Repetitive Episodes Of Ischemia Research Articles

Ischemic left ventricle systolic dysfunction: An evidence-based approach in diagnostic tools and therapeutics

Coronary artery disease (CAD) associated with left ventricular systolic dysfunction is a condition related to poor prognosis. There is a lack of robust evidence in many aspects related to this condition, from definition to treatment. Ischemic cardiomyopathy is a spectrum ranging from stunned myocardium associated with myocardial fibrosis to hibernating myocardium and repetitive episodes of ischemia. In clinical practice, relevance lies in identifying the myocardium that has the ability to recover its contractile reserve after revascularization. Methods to evaluate cellular integrity tend to have higher sensitivity, while the ones assessing contractile reserve have greater specificity, since a larger mass of viable myocytes is required in order to generate contractility change. Since there are many methods and different ways to detect viability, sensitivity and specificity vary widely. Dobutamine-cardiac magnetic resonance with late gadolinium enhancement has the best accuracy is this setting, giving important predictors of prognostic and revascularization benefit such as scar burden, contractile reserve and end-systolic volume index. The latter has shown differential benefit with revascularization in some recent trials. Finally, authors discuss interventional procedures in this population, focusing on coronary artery bypass grafting and evolution of evidence from CASS to post-STICH era.

Abstract P50: Ischemic Post-Conditioning Following Global Ischemia Due to Cardiac Arrest Failed to Improve Cardiac Function and Survival

Introduction : Repetitive episodes of ischemia and reperfusion following regional myocardial and cerebral ischemia, representing ischemic post-conditioning (IPC), protect against ischemic injury. The possibility that such may have functional application for myocardial injury and survival in settings of cardiac arrest and resuscitation was examined. We hypothesized that repetitive cycles of ventricular fibrillation and reperfusion following resuscitation, representing IPC, would improve cardiovascular function and survival. Methods : Ventricular fibrillation (VF) was electrically induced in 10 SD rats weighing 536±15 g and left untreated for 8 minutes prior to 6 minutes of uninterrupted pre-cordial compressions followed by attempted defibrillation. Resuscitated animals were randomized to either IPC or control. IPC was induced at 5 minutes with electrical re-fibrillation lasting 30 sec followed by spontaneous reversion to a perfusing rhythm. The IPC was repeated 5 minutes later. Except for IPC, controls were identically treated. Frontal plane ECG, mean arterial blood pressure, left ventricular pressures and end tidal CO 2 were continuously recorded. Left ventricular ejection fraction (EF) and cardiac output (CO) were measured echocardiographically at hourly intervals together with blood gases for a total of four hours. Survival was documented at the end of 72 hours. Results : Baseline values did not differ between the IPC and control group. No statistically significant differences between the groups were demonstrated. A power calculation indicates that a minimum of 240 animals would be required to find a difference that would be potentially significant, accordingly the study was concluded. Table . Mean values with standard deviation. Conclusion : The potential value of ischemic post-conditioning represented by repetitive episodes of VF, under the conditions of global ischemia of cardiac arrest, failed to demonstrate a survival value.

The pathological basis of myocardial hibernation.

Myocardial hibernation refers to a state of persistent regional ventricular dysfunction, in patients with coronary artery disease that is reversible with revascularization. It is part of the spectrum of pathophysiological responses to myocardial ischemia and is a particularly important concept in understanding the development and progression of ischemic cardiomyopathy. Hibernating myocardium may be associated with chronic hypoperfusion, or result from repetitive episodes of ischemia with a cumulative effect on contractile function. Mechanistic studies on myocardial hibernation have been hampered by the difficulty in developing a reproducible and reliable animal model. This review describes the pathologic changes found in hibernating myocardial segments discussing the potential mechanisms involved in their development. Depletion of cardiomyocyte contractile elements, loss of myofilaments and disorganization of cytoskeletal proteins are among the most consistently reported morphological alterations found in hibernating myocardial segments. In addition, the cardiac intersitium exhibits inflammatory changes, leading to fibrotic remodeling. Induction of cytokines and chemokines suggests an active continuous inflammatory process leading to fibrosis and dysfunction. Although, the initial response may be adaptive to ischemia, if timely revascularization is not performed, irreversible tissue injury, fibrosis and myocyte degeneration may develop. Understanding the role of inflammatory mediators in the development and progression of the cardiomyopathic process may lead to the development of specific therapeutic strategies aiming at preventing irreversible fibrosis and dysfunction.

Expression of VEGF and angiopoietins-1 and -2 during ischemia-induced coronary angiogenesis.

The mechanisms underlying coronary capillary growth in response to ischemia are undefined. We hypothesized that the expression of vascular endothelial growth factor (VEGF) and angiopoietin (Ang)/Tie-2 were involved in capillary growth as an adaptation to ischemia. To test this hypothesis we measured capillary density, and the expressions of VEGF, Ang-1, Ang-2, and the Tie-2 receptor and its phosphorylation state during repetitive episodes of myocardial ischemia in chronically instrumented canines. Repetitive episodes of ischemia were induced by multiple (once/hour; 8/day), brief (2 min) occlusions of the left anterior descending coronary artery for 1, 7, 14, or 21 days. A sham group received the same instrumentation as the experimental groups but not the occlusion protocol. Collateral blood flow (microspheres) progressively increased from 9 +/- 3 to 83 +/- 10 ml. min-1. 100 g-1 on day 21. Capillary density increased at day 7 from 2378 +/- 53 (sham) to 2962 +/- 60/mm2, but it decreased to 2594 +/- 39/mm2 at day 21. Both VEGF and Ang-2 expression in myocardial interstitial fluid (Western analyses) peaked at day 3 of the repetitive occlusions but waned thereafter. In contrast the expression of Ang-1 remained relatively constant at all times in the occlusion groups. In shams, the expression of VEGF and Ang-2 was low and constant at all times. Tie-2 phosphorylation myocardial decreased decreased at day 7 but increased at 21 days of occlusions (P < 0.05). Our results indicate that capillary density was augmented by myocardial ischemia, but after development of collaterals and restoration of flow to the ischemic zone, capillary density returned to control levels. The change in capillary density paralleled with VEGF and Ang-2 expression but was inversely related to Tie-2 phosphorylation. We speculate the coronary angiogenesis is a coordinated event involving the expression of both VEGF and Ang-2 and that therapeutic angiogenic strategies may ultimately require treatment with more than a single factor.

Hibernating myocardium

According to estimates, up to 50% of patients with coronary artery disease and impaired left ventricular function have areas of viable myocardium. This dysfunctional, yet viable myocardial tissue, which can improve functionally after myocardial oxygen supply is reestablished, has been called hibernating myocardium. The possible pathophysiological mechanism that leads to hibernating myocardium is controversial: is the phenomenon due to persistent ischemia or is it the result of repetitive episodes of ischemia and reperfusion, such as myocardial stunning? Regardless of the mechanism, the presence of viable myocardial tissue indicates that structural and biochemical cellular changes occur, and the recovery of left ventricular function after revascularization depends on the severity and extent of these changes. Whether these changes reflect a long-lasting state of cellular dedifferentiation, an adaptive process that is reversible, or eventually lead to cellular degeneration has not been determined. Perhaps early detection of hibernating myocardial tissue via noninvasive imaging techniques used to assess contractile response, integrity of the cellular membrane, myocardial metabolism, and myocardial blood flow and subsequent early coronary revascularization may prevent infarction and deterioration in left ventricular function. Knowledge that reversible changes and areas of viable myocardium can occur in patients with left ventricular dysfunction will assist healthcare providers in the care and management of patients with hibernating myocardium.

Effect of intermittent delivery of warm blood cardioplegia on myocardial recovery

Continuous warm blood cardioplegia is often temporarily interrupted during coronary artery operations to provide the surgeon with a bloodless operating field. To determine the effects of intermittent warm ischemia on myocardial recovery, we randomized 15 adu't mongrel dogs to receive either multidose cold or warm blood cardioplegia during a 90-minute arrest. Myocardial metabolic and functional recovery was assessed before clamping of the aorta and after 30 and 60 minutes of reperfusion. Systolic function was well preserved, whereas diastolic function decreased slightly in both groups after arrest. Myocardial oxygen consumption increased during reperfusion after cold heart protection but was unchanged after warm blood Cardioplegia. Highenergy phosphates decreased significantly in both groups during reperfusion. Two conclusions were reached. (1) Myocardial functional recovery was well preserved, whereas metabolic recovery was impaired after either technique of myocardial preservation. (2) Preserved functional recovery after multidose warm blood cardioplegia suggests that repetitive episodes of ischemia may condition the myocardium, thus preventing injury during prolonged aortic cross-clamping.

Acadesine attenuates ischemic cardiac dysfunction in the isolated blood‐perfused rabbit heart

AbstractAcadesine (AICA‐riboside) is a nucleoside analog with cardioprotective properties. Most previous studies demonstrating cardioprotection with acadesine have been conducted in buffer‐perfused hearts, and no study has investigated the dose‐response relationship to acadesine in a blood‐perfused model. The objective of this study was to investigate the dose‐related cardioprotective effects of acadesine in donor‐perfused, isolated rabbit hearts subjected to 12 × 3 min episodes of global ischemia with intervening periods of reperfusion of 5 min duration. Five groups of hearts were studied: saline control and four treatment groups of acadesine, 0.1, 0.2, 0.5, 2.0 gm/kg/min (0.4, 0.8, 2.0, 8.0 μmol/kg/min) constant intravenous infusion to the support animal. Left ventricular (LV) pressure and coronary blood flow (CBF) in the isolated hearts were measured. In control hearts, baseline LV developed pressure averaged 129 ± 7 mmHg and declined to 43 ± 3% of baseline after 12 periods of ischemia and reperfusion. Acadesine significantly improved recovery of function at the lower doses tested, i.e., hearts treated with 0.1, 0.2, and 0.5 mg/kg/min (0.4, 0.8, 2.0 μmol/kg/min) recovered 61 ± 5%, 67 ± 7%, and 65 ± 7% of LV pressure, respectively (P &lt; 0.05 vs. saline). This protective effect was not observed with the highest dose of acadesine, 2.0 mg/kg/min (8.0 μmol/kg/min) (52 ± 6%). The greatest recovery of function corresponded to plasma acadesine concentrations of 27 ± 6.0 μM, but the beneficial effect was lost when plasma concentrations reached 205 ± 28 μM. These results suggest that repetitive episodes of ischemia and reperfusion induced stunning in isolated blood‐perfused rabbit hearts, and that the severity of this dysfunction is attenuated by treatment with acadesine. © 1994 Wiley‐Liss, Inc.