Effect of norepinephrine on coronary hemodynamics in coronary stenotic canine model

The effect of intracoronary injection of 1μ norepinephrine was assessed in 14 open-chest dogs anesthetized with alpha chloralose. Studies were performed before and after partial coronary artery constriction by a circumferential snare. Aortic pressure, coronary pressure distal to the stenosis, and coronary flow were monitored before and after injection of norepinephrine. Calculated values were stenotic resistance and distal coronary resistance. Before coronary constriction, norepinephrine resulted in an early minimal increase in coronary flow and decrease in distal coronary resistance with prompt return to control values. In contrast with high grade coronary constriction, at 15 seconds after norepinephrine coronary flow decreased (29.8 ± 3.4 to 22.9 ± 3.6 ml./minute) (p < 0.05), coronary pressure decreased (58.8 ± 1.3 to 28.8 ± 2.6 mm. Hg) (p < 0.05), and stenotic resistance increased (2.04 ± 0.26 to 4.25 ± 2.66 mm. Hg/ml. min.^?1) (p < 0.05) without change in heart rate or aortic pressure. These changes persisted over a two minute period of observation following norepinephrine. In the stenotic model the decrease in coronary pressure and coronary flow and increase in stenotic resistance were blocked by pretreatment with propranolol but not by phenoxybenzamine. Administration of isoproterenol resulted in changes similar to those induced by norepinephrine in the stenotic model. Simulation of alteration of peripheral resistance in an in vitro model demonstrated that with a high initial stenotic resistance, a decrease in peripheral resistance resulted in an increase in stenotic resistance. We conclude that the decrease in coronary pressure following norepinephrine was mediated by beta₁ or beta₂ adrenergic stimulation. We further postulate that the decreased coronary flow and increased stenotic resistance were caused by a passive decrease in radius at the stenotic site.     

Coexisting ventricular and blocked atrial parasystole.

A rare instance showing non-conducted atrial parasystole coexisting with ventricular parasystole is presented and a related subject is briefly discussed. The importance of recognizing parasystole is again emphasized because the ordinary extrasystoles, particularly ventricular in origin, are frequently digitalis-induced, while parasystole, which superficially resembles the ordinary extrasystoles, does not seem to be related to digitalis.     

Clinical implication of surface morphology of ventricular premature contractions

VPC morphology was studied in the surface 12-lead ECGs (resting) in one hundred and thirty-six patients over a nine-month period (January–September, 1978). Seventy four (54%) of these had coronary artery disease proven by cardiac catheterization (61) or by evidence of acute transmural myocardial infarction (13) diagnosed by ECG and serum enzyme study. Twenty-three of the patients (17%) had other organic heart diseases documented by cardiac catheterization. The remaining thirty-nine (29%) were healthy individuals.Three common types of VPCs are recognized as right, left and septal in origin. There is no significant difference in the prevalence of these types in the presence of heart disease (right, 35%, left 31%, and septal 34%). However, if septal VPCs are considered along with left VPCs, these are twice as common as right VPCs. VPCs occurring in healthy individuals are overwhelmingly (74%) right ventricular in origin.In general, VPCs are most likely to occur in the presence of ventricular dyssynergy and multiple coronary arterial lesions.     

Captopril in severe treatment-resistant hypertension

The blood pressure of the majority of hypertensive patients can be controlled by sodium restriction and by one or at most two antihypertensive drugs. When the blood pressure does not respond, a widely recommended three-drug regimen is an oral diuretic, propranolol and hydralazine.¹⁰ Our 16 patients had essential and renovascular hypertension and were refractory to all previous therapy. The majority had end-organ manifestations of severe hypertension such as left ventricular hypertrophy, renal impairment, retinopathy and neurologic sequelae. When they were placed on STT, their blood pressure remained uncontrolled (SDBP > 100 mm. Hg). Because of the resistance of their blood pressure to STT, all our patients were ultimately switched to captopril in an effort to achieve better control.According to the protocol, patients were hospitalized after stopping STT the night before. Captopril was started in a dose of 25 mg. and increased according to the response. After the first dose, no patient had a symptomatic hypotensive response though one patient's SDBP did fall $\text{60}\text{30}$ mm. Hg. The maximum response to the initial dose usually occurred by 30 minutes, rapid for an oral medication. This initial response was often greater than the response to subsequent doses, most likely due to the residual effects of STT. It is controversial as to whether the pretreatment PRA is a predictor of the response to captopril.^{7, 12} In our study, it was not possible to determine PRA unifluenced by drugs on a controlled sodium intake because of the severity of the hypertension. PRA increased after captopril, a response consistent with interruption of negative feedback inhibition of renin release.¹³As a group, the patients' blood pressure on captopril alone approximated that on STT, but no one was adequately controlled. The addition of a diuretic enhanced the effectiveness of captopril and in six of the 16 patients it resulted in satisfactory blood pressure control. Several of these patients who had hypertension in association with renal artery stenosis, howeve, manifested an upright tachycardia. Worsening of angina pectoris occurred in one man and he and another woman developed subendocardial myocardial infarctions; the role of the tachycardia in the precipitation of these events is unclear. Nonetheless, diuretic-induced volume depletion with blockade of the renin-angiotensin system by captopril may cause standing tachycardia, which may constitute a problem in patients with compromised coronary or cerebral circulation.In this regard, two of the eight patients in Group 2, though well controlled on captopril and diuretic, had propranolol added in small doses (40 mg./day) to control symptomatic standing tachycardia. In the other six patients in this group, blood pressure was normalized by this new three-drug regimen and the regimen was well tolerated. Two patients (Group 3) could not be controlled even with this regimen, and were considered treatment failures. It is of interest that propranolol produced additional blood pressure lowering in the presence of captopril, which supports a hypotensive action of propranolol not due wholly to blockade of renin release.¹⁴In general, captopril was well tolerated; a number of patients remarked how much better they felt on captopril as compared to their previous regimens, especially with regard to central side effects. Five patients manifested a maculopapular and pruritic rash, but in only one did discontinuation of captopril prove necessary. In three patients, the rash disappeared in 7 to 10 days with only a temporary reduction of captopril dosage. Two men developed a loss of taste which similarly resolved despite continuation of captopril. No other adverse effects have been noted in our patients. Renal function was maintained, as serum creatinine did not change during the study. Captopril-induced proteinuria has been reported since the start of our study,¹⁵ but could not be documented retrospectively in our patients. However, continued surveillance of captopril's side effects, especially proteinuria, is necessary.In summary, in our three month trial, captopril appears to provide a useful and important alternative for the management of severe, refractory hypertension. Its mechanism of action seems to be ideal for such patients in whom the renin-angiotensin system appears to play an important role. Although alone it was insufficient to adequately control the blood pressure in our severely hypertensive patients, its combination with a diuretic or a diuretic and a beta-blocker often provided an effective and well-tolerated combination. Nevertheless, even with the latter three-drug combination, there were two treatment failures. Adverse effects such as skin rash, which occurred in 30% of our patients, and loss of taste, do not seem to seriously limit the use of the drug. The development of a sustained standing tachycardia when a diuretic is added to captopril may be harmful in some patients with a compromised cardiovascular system and requires careful consideration before treatment. Addition of low doses of beta-adrenergic blocking agents, if not contraindicated, will control these heart rate increases. The benefits and hazards of long-term captopril therapy in severe hypertension requires further assessment.     

Stabilization of cardiac lysosomal and cellular membranes in protection of ischemic myocardium due to coronary occlusion: Efficacy of the nonsteroidal antiinflammatory agent,naproxen

The combined cellular membrane stabilizing and prostaglandin-inhibiting agent, naproxen, administered either 30 minutes before of after left coronary occlusion, induced significant preservation of the acutely ischemic experimental animal myocardium. A consistent extent of myocardial protection was provided as measured by ST segment elevation, plasma accumulation of CK activity, tissue CK activities, and amino-nitrogen concentrations, and ultrastructural integrity. Protection did not appear to be via hemodynamic mechanisms since naproxen neither altered pressure-rate product nor decreased coronary resistance. While the degree that inhibition of platelet throm?ane A₂ generation contributes to these salutary results requires clarification due to possible simultaneous decrease of coronary endothelial PGI₂ formation, the present study emphasizes the value of the concomitant special lysosomal and cellular stabilizing actions of naproxen. In contrast to acetylsalicylic acid, meciofenamate, and indomethacin which do not effect such benefit in the same experimental conditions, our results indicate that naproxen resembles the nonsteroidal anti-inflammatory agents which also possess membrane stabilizing properties, such as ibuprofen and flurbiprofen, and protects ischemic myocardium in similar adverse circumstances.     

Myocardial infarction without obstructive coronary artery disease

The present report describes five cases of transmural myocardial infarction occurring in patients without occlusive coronary artery disease or other discernible abnormalities. It is apparent from these cases and others described in the literature that such patients may present with or without angina and, in some, the clinical course will be complicated by recurrent infarction and/or significant residual myocardial dysfunction. At present the exact incidence and natural history of this syndrome is unclear. Undoubtedly the increasing application of coronary arteriography will identify many more such patients. Delineation of the genesis and the full clinical spectrum of myocardial infarction without coronary artery disease warrants further investigative attention.     

Monitoring tissue oxygenation of the heart after myocardial revascularization.

A polarographic technique capable of simultaneous monitoring of myocardial tissue oxygen tension (MPO2) and intramyocardial electrograms by way of the same electrodes has been developed. Initially, the method was evaluated in dogs to verify the appropriateness of the directional changes of MPO2 in function of selected determinants of myocardial oxygen supply (regional coronary blood flow, arterial blood oxygen tension) and demand (heart rate, force of ventricular contraction). A combined reduction of MPO2 and elevation of the S-T segment in the corresponding electrograms was observed only when a 50 percent or greater reduction of blood flow to the sampled area was effected. Subsequently, in nine patients undergoing aortocoronary bypass surgery, MPO2 was measured from 48 areas for 2 weeks postoperatively. In 11 normal and 31 revascularized areas, MPO2 increased during the postoperative period. In four areas subsequently found to be supplied by occluded grafts MPO2 decreased from 12.7 +/- 3.1 (mean +/- standard error) to 10.1 +/- 3.3 mm Hg (P less than 0.05). In two areas, MPO2 decreased during the 3rd postoperative day from 16 to 3 and from 14 to 4.2 mm Hg, respectively. This reduction was attended by a significant rise in the S-T segment of the corresponding electrograms. This finding preceded by 24 hours standard electrocardiographic evidence of myocardial infarction. This technique appears to be sensitive and reliable, and thereby capable of enhancing the management of patients during the high risk early postoperative period after coronary bypass surgery.     

Review: Electrolyte and antiarrhythmic drug interaction

When one considers the complex interaction of antiarrhythmic drugs, either among the various groups or in the presence of altered electrolytes, the number of possible antagonistic and synergistic actions becomes almost infinite. This overview has attempted to amalgamate present information concerning drug and electrolyte interactions. Fortunately, in the clinical setting one is usually operating within the physiologic range for serum electrolytes, and many of these alterations shown in laboratory studies may not be pertinent. It should be remembered, however, that when serum electrolyte derangements are present, the usual or expected effects of antiarrhythmic drugs may be masked, leading to erroneous therapy or to the conclusion that the therapy is either inadequate or useless.This summary also points out that marked beneficial effects can be achieved, particularly by the use of digitalis and propranolol, in slowing AV conduction in the presence of supraventricular arrhythmias and that low potassium completely nullifies the action of the quinidine-like or Group 1 agents.The antagonism of bretylium to quinidine-like agents should alert the clinician to the possibility that the administration of Group 1 drugs in the wake of Group 3 or possibly other antiarrhythmic drugs may either nullify or aggravate certain pharmacologic actions. Although it is true that quinidine, lidocaine, and procainamide can be used with increased efficacy in the presence of propranolol, the opposite may be true when they are used in the presence of bretylium. Precise monitoring of serum electrolytes would appear essential before and during antiarrhythmic drug therapy.     

Effects of dexamethasone on myocardial cells in the early phase of acute myocardial infarction.

Dexamethasone exerted no significant hemodynamic effect in sham-operated cats or in cats subjected to acute myocardial ischemia. However, the glucoccortcoid did normalize elevated S-T segments toward pre-ischemic values, and prevented much of the increase in plasma CPK activity following coronary artery ligation. Moreover, dexamethasone prevented loss of CPK activity and restricted the loss of lysosomal hydrolase within ischemic myocardial tissue. These data indicate that lysosomal disruption is an early consequence of myocardial ischemia and that treatment with dexamethasone prevents the loss of myocardial lysosomal and cellular enzymes as reflected in normalization of the ECG and plasma CPK activity of ischemic cats. In this way, dexamethasone may act to retard the spread of the developing infarct within the ischemic myocardium.     

Reperfusion arrhythmia: a marker of restoration of antegrade flow during intracoronary thrombolysis for acute myocardial infarction

We studied the effects of coronary recanalization on arrhythmogenesis in patients undergoing intracoronary thrombolysis during the early hours of myocardial infarction. Catheterization, ventriculography, coronary angiography, and intracoronary streptokinase infusion were performed in 22 patients. Twenty-one of 22 had thrombotic total occlusion of the infarct-related transient thrombolysis with reocclusion by the end of the procedure. In 12 of these 17 patients, restoration of antegrade coronary flow was accompanied by transient arrhythmia. In these 12 patients coronary angiography within seconds of onset of arrhythmia showed vessel patency in a previously totally occluded coronary artery. Two additional patients developed arrhythmias during streptokinase infusion but after reperfusion had already been established. Accelerated idioventricular rhythm was most often noted. Sinus bradycardia and atrioventricular block with hypotension occurred during restoration of flow in arteries supplying the inferoposterior left ventricle. These arrhythmias may be useful noninvasive markers of successful reperfusion during thrombolytic therapy in acute myocardial infarction.     

Isolated ultrafiltration in the therapy of volume overload accompanying oliguric vascular shock states.

Isolated ultrafiltration (removal of plasma water and solute without dialysis) was used as a "last resort" therapy in three patients with diuretic and pressor resistant oliguria complicating severe volume overload and vascular shock. The improvement in clinical and hemodynamic parameters is reported and the possible mechanisms of action (decreased pulmonary capillary wedge pressure and increased colloid osmotic pressure) are discussed.     

Reperfusion ventricular tachyarrhythmias: Correlation with antecedent coronary artery occlusion tachyarrhythmias and duration of myocardial ischemia

The incidence and severity of reperfusion ventricular tachyarrhythmias were correlated with: (1) the duration of antecedent acute coronary artery occlusion and (2) the incidence, severity, and time course of ventricular tachyarrhythmias occurring during the antecedent period of coronary occlusion in 98 dogs studied postligation for 5 to 60 minutes. The incidence of reperfusion ventricular fibrillation (VF) increased significantly as coronary artery ligation periods were lengthened from 5 minutes to either 20 minutes (2 of 19 dogs vs 12 of 18 dogs,p < 0.001) or 30 minutes (16 of 24,p < 0.001), but notably decreased when reperfusion was delayed further from 30 minutes to 60 minutes after coronary artery ligation (4 of 18 dogs,p < 0.001). Seven dogs were resuscitated from VF during coronary ligation and all seven suffered VF on reperfusion, whereas 37 dogs were arrhythmia-free during ligation and only one (3%,p < 0.001) had VF on reperfusion, in addition, reperfusion ventricular tachyarrhythmias correlated with the occurrence of both immediate ventricular tachyarrhythmias (those peaking at 5 to 6 minutes postligation) and delayed ventricular tachyarrhythmias (those peaking at 18 minutes' postligation) of the antecedent acute ligation period. These observations provide a further basis for improved clinical understanding and management of potentially malignant tachyarrhythmias consequent to early myocardial reperfusion following acute myocardial ischemia and infarction.     

Correlation between changes in R wave amplitude and left ventricular volume induced by rapid atrial pacing

To examine the Brody effect in humans, we studied 15 patients by means of coronary sinus pacing. We measured left ventricular (LV) volumes from the cardiac output (measured by the thermodilution technique) and LV ejection fraction (measured by radionuclide ventriculography). Pulmonary blood volume was determined by means of cardiac output and mean pulmonary transit time. In six patients, pacing was performed at two different rates, resulting in 21 pacing measurements. The heart rate increased with pacing from 73 ± 11 to 119 ± 19 bpm (mean ± standard deviation, p < 0.001). The end-diastolic volume (EDV) and the end-systolic volume (ESV) decreased with pacing (p < 0.001 each). The R wave amplitude decreased with pacing (1.44 ± 0.63 mV control vs 1.32 ± 0.58 mV with pacing; p < 0.01). R wave amplitude decreased in 19 of the 21 pacing studies (90%); EDV and ESV decreased in all 21 pacing studies, and pulmonary blood volume decreased in 14 of the 15 pacing studies (93%) performed in 11 patients. There was a significant correlation between the percentage of change in R wave amplitude with the percentage of change in EDV (r = 0.54, p < 0.01) and with the percentage of change in ESV (r = 0.54, p < 0.01). These results, therefore, validate Brody's hypothesis and indicate that changes in LV volumes affect the R wave amplitude.     

Cross-sectional echocardiographic spectrum of papillary muscle dysfunction.

Cross-sectional echocardiography identified two abnormal patterns of mitral valve closure in 14 patients with mitral regurgitation due to papillary muscle dysfunction: (1) in three patients with an akinetic inferior-posterior wall but normal cavity size, papillary muscle fibrosis was associated with late systolic mitral valve prolapse, and (2) in nine patients with ventricular dilatation or ventricular aneurysm, the point of mitral valve coaptation was displaced towards the apex of the left ventricle. In two of these patients both abnormalities were observed. In contrast, abnormal patterns were identified in only four of a group of 40 patients without angiographic evidence of mitral regurgitation (10, normal; 27, coronary artery disease; three, congestive cardiomyopathy). Thus, cross-sectional echocardiography can be useful to identify mitral regurgitation secondary to papillary muscle dysfunction.     

Angina pectoris and coronary artery disease in patients with severe aortic valvular disease

We studied the clinical, hemodynamic, and angiographic findings of 90 consecutive patients with significant symptomatic aortic valve disease, 40 years of age or older, to evaluate the prevalence of angina pectoris in relation to coronary artery disease and the effect upon cardiac function.The prevalence of chest pain was 66% (typical angina, 39%; atypical chest pain, 27%), and the prevalence of coronary artery disease was 39%. The prevalence of coronary artery disease in patients with typical angina was 77%, in contrast to 25% in patients with atypical chest pain $\text{(}\text{P}\text{= 0.001)}$. Only two of the 35 patients (6%) with coronary artery disease were free of chest pain. Although the incidence of coronary artery disease in patients with aortic stenosis was slightly higher than in patients with aortic regurgitation or aortic stenosis-aortic regurgitation, it was not statistically significant.Patients with aortic regurgitation and coronary artery disease had significantly lower ejection fraction than patients with aortic stenosis and coronary artery disease. There were no significant differences between ejection fraction in patients without coronary artery disease in the different groups. Patients with aortic stenosis and coronary artery disease tend to have lower mean pressure gradients than those without coronary artery disease. Patients with coronary artery disease in aortic regurgitation and aortic stenosis-aortic regurgitation tend to have higher left ventricular end-diastolic pressure.This study indicates that although patients with aortic valve disease and typical angina are most likely to have associated coronary artery disease, it is not possible to predict this disorder with accuracy by means of clinical or hemodynamic findings.Since the presence or absence of coronary artery disease in patients undergoing aortic valve replacement has prognostic and therapeutic significance, we recommend that coronary arteriography be performed in all patients with significant aortic valve disease undergoing cardiac catheterization when they present with any form of chest pain, or in patients over the age of 40 years even if no chest pain is present. Coronary arteriography would also rule out anomalous aortic origin of the coronary arteries.