Exercise-induced Myocardial Dysfunction Research Articles

Exercise-induced myocardial dysfunction detected by cardiopulmonary exercise testing is associated with increased risk of mortality in major oncological colorectal surgery

BackgroundCardiopulmonary exercise testing (CPET) identifies high-risk patients before major surgery. In addition to using oxygen uptake and ventilatory efficiency to assess functional capacity, CPET can be used to identify underlying myocardial dysfunction through the assessment of the oxygen uptake to heart rate response (oxygen pulse response). We examined the relationship of oxygen pulse response, in combination with other CPET variables and known cardiac risk factors, with mortality after colorectal cancer surgery. MethodsThis work focused on a retrospective cohort study of patients who had CPET and underwent colorectal cancer surgery. The primary outcome was a composite of in-hospital and 30-day mortality. Ventilatory inefficiency (Ve/Vco2>34) and exercise-induced myocardial dysfunction (abnormal oxygen pulse response) were investigated for an association with mortality using bivariable analysis and multivariable Cox regression. ResultsA total of 1214 patients who underwent colorectal cancer surgery were included, and the primary outcome occurred in 26 patients (2.1%). Multivariable Cox regression showed abnormal oxygen pulse response was independently associated with the primary outcome (odds ratio [OR]=2.75; 95% confidence interval [CI], 1.17–6.47). Bivariable analysis showed that Ve/Vco2 >34 was associated with the primary outcome (OR=3.43; 95% CI, 1.47–8.01). Combining Ve/Vco2 >34 and abnormal oxygen pulse response conferred an increased risk for the primary outcome (OR=4.47; 95% CI, 1.62–12.34), compared with Ve/Vco2 >34 and normal oxygen pulse response. ConclusionVentilatory inefficiency and an abnormal oxygen pulse response were independently associated with short- (30-day) and long-term (2-yr) mortality. Oxygen pulse response may provide additional information when considering perioperative risk stratification.

P1497Reversible exercise-induced left ventricular dysfunction in symptomatic patients with previous Takotsubo syndrome - Insights from exercise echocardiography

Abstract Introduction Takotsubo syndrome (TTS) is an acute heart failure syndrome usually associated with rapid and spontaneous recovery of left ventricular (LV) function. However, approximately 10% of patients have persistent symptoms and seek further medical advice. Purpose To determine the cardiovascular haemodynamic and LV contractile response to exercise in these TTS survivors with ongoing symptoms. Methods This was a case-control study of 20 symptomatic patients with previous TTS referred for treadmill exercise echocardiography (EE), and 20 age-, sex- and ethnicity-matched control subjects with normal treadmill EE. Among the TTS group, EE was performed at a median of 8 months (mean 17±21 months) following the index event. Demographic characteristics, resting and EE data were collected. LV ejection fraction (EF) was measured at rest and peak stress. Global longitudinal and circumferential strain (GLS, GCS) were measured at rest. Results All 20 TTS patients were Caucasian postmenopausal females (mean age 63.5±6.6 years). There were no significant differences in body mass index (BMI), resting heart rate (HR) and the prevalence of cardiovascular risk factors compared to controls. Resting systolic and diastolic blood pressure (SBP, DBP) were higher in TTS patients (144±17 mmHg versus 128±18 mmHg, and 81±10 mmHg versus 74±9 mmHg, respectively). A comparative analysis of the resting and stress echo data is given in Table 1. The stress echo data showed similar exercise time and peak HR, but higher peak SBP in TTS patients. TTS patients had blunted contractile response to exercise with lower peak LVEF, ΔLVEF (exercise minus resting EF) and peak wall motion score index (WMSI) compared to controls. Among the 20 TTS patients, 12 had exercise-induced wall motion abnormalities: 6 involved the apical segments and 6 developed global dysfunction. In these 12 patients, the mean ΔLVEF was reduced (4%). In the other 8 patients, the ΔLVEF was 16% and pooled the TTS cohort had blunted contractile response with exercise compared to controls (ΔLVEF 8% vs. 19% in the control group, p=0.001). Table 1 Conclusions Our study shows that symptomatic patients with previous TTS have a blunted contractile response to exercise manifest as reversible apical or global LV dysfunction. These findings might indicate the need for treatment. Further systematic investigation of the therapeutic and prognostic implications of this reversible exercise-induced myocardial dysfunction is needed.

Relationship between Inflammatory Cytokines and Indices of Cardiac Dysfunction following Intense Endurance Exercise

ObjectivesPro-inflammatory cytokines have been noted to increase following exercise but their relationship to exercise-induced cardiac dysfunction has not previously been investigated. We sought to evaluate whether exercise-induced cardiac dysfunction was associated with increases in cytokines, particularly the pro-inflammatory cytokines IL-1β, IL-12p70 and TNFα, which have been most implicated in cardiac pathology.Methods40 well-trained endurance athletes underwent evaluation prior to and immediately following one of four endurance sporting events ranging from 3 to 11 hours duration. Cytokines (IL-1β, IL-6, IL-8, IL-10, IL-12p70 and TNFα) were analyzed by flow cytometry from serum samples collected within 50 minutes of race completion. Cardiac troponin (cTnI) and B-type natriuretic peptide were combined with an echocardiographic assessment of cardiac function, and a composite of cTnI > 0.04 μg/L, BNP increase > 10 ng/L and a decrease in right ventricular ejection (RVEF) > 10% were prospectively defined as evidence of myocardial dysfunction.ResultsRelative to baseline, IL-6 IL-8 and IL-10 increased 8.5-, 2.9-, and 7.1-fold, respectively, P<0.0001. Thirty-one (78%), 19 (48%) and 18 (45%) of the athletes met the pre-specified criteria for significant cTnI, BNP and RVEF changes, respectively. TNFα, IL-12p70 were univariate predictors of ΔRVEF and ΔBNP whilst none of the anti-inflammatory cytokines were significantly associated with these measures. Ten athletes (25%, all athletes competing in the endurance event of longest duration) met criteria for exercise-induced myocardial dysfunction. In these 10 athletes with myocardial dysfunction, as compared to those without, there was significantly greater post-race expression of the pro-inflammatory cytokines IL-12p70 (8.1±3.8pg/ml vs. 2.5±2.6pg/ml, P<0.0001) and TNFα (6.5±3.1pg/ml vs. 2.0±2.5pg/ml, P<0.0001).ConclusionCardiac dysfunction following intense endurance exercise was associated with increased expression of pro-inflammatory cytokines. This does not prove a causal relationship but provides rationale for further investigations into whether inflammation mediates exercise-induced myocardial dysfunction.

Cardiac and renal function in a large cohort of amateur marathon runners

BackgroundParticipation of amateur runners in endurance races continues to increase. Previous studies of marathon runners have raised concerns about exercise-induced myocardial and renal dysfunction and damage. In our pooled analysis, we aimed to characterize changes of cardiac and renal function after marathon running in a large cohort of mostly elderly amateur marathon runners.MethodsA total of 167 participants of the BERLIN-MARATHON (female n = 89, male n = 78; age = 50.3 ± 11.4 years) were included and cardiac and renal function was analyzed prior to, immediately after and 2 weeks following the race by echocardiography and blood tests (including cardiac troponin T, NT-proBNP and cystatin C).ResultsAmong the runners, 58% exhibited a significant increase in cardiac biomarkers after completion of the marathon. Overall, the changes in echocardiographic parameters for systolic or diastolic left and right ventricular function did not indicate relevant myocardial dysfunction. Notably, 30% of all participants showed >25% decrease in cystatin C-estimated glomerular filtration rate (GFR) from baseline directly after the marathon; in 8%, we observed a decline of more than 50%. All cardiac and renal parameters returned to baseline ranges within 2 weeks after the marathon.ConclusionsThe increase in cardiac biomarkers after completing a marathon was not accompanied by relevant cardiac dysfunction as assessed by echocardiography. After the race, a high proportion of runners experienced a decrease in cystatin C-estimated GFR, which is suggestive of transient, exercise-related alteration of renal function. However, we did not observe persistent detrimental effects on renal function.Electronic supplementary materialThe online version of this article (doi:10.1186/s12947-015-0007-6) contains supplementary material, which is available to authorized users.

HBOC Attenuates Intense Exercise-Induced Cardiac Dysfunction

The purpose of this study was to investigate whether hemoglobin-based oxygen carrier (HBOC) could protect the heart from intense exercise-induced myocardial dysfunction. Adult male Sprague-Dawley rats were subjected to 5-h intense prolonged running on treadmill with or without HBOC pre-treatment. Immediately after exercise, the heart rate (HR) and oxygen delivery capacity of the blood were measured. After 1 h of rest, echocardiography was performed to assess the post-exercise cardiac function. Then all the hearts were isolated and perfused using the Langendorff model for 1 h. Our results proved that pronged exercise caused significant LV dysfunction, while HBOC pre-treatment attenuated such a damage, as evidenced by the increased oxygen delivery, cardiac fractional shortening (FS), rate-pressure product (RPP), ± dp/dt and coronary flow rate (CF) and decreased myocardial necrosis. The releases of cardiac enzymes, including creatine kinase-MB (CK-MB) and cardiac troponin-I (cTnI) were markedly reduced. No significant difference of cardiac infarct size was observed among groups. In addition, HBOC significantly elevated superoxide dismutase (SOD) activity and decreased hydrogen peroxide (H2O2) formation, which indicated the exercise-induced cardiac oxidative damage was inhibited. In conclusion, HBOC pre-treatment showed a promising cardioprotective effect on prolonged exercise-induced cardiac dysfunction, which was probably associated with its ability to decrease myocardium oxidative stress.

Cumulative exercise-induced left ventricular systolic and diastolic dysfunction in hypertrophic cardiomyopathy

The phenomenon of cumulative exercise-induced left ventricular function impairment was studied in 40 patients with non-obstructive hypertrophic cardiomyopathy with resting normal left ventricular function and no increase in ejection fraction on exercise. All patients underwent two symptom-limited exercise tests one-hour apart. Cumulative myocardial dysfunction was seen in 13 patients (group I) but not in the remaining 27 patients (group II). During follow-up, group I showed more commonly than group II a deterioration in symptoms (67% vs 22%, P = 0.025) and left ventricular function (50% vs 9%, P = 0.019). In conclusion, cumulative exercise-induced myocardial dysfunction can occur in hypertrophic cardiomyopathy and may be associated with clinical deterioration and worse outcome.

Exercise and pharmacological stress echocardiography in healthy horses

Stress echocardiography could be a useful diagnostic test in horses suspected to suffer from exercise-induced myocardial dysfunction as a cause of exercise intolerance. To evaluate the effect of treadmill exercise and pharmacological stress test on left ventricular echocardiographic parameters. Echocardiography was performed in 2 groups of 5 healthy horses, either immediately after a near-maximal treadmill exercise (Group EXE) or during a pharmacological challenge (Group DOB) consisting of 35 microg/kg atropine, followed by incremental dobutamine infusion rates of 2-6 microg/kg bwt/min for 5 min duration each, which led to a cumulative dobutamine dose of 100 microg/kg. Left ventricular M-mode parameters were compared at rest and at heart rates of 80, 100, 110, 120 130, and 140 beats/min, within each group. In 2 horses of Group EXE, echocardiographic measurements were impossible at 140 and 130 beats/min, as their heart rates dropped too fast in the immediate post exercise period. In the remaining 3 horses image quality was not always satisfactory at heart rates of 130 and 140 beats/min. Systolic left ventricular parameters and fractional shortening measured at 130 and 140 beats/min were significantly different from values obtained at lower heart rates. Horses in Group DOB reached expected heart rates of 80 and 100 beats/min, after the administration of atropine and during a dobutamine infusion rate of 2 microg/kg bwt/min, respectively. Heart rates targets of 110, 120, 130, and 140 beats/min were reached at mean (+/- s.d.) dobutamine infusion rates of 2.8 +/- 0.4, 3.2 +/- 0.4, 4.0 +/- 0.7, 5 +/- 0.7 microg/kg bwt/min, respectively. Systolic left ventricular parameters and fractional shortening at heart rates of 110, 120, 130, and 140 beats/min, were significantly different from values obtained at lower heart rates. The pharmacological stress test induced changes in ventricular dimensions at heart rates of 80 to 140 beats/min. Using this test, high quality images can easily be obtained at heart rates of 140 beats/min. Conversely, in post exercise echocardiography, obtaining good quality images at heart rates of 130 and 140 beats/min is difficult, which limits use of the technique in routine clinical settings. Further studies should demonstrate the potential of pharmacological stress test as a diagnostic tool in horses suffering from exercise-induced myocardial dysfunction.

CIRCULATING SURFACTANT PROTEIN‐B LEVELS INCREASE ACUTELY IN RESPONSE TO EXERCISE‐INDUCED LEFT VENTRICULAR DYSFUNCTION

1. As a result of its enormous surface area and necessary thinness for gas exchange, the alveolocapillary barrier is vulnerable to mechanical disruption from raised pulmonary microvascular pressure (Pmv). 2. Because surfactant protein-B (SP-B) leaks into the blood stream from the alveoli in response to alveolocapillary barrier damage and exercise leads to increased Pmv, we sought to determine whether exercise results in increased plasma SP-B. Moreover, in the setting of exercise-induced left ventricular dysfunction, the consequent increase in left heart filling pressure and, therefore, P(mv) would be expected to further increase plasma SP-B levels. 3. Twenty consecutive subjects referred for treadmill exercise stress echocardiography (ESE) had venous blood sampled immediately before and after ESE for batch atrial natriuretic peptide (ANP) and SP-B assay. Echocardiographic measures of pulmonary haemodynamics (pulmonary artery flow acceleration time (pafAT) and right ventricular outflow tract velocity time integral (rVTI)) were also taken pre- and post-exercise. 4. Although circulating ANP levels increased following exercise (P < 0.001), there was no change in circulating SP-B levels in the entire cohort. 5. Ten subjects had a positive ESE for ventricular dysfunction. Although circulating ANP was increased post-exercise in both the negative and positive ESE groups (P < 0.05 and P < 0.01, respectively), circulating SP-B only increased post-exercise in the positive ESE group (P < 0.05). Echocardiographic parameters supported an increment in P(mv) in the cohort with exercise-induced left ventricular dysfunction because this group had an increase in pafAT (P < 0.05; reflecting pulmonary artery pressure) and no change in rVTI. 6. Physical exertion associated with a Bruce protocol ESE is insufficient to increase circulating SP-B, despite evidence of increased left atrial and pulmonary vascular pressure. However, in the setting of exercise-induced myocardial dysfunction, there is a detectable increase in circulating SP-B. 7. The exaggerated increase in pulmonary vascular pressure in exercise-induced myocardial dysfunction may result in increased SP-B leakage from the alveoli into the circulation by altering the integrity of the alveolocapillary barrier to protein.

Usefulness of gated myocardial perfusion SPECT imaging soon after exercise to identify postexercise stunning in patients with single-vessel coronary artery disease

This study determines the value of gated single photon emission computed tomography (SPECT) imaging soon after exercise to identify patients with single-vessel disease and exercise-induced prolonged myocardial dysfunction (ie, postischemic stunning). We examined 19 normal individuals and 52 patients with single-vessel disease by use of 2-day technetium 99m tetrofosmin exercise/rest gated SPECT imaging. Sequential imaging was started 10, 30, and 50 minutes after exercise. The ejection fraction (EF) values were calculated with the Cedars-Sinai program. The participants were classified as follows: group A (normal individuals, n = 19), group B (individuals with coronary stenosis without Q-wave infarction, n = 18), group C (individuals with Q-wave infarction without myocardial ischemia, n = 15), and group D (individuals with Q-wave infarction and ischemia, n = 19). The post-stress EF values at 10 minutes (69.8% +/- 9.6% and 59.8% +/- 11.8%, respectively) were higher in groups A and C than those at 30 minutes (67.6% +/- 10.2% and 57.2% +/- 11.3%, respectively) ( P < .05) but were lower in group B (61.7% +/- 9.2%) than both the 30- and 50-minute values (64.2% +/- 9.5% and 64.6% +/- 9.4%, respectively; P < .05). The EF value did not significantly change in group D. Tc-99m gated SPECT imaging soon after exercise is superior to conventional late imaging to discriminate patients with single-vessel disease and postexercise stunning.

Exercise-induced myocardial dysfunction in patients with coronary artery disease with and without angina

Left ventricular dysfunction during exercise is considered a relatively sensitive marker of ischemia in patients with coronary artery disease. The purpose of this study was to determine whether exercise-induced myocardial dysfunction was more severe in patients with angina than in patients with ischemia without angina. Seventy-seven patients with angiographically documented coronary artery disease and an abnormal left ventricular response to exercise were studied by means of gated blood pool imaging. The arteriographic and functional parameters of 24 patients with angina during exercise testing were compared with those of 53 patients who were pain free at the time of the test. Both groups were similar with regard to rate of multivessel disease (50% vs 51%, p = NS) and prior myocardial infarction (46% vs 51%, p = NS), as well as age, sex, and history of angina. Mean global ejection fraction remained unchanged (but abnormal) in both groups of patients during exercise. Furthermore, evidence of new regional asynergy during exercise assessed by a five-point scoring system was found to be equally abnormal in the two groups. Results of this study suggest that the severity of exercise-induced global and regional left ventricular dysfunction is independent of the presence or absence of angina during exercise testing.

Cardiac and Hemodynamic Effects of Diltiazem During Exercise-Induced Myocardial Dysfunction in Dogs

The effects of diltiazem were tested in chronically instrumented dogs in a model of exercise-induced myocardial dysfunction. Since various bradycardiac agents have beneficial effects on myocardial function during ischemia, it was of interest to find out how a decrease in afterload, possibly combined with a decrease in myocardial oxygen demand, influences dysfunction. Therefore, diltiazem (1 mg/kg i.v.) was tested during critical stenosis of the circumflex branch of the left coronary artery, which led to exercise-induced myocardial dysfunction. At rest, diltiazem causes a reflex increase in heart rate. During exercise, a decrease in heart rate and hence in myocardial oxygen demand was neutralized by a decrease in arterial blood pressure and hence a lowered myocardial perfusion pressure. Therefore, systolic shortening in the ischemic area improved neither at rest nor during exercise after diltiazem.

Cardiac and hemodynamic effects of the selective bradycardic agent KC 8857 during exercise-induced myocardial ischemia

The effects of an in vitro bradycardic agent without negative inotropism, KC 8857 (3,7-di-(cyclopropylmethyl)-9,9-tetramethylene-3, 7-diazabicyclo-[3.3.1]-nonane dihydrochloride), were tested in chronically instrumented dogs in a model of exercise-induced myocardial ischemia. KC 8857 was i.v. infused during critical stenosis of the circumflex branch of the left coronary artery which led to exercise-induced myocardial dysfunction. KC 8857 caused a decrease in heart rate, left ventricular dp/dt max and calculated myocardial oxygen demand at rest and during exercise. Since positive dp/dt max values at a given heart rate were not altered by KC 8857 it may be assumed that myocardial function was restored mainly by the decrease in heart rate.

The effects of nitroglycerin on exercise-induced regional myocardial contractile dysfunction are not diminished by pretreatment with dihydroergotamine.

1 Because controversy exists regarding the effects of dihydroergotamine (DHE) on the performance of underperfused myocardium, the effects of DHE were investigated in a model of exercise-induced regional myocardial dysfunction in conscious dogs. 2 We also investigated a possible functional antagonism between DHE and nitroglycerin that might reduce the latter drug's antianginal efficacy. 3 Investigations were carried out in conscious dogs. After stenosis of the circumflex branch of the left coronary artery that minimally affected resting myocardial function, treadmill exercise induced transient regional contractile dysfunction. Heart rate, arterial blood pressure, left ventricular dp/dtmax and left ventricular end-diastolic pressure were registered. Regional contractile performance was assessed by ultrasonic distance measurement in the underperfused and in a normally perfused area. 4 DHE (5 micrograms kg-1, i.v.) induced a decrease in left ventricular dp/dtmax at rest and during exercise. DHE did not cause a deterioration in contractile function in the ischaemic myocardium, but led to a slight although not significant improvement in regional myocardial function. 5 After pretreatment with DHE, infusion of nitroglycerin (15 micrograms kg-1, i.v.) induced an improvement in the underperfused myocardial area during treadmill exercise, accompanied by a decrease in diastolic arterial pressure and left ventricular end-diastolic pressure and an increase in left ventricular dp/dtmax. 6 These results suggest that DHE will not worsen exercise-induced angina pectoris, and that the antianginal efficacy of nitroglycerin will not be neutralized by pretreatment with DHE.

Significance of abnormal blood pressure response during exercise-induced myocardial dysfunction after recent acute myocardial infarction

The relation between exercise left ventricular ejection fraction and blood pressure (BP) responses after an acute myocardial infarction (AMI) was investigated. Twenty-eight to 37 days after an uncomplicated AMI, 224 consecutive patients underwent exercise radionuclide angiography in the 40 ° semisupine position. In 180 patients (group A, 80%), BP increased more than 5 mm Hg every stage; in 44 patients, BP responses were abnormal; in 33 (group B, 15%), BP did not increase during 2 stages; in 11 (group C, 5%), it decreased more than 5 mm Hg after an initial increase. Ejection fraction did not differ significantly among the 3 groups at rest (51 ± 13 in group A, 50 ± 18 in group B, 47 ± 13 in group C [difference not significant]) or at peak exercise (51 ± 16% in group A, 46 ± 19% in group B, and 43 ± 16% in group C, [difference not significant]). Exercise-induced left ventricular failure or hemodynamic decompensation occurred in 22 patients. In these patients, ejection fraction at rest was 44 ± 19% and decreased to 35 ± 16% (p < 0.05) with exercise. Only 9 of these patients (41 %) had abnormal BP responses, with the other 13 (59%) showing a normal BP response. The 35 patients with abnormal BP responses in the absence of hemodynamic decompensation were asymptomatic, terminating exercise because of fatigue. The ejection fraction at rest and during exercise in these patients was similar to that in patients with normal BP responses. Thus, after a recent AMI, abnormal BP responses during exercise associated with clinical evidence of hemodynamic decompensation are related to myocardial dysfunction. However, in the absence of symptoms, such abnormal BP responses are not related to severity of left ventricular dysfunction, and in some patients may be ascribed to exertional reduction in systemic resistance.

Mechanism of beneficial effect of beta-adrenergic blockade on exercise-induced myocardial ischemia in conscious dogs.

We examined the importance of decreased heart rate in the beneficial effect of beta-adrenergic blockade on exercise-induced regional myocardial ischemia and contractile dysfunction in conscious dogs with single vessel coronary stenosis (ameroid constrictor). Studies were performed during control treadmill exercise, which produced regional myocardial ischemia (blood flow measured with microspheres) and wall dysfunction (measured using sonomicrometers). A second run was performed after the administration of atenolol (0.3-1.0 mg/kg i.v.), and the reduced heart rate caused by atenolol during early steady-state running was then prevented by atrial pacing during the latter portion of the run. Atenolol reduced the exercise heart rate from 217 +/- 25 beats per minute (SD, n = 9) to 166 +/- 15, and ischemic zone wall thickening during systole improved from 27 +/- 22% of the resting value in the control run to 50 +/- 25% of the resting value in the atenolol run (p less than 0.01). Atrial pacing then increased heart rate to 217 +/- 23 beats per minute, and regional wall thickening deteriorated to 15 +/- 25% of the resting value. Regional subendocardial blood flow in the ischemic zone during atrial pacing with atenolol was slightly less than that observed in the control run, in both ischemic and control zones, indicating no remaining beneficial effect of atenolol when heart rate reduction was eliminated. We conclude that the only significant mechanism for the improvement in exercise-induced ischemia and wall motion produced by atenolol is a reduction in the exercise heart rate.(ABSTRACT TRUNCATED AT 250 WORDS)

Elimination of exercise-induced regional myocardial dysfunction by a bradycardiac agent in dogs with chronic coronary stenosis.

We have previously demonstrated that the beneficial effect of cardioselective beta-blockade on exercise-induced ischemia is due entirely to negative chronotropism. Therefore we studied the effect of a new bradycardiac agent (UL-FS 49) in 10 dogs with chronic coronary artery stenosis produced by an ameroid constrictor. Regional myocardial function (sonomicrometers, wall thickness) and blood flow (microspheres) were measured during a control treadmill exercise bout and an identical run 3 hr later after the administration of UL-FS 49 (1.0 mg/kg iv). In the control run, heart rate increased from 114 +/- 20 to 230 +/- 19 beats/min and systolic wall thickening (%WT) in the poststenotic myocardium decreased from 23.3 +/- 5.2% at rest to 9.3 +/- 5.0%, a 60% reduction. Subendocardial blood flow in the ischemic area decreased from 1.04 +/- 0.30 to 0.55 +/- 0.40 ml/min/g, blood flow per beat decreased from 9.1 X 10(-3) to 2.5 X 10(-3) ml/g, and mean transmural flow failed to increase (1.06 +/- 0.30 vs 1.08 +/- 0.39 ml/min/g). During exercise with UL-FS 49, heart rate increased from 89 +/- 10 to only 139 +/- 10 beats/min. End-diastolic left ventricular pressure was increased compared with that during the control run (35.7 +/- 3.0 vs 28.9 +/- 5.5 mm Hg) but left ventricular peak systolic pressure and dP/dt were unchanged. %WT in the ischemic zone did not change significantly during exercise with UL-FS 49 (23.3 +/- 7.9% at rest, 21.5 +/- 8.4% during the run), and in the nonischemic zone it increased to the same extent as during the control run.(ABSTRACT TRUNCATED AT 250 WORDS)

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 submit 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 dt max 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.

PROPRANOLOL AMELIORATES EXERCISE‐INDUCED REGIONAL MYOCARDIAL DYSFUNCTION IN DOGS

The effects of propranolol (0.5 mg/kg) on exercise-induced regional myocardial dysfunction were investigated in an animal model with limited coronary reserve. Limited coronary reserve was accomplished in conscious, chronically instrumented dogs by external filling of a hydraulic cuff occluder placed on a coronary vessel which did not impair resting myocardial function but induced severe dysfunction during treadmill exercise. Propranolol led to a distinct reduction of heart rate, myocardial contractility and systolic blood pressure, thereby ameliorating exercise-induced regional myocardial dysfunction.

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

Propranolol (0.5 mg X kg-1 X 5 min-1), alinidine (1 mg X kg-1 X 5 min-1) and the benzazepinon UL-FS 49 (0.5 mg X kg-1 X 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 branch of the left coronary artery. All three drugs abolished exercise-induced regional contractile dysfunction. Propranolol and alinidine comparably decreased heart rate and positive dp/dtmax during exercise. UL-FS 49 showed a marked negative chronotropic effect without affecting positive dp/dtmax. Thus, prevention of exercise-induced regional contractile dysfunction has been shown for the first time using a selective bradycardic agent.

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.