G. Krumpl

Mode of QT correction for heart rate: Implications for the detection of inhomogeneous repolarization after myocardial infarction

In 22 conscious, chronically instrumented dogs, the relationship between R-R interval and QT interval was better explained by linear regression than by nonlinear regression according to Bazetts formula. The correction formula QTL = QT-0.1*(RR-1000), which is based on the assumption of a linear relationship between QT and R-R interval, was then compared with Bazetts formula regarding its capability to detect inhomogeneous repolarization 5 to 7 days after temporary occlusion of the left anterior descending coronary artery. This comparison was performed only in those dogs exhibiting changes in QRS duration of less than 5 msec in response to myocardial infarction (n = 12). In these animals, myocardial infarction resulted in a significant dispersion of repolarization between the left ventricular normal zone and the infarct zone and a shift to the right of strength-interval curves of the infarct zone with respect to the normal zone, indicating local dispersion of refractoriness. As opposed to QTc (Bazetts formula), QTL was significantly (p = 0.04) prolonged after occlusion. Hence the adequacy of QT correction contributes significantly to the detection of inhomogeneous ventricular recovery after acute myocardial infarction.

Can exercise-induced regional contractile dysfunction be prevented by selective bradycardic agents?

SummaryPropranolol (0.5 mg×kg−1×5 min−1), alinidine (1 mg×kg−1×5 min−1) and the benzazepinon UL-FS 49 (0.5 mg×kg−1×5 min−1) were investigated in a canine model of exercise-induced transient myocardial dysfunction, mimicking exercise-induced functional impairment during angina pectoris in man. Each drug was infused intravenously, after two control treadmill exercise runs had shown comparable, ultrasonically assessed regional contractile dysfunction in an area supplied by a partly stenosed brach of the left coronary artery. All three drugs abolished exercise-induced regional contractile dysfunction. Propranolol and alinidine comparably decreased heart rate and positivedp/dtmax during exercise. UL-FS 49 showed a marked negative chronotropic effect without affecting positivedp/dtmax. Thus, prevention of exercise-induced regional contractile dysfunction has been shown for the first time using a selective bradycardic agent.

Comparison of the haemodynamic effects of the selective bradycardic agent UL‐FS 49, with those of propranolol during treadmill exercise in dogs

1 To clarify whether the bradycardic agent UL‐FS 49 exhibits a positive inotropic effect even in the absence of improvement in regional myocardial function of an underperfused myocardial area, this study was undertaken in dogs with unimpaired coronary flow. 2 We also investigated the haemodynamic and functional effects of the negative chronotropic and inotropic β‐adrenoceptor blocker propranolol. 3 UL‐FS 49 did not depress total or regional myocardial performance. Moreover, an increase in positive left ventricular dp/dt max at rest suggests a positive inotropic effect of UL‐FS 49. 4 Propranolol, in contrast to UL‐FS 49, led to a marked reduction in positive dp/dt max, stroke volume and systolic wall thickening at rest and during exercise. Additionally, propranolol decreased the exercise values of cardiac output, left ventricular work and left ventricular power to a far greater extent than UL‐FS 49. 5 In contrast to propranolol, the selective bradycardic agent UL‐FS 49 did not decrease total or regional ventricular performance and caused less reduction in cardiodynamic parameters during exercise. 6 These results suggest that patients with moderate coronary insufficiency or patients with coronary vessel disease and mild left ventricular failure may attain a higher exercise limit under selective bradycardia with UL‐FS 49 in comparison to that possible with a β‐adrenoceptor antagonist, such as propranolol.

Effects of the bradycardic agent UL-FS 49 on exercise-induced regional contractile dysfunction in dogs

The effects of the bradycardic agent UL-FS 49 on hemodynamic and segmental parameters were studied in a canine model of exercise-induced myocardial dysfunction which mimics exercise-induced angina pectoris. Ten dogs, trained to subunit to five treadmill exercise cycles consisting of 4 min of running and 11 min of recovery, were chronically instrumented with a microtip manometer in the left ventricle, two pairs of crystals for sonomicrometry, a hydraulic occluder around the circumflex branch of the left coronary artery and arterial and venous catheters. Control experiments with coronary stenosis clarified the reproducibility of exercise-induced regional contractile dysfunction and recovery of function in the intervening resting periods. In each individual dog, a similar degree of stenosis was used in the subsequent experiments with UL-FS 49. After two control runs, which exhibited regional contractile dysfunction of comparable magnitude, UL-FS 49 was administered intravenously at a dosage of 0.5 mg/kg/5 min (6 dogs) or 0.25 mg/kg/5 min (4 dogs). Both doses of UL-FS 49 markedly reduced heart rate without alteration of left ventricular positive dp/dtmax at rest and during exercise. A marked improvement of regional function in the area perfused by the stenosed coronary artery was also observed during exercise. This beneficial effect of selective bradycardia, here observed with UL-FS 49, remains to be confirmed in clinical trials.

Effects of alinidine on exercise-induced regional contractile dysfunction in dogs

The effects of the bradycardiac agent alinidine on hemodynamic parameters and regional contractile function were investigated in 6 chronically instrumented dogs trained to submit to 5 consecutive treadmill exercise runs. The experiments were performed during stenosis of the circumflex branch of the left coronary artery (LCX). After 2 control runs which had induced regional contractile dysfunction of comparable intensity, alinidine was infused intravenously at a dosage of 1 mg/kg per 5 min. The drug significantly reduced the resting function of both the LCX area (-16%) and the area perfused by the unstenosed anterior descending branch of the left coronary artery (LAD, -3%). However, the exercise-induced dysfunction of the LCX area was markedly improved in the 1st post-drug run and completely abolished during the 2nd and 3rd post-drug runs. As indicated by the reduction of heart rate (-18%) and positive dp/dtmax (-24%) during peak exercise, this improvement may be attributed to a bradycardiac and a negative inotropic effect of this drug. Further benefit may be ascribed to a decreased in arterial blood pressure after alinidine.

A model of transient myocardial dysfunction in conscious dogs: Regional shortening in the presence of impaired coronary flow reserve and treadmill exercise

An experimental model of treadmill exercise-induced regional myocardial dysfunction was developed in conscious dogs to mimic exertional angina pectoris in man. Twenty mongrel dogs, trained to run on a treadmill, were chronically instrumented with a miniature pressure transducer in the left ventricle and a hydraulic occluder placed around the circumflex branch of the left coronary artery. Two pairs of piezoelectric crystals for sonomicrometry were implanted subendocardially to measure regional myocardial function. Experiments were started 1 week after surgery. In the first group of ten dogs exercise with constant work load of 10 km/hr and 10% elevation during partial left coronary artery stenosis, induced by external filling of the occluder, produced comparable episodes of regional dysfunction in the left coronary artery area during five subsequent treadmill runs and recovery of function after each run. The second group of ten dogs, exercised with left coronary artery stenosis and increasing working load, exhibited minimal regional dysfunction in the left coronary artery area while running at 6 km/hr and 6% elevation, but maximal regional dysfunction during peak exercise (10 km/hr and 10% elevation). This load dependency and recovery of function after the runs was demonstrated during five identical consecutive exercise cycles. This model, in contrast to those using ameroid constrictors, enables various drugs to be tested in a single instrumented dog over a period of several weeks.

Holter monitoring in conscious dogs: assessment of arrhythmias occurring during ischemia and in the early reperfusion phase

Myocardial ischemic episodes of 5 min, 15 min, and 4 hr duration, with interposed reperfusion periods, were induced in the same conscious, chronically instrumented dogs. A drop in systolic blood pressure and an increase in heart rate and in the arrhythmic ratio (AR% = number of ectopic beats x 100/total number of beats, as assessed by Holter monitoring) was registered in response to the induction of myocardial ischemia. Reperfusion-induced salvage after coronary occlusion of 5 and 15 min duration was documented by an immediate return of systolic blood pressure, heart rate, and AR to the preocclusion control level. However, after coronary occlusion lasting for 4 hr, reperfusion induced a further drop in blood pressure and an increase in heart rate and in AR. We conclude that in conscious dogs, reperfusion-induced arrhythmias do not occur after short-lasting myocardial ischemic episodes. Reperfusion after long-lasting ischemia induces marked ventricular ectopic activity, yielding an arrhythmic ratio of more than 80%. Although these reperfusion-induced arrhythmias impair the hemodynamic state, they are well tolerated in the conscious dog and can be assessed by the Holter monitoring technique. This new experimental approach promises to be of clinical relevance for investigations on the therapeutic efficacy of new antiarrhythmic drugs.

Holter monitoring in conscious dogs: Assessment of arrhythmias occurring in the late reperfusion phase after coronary occlusion

Arrhythmias occurring in the late reperfusion phase, i.e., up to 3 days after episodes of 5 min, 15 min, and 4 hr of coronary occlusion (CAO), were investigated in six conscious, chronically instrumented dogs using the Holter monitoring technique. The arrhythmic ratio (AR% = number of premature ventricular complexes x 100/total number of beats) of a 24-hr preocclusion control record was 0.004% and did not differ from the values assessed for day 1 (0.004%) and 2 (0.001%) of the late reperfusion phase after 5 min CAO. After 15 min, CAO increased, but insignificantly elevated AR values were registered on days 1 (2.5%), 2 (0.26%), and 3 (0.1%) of the late reperfusion phase. On day 1 of the late reperfusion phase after 4 hr CAO, the AR increased markedly to 75%. On day 2 of this phase, the AR was lower (20%) but still significantly elevated. On day 3, the AR was 3.5%, a value still markedly, although not significantly, above the preocclusion control level. We conclude that in conscious dogs, arrhythmias in the late reperfusion phase do not occur after 5 min CAO. However, after 15 min CAO and, especially, after 4 hr CAO, an increase in arrhythmic activity occurs in the late reperfusion phase and gradually declines towards the preocclusion control level over a period of 3 days. Thus, it could be demonstrated that the long-term assessment of reperfusion arrhythmias by ECG monitoring using the Holter technique is feasible in conscious dogs. This method represents a promising approach to clinically relevant experimental investigations on the therapeutic efficacy of a new antiarrhythmic drugs.

Bepridil abolishes exercise-induced regional contractile dysfunction in dogs

The effects of bepridil, a calcium antagonist, on hemodynamic parameters and regional contractile function were investigated in six dogs trained to submit to five treadmill exercise cycles consisting of 4 min of running and 11 min of recovery. The animals were chronically instrumented with a microtip manometer in the left ventricle, two pairs of piezoelectric crystals for sonomicrometry and a hydraulic occluder around the circumflex branch of the left coronary artery and arterial and venous catheters. Experiments were started 1 week after surgery. After a warming-up exercise the vessel was partly stenosed by external filling of the hydraulic occluder. Stenosis was considered adequate and maintained when hemodynamic and functional parameters were virtually unchanged at rest, but episodes of comparable regional contractile dysfunction of the area perfused by the stenosed artery occurred in response to exercise in five subsequent runs; the same degree of stenosis was used for the experiments with bepridil. After two runs with comparable regional contractile dysfunction bepridil was infused intravenously at a dosage of 2 mg/kg per 5 min. The exercise-induced dysfunction was minimally improved in the 1st post-drug run but completely abolished during the 2nd and 3rd post-drug runs. This marked improvement may be partly attributable to the hemodynamic effects of this drug, namely a diminished increase in heart rate and left ventricular end-diastolic pressure and even a reduction in end-diastolic segment length during exercise. These results support the findings of initial clinical trials and suggest a beneficial effect of bepridil in the treatment of exercise-induced angina pectoris in man.

Further Evidence Against Adenosine-Catecholamine Antagonism In Vivo: Investigations with Treadmill Exercise in Dogs

The coronary dilatory action of adenosine has been known for a long time. This, together with the knowledge of the formation of adenosine in the heart during anoxia, hypoxia, exercise, and stress led to the adenosine hypothesis of coronary blood flow regulation. Since adenosine was shown to abolish or at least to partially reduce the cardiostimulatory effects of isoproterenol in the isolated perfused guinea pig heart, adenosine-catecholamine antagonism was suggested. This antagonism should come into play during sympathetic stimulation and protect the heart from excessive activation. In anesthetized dogs, however, no antagonism between adenosine and isoproterenol was found. To further investigate this proposed antagonism, conscious, chronically instrumented dogs were exercised on a treadmill. Treadmill exercise leads to an increase in heart rate, left ventricular dp/dt, and subendocardial function. Since exercise evokes both sympathetic activation and adenosine formation, cardiac stimulation during exercise should be influenced by drugs which interfere with the action of adenosine if the adenosinecatecholamine antagonistic theory applies. But neither 8-phenyltheophylline, an adenosine receptor antagonist, nor L-homocysteine, which binds adenosine intracellularly, nor hexoben-dine, which enhances the effects of adenosine, had any influence on the exercise-induced increase in heart rate, left ventricular dp/dt or regional subendocardial function. These results confirm data previously obtained in anesthetized dogs and suggest that adenosine-catecholamine antagonism is of no physiological importance in conscious dogs, even during exercise.