Postischemic Left Ventricular Dysfunction Research Articles

Remuscularization with triiodothyronine and β1-blocker therapy reverses post-ischemic left ventricular dysfunction and adverse remodeling

Renewal of the myocardium by preexisting cardiomyocytes is a powerful strategy for restoring the architecture and function of hearts injured by myocardial infarction. To advance this strategy, we show that combining two clinically approved drugs, but neither alone, muscularizes the heart through cardiomyocyte proliferation. Specifically, in adult murine cardiomyocytes, metoprolol, a cardioselective β1-adrenergic receptor blocker, when given with triiodothyronine (T3, a thyroid hormone) accentuates the ability of T3 to stimulate ERK1/2 phosphorylation and proliferative signaling by inhibiting expression of the nuclear phospho-ERK1/2-specific phosphatase, dual-specificity phosphatase-5. While short-duration metoprolol plus T3 therapy generates new heart muscle in healthy mice, in mice with myocardial infarction-induced left ventricular dysfunction and pathological remodeling, it remuscularizes the heart, restores contractile function and reverses chamber dilatation; outcomes that are enduring. If the beneficial effects of metoprolol plus T3 are replicated in humans, this therapeutic strategy has the potential to definitively address ischemic heart failure.

Intracoronary pressures to predict myocardial viability in patients with ischemic left ventricular dysfunction.

To investigate the role of intracoronary pressure parameters in the assessment of viability in the myocardium subtending a significant coronary stenosis. In patients with ischemic left ventricular dysfunction, the presence of myocardial viability is related to the expected benefits derived from coronary revascularization. Intracoronary pressure wire-based measurements were performed in 64 coronary lesions of ≥50% stenosis severity of 59 patients with postischemic left ventricular dysfunction, segmental left ventricular wall motion abnormalities, and substantial viability in the myocardial territory subtending the investigated stenotic coronaries, defined as the percent summed rest score in the target territory (%SRStarget ) ≤60% at the single-photon emission tomography. Invasive pressure-derived indexes like resting and hyperemic Pd/Pa, ΔPd/Pa, and %ΔPd/Pa (defined as the absolute difference and percent decrease between resting and hyperemic Pd/Pa respectively) were compared with %SRStarget . A significant correlation was found between ΔPd/Pa (Spearman's p: -0.760, p < 0.001) and %ΔPd/Pa (p: -0.733; p < 0.001) with %SRStarget. These results were confirmed after correction for potential confounders. According to %SRStarget median value, myocardial areas with high and low viability were compared: ΔPd/Pa and %ΔPd/Pa were significantly higher in areas with high viability (p < 0.001 for both). According to receiver operating characteristic curves, we identified two cut-offs (ΔPd/Pa > 0.11 and %ΔPd/Pa > 15%) able to predict >80% viability with good sensitivity and specificity. Our study suggests that, in patients with postischemic left ventricular dysfunction and significant coronary stenosis, intracoronary pressures indexes like ΔPd/Pa and %ΔPd/Pa are able to predict the magnitude of downstream myocardial viability.

Classic Papers Revisited: An Early Study of Cardioprotection by Volatile Anesthetics

Abstract Recovery of Contractile Function of Stunned Myocardium in Chronically Instrumented Dogs Is Enhanced by Halothane or Isoflurane. By Warltier DC, al-Wathiqui MH, Kampine JP, and Schmeling WT. Anesthesiology 1988; 69:552–65. Reprinted with permission. Following brief periods (5–15 min) of total coronary artery occlusion and subsequent reperfusion, despite an absence of tissue necrosis, a decrement in contractile function of the postischemic myocardium may nevertheless be present for prolonged periods. This has been termed “stunned” myocardium to differentiate the condition from ischemia or infarction. Because the influence of volatile anesthetics on the recovery of postischemic, reperfused myocardium has yet to be studied, the purpose of this investigation was to compare the effects of halothane and isoflurane on systemic and regional hemodynamics following a brief coronary artery occlusion and reperfusion. Nine groups comprising 79 experiments were completed in 42 chronically instrumented dogs. In awake, unsedated dogs a 15-min coronary artery occlusion resulted in paradoxical systolic lengthening in the ischemic zone. Following reperfusion active systolic shortening slowly returned toward control levels but remained approximately 50% depressed from control at 5 h. In contrast, dogs anesthetized with halothane or isoflurane (2% inspired concentration) demonstrated complete recovery of function 3–5 h following reperfusion. Because the anesthetics directly depressed contractile function, additional experiments were conducted in which a 15-minute coronary artery occlusion was produced during volatile anesthesia; however, each animal was allowed to emerge from the anesthetized state at the onset of reperfusion. Similar results were obtained in these experiments, demonstrating total recovery of contractile function within 3–5 h following reperfusion. Thus, despite comparable degrees of contractile dysfunction during coronary artery occlusion in awake and anesthetized dogs, the present results demonstrate that halothane and isoflurane produce marked improvement in the recovery of segment function following a transient ischemic episode. Therefore, volatile anesthetics may attenuate postischemic left ventricular dysfunction occurring intraoperatively and enhance recovery of regional wall motion abnormalities during reperfusion.

Limitation of Infarct Size and the Open Artery Hypothesis: A Conversation With Eugene Braunwald, MD.

Eugene Braunwald received an MD from the New York University School of Medicine. He completed an internal medicine residency at Johns Hopkins Hospital and cardiology fellowships at Mount Sinai Hospital, Columbia University, and the National Heart Institute. He served as chief of cardiology and subsequently clinical director of the institute. From 1968 to 1972, he was the founding chair of medicine at the University of California, San Diego. From 1972 to 1996, he served as chair of medicine at the Brigham and Women’s Hospital. In 1975, he was elected to the National Academy of Sciences. He is now the Distinguished Hersey Professor of Medicine at Harvard Medical School and a senior investigator of the TIMI Study Group, which he founded in 1984. Dr Braunwald replies: I became aware of the importance of AMI in 1951 during an elective in cardiology during my senior year at the New York University School of Medicine. At the time, AMI was by far the most common cause of death in adults in the United States. Of the patients who survived to be admitted to hospitals (no one knew how many AMI patients failed to reach hospital emergency departments), about one third died before discharge, either suddenly, presumably from an arrhythmia, or secondary to pump failure. Of the patients who were discharged alive, about one quarter died within a year, most frequently as a consequence of heart failure or recurrent MI. Pathologists had taught that AMI was usually associated with coronary thrombosis. Indeed, during my cardiology elective, Herrick’s classic article describing AMI was required reading. Its title, “Clinical Features of Sudden Obstruction of the Coronary Arteries,” showed how these 2 conditions (coronary occlusion and AMI) were intertwined.1 My direct involvement in the care of several patients who did not survive the acute event left …

Effects of Combined Milrinone and Levosimendan Treatment on Systolic and Diastolic Function During Postischemic Myocardial Dysfunction in a Porcine Model.

It is not known whether there are positive or negative interactions on ventricular function when a calcium-sensitizing inotrope is added to a phosphodiesterase inhibitor in the clinical setting of acute left ventricular (LV) dysfunction. We hypothesized that when levosimendan is added to milrinone treatment, there will be synergetic inotropic and lusitropic effects. This was tested in an anesthetized porcine postischemic global LV injury model, where ventricular pressures and volumes (conductance volumetry) were measured. A global ischemic injury was induced by repetitive left main stem coronary artery occlusions. Load-independent indices of LV function were assessed before and after ventricular injury, after milrinone treatment, and finally after addition of levosimendan to the milrinone treatment. Nonparametric, within-group comparisons were made. The protocol was completed in 12 pigs, 7 of which received the inotrope treatment and 5 of which served as controls. Milrinone led to positive lusitropic effects seen by improvement in tau after myocardial stunning. The addition of levosimendan to milrinone further increased lusitropic state. The latter effect could however not be attributed solely to levosimendan, since lusitropic state also improved spontaneously in time-matched controls at the same rate during the corresponding period. When levosimendan was added to milrinone infusion, there was no increase in systolic function (preload recruitable stroke work) compared to milrinone treatment alone. We conclude that in this model of postischemic LV dysfunction, there appears to be no clear improvement in systolic or diastolic function after addition of levosimendan to established milrinone treatment but also no negative effects of levosimendan in this context.

Stunned Myocardium due to Decompensation from Hypovolemic Shock in a Pregnant Woman with Uterine Atony Following Cesarean Section

Transient post ischemic left ventricular dysfunction has been called stunned myocardium. The stunned myocardium can lead cardiac problems such as arrhythmias, left ventricular dysfunction, and a myocardial infarction. Stunned myocardium is a reversible condition. In this case, a 25 year old female patient with a history of mild intermittent asthma became hypovolemic and got into shock after developing uterine atony following a cesarean section. The patient did not respond to rapid volume replacement therapy. Subsequently, the patient had acute pulmonary edema, hypotension, and tachycardia developed. Echocardiogram was done showing severe left ventricular dysfunction (ejection fraction (EF), 25-35%) with left inferobasal wall hypokinesis and no right ventricular dysfunction or severe tricuspid regurgitation or right ventricular hypertrophy. Chest x-ray showed newly diagnosed cardiomegaly and bilateral pulmonary congestion. Initial troponin I was elevated, however, the level of troponin I remained stable with the same baseline value. Patient was at high risk for pulmonary embolism (PE) based on risk assessment, therefore, anticoagulation was started. Chest CT for pulmonary embolism was performed, and the result was negative. Two days after, repeated echocardiogram showed improved EF was 35%. Patient was discharged with beta –blocker to reduce oxygen demand of myocardium. This case supports hypovolemic shock not responding to volume replacement therapy can cause myocardium damage which is able to be diagnosed with stunned myocardium.

Myosin Activator Omecamtiv Mecarbil Increases Myocardial Oxygen Consumption and Impairs Cardiac Efficiency Mediated by Resting Myosin ATPase Activity.

Omecamtiv mecarbil (OM) is a novel inotropic agent that prolongs systolic ejection time and increases ejection fraction through myosin ATPase activation. We hypothesized that a potentially favorable energetic effect of unloading the left ventricle, and thus reduction of wall stress, could be counteracted by the prolonged contraction time and ATP-consumption. Postischemic left ventricular dysfunction was created by repetitive left coronary occlusions in 7 pigs (7 healthy pigs also included). In both groups, systolic ejection time and ejection fraction increased after OM (0.75 mg/kg loading for 10 minutes, followed by 0.5 mg/kg/min continuous infusion). Cardiac efficiency was assessed by relating myocardial oxygen consumption to the cardiac work indices, stroke work, and pressure-volume area. To circumvent potential neurohumoral reflexes, cardiac efficiency was additionally assessed in ex vivo mouse hearts and isolated myocardial mitochondria. OM impaired cardiac efficiency; there was a 31% and 23% increase in unloaded myocardial oxygen consumption in healthy and postischemic pigs, respectively. Also, the oxygen cost of the contractile function was increased by 63% and 46% in healthy and postischemic pigs, respectively. The increased unloaded myocardial oxygen consumption was confirmed in OM-treated mouse hearts and explained by an increased basal metabolic rate. Adding the myosin ATPase inhibitor, 2,3-butanedione monoxide abolished all surplus myocardial oxygen consumption in the OM-treated hearts. Omecamtiv mecarbil, in a clinically relevant model, led to a significant myocardial oxygen wastage related to both the contractile and noncontractile function. This was mediated by that OM induces a continuous activation in resting myosin ATPase.

Catheter-Based Endomyocardial Delivery of Mesenchymal Precursor Cells Using 3D Echo Guidance Improves Cardiac Function in a Chronic Myocardial Injury Ovine Model

The administration of bone marrow-derived stem cells may provide a new treatment option for patients with heart failure. Transcatheter cell injection may require multi-imaging modalities to optimize delivery. This study sought to evaluate whether endomyocardial injection of mesenchymal precursor cells (MPCs) could be guided by real-time 3D echocardiography (RT3DE) in treating chronic, postinfarction (MI) left ventricular (LV) dysfunction in sheep. Four weeks after induction of an anterior wall myocardial infarction in 39 sheep, allogeneic MPCs in doses of either 25 × 10(6) (n = 10), 75 × 10(6) (n = 9), or 225 × 10(6) (n = 10) cells or nonconditioned control media (n = 10) were administered intramyocardially into infarct and border zone areas using a catheter designed for combined fluoroscopic and RT3DE-guided injections. LV function was assessed before and after injection. Infarct dimension and vascular density were evaluated histologically. RT3DE-guided injection procedures were safe. Compared to controls, the highest dose MPC treatment led to increments in ejection fraction (3 ventricula 3% in 225M MPCs vs. -5 ± 4% in the control group, p < 0.01) and wall thickening in both infarct (4 ± 4% in 225M MPCs vs. -3 ± 6% in the control group, p = 0.02) and border zones (4 ± 6% in 225M MPCs vs. -8 ± 9% in the control group, p = 0.01). Histology analysis demonstrated significantly higher arteriole density in the infarct and border zones in the highest dose MPC-treated animals compared to the lower dose or control groups. Endomyocardial implantation of MPCs under RT3DE guidance was safe and without observed logistical obstacles. Significant increases in LV performance (ejection fraction and wall thickening) and neovascularization resulted from this technique, and so this technique has important implications for treating patients with postischemic LV dysfunction.

Cardioprotective Properties of Dimethyl Sulfoxide during Global Ischemia–Reperfusion of Isolated Rat Heart

Cardioprotective properties of dimethyl sulfoxide (DMSO) were studied in the isolated rat heart model. Intraperitoneal administration of DMSO to animals for 3 days before the experiment, but not addition of DMSO to the perfusate, reduced infarction size. Both intraperitoneal and intracoronary administration of DMSO reduced the severity of postischemic left-ventricular dysfunction.

Stabilizing endothelium of donor hearts with fusogenic liposomes reduces myocardial injury and dysfunction

BackgroundMyocardial injury after heart transplantation is a consequence of pathophysiologic events initiated by local ischemia/reperfusion injury that is further aggravated by the inflammatory response due to blood exposure to the pump’s artificial surfaces during cardiopulmonary bypass. The purpose of the present study was to determine the effectiveness of fusogenic lipid vesicles (FLVs) in enhancing the cardioprotective effect of St. Thomas organ preservation solution (ST). We hypothesized that donor hearts preserved with ST+FLVs will stabilize the endothelium during reperfusion, which, in turn, will reduce both endothelial barrier dysfunction and myocardial damage. MethodsTo examine the effect of ST+FLVs therapy in vitro, C3b deposition and adhesion molecule expression studies were performed on human umbilical vein endothelial cells challenged with plastic contact-activated plasma. To assess the therapy in vivo, a cervical heterotopic working heart transplantation model in rats was used. Donor hearts were preserved for 1 h at 27°C (15 min) and 4°C (45 min) and, after transplantation, were followed up for 2 h. Left ventricular function and the blood cardiac troponin I levels were quantified. ResultsHuman umbilical vein endothelial cells treated with ST+FLVs had reduced C3b deposition and expression of adhesion molecules compared with ST alone (P < 0.05). Donor hearts receiving ST+FLVs therapy had reduced left ventricular dysfunction and cardiac troponin I compared with ST alone. ConclusionsWe concluded that FLVs enhanced the cardioprotective effect of ST and reduced postischemic left ventricular dysfunction and myocardial damage. The mechanism of protection appears to be associated with the stabilization of endothelial cell membranes owing to incorporation of FLV-derived lipids.

Visualization and simulated surgery of the left ventricle in the virtual pathological heart of the Virtual Physiological Human

Ischaemic heart failure remains a significant health and economic problem worldwide. This paper presents a user-friendly software system that will form a part of the virtual pathological heart of the Virtual Physiological Human (VPH2) project, currently being developed under the European Commission Virtual Physiological Human (VPH) programme. VPH2 is an integrated medicine project, which will create a suite of modelling, simulation and visualization tools for patient-specific prediction and planning in cases of post-ischaemic left ventricular dysfunction. The work presented here describes a three-dimensional interactive visualization for simulating left ventricle restoration surgery, comprising the operations of cutting, stitching and patching, and for simulating the elastic deformation of the ventricle to its post-operative shape. This will supply the quantitative measurements required for the post-operative prediction tools being developed in parallel in the same project.

Effect of preischemic β-adrenoceptor stimulation on postischemic contractile dysfunction

Aims Short periods of preischemic β-adrenoceptor stimulation protect hearts against postischemic left ventricular dysfunction. It was the aim of this study to decide whether this procedure mimics ischemic preconditioning by the generation of preischemic hemodynamic and energetic stress or whether it represents an endogenous phenomenon and to investigate the influence of age and hypertension. Main methods Isolated rat hearts were investigated ex vivo by Langendorff perfusion and exposed to an established ischemia/reperfusion protocol (45 min no-flow ischemia and 90 min reperfusion). Left ventricular developed pressure (LVDP), rate pressure product, and ± d P/d t were analyzed. Key findings Isoprenaline concentration dependently increased LVDP up to 40 ± 15 mm Hg (approximately EC 50 of 9.9 ± 0.5 nM). Isoprenaline given prior to ischemia attenuated the subsequent postischemic ventricular dysfunction (approximately EC 50 of 1.4 ± 0.2 pM). However, concentrations high enough to improve LVDP in normoxic hearts did not improve postischemic recovery albeit a significant reduction of hypercontraction-induced cell damage. The effect on functional recovery was attenuated by atenolol, H89, and wortmannin suggesting that β-adrenoceptor stimulation, protein kinase A, and PI 3-kinase activation are involved. The effect was conserved in hearts from 13 month old rats but lost in age-matched spontaneously hypertensive rats. Significance The study identifies preischemic β-adrenoceptor stimulation as a pharmacological preconditioning protocol that does not simply mimic classical ischemic preconditioning by induction of hemodynamic or energetic stress prior to a prolonged ischemic period. The observed loss of effectiveness in hypertensives may contribute to the reduced ischemic tolerance of hypertensives.

Stunning, Hibernation, and Assessment of Myocardial Viability

The last 3 decades have witnessed an unprecedented improvement in the outcome of patients with acute coronary syndromes. The widespread use of thrombolytic therapy and percutaneous coronary interventions, in association with increasingly potent antithrombotic agents, has contributed to significant reductions in mortality and morbidity in these patients. Although overall survival has improved, a downside of this success has been the greater number of patients with residual left ventricular (LV) dysfunction undergoing progressive LV remodeling and congestive heart failure. This problem is compounded by the rising age of our population and the higher prevalence of comorbidities such as diabetes mellitus that confer an increased risk of coronary artery disease (CAD) and congestive heart failure. Patients with CAD represent by far the most numerous cohort among those with congestive heart failure, and their treatment remains a partial success.1 Typically, these patients have multivessel disease, increased LV volumes, and variable degrees of regional and/or global systolic dysfunction, although more cases of isolated diastolic dysfunction have been reported recently.2–4 In these patients, coronary revascularization may lead to symptomatic and prognostic improvement, and these clinical benefits are accompanied by evidence of reverse LV remodeling. In this context, the concept of myocardial viability was developed and a number of different techniques have been used to demonstrate the presence of viable tissue before coronary revascularization. The aim of this review article is to summarize our current understanding of the concept of myocardial viability and its clinical implications in patients with CAD and chronic LV dysfunction. Throughout this review, we use the term viability to describe dysfunctional myocardium subtended by diseased coronary arteries with limited or absent scarring that therefore has the potential for functional recovery. Viability is a prospective definition, but it does not imply evidence of functional recovery after interventions. The term hibernation, which …

N-terminal pro-brain natriuretic peptide predicts myocardial ischemia and is related to postischemic left-ventricular dysfunction in patients with stable coronary artery disease

The N-terminal-pro-B natriuretic peptide (Nt-pro-BNP) is of diagnostic and prognostic value in coronary artery disease (CAD). We assessed the relationship between Nt-pro-BNP and (1) the extent of ischemia on stress myocardial perfusion imaging (MPI), and (2) changes between the basal and postexercise ejection fraction (EF), in stable patients with a normal EF. One hundred and two patients with stable, documented CAD (EF, 62% +/- 8%) underwent an exercise-rest thallium-201 gated-MPI and serial Nt-pro-BNP assays. Myocardial perfusion imaging produced abnormal results in 57 patients (56%; group 1), and normal results in 45 patients (44%; group 2). Median baseline, immediate postexercise, and 3-hour postexercise Nt-pro-BNP values were higher in group 1 than in group 2: 182 vs 85, 201 vs 86, and 212 vs 99 pg/mL, respectively (P < .001 for all). Postexercise EF decreased in group 1 (53% +/- 11% vs 62% +/- 10%, P < .001), but not in group 2 (61% +/- 9% vs 62% +/- 7%, NS). The Nt-pro-BNP ruled out significant ischemia with a negative predictive value of 0.90, whereas patients within the higher tertile of Nt-pro-BNP had a fivefold higher risk of ischemia compared with patients within the lower tertile. The post-stress increase in Nt-pro-BNP is related to myocardial ischemia and to postischemic left-ventricular dysfunction, and accurately predicts the presence or absence of myocardial perfusion defects.

Contribution of Protons to Post‐Ischemic Na+ and Ca2+ Overload and Left Ventricular Mechanical Dysfunction

The intracellular accumulation of Na(+) and Ca(2+) plays a key role in ischemia-induced myocardial injury that may be manifest as left ventricular (LV) mechanical dysfunction, dysrhythmias, or infarction. This review considers the potential contributions of protons (H(+)) produced during ischemia as well as reperfusion to intracellular Na(+) and Ca(2+) homeostasis. ATP hydrolysis produces H(+) and the resulting intracellular acidosis directly impairs LV contractility. However, it is the accumulation of intracellular H(+) and the activation of Na(+)-dependent pH regulatory mechanisms, including the Na(+)-H(+) exchanger (NHE-1) and the Na(+)-HCO(3) (-) cotransporter, which contribute to Na(+) accumulation. Intracellular Na(+) accumulation, coupled with the NHE-1, then causes Ca(2+) overload and further LV mechanical dysfunction. As glycolysis uncoupled from glucose oxidation is an important determinant of the rate of H(+) production, factors that affect glucose metabolism, including degree of ischemia, myocardial workload, and competition from other energy substrates, are expected to influence Na(+) and Ca(2+) accumulation, and hence the recovery of post-ischemic LV mechanical function. Whereas an increase in the uncoupling of glycolysis from glucose oxidation accelerates H(+) production and worsens the recovery of LV mechanical function, inhibition of H(+) production improves recovery of post-ischemic LV mechanical function. Thus, alteration of glucose metabolism, either by inhibition of an excessive rate of glycolysis or by stimulation of glucose oxidation, is an attractive drug target to reduce H(+) production and limit Na(+) and Ca(2+) accumulation and thereby prevent post-ischemic LV dysfunction.

Nicorandil Improves Post-Ischemic Myocardial Dysfunction in Association With Opening the Mitochondrial K&lt;sub&gt;ATP&lt;/sub&gt; Channels and Decreasing Hydroxyl Radicals in Isolated Rat Hearts

Nicorandil has been reported to induce cardioprotection by opening the mitochondrial K(ATP) channels. However, whether nicorandil affects reactive oxygen species is unclear. The hearts of male Sprague-Dawley rats were excised and perfused on a Langendorff apparatus with Krebs-Henseleit solution with a gas mixture of 95% O(2) and 5% CO(2). 1 mmol/L of nicorandil was given 10 min before ischemia. Left ventricular developed pressure (LVDP, mmHg), +/-dP/dt (mmHg/s) and coronary flow (ml/min) were continuously monitored. All hearts were perfused for a total of 120 min consisting of a 30 min pre-ischemic period, followed by a 30 min global ischemia and 60 min reperfusion with and without 5-hydroxydecanoic acid sodium salt (5-HD), a mitochondrial K(ATP) channel blocker. The concentrations of 2,3-dihydroxybenzoic acid (2,3-DHBA), an indicator of hydroxyl radicals, in the perfusate during reperfusion period were also measured. Nicorandil significantly improved LVDP and +/-dP/dt, and increased coronary flow during reperfusion. Pretreatment with 5-HD abolished the improvement of LVDP and +/-dP/dt, and the increase in coronary flow induced by nicorandil. Nicorandil significantly attenuated the concentrations of 2,3-DHBA during reperfusion, which were restored by 5-HD. Nicorandil is protective against post-ischemic left ventricular dysfunction in association with opening the mitochondrial K(ATP) channels, decreasing hydroxyl radicals and increasing coronary flow in the isolated rat heart.

Adenosine-Induced Long-standing Postischemic Left Ventricular Dysfunction Evaluated With Gated SPECT

This study was performed to determine the after-effects of pharmacologic stress (adenosine) on left ventricular (LV) function-end-diastolic volume (EDV), end-systolic volume (ESV), and ejection fraction (LVEF)-with Tl-201 and Tc-99m MIBI SPECT. A total of 263 patients were grouped according to the time interval between isotope injection and imaging. Group A: within 1 hour (n = 99; men, n = 48; women, n = 51; mean age: 63.2 years), subgrouped as patients with no perfusion defect (NPD; n = 61), reversible defect (RD; n = 33), and fixed defect (FD; n = 5). Group B: 1 to 2 hours (n = 110; men, n = 66; woman, n = 44; mean age, 63 years), NPD (n = 64), RD (n = 26), and FD (n = 20). 3) Group C: 2 to 3 hours (n = 54; men, n = 30; women, n = 24; mean age, 62 years); NPD (n = 22), RD (n = 17), and FD (n = 15). All patients were in sinus rhythm during the study and had no prior history of myocardial infarction. In group A, in the patients with RD, poststress LVEF was significantly depressed after adenosine infusion (53.1 +/- 9.5% vs 58.3 +/- 10.2%, P < 0.001) and showed a wall motion abnormality, which was worse after stress than during rest. The mean difference in LVEF (DeltaLVEF) between rest and stress was 5.2%. The DeltaLVEF in those patients with RD was significantly higher than that in the NPD (0.9%, P < 0.01) or FD (2.1%, P < 0.05) subgroups. Twenty of the 33 patients (60.6%) with RD showed an increase in LVEF > or = 5% from poststress to rest, and the poststress ESV (43.3 +/- 19.0 mL) was significantly higher than the ESV (38.5 +/- 18.4 mL, P < 0.01) at rest, but there was no significant difference in the EDV (90.5 +/- 26.4 vs 89.7 +/- 26.2 mL). In group B, DeltaLVEF was 1.5%, 4.4%, and 1.2% in patients with NPD, RD, and FD respectively. In group C, DeltaLVEF was 2.5%, 3.2%, and 0.9% in patients with NPD, RD, and FD respectively, and there was no significant difference in DeltaLVEF among patients. In group C, 4 of 17 patients (23.5%) with RD showed an increase in LVEF > or = 5% from poststress to rest. These results showed that adenosine stress-induced postischemic LV dysfunction is well noted on early quantitative gated SPECT in patients with RD and can also be observed on delayed gated SPECT, even though the incidence of LV dysfunction is less than that in early gated SPECT.

Post-ischemic left ventricular dysfunction is detected on adenosine gated SPECT in patients with extensive coronary artery disease

Background: Ischemic left ventricular (LV) dysfunction may occur after exercise, but is regarded as uncommon after vasodilator stress. We evaluated the prevalence of LV dysfunction post-adenosine (ado) in relation to the extent of reversible perfusion defects (PD) and angiographic coronary artery disease (CAD). Methods: 86 patients (pts.) referred for adenosine dual-isotope gated SPECT were studied: 43 with ≥ 1 reversible PD, and 43 age and sex matched controls without CAD who had normal LV perfusion and function. Extent of reversible PD was defined by 20-segment/5-point summed difference score (SDS), and SDS≥ 8 defined severe PD. LV ejection fraction (EF) and segmental wall thickening (WT) were quantified at rest and 60 minutes post-adenosine by QGS (Cedars-Sinai Medical Center, Los Angeles, CA). Coronary angiography was performed in 36/43 pts. with PD. Results: See Table Extent PD EF ado Drop in WT ado vs. rest Stenosis Vessels with stenosis ≥ 50% LAD stenosis ≥ 50% (% pts) SDS < 8 (n = 18) 55 ± 12% −3 ± 13% 38 ± 33% 1.1 ± 1.1 38% SDS ≥ 8 (n = 25) 44 ± 15% −13 ± 16% 69 ± 28% 2.5 ± 1.1 82% p <0.02 0.04 <0.01 <0.01 0.02 LAD = left anterior descending. SD = standard deviation. Conclusion: Global and segmental LV dysfunction indicative of stunning was observed in pts. with severe reversible PD post-adenosine, and identified pts. with more extensive CAD.

Acute Heart Failure Complicating Acute Coronary Syndromes

Patients manifesting symptomatic pulmonary congestion during an acute myocardial infarction have long been recognized to be at heightened risk of both short- and long-term mortality.1–3 Acute heart failure (AHF) complicates acute myocardial infarction as a result of a complex interaction of structural, hemodynamic, neurohormonal, and genetic maladaptations. Abrupt myocyte loss leading to contractile dysfunction and AHF is an obvious mechanism, and the extent of biomarker elevation correlates with prognosis and the range of functional recovery.4 In those without extensive myocyte necrosis, postischemic left ventricular systolic dysfunction (LVSD) leading to AHF can result from transient myocardial stunning or hibernation depending on the extent of coronary reperfusion.5 Ventricular remodeling can increase wall stress to viable regions that may be relatively underperfused, furthering ischemia and adding to this cycle. Ischemia-induced impairment in myocardial relaxation can increase left ventricular filling pressures irrespective of global systolic function and lead to AHF. Furthermore, ischemia can also precipitate acute mitral regurgitation in some patients, contributing to the risk of pulmonary congestion. Recent data also suggest that AHF potentiates apoptosis in and outside the infarct zone,6 which focuses attention beyond mechanics, hemodynamics, and perfusion to alterations in signaling pathways and genetic expression. Regardless of which processes dominate in individual patients, it is clear that the intersection of AHF and myocardial infarction remains deadly even in the current era of acute reperfusion.7 See p 494 In this issue of Circulation , the Global Registry of Acute Coronary Events (GRACE) investigators8 expand on our understanding of the interrelation between AHF and acute coronary syndrome (ACS), clarify the impact for patients across the spectrum of ACS presentations, and provide disturbing revelations on …

Lindera strychnifolia is protective against post-ischemic myocardial dysfunction through scavenging hydroxyl radicals and opening the mitochondrial KATP channels in isolated rat hearts.

Lindera strychnifolia (tendai-uyaku), a medicinal plant, has long been used for the treatment of cardiac, renal and rheumatic diseases in Japan. We aim to clarify (1) whether L. strychnifolia is protective against post-ischemic myocardial dysfunction, and (2) whether its effect is related to scavenging hydroxyl radicals and opening the mitochondrial KATP channels in isolated rat hearts. Male Sprague-Dawley rats were orally given 1 ml/day of L. strychnifolia, which was extracted from 0.75 and 1.5 g/kg of roots of L. strychnifolia for 4 days. The rat hearts were excised and perfused on a Langendorff apparatus with Krebs-Henseleit solution with a gas mixture of 95% O2 and 5% CO2. The hearts were paced at 320 beats/min except during ischemia. Left ventricular developed pressure (LVDP, mmHg), +/- dP/dt (mmHg/sec) and coronary flow (ml/min) were continuously monitored. All hearts were perfused for a total of 120 minutes consisting of a 30-minute pre-ischemic period followed by 30 minutes of global ischemia and 60 minutes of reperfusion with or without 5-HD, a mitochondrial KATP channel blocker. The levels of lactate, LDH and 2,5-DHBA, an indicator of hydroxyl radicals, in the perfusate during reperfusion period were also measured. Treatment with L. strychnifolia significantly improved LVDP and +/- dP/dt without altering coronary flow during reperfusion. The 100 microM of 5-HD in Krebs-Henseleit solution was perfused during the 10 minutes of pre-ischemic periods. Pretreatment with 5-HD abolished the improvement of LVDP and +/- dP/dt by L. strychnifolia. L. strychnifolia significantly attenuated the levels of lactate, LDH and 2,5-DHBA during reperfusion, and which were restored by pretreatment with 5-HD. In conclusion, L. strychnifolia is protective against post-ischemic left ventricular dysfunction through scavenging hydroxyl radicals and opening the KATP channels in the isolated rat heart.