Peter B. Corr

Amphipathic metabolites and membrane dysfunction in ischemic myocardium.

MANY laboratory and clinical observations have implicated altered lipid metabolism as a contributor to membrane dysfunction, electrophysiological derangements, malignant arrhythmia, and cellular injury in ischemic myocardium. Amphipathic metabolites, moieties with both hydrophobic and hydrophilic properties, are capable of exerting deleterious effects on biological membrane systems through multiple mechanisms. Because of their structure, amphiphiles can alter membrane function by inserting into the phospholipid bilayer, and, under some conditions, can act as detergents with resultant dissolution of membrane constituents including cholesterol and phospholipids. This selective review will consider the metabolism of fatty acids, fatty acid esters, and phospholipid catabolites which increase in ischemic myocardium and have been implicated as biochemical mediators of membrane dysfunction. Two reviews dealing with the biophysics of lipid alterations in membranes and alterations of carbohydrate and fatty acid metabolism during ischemia have been published recently (Liedtke, 1981; Katz and Messineo, 1981).

Alpha adrenergic contributions to dysrhythmia during myocardial ischemia and reperfusion in cats.

Alpha compared to beta adrenergic contributions to dysrhythmias induced by left anterior descending coronary occlusion and by reperfusion were assessed in chloralose-anesthetized cats (n = 96). Alpha receptor blockade with either phentolamine or prazosin significantly reduced the number of premature ventricular complexes during coronary reperfusion (321 +/- 62-14 +/- 10 premature ventricular complexes, P less than 0.001), abolished early ventricular fibrillation (from 25% in controls to 0%), and prevented the increase in idioventricular rate seen with coronary reperfusion. However, beta-receptor blockade was without effect. Ventricular dysrhythmias induced by coronary occlusion alone (without reperfusion) were attenuated markedly by alpha-receptor blockade under conditions in which perfusion (measured with radiolabeled microspheres) within ischemic zones was not affected. Alternative sympatholytic interventions including pretreatment with 6-hydroxydopamine to deplete myocardial norepinephrine from 8.8 +/- 1.4 to 0.83 +/- 0.2 ng/mg protein and render the heart unresponsive to tyramine (120 microgram/kg) attenuated dysrhythmias induced by both coronary occlusion and reperfusion in a fashion identical to that seen with alpha-receptor blockade. Although efferent sympathetic activation induced by left stellate nerve stimulation increased idioventricular rate from 66 +/- 6 to 144+/- 7 beats/min (P less than 0.01) before coronary occlusion, this response was blocked by propranolol but not by phentolamine. In contrast, during reperfusion the increase in idioventricular rate induced by left stellate nerve stimulation (to 203 +/- 14) was not inhibited by propranolol but was abolished by phentolamine (79 +/- 10). Intracoronary methoxamine (0.1 microM) in animals depleted of myocardial catecholamines by 6-hydroxydopamine pretreatment did not affect idioventricular rate before coronary occlusion. However, early after coronary reperfusion, methoxamine increased idioventricular rate from 33 +/- 7 to 123 +/- 21 beats/min (P less than 0.01). Thus, enhanced alpha-adrenergic responsiveness occurs during myocardial ischemia and appears to be primary mediator of the electrophysiological derangements and resulting malignant dysrhythmias induced by catecholamines during myocardial ischemia and reperfusion.

Accumulation of lysophosphoglycerides with arrhythmogenic properties in ischemic myocardium.

Lysophosphoglycerides, products of membrane phospholipid catabolism known to influence membrane function in several systems, appeared in the effluents of anoxic isolated rabbit hearts perfused at low flow and accumulated in perfused hearts and myocardium rendered ischemic in situ. Comparable concentrations of lysophosphoglycerides bound to albumin markedly and reversibly altered action potentials of isolated canine Purkinje fibers in vitro. Changes induced included diminution of the maximum diastolic potential, peak dV/dt of phase zero, amplitude, and action potential duration--alterations resembling those seen in ischemic myocardium in vivo. These electrophysiological alterations are compatible with changes implicated in predisposing to dysrhythmia dependent on reentry, a phenomenon potentiated by the presence of zones of decreased conduction. Thus, accumulation of lysophosphoglycerides induced by ischemia may contribute to the genesis of malignant dysrhythmia early after its onset.

Demonstration of a widely distributed atrial pacemaker complex in the human heart.

Atrial depolarization was analyzed in 14 patients with the Wolff-Parkinson-White syndrome undergoing surgery to ablate accessory atrioventricular pathways associated with tachyarrhythmias. Bipolar potentials were recorded simultaneously from 156 atrial epicardial electrodes arranged in three templates to fit the anterior and posterior aspects of both atria. Spontaneous or sinus rhythms were recorded, as were atrial escape rhythms after overdrive pacing at rates of 150 and 200 beats/min. Atrial activation maps revealed different patterns of impulse initiation varying from typical unifocal sinus node impulse origin, unifocal extranodal impulse origin, and multicentric impulse origin from two to four widely distributed atrial pacemaker sites. In subjects demonstrating only unifocal impulse origin during control or sinus rhythm, other widely divergent pacemaker sites were recorded in other maps during subsequent rhythms. In addition to sites located at the upper superior vena cava-right atrium junction, pacemakers also dominated at sites anterior and inferior to the sinus node region during both control and escape depolarizations. Most of the subjects were found to have two or more pacemaker sites when maps of all control and postpacing conditions were analyzed. The right atrial pacemaker region encompassed a zone of 7.5 X 1.5 cm centered about the long axis of the sulcus terminalis posteriorly and the precaval band anteriorly. An unexpected finding was the participation of left atrial escape pacemakers. The functional behavior of both the control and escape pacemakers, as assessed by sinus node recovery time, was normal, indicating physiologic operation of the extranodal sites as part of an overall system of distributed pacemakers involved in the control of rate. Although functional assessment was limited in these initial patient studies, correspondence with similar observations in extensive previous canine studies supports the concept of a widely distributed atrial pacemaker complex in man.

Reentrant and focal mechanisms underlying ventricular tachycardia in the human heart.

BackgroundTo determine the mechanisms of ventricular tachycardia (VT) in humans, three-dimensional intraoperative mapping of up to 156 intramural sites was performed in 13 patients with healed myocardial infarction and refractory VT. Methods and ResultsMapping was of sufficient density to define the mechanism of 10 VTs in eight patients. In five of 10 cases, sustained VT was initiated in the subendocardium or epicardium by intramural reentry with marked conduction delay as well as functional and anatomic block most prominent in the subendocardium and midmyocardium. The initiating beats of reentrant VT induced by programmed electrical stimulation arose in the endocardium or midmyocardium by progressive slowing of conduction leading to unidirectional block. Multiple simultaneous reentrant circuits can be present. In contrast, five of the 10 sustained VTs were initiated by a focal mechanism as defined by the absence of electrical activity between the termination of one beat and the initiation of the next despite the presence of multiple intervening intramural electrode recording sites. Comparisons of the mapping data with results of histopathological analysis of tissue demonstrated that the location of infarction as well as that of adjacent fibrotic muscle determined sites of both fixed and functional conduction block during macroreentrant VT and that slowing of conduction occurred in a direction transverse rather than longitudinal to fiber orientation. ConclusionsBoth intramural reentry and a focal mechanism underlie sustained VT in patients with healed myocardial infarction.

Increased alpha-adrenergic receptors in ischemic cat myocardium. A potential mediator of electrophysiological derangements.

We have recently demonstrated enhanced alpha-adrenergic responsiveness assessed electrophysiologically in ischemic and reperfused myocardium. This study was performed to determine whether ischemia alters alpha 1-adrenergic receptor number (Bmax) of affinity (KD) based on [3H]prazosin binding. Within 30 min after occlusion, Bmax increased in ischemic regions to 207% of control to 27 +/- 2 fmol/mg protein, with the increase persisting (+ 141% of control) during early reperfusion (2 min), before returning to control base-line values (13 +/- 1.6) after 15 min of reperfusion. KD was not altered at any interval studied. Beta receptor number of ([3H]dihydroalprenolol) and Na+-K+ ATPase activity were comparable in control compared to ischemic myocardium although beta-receptor Bmax and KD in both regions decreased during early reperfusion. Thus, the enhanced alpha-adrenergic responsivity previously recognized with ischemia and reperfusion is correlated with an increase in alpha 1-adrenergic receptors.

Prophylaxis of early ventricular fibrillation by inhibition of acylcarnitine accumulation.

Hypoxia in isolated myocytes results in accumulation of long-chain acylcarnitines (LCA) in sarcolemma. Inhibition of carnitine acyltransferase I (CAT-I) with sodium 2-[5-(4-chlorophenyl)-pentyl]-oxirane-2-carboxylate (POCA) prevents both the accumulation of LCA in the sarcolemma and the initial electrophysiologic derangements associated with hypoxia. Another amphiphilic metabolite, lysophosphatidylcholine (LPC), accumulates in the ischemic heart in vivo, in part because of inhibition of its catabolism by accumulating LCA. It induces electrophysiologic alterations in vitro analogous to early changes induced by ischemia in vivo. The present study was performed to determine whether POCA could prevent accumulation of both LCA and LPC induced by ischemia in vivo and if so, whether attenuation of early arrhythmogenesis would result. LAD coronary artery occlusions were induced for 5 min in chloralose-anesthetized cats. Coronary occlusion in untreated control animals elicited prompt, threefold increases of LCA (73 +/- 8 to 286 +/- 60 pmol/mg protein) and twofold increase of LPC (3.3 +/- 0.4 to 7.5 +/- 0.9 nmol/mg protein) selectively in the ischemic zone, associated with ventricular tachycardia (VT) or ventricular fibrillation (VF) occurring within the 5-min interval before acquisition of myocardial samples in 64% of the animals. POCA prevented the increase of both LCA and LPC. It also prevented the early occurrence of VT or VF (within 5 min of occlusion) in all animals studied. The antiarrhythmic effect of POCA was not attributable to favorable hemodynamic changes or to changes in myocardial perfusion measured with radiolabeled microspheres. Thus, inhibition of CAT-I effectively reduced the incidence of lethal arrhythmias induced early after the onset of ischemia. Accordingly, pharmacologic inhibition of this enzyme provides a promising approach for prophylaxis of sudden cardiac death, that typically occurs very soon after the onset of acute ischemia, in man.

Mechanisms Contributing to Malignant Dysrhythmias Induced by Ischemia in the Cat

Continuously recorded bipolar electrograms were obtained simultaneously from epi-, endo-, and mid-myocardial regions of the ischemic and normal zones of cat left ventricle in vivo after coronary occlusion, analyzed by computer, and compared to regional cyclic AMP levels. Regional cyclic AMP content was used as an index of the combined local effects of: (a) efferent sympathetic nerve discharge; (b) release of myocardial catecholamines due to ischemia; and (c) circulating catecholamines. Ischemia resulted in a progressive increase in pulse width and rise time and a decrease in rate of rise of voltage (dV/dt) of the local electrograms from ischemic zones reaching a maximum within 2.4+/-0.3 min (mean+/-SE) at the time of onset of severe ventricular dysrhythmias, all of which returned toward control before the cessation of the dysrhythmia (33.5+/-1.5 min after coronary occlusion). Increases in cyclic AMP in ischemic zones preceded corresponding increases in the frequency of premature ventricular complexes (PVCs). Propranolol inhibited the increases in cyclic AMP and reduced the frequency of PVCs in animals without ventricular fibrillation. In animals with ventricular fibrillation, cyclic AMP was significantly elevated in normal and ischemic zones compared to animals with PVCs only. Electrical induction of PVCs or ventricular fibrillation in ischemic and nonischemic hearts failed to increase cyclic AMP. The results suggest that the changes in regional adrenergic stimulation of the heart may contribute to perpetuation of ventricular dysrhythmia and the genesis of ventricular fibrillation early after the onset of myocardial ischemia.

Mechanisms underlying the development of ventricular fibrillation during early myocardial ischemia.

The mechanisms underlying the development of ventricular fibrillation (VF) during early myocardial ischemia were assessed by use of a computerized three-dimensional mapping system capable of recording simultaneously from 232 intramural recording sites throughout the entire feline heart in vivo. Occlusion of the proximal left anterior descending coronary artery led to ventricular tachycardia (VT), which degenerated to VF in 1-5 minutes in four of 15 animals. Normal sinus beats immediately preceding the initiation of VT leading to VF demonstrated delayed activation (total activation time 133 +/- 14 msec), which was not significantly different from the activation time for normal sinus beats immediately preceding nonsustained VT (149 +/- 7 msec). Most of the conduction delay occurred in the subendocardial and midmyocardial regions in both groups. Initiation of VT leading to VF occurred by intramural reentry in three of the four cases. In one case, a mechanism responsible for the initiation of VT could not be assigned. The coupling interval of the initiating beats of VT ultimately leading to VF (210 +/- 15 msec) did not differ from that of nonsustained VT. Maintenance of the VT that led to VF was due primarily to intramural reentry (84% of cases) involving multiple activation sites in and around the border region of the ischemic zone. Nonreentrant mechanisms, arising in the subendocardium and subepicardium, also contributed to the maintenance of VT before development of VT. The transition from VT to VF was due exclusively to intramural reentry with initiation of the reentrant beats in the subendocardium and, occasionally, the subepicardium. Acceleration of the tachycardia by intramural reentry, along with very rapid and inhomogeneous recovery of excitability (as low as 50-60 msec), led to increased functional block and conduction delay. As a result, the total activation time for a given beat exceeded the coupling interval for that beat and led to the multiple reentrant circuits and multiple simultaneous activations characteristic of VF. Thus, the initiation and maintenance of VT leading to VF during early ischemia is due to intramural reentry, although nonreentrant mechanisms also contribute. However, the development of VF is due to continued intramural reentry and rapid recovery of excitability.

Intramural reentry as a mechanism of ventricular tachycardia during evolving canine myocardial infarction.

We evaluated the contribution of intramural electrical events in initiation and maintenance of ventricular tachycardia in 15 dogs 3–8 days after either permanent (n = 2) or transient (n = 13) coronary artery occlusion. Seven of the dogs (47%) demonstrated eight distinct monomorphic ventricular tachycardia patterns which were mapped by means of a recently designed computerized system capable of simultaneously detecting, storing, and assessing information from 232 individual cardiac sites. Using both epicardial and intramural electrodes, we found definitive evidence for intramural reentry in seven of the eight monomorphic tachycardias analyzed. Furthermore, five of these animals (71%) demonstrated microreentry, in which small epicardial conduction loops exited intermittently into nonrefractory subendocardium to initiate succeeding beats, while, in the remaining two dogs, ventricular tachycardia was due to macroreentry, during which the broad subendocardial wavefronts depolarizing the ventricle constituted the proximal (fast) reentry limbs. Detailed anatomical analysis of the resultant infarcts demonstrated the thin surviving epicardial tissue rim to be the site of conduction delay necessary for reentry, whereas ‘preferred pathways’ of exit into the subendocardial plane occurred at the infarct borders and were of variable configuration. Successful interruption of these rhythms should accompany interference with the process of exit into nonrefractory subendocardial tissue.