Effect of α-tocopherol on hypoxic-perfused and reoxygenated rabbit heart muscle☆

Myocardial ischemia due to increased oxygen demand (pacing tachycardia plus critical coronary stenoses) alters diastolic distensibility and relaxation more than ischemia of comparable duration due to coronary occlusion. To investigate the relationship between myocardial diastolic function and metabolism, we compared myocardial high energy phosphate content, tissue pH, and regional blood flow for these two types of ischemia in anesthetized open-chest dogs. Myocardial biopsies were done with a high-speed air-turbine biopsy drill, permitting rapid (less than 1-second) freezing of tissue samples from both nonischemic and ischemic areas, while myocardial pH was measured with a hydrogen ion-selective polymer membrane implanted in the subendocardium. After 3 minutes of pacing tachycardia in dogs with critical coronary stenoses (demand-type ischemia, n = 14), regional systolic function (% segment shortening by ultrasonic crystals) was mildly depressed (from 19 +/- 2% control to 13 +/- 2% post-pacing, P less than 0.01), while left ventricular diastolic pressure-segment length relations shifted upward, indicating decreased distensibility of the ischemic myocardial segment. Associated with these changes in function, subendocardial adenosine triphosphate decreased (from 31.3 +/- 1.5 to 27.9 +/- 1.0 nmol/mg protein, P less than 0.01), as did creatine phosphate (53.8 +/- 2.1 to 39.6 +/- 2.5 nmol/mg protein, P less than 0.01), while myocardial pH declined slightly (delta pH = -0.14 +/- 0.02, P less than 0.01). In contrast, at 3 minutes of coronary artery occlusion (primary ischemia, n = 14), regional segment shortening was replaced by systolic bulging (% shortening decreased from 17 +/- 2% to -2 +/- 1% during occlusion, P less than 0.01), while left ventricular pressure-segment length relations were not shifted upward, and there was no decrease in diastolic distensibility of the ischemic segment. With coronary artery occlusion, subendocardial adenosine triphosphate declined slightly (33.2 +/- 0.5 to 29.2 +/- 2.0 nmol/mg, P less than 0.05), while creatine phosphate decreased substantially (51.1 +/- 2.3 to 7.8 +/- 1.4 nmol/mg protein, P less than 0.01). Myocardial pH fell strikingly (delta pH = -0.33 +/- 0.03, P less than 0.01), and the decline was 236% of that seen with demand-type ischemia. Regional myocardial blood flow (microsphere technique) showed a decreased endocardial:epicardial (endo:epi) ratio (1.04 +/- 0.04 control vs. 0.40 +/- 0.05 during pacing, P less than 0.01) and absolute subendocardial flow (1.02 +/- 0.47 to 0.47 +/- 0.05 ml/min per g, P less than 0.01) with demand-type ischemia.(ABSTRACT TRUNCATED AT 400 WORDS)

The relationships of high energy phosphates, tissue pH, and regional blood flow to diastolic distensibility in the ischemic dog myocardium.

Heart failure (HF) and sleep apnoea are common disorders which frequently coexist. Two main types of apnoea occur: one is obstructive which, through recurring episodes of snoring, hypoxaemia, large negative intra-thoracic pressures and arousals from sleep leading to downstream inflammatory and autonomic nervous system changes, is thought to be a causative factor to the development of systemic hypertension and HF. The other type of apnoea, Cheyne-Stokes respiration with central sleep apnoea (CSR-CSA), is characterized by an oscillatory pattern of ventilation with a prevailing hyperventilation-induced hypocapnia, often in the absence of significant hypoxaemia and snoring, and is thought to be a consequence of advanced HF-related low cardiac output, high sympathetic nervous system activation and pulmonary congestion. CSR-CSA may be a compensatory response to advanced HF. Rostral fluid shift during sleep may play an important role in the pathogenesis of both obstructive sleep apnoea (OSA) and CSA. Studies of positive airway pressure (PAP) treatment of OSA and CSA in HF have shown short-term improvements in cardiac and autonomic function; however, there is no evidence of improved survival. Loop gain may provide useful marker of continuous PAP (CPAP) responsiveness in patients with central apnoea. A greater understanding of the pathophysiology of the interaction between obstructive and central apnoea and the various types of HF, and the mechanisms of therapies, such as PAP, is required to develop new strategies to overcome the disabling symptoms, and perhaps improve the mortality, that accompany HF with sleep apnoea.

Sleep apnoea in heart failure: To treat or not to treat?

Improvement of cardiac preservation by preoperative high insulin supply

We performed morphological studies of myocardial contracture to define its nature and relationship to mechanical changes occurring during metabolic blockade. Isolated rat papillary and trabecular muscles were stretched to the apices of their length-tension curves and stimulated to contract isometrically 12 times a minute at a temperature of 28 degrees C. Incomplete and total metabolic blockade were induced by 1 hour of hypoxia (95% N2, 5% CO2) or by hypoxia plus glycolytic blockade with iodoacetic acid, 10-4M, respectively. In oxygenated control preparations, mechanical performance was stable for the 60-minute experimental period. In preparations exposed to hypoxia, developed tension fell to 7 +/- 2% of prehypoxia values at 60 minutes. Contracture tension increased progressively to 2.5 +/- 0.4 g/mm2. With total metabolic blockade, developed tension declined to zero by 10 minutes, contracture tension rose to an average peak value of 5.3 +/- 0.4 g/mm2 by 15 minutes, and subsequently slowly declined. All preparations were fixed at Lmax in the muscle bath. Light and electron microscopic studies revealed focal irregularities of A, I, and Z bands with sarcomere malalignment, hypercontraction, and fiber disruption, which increased in severity with increasing metabolic blockade. Linear densities appeared in mitochondria following total metabolic blockade, but mitochondria appeared normal otherwise. Thus, myocardial contracture after metabolic blockade is a focal process beginning within the sarcomere; morphological alterations in the contractile apparatus correlate with mechanical changes and are more severe than those in the mitochondria.

Mechanical and structural correlates of contracture induced by metabolic blockade in cardiac muscle from the rat

The effects of isoproterenol, glucose, and pH on the responses of isolated rat cardiac muscle to hypoxia (95% N2, 5% CO2) were examined while the muscles were contracting isometrically 12 times a minute at 28 degrees C. In the presence of 5.5 mM glucose, 10(-5) M isoproterenol and alkaline pH (7.8) improved the performance of cardiac muscle during early hypoxia. This was followed by a premature decline in developed tension, and contracture appeared. Recovery of function following reoxygenation with 95% O2 and 5% CO2 after a 60-min period of hypoxia was poor. Acid pH (6.8) resulted in an early decline of mechanical activity during hypoxia; but contracture did not appear, and full recovery of developed tension was seen upon reoxygenation after 60 min of hypoxia. When 22 mM glucose was used as substrate, the early responses to hypoxia were not altered; but late performance was improved, contracture did not appear, and full recovery after 60 min of hypoxia was seen. If additional glucose was added to the bath after 30 min of hypoxia (concentration 22 mM), little effect on developed tension was evident; but contracture diminished and recovery after 60 min of hypoxia was improved. Addition of 22 mM glucose allowed isoproterenol to exert its inotropic effect in the absence of late deleterious changes. The data support the concept that factors tending to increase the utilization of limited stores of anaerobic substrate during hypoxia facilitate deterioration. By increasing exogenous glucose, the support of inotropic activity without late adverse effects appears possible, and recovery is improved upon reoxygenation.

Factors influencing tolerance of cardiac muscle to hypoxia.

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Factors influencing tolerance of cardiac muscle to hypoxia.