analysis such as mitral flow and superior left pulmonary vein flow were significantly lower in the sinus rhythm restoration group than in the control group. Among them the end-diastolic mitral flow velocity amplitude and flow velocity integral as well as the maximum pulmonary retrograde velocity were significantly worse in the group treated with propafenone than in patients receiving amiodarone. All the atrial appendage Doppler velocity parameters were significantly reduced after the sinus rhythm restoration in both groups. In the patients treated with propafenone, values of these parameters were significantly decreased compared with the patients receiving amiodarone. CONCLUSIONS: Successful pharmacological cardioversion of atrial fibrillation causes the left atrium and left atrial appendage contractility impairment similar to that observed with other methods of the sinus rhythm restoration. Following the AF cardioversion the level of left atrial stunning is higher in the patients treated with propafenone than in subjects receiving amiodarone.

Characteristic dysfunction of stunned myocardium induced by 2,3-butanedione monoxime without ischaemia.

1. In the present study, we tested the hypothesis that, even in the absence of prior ischaemia, 2,3-butanedione monoxime (BDM), an inhibitor of contraction at the actin-myosin level, could produce the postischaemic dysfunction characteristic of stunned myocardium. 2,3-Butanedione monoxime was injected directly into the left anterior descending coronary artery (LAD) before and again after myocardial stunning produced by 15 min occlusion of the LAD followed by 30 min reperfusion. 2. Regional myocardial force, segment shortening and regional work were measured in both the LAD-perfused area and the area perfused by the circumflex coronary artery, which served as a control area. Regional dysfunction produced by BDM injection or ischaemia-reperfusion was assessed quantitatively by five parameters: end-diastolic length (EDL), shortening onset delay (delay), systolic bulge (bulge), end-shortening time delay (EST) and tail work ratio (TWR). 3. It was found that injection of BDM into the LAD caused dyskinesis similar to that caused by occlusion-reperfusion. Both displayed elevated EDL and marked increases in delay, bulge, EST and TWR; these parameters were significantly higher in the dyskinesis caused by BDM injection. Despite dysfunctional fibre shortening, intracoronary BDM injection did not reduce regional force. 4. Thus, BDM can elicit changes similar to those characteristic of postischaemic dysfunction. Because contractility was not impaired, dysfunction was apparently caused by disrupting the association between contractile force and muscle motion.

Detection of myocardial cell damage in isolated rat hearts with near-infrared spectroscopy.

One hallmark of cell death resulting from prolonged ischemia is cell membrane disruption. We apply optical spectroscopy to gauge membrane disruption in isolated rat hearts by monitoring (1) the washout of myoglobin (Mb) and (2) the accumulation of an exogenous contrast agent in permeabilized cells. The contrast agent, a neodymium (Nd) chelate, has several absorptions in the visible and near-IR, and when present in the perfusate, it cannot penetrate cellular membranes. When membrane integrity is disrupted, however, it is expected to accumulate within the intracellular space; moreover, cellular Mb is expected to wash out. To test this hypothesis, rat hearts (n=12) are perfused with Krebs-Henseleit buffer (KHB), followed by perfusion with KHB in which a 5 mM Nd-DTPA solution is present. Membrane damage is then induced by infusion of digitonin into the Nd-KHB perfusate to provide a digitonin concentration of 2.5, 5, or 10 microg/mL. After 30 min of infusion, Mb levels fall to 46+/-14% of baseline levels and Nd-DTPA rises to 161+/-19% of predigitonin levels. No apparent dependence of total membrane disruption on digitonin concentration over the concentration range studied is found, although higher concentrations do lead to more rapid membrane disruption.

Transient ischemic stunning of the myocardium in stress thallium-201 gated SPET myocardial perfusion imaging: segmental analysis of myocardial perfusion, wall motion and wall thickening changes.

Prolonged and persistent myocardial stunning has recently been demonstrated using technetium-99m sestamibi gated single-photon emission tomography (SPET) myocardial perfusion imaging post exercise or pharmacological stress test. In this study, we investigated the early postischemic transient myocardial stunning on early and delayed poststress thallium-201 gated SPET myocardial perfusion imaging using segmental wall motion (WM) and wall thickening (WT) analysis. A total of 1,680 segments from 84 patients' studies (53 men and 31 women, mean age 60 years) were evaluated on both early and delayed thallium-201 gated SPET treadmill exercise (59) or dobutamine stress (25) myocardial perfusion imaging. Semiquantitative analysis of perfusion, WM and WT in all segments was performed by two observers. Segments were classified according to changes in WM and WT between early and delayed images into normal, fixed abnormality, or improved abnormality (transient stunning), and were further classified according to changes in perfusion into normal, fixed defects, or ischemic. There were significant correlations between perfusion and WM, perfusion and WT, and WM and WT segmental scores on both early and delayed images. Transient stunning was seen significantly ( P < 0.001) more often in ischemic segments than were normal or fixed perfusion defects using WM (58%) and WT (50%) assessments. There was also a significant correlation between the severity of ischemia and transient stunning with either WM ( P < 0.05) or WT ( P < 0.005) evaluation. Segmental myocardial contractility assessment from gated SPET (201)Tl myocardial perfusion imaging using WM and WT was comparable, and results correlated well with the myocardial perfusion assessment. Early transient myocardial stunning was frequently observed in ischemic segments and was related to the severity of myocardial ischemia.