A. James Liedtke

Pathophysiological Mechanisms of Chronic Reversible Left Ventricular Dysfunction due to Coronary Artery Disease (Hibernating Myocardium)

The long-term consequences of CAD remain a prominent clinical problem. Particularly with new therapeutic strategies that reduce the mortality associated with acute coronary syndromes, more patients suffer from the long-term sequelae of this condition. In this setting, the identification of those segments of myocardium that appear dysfunctional distal to coronary stenoses and that can improve after coronary revascularization is of considerable clinical importance. Although the diagnostic and therapeutic aspects of this problem are clearly defined, the pathophysiological mechanisms underlying the dysfunctional myocardium are controversial. It was demonstrated more than 20 years ago1 2 that resting wall-motion abnormalities in patients with CAD can improve after administration of an inotropic agent or after coronary bypass. An article published in 1978 by Diamond et al3 presaged the concept of hibernating myocardium: “Reports of sometimes dramatic improvement in segmental left ventricular function following coronary bypass surgery, although not universal, leaves the clear implication that ischemic non-infarcted myocardium can exist in a state of function hibernation.” Rahimtoola, in an article published in 1985,4 popularized this concept and later suggested that “hibernating myocardium is a state of persistently impaired myocardial and left ventricular function at rest due to reduced coronary blood flow that can be partially or completely restored to normal either by improving blood flow or by reducing oxygen demand.”5 Since the introduction of the term “hibernation,”3 4 5 6 the clinical importance of reversible left ventricular dysfunction has been widely accepted. The concept of an adaptive process that decreases myocardial oxygen consumption in the presence of either chronically or intermittently reduced oxygen delivery has generated considerable clinical and experimental interest. Accordingly, our aims were to (1) review the current criteria of the definition of hibernating myocardium, (2) summarize recent clinical as well as experimental data pertaining to this subject, …

Effects of carnitine in ischemic and fatty acid supplemented swine hearts.

FREE FATTY ACIDS (FFA) IN EXCESS FFA: albumin molar ratios have been determined to additionally compromise mechanical performance in ischemic hearts. Carnitine, an intracellular carrier of FFA and an agent which is lost to the heart during ischemia, has been postulated to in part restore function with its replacement. To test whether its benefits are also operative in a setting of excess FFA, these studies were performed. In the main protocol, four groups of perfused swine hearts (n = 45) were compared during 50 min of control flow (179.7 ml/min) and 40 min of global ischemia (106.1 ml/min). Initial base-line serum FFA:albumin molar ratios and carnitine levels in all groups were 1.3:1 and 8.5 nmol/ml, respectively. In two of these groups FFA:albumin ratios were increased to 5.9:1 with constant infusions of Intralipid. In two alternate groups (one with and one without extra FFA supplements) dl-carnitine was supplied, sufficient to increase serum levels nearly 200-fold. Ischemia per se in 14 hearts significantly decreased several parameters of global and regional mechanical function including left ventricular (LV) and mean aortic pressures, LV isovolumetric pressure development (max dp/dt), LV epicardial motion, and LV work, together with concomitant decreases in myocardial oxygen consumption. Elevated FFA in 12 hearts rendered similarly ischemic further decreased mechanical function (LV pressure: -20.8%, P < 0.05; mean aortic pressure -26.9%, P < 0.05; LV max dp/dt: -39%, P < 0.05; regional LV shortening: -51.1%, P < 0.05; and LV work: -50.3%, P < 0.05) as compared with nonsupplemented hearts. dl-Carnitine treatments in nine hearts, not supplemented with extra FFA were without apparent effect in improving overall hemodynamic performance. However, dl-carnitine in 10 high FFA-ischemic hearts effected several improvements as compared with the untreated group: LV pressure was increased 25.6%, P < 0.025; mean aortic pressure: +43.5%, P < 0.05; LV max dp/dt: +41.5%, P < 0.05; regional LV shortening: +241.3%, P < 0.001; and LV work: +76.2%, P < 0.05 at comparable levels of myocardial oxygen consumption. In a separate protocol, the effects of stereospecificity were also studied by comparing l- with dl-carnitine in globally perfused, palmitate-supplemented hearts (five hearts in each treatment group). At similar conditions of flow and serum FFA, changes in mechanical function were comparable, except for a tendency to perform greater LV work at reduced flows in the l-carnitine-treated hearts. Thus, it was demonstrated that carnitine in ischemic hearts is capable of preserving mechanical function under conditions of excess FFA, presumably by modifying the toxic effects of FFA intermediates. The major therapeutic actions appeared to derive from the l-isomer of carnitine.

Effects of blunt cardiac trauma on coronary vasomotion, perfusion, myocardial mechanics, and metabolism.

: Blunt injury to heart muscle can result in a variety of dysrhythmias and mechanical dysfunction. In the present studies of 24 open-chest, working swine hearts with controlled perfusion of the left anterior descending (LAD) coronary artery, changes in proximal and distal coronary vascular resistance (CVR), small-vessel perfusion (using radioactively-labeled microspheres), and regional and global mechanical function and metabolism (myocardial oxygen consumption [MVO2] and lactate extraction) were observed before and for 1 hour following a single impact involving the LAD artery. Trauma caused no spasm, thrombosis, hemorrhage, or laceration of the LAD artery but resulted in significant perfusion redistributions of small vessels. Within minutes of the impact, epicardial/endocadial flow ratios in the myocardial tissue perfused by the traumatized vessel increased (p < 0.005) and were associated with a significant decrease in the distal CVR (p < 0.001). In this same region, significant decreases were also observed in an index of regional work (p < 0.01), shortening (p < 0.005), MVO2 (p < 0.001), and per cent lactate extraction (p < 0.01). Also noted were declines in left ventricular (LV) pressure development and contractility (LV max dp/dt). The regional changes in flow patterns and function in general persisted throughout the course of perfusion. These data suggest that cardiac trauma can induce major changes in vasomotor tone and perfusion distributions of the coronary vasculature, and demonstrate how blunt cardiac-coronary trauma can result in some of the hemodynamic and electrocardiographic abnormalities previously reported.Blunt injury to heart muscle can result in a variety of dysrhythmias and mechanical dysfunction. In the present studies of 24 open-chest, working swine hearts with controlled perfusion of the left anterior descending (LAD) coronary artery, changes in proximal and distal coronary vascular resistance (CVR), small-vessel perfusion (using radioactively-labeled microspheres), and regional and global mechanical function and metabolism (myocardial oxygen consumption [MVO2] and lactate extraction) were observed before and for 1 hour following a single impact involving the LAD artery. Trauma caused no spasm, thrombosis, hemorrhage, or laceration of the LAD artery but resulted in significant perfusion redistributions of small vessels. Within minutes of the impact, epicardial/endocadial flow ratios in the myocardial tissue perfused by the traumatized vessel increased (p < 0.005) and were associated with a significant decrease in the distal CVR (p < 0.001). In this same region, significant decreases were also observed in an index of regional work (p < 0.01), shortening (p < 0.005), MVO2 (p < 0.001), and per cent lactate extraction (p < 0.01). Also noted were declines in left ventricular (LV) pressure development and contractility (LV max dp/dt). The regional changes in flow patterns and function in general persisted throughout the course of perfusion. These data suggest that cardiac trauma can induce major changes in vasomotor tone and perfusion distributions of the coronary vasculature, and demonstrate how blunt cardiac-coronary trauma can result in some of the hemodynamic and electrocardiographic abnormalities previously reported.

Myocardial Kinetics of a Putative Hypoxic Tissue Marker, 99mTc-Labeled Nitroimidazole (BMS-181321), After Regional Ischemia and Reperfusion

BACKGROUND A new nitroimidazole complex, 99mTc-propylene amine oxime-1,2-nitroimidazole (BMS-181321), has been developed to allow the positive imaging of hypoxic myocardium by standard gamma camera techniques. METHODS AND RESULTS To determine the myocardial kinetics of BMS-181321 during myocardial ischemia and reperfusion, seven open-chest swine were prepared according to a model of extracorporeal coronary perfusion in which left ventricular wall thickening (percent end-diastolic thickness) and substrate use in the left anterior descending (LAD) region ([14C]palmitate and [3H]glucose infusions) were determined. Measurements were obtained at baseline, during 40 minutes of ischemia produced by reducing flow in the LAD distribution by 60%, and during 70 minutes of reperfusion. Three aerobic control hearts were also studied in which LAD blood flow was not reduced. Regional coronary circulation was further assessed in all hearts by use of radiolabeled microspheres injected during ischemia. BMS-181321 (20 to 30 mCi) was injected after 30 minutes of ischemia, and its myocardial uptake was assessed by dynamic planar gamma imaging. Ischemia was associated with declines in fatty acid metabolism (15 +/- 11 mumol.h-1.g dry wt-1, mean +/- SEM), systolic wall thickening (20 +/- 6%), and myocardial oxygen consumption (3 +/- 1 mL.min-1.100 g-1) and an increase in exogenous glucose utilization (75 +/- 13 mumol.h-1.g dry wt-1). Systolic wall thickening recovered by only 8 +/- 3% with reperfusion. Initial distribution of BMS-181321 in the aerobic hearts appeared homogeneous. Washout from the ischemic and reperfused LAD bed was slower than the aerobically perfused LAD bed in the control group (t1/2 = 136 +/- 1 versus 80 +/- 1 minutes, P < .05), allowing visualization of the LAD region during reperfusion. Tissue activity of BMS-181321 was inversely related to LAD blood flow during ischemia (r = -.68 +/- .05), and the ratio of BMS-181321 in the LAD region versus normal myocardium was 1.7 +/- 0.2. Control swine lacked regional deposition of the tracer in the normally perfused LAD distribution. CONCLUSIONS Thus, acute regional ischemia in these studies was visualized as an increase in retention of BMS-181321, suggesting its applicability in the imaging of clinical conditions of myocardial hypoperfusion.

Alterations in fatty acid oxidation in ischemic and reperfused myocardium

The focus of this review centered on describing the effects of excess fatty acids on myocardial recovery during reperfusion following ischemic stress. Effects on mechanical function were modest in our studies and are likely to remain difficult/impossible to measure due to the independent phenomenon of stunning which obfuscates and no doubt dominates the influences of other mechanical determinants. Mitochondria appear capable of again using long-chain fatty acids as a preferred substrate and in the presence of restored oxygen delivery can produce normal levels of CO2. These changes in oxidative metabolism are not mirrored by equal recoveries in mitochondrial energetics. Because of inefficiencies in electron transport and oxidative phosphorylation together with moderate uncoupling of electron transport from oxidative phosphorylation, ATP resynthesis is blunted. This explains in part the absolute decrease in contents of exchangeable nucleotides noted both in cytosol and mitochondria. Further impairments in recovery reside in the inability of the mitochondria to exchange adenine nucleotides into cytosol through the adenine nucleotide translocase antiport. These findings contribute to our understanding of mechanical stunning and may be of value in designing future strategies to optimize the handling of substrates during myocardial reperfusion.

Detrimental effects of fatty acids and their derivatives in ischemic and reperfused myocardium

In 1850, Richard Quain reported in a series of 83 autopsied patients, some of whom in life were troubled by chest and arm pains, shortness of breath, syncopy and fits of coma, a peculiar patchy, pale dirty brown appearance to the surface of the heart on morbid anatomical inspection [1]. This change in color and consistency, which was accompanied by surface or interstitial fat, like ‘oil globules of milk bound in an albuminous envelope’, in a setting of friable muscle fibers ‘appeared to be connected with the causes on which the disease condition depend(ed) — such as obstruction of the coronary arteries’. Rokitansky and Virchow, both of whom thought (erroneously) that atherosclerosis and myocardial fibrosis were due to inflammation, felt this interlarding or fatty metamorphosis of cardiac muscle was an actual conversion of muscle fibrils to molecular fat [2, 3]. Virchow specifically advised that this formation of adipose tissue from connective tissue and parenchyma affected a derangement in motor power [4] or myomalacia cordes, a term that survived into the early twentieth century. From these rudimentary concepts evolved our modern understanding of myocardial ischemia, injury, and infarction and their interdependent relationships with fatty acids and altered lipid metabolism in heart muscle.

Effects of propionate on mechanical and metabolic performance in rat hearts

SummaryThe purpose of this report is to describe the contribution of propionate as an adjunct source of oxidative metabolism in aerobic myocardium. In the first series of studies, six groups of isolated working rat hearts (n=6–8 per group) were perfused for 40 minutes with Krebs-Henseleit media containing 11 mM glucose. Propionate treatment was provided to the media at a constant dose per heart group and extended over a range of dosages, including: 0 (placebo control), 0.1, 0.5, 1.0, 5.0, and 10.0 mM, buffered to pH 7.4. Average aerobic coronary blood flow for all groups was 21.5\+-0.6 ml/min; average left ventricular peak systolic pressure was 123.7\+-1.4 mmHg. There were no significant differences among groups compared with placebo hearts for aortic flow, heart rate x aortic pressure product, or myocardial oxygen consumption, although performance tended to decline in the 10 mM group. A clear dose-response relationship was observed in 14CO2 production from labeled propionate, with a 12-fold increase between the 0.1 and 10 mM groups. Most of the increase occurred at the lower dosages, with a relative leveling off at the 1.0, 5.0, and 10.0 mM doses. In part 2, prpionate was examined as a sole substrate. At 1.0 mM without glucose, proionate per se was unable to support mechanical function over the course of the perfusions, but still maintained high rates of oxidation, comparable to that of the 1.0 mM group with glucose in part 1. Thus propionate proved to be a useful intermediate for substrate oxidation in mammalian hearts, and its resulting contribution to energy metabolism may provide one mechanism to understand the benefits of the propionyl-L-carnitine compound.

Mechanical recovery with propionyl-L-carnitine

Carnitine has received attention in the past as a naturally occurring compound which can transiently improve or preserve cardiac performance during myocardial ischemia [1]. An example of this preservative effect on mechanical function is shown in Figure 1 from experimental observations in extracorporeally perfused pig hearts at conditions of moderate global ischemia and excess fatty acids (FFA) in coronary perfusion fluid [2]. The exact mechanism for this therapeutic influence has never been identified but hypotheses have centered on a sparing effect from a deleterious lipid burden known to occur in ischemic heart muscle which drains essential energy stores and disrupts membrane integrity and enzyme functions via accumulation of amphiphiles [3, 4]. Unfortunately, by definition, the benefits of carnitine (or any other therapy) in ischemic myocardium must be short-lived since any treatment strategy in the absence of expeditious repletion of oxygen delivery cannot be sustained for long. Irreversible cardiac injury with its accompanying mechanical dysfunction must occur in a matter of minutes-to-hours.