Heart rate after an acute myocardial infarction (AMI) is an index of late mortality. The hypothesis--that the potential beneficial effect of beta-blocking drugs after an AMI is quantitatively dependent on the reduction of heart rate obtained by such treatment--was examined by reviewing available data from acute and long-term intervention trials. Only properly randomized and double-blind trials were considered. In acute intervention trials only patients who received treatment within 12 hours after onset of pain were included. In early intervention trials there was a close relation between the reduction in heart rate and infarct size as determined by accumulated creatine kinase release (r = 0.97, p less than 0.001). A reduction in heart rate of at least 15 beats/min during infarct evolution was associated with a reduction of infarct size between 25 and 30%. The data suggest that a reduction in heart rate less than 8 beats/min has no effect or may actually increase infarct size. Comparison of post-AMI trials indicated a relation between the actual reduction of resting heart rate and percentage of reduction in mortality obtained in each trial (r = 0.60, p less than 0.05). An almost similar relation was demonstrated between the reduction in resting heart rate and nonfatal reinfarctions (r = 0.59, p less than 0.05). Confounding properties of a beta blocker, such as intrinsic sympathomimetic activity or prolongation of the QT interval, may reduce its efficacy. These results strongly suggest that the beneficial effect of beta blockers is related to a quantitative reduction in heart rate, probably indicating an antiischemic effect. However, the data do not exclude the possibility that other protective mechanisms may be operative.

Importance of heart rate in determining beta-blocker efficacy in acute and long-term acute myocardial infarction intervention trials.

All mammals and birds must develop effective strategies to cope with reduced oxygen availability. These animals achieve tolerance to acute and chronic hypoxia by (a) reductions in metabolism, (b) the prevention of cellular injury, and (c) the maintenance of functional integrity. Failure to meet any one of these tasks is detrimental. Birds and mammals accomplish this triple task through a highly coordinated, systems-level reconfiguration involving the partial shutdown of some but not all organs. This reconfiguration is achieved through a similarly complex reconfiguration at the cellular and molecular levels. Reconfiguration at these various levels depends on numerous factors that include the environment, the degree of hypoxic stress, and developmental, behavioral, and ecological conditions. Although common molecular strategies exist, the cellular and molecular changes in any given cell are very diverse. Some cells remain metabolically active, whereas others shut down or rely on anaerobic metabolism. This cellular shutdown is temporarily regulated, and during hypoxic exposure, active cellular networks must continue to control vital functions. The challenge for future research is to explore the cellular mechanisms and conditions that transform an organ or a cellular network into a hypometabolic state, without loss of functional integrity. Much can be learned in this respect from nature: Diving, burrowing, and hibernating animals living in diverse environments are masters of adaptation and can teach us how to deal with hypoxia, an issue of great clinical significance.

Hypoxia tolerance in mammals and birds: from the wilderness to the clinic.

The sections in this article are:


1
Historical Landmarks

2
The Basic Problem for Diving Animals

3
Decreased Sensitivity to Asphyxia

4
Oxygen Stores and Principles of Their Utilization

5
Cardiovascular Adjustments During and After Diving
5.1
General Aspects

5.2
Cardiac Output

5.3
Regional Circulation During Diving and on Emersion




6
Morphological Specializations in Vascular Beds of Diving Animals
6.1
Arteries

6.2
Shunts

6.3
Veins




7
Metabolic Consequences

8
Central Integration of Cardiovascular Responses
8.1
Medullary Reflex Mechanisms

8.2
Suprabulbar Influences

8.3
Other Reflex Influences




9
Diving Responses in Humans and Some Clinical Applications
9.1
Responses in Humans

9.2
Clinical Applications

Cardiovascular Adjustments to Diving in Mammals and Birds

Interest in comparative acid-base physiology has considerably grown during last decades even in the absence of major technical or conceptual advances. This is firstly because it has become clear that the extracellular acid-base state reflects the performance of many exchange functions at the organism level: respiration and ventilation of the gas exchange surfaces, metab olism, iono-and osmoregulation. Such functions are much in fluenced by ambient conditions, and the measurement of acid base parameters thus provides useful information about the organism's responses to environmental challenges. Secondly, many processes at the molecular level are now known to be pH sensitive, and acid-base regulation thus appears to be a major requirement for the functional integrity of cells and organisms. How extracellular acid-base balance can be maintained in a wide variety of animals living in different conditions is the sub ject of this book. The approach is comparative and environ mental throughout. All body fluids share similar buffer proper ties, and common physicochemical principles apply to any acid base system. However, in accord with differing designs and con straints along animal evolution, varying effector organs and mechanisms are at work to maintain an appropriate acid-base state in the organism. Particular emphasis is placed on the fun damental differences between water and air breathers and on the acid-base and respiratory problems arising at the transition from an aquatic to a terrestrial life. Also the complex array of factors influencing the acid-base state in water-dwelling animals is thoroughly discussed."

Comparative Aspects of Extracellular Acid-Base Balance

Trigemino-cardiac reflex during transsphenoidal surgery for pituitary adenomas.

The survival of ischemic myocardium is critically dependent on effective adjustments between myocardial residual flow and energy requirement in the ischemic regions. The quantitative and qualitative changes for optimal adjustments may be studied in diving animals, normally exposed to long periods of hypoxemia and anaerobiosis.



A series of studies have therefore been performed in seals in order to examine the regulations of myocardial blood flow, metabolism and left ventricular mechanics during diving asphyxia.



Unanesthetized animals instrumented with catheters in the left ventricle and in the coronary sinus were submerged for periods of 10 to 16 minutes. The heart rate decreased from 135 to 12 beats/minute. End diastolic and systolic ventricular pressures were almost unchanged while LVdP/dt was reduced by 25%. Myocardial distance gauges implanted in the left ventricular wall showed that left ventricular dimensions during diastole and systole remained essentially constant. Consequently dilatation of the heart and developed wall tension were strictly controlled during diving asphyxia. Average myocardial blood flow, determined by microsphere injections, decreased to 10% of predive values and remained constant during the dive.



Animals instrumented with mineature flow probes on the left circumflex coronary artery demonstrated that blood flow during diving ceases abruptly after the animal is submerged.



Small bursts of flow are periodically observed in steadily increasing magnitude at 30 to 45 second intervals throughout dives lasting up to 15 minutes. The progressive reduction in arterial oxygen content was associated with a time dependent increase in myocardial lactate and hydrogen ion production. Glucose extraction was reduced while free fatty acid extraction remained unchanged. Following restoration of breathing a reactive myocardial hyperemia was observed along with an immediate return to myocardial uptake of lactate. Arterial lactate concentration increased temporarily after emergence. Despite increased glycolytic activity throughout the dive, coronary flow distribution was fully controlled and no evidence of ischemic dilatation of the left ventricle or ST-segment elevation in the electrocardiogram was observed. Thus, coronary flow during diving was regulated jointly by a marked reduction in myocardial oxygen requirement (metabolic) and vasoconstrictor control (neurogenic).



Glycolytic energy production became increasingly important througout the dive and was not associated with depressed myocardial function. These adaptations to diving asphyxia in the seal myocardium permit a reduction of coronary blood flow which is comparable to that in the infarcted dog myocardium, and therefore have relevance for therapeutic approaches to reduction of myocardial ischemic injury in man.

The multifactorial approach to myocardial salvage. The experience from diving seals.

The adaptations of myocardial metabolism to diving asphyxia have been studied in 12 harbor seals (Phoca vitulina). Unanesthetized animals were submerged for periods of 10-16 min. Heart rate decreased from 135 to 12 beats/min. Myocardial blood flow decreased to an average of 10% of predive values and remained constant during the dive. The progressive reduction in arterial O2 content was associated with an increase in myocardial lactate and hydrogen ion production, but no change in glucose or free fatty acid extraction occurred. After restoration of breathing a reactive myocardial hyperemia and an immediate return to myocardial uptake of lactate were observed. Despite increased glycogenolytic activity throughout the dive, coronary flow distribution was fully controlled, and no evidence of ischemic dilatation of the left ventricle or S-T segment elevation in the electrocardiogram was observed. These adaptations to diving asphyxia in the seal myocardium permit a reduction of coronary blood flow comparable to that observed in the infarcted dog myocardium and therefore have relevance for therapeutic approaches to reduction of myocardial ischemic injury in humans.

Myocardial blood flow and metabolism in the diving seal

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The multifactorial approach to myocardial salvage. The experience from diving seals.

Myocardial blood flow and metabolism in the diving seal