Costas T. Lambrew

Idiopathic Hypertrophic Subaortic Stenosis: I. A Description of the Disease Based Upon an Analysis of 64 Patients

Idiopathic hypertrophic subaortic stenosis (IHSS) is a disease characterized by marked hypertrophy of the left ventricle, involving in particular the interventricular septum and the left ventricular outflow tract. During systole, the hypertrophied muscle in the outflow tract often narrows this region sufficiently to produce obstruction to left ventricular ejection. Although the reports of Schmincke and of Bernheim early in this century indicate that IHSS has been recognized for many years, particular attention has been directed to the disease only during the last 7 years.In most instances left ventricular hypertrophy is asymmetric, but occasionally it is diffuse and the lumen of the outflow tract is reduced by the concentrically hypertrophied muscle. Marked enlargement of the papillary muscles and of the trabeculae carneae, deformation of the mitral valve by the thickened ventricular septum, and thickening of the anterior mitral leaflet are commonly noted. In many hearts the hypertrophied septum bulges into the right ventricular outflow tract as well as into the left.On microscopic examination, the muscle bundles in the left ventricle are often arranged in a bizarre fashion and are separated by clefts. Individual muscle fibers obtained from the left ventricle are often greatly thickened, but tend to be shorter than normal. There is an increase in the size and numberof nerve fibrils and in the quantity of fluorescent material, presumably norepinephrine, in the affected muscle.Of the 64 patients with IHSS on which the present report is based, 67% were males and 33% were females. The patients with the familial form of the disease were distributed approximately equally between the 2 sexes. On the other hand, in the patients without a family history, 78% were males and only 22% were females. The average age was 25.7 years; the female patients were significantly older than the males. The discovery of a heart murmur was usually the first clinical manifestation of the disease. From a consideration of our patients, as well as those reported in the literature, it is evident that clinical findings may or may not be present at birth or in early childhood. The finding of a murmur before the age of 1 year in 9 of the 64 patients, and the reports of IHSS in a stillborn baby and in several infants, as well as the association of IHSS with congenital cardiac malformations, all support the concept that the disease may, at least in some instances, be congenital. On the other hand, in 20 of the 64 patients at least 1 detailed examination revealed no evidence of a heart murmur prior to the eventual discovery of the murmur, and in them it appears likely that many of the manifestations of the disease were acquired.Forty-eight of the 64 patients with IHSS were symptomatic, the most common symptoms being dyspnea, angina, dizziness and syncope. Although others have commented upon the absence of the clinical findings of congestive heart failure, clear evidence of cardiac decompensation was present in 14 of our patients.On physical examination the heart was usually enlarged, with a left ventricular lift. A double apical impulse was often palpable. Apex cardiograms usually showed an abnormally tall presystolic expansion wave (a wave). A systolic thrill was palpable in approximately one-half of the patients and tended to be present more frequently in patients with severe than in those with mild obstruction. Paradoxical splitting of the second heart sound during the respiratory cycle was present in 22 patients, and in them the systolic pressure gradients were significantly higher than in those without this finding. A fourth heart sound was audible in almost all of the patients in sinus rhythm while a third heart sound was heard less frequently. Seven of the 64 patients had early systolic ejection sounds. An ejection type systolic heart murmur was heard in all patients, and was most prominent along the left sternal border or at the apex. The systolic pressure gradients were significantly lower in the patients in whom the murmurs were relatively soft than in those with louder murmurs.Although the electrical axis in the frontal plane was usually normal, left axis deviation was noted in 14 patients. Normal sinus rhythm was present in all but 2 patients, who had atrial fibrillation. The patients with normal P waves were generally asymptomatic, but patients with electrocardiographic findings of left atrial or combined atrial enlargement were usually markedly disabled by their disease. The classical WPW pattern was present in 2 patients, and in a number of others an incomplete form was seen with a shortened P-R interval and/or a delta wave and a normal QRS duration. The obstruction to left ventricular outflow tended to be significantly more severe in the 27 patients with delta waves than in the 37 patients without this finding. Sixteen patients exhibited abnormally deep and broad Q waves. This finding occurred significantly more often in patients with the familial form of IHSS than in those with the nonfamilial form. It is likely that these abnormal Q waves are related to gross septal hypertrophy rather than myocardial infarction. Although the voltage criteria for left ventricular hypertrophy in the precordial leads were usually satisfied, there was no correlation between the height of RV5 or the sum of RV5 and SV1 and the magnitude of the systolic pressure gradient.On the conventional chest roentgenograms an abnormally large cardiothoracic ratio was noted in approximately one-half of the patients, and the left ventricle was consideredto be enlarged in almost all of the patients, but the magnitude of the cardiothoracic ratio and the extent of the left ventricular enlargement did not correlate with the systolic pressure gradient or the functional classification of the patient. Aortic dilatation is an uncommon finding in IHSS and the presence of marked dilatation in a patient with obstruction to left ventricular outflow suggests that valvular or discrete subvalvular stenosis rather than IHSS is present. Intracardiac calcification was never noted.The thickness of the free wall of the left ventricle and the width of the left ventricular cavity were measured on angiographic films exposed in the frontal projection at the end of diastole. No patient with IHSS exhibited an abnormally wide left ventricular cavity, and in a significant number of patients the width of the left ventricular cavity was less than that observed in patients with normal left ventricles or in those with valvular or discrete subvalvular aortic stenosis. The free wall of the left ventricle was thicker than normal in almost every patient with IHSS, and in some the left ventricular wall was found to be thicker than in any patient with discrete obstruction. However, there was no correlation between the thickness of the left ventricular myocardium during diastole and the peak systolic pressure gradient. The shape of the left ventricular cavity was abnormal in the majority of patients; an inward concavity at the midportion of the right inferior margin being the most common finding. It is presumed that this results from the bulging of the greatly hypertrophied interventricular septum into the left ventricular cavity. A long subvalvular area of narrowing commonly appeared to be responsible for the obstruction. Mitral regurgitation was present in nearly one-half of the patients, who were significantly older, and tended to have more clinical disability and a higher left ventricular end-diastolic pressure than those without this finding.In patients with IHSS the arterial pulse rises sharply, the upstroke times in the indirect carotid arterial pulses averaging 0.062 sec. in IHSS, compared to a normal average value of 0.088 sec. A carotid pulse with two peaks in systole was recorded in 35 of the 47 patients with IHSS, and in the other 12 patients in whom there was only a single peak there tended to be little if any obstruction to left ventricular outflow. The first derivative of the arterial pressure pulse tended to be greater than normal in IHSS, and was always higher in patients with IHSS than in those with valvular aortic stenosis.The systemic arterial pressure was normal in the majority of patients. The pulmonary artery systolic pressure exceeded 30 mm. Hg in 16 patients. A systolic pressure gradient within the right ventricular outflow tract was recorded in 10 patients and the right ventricular end-diastolic pressure was abnormally elevated in 21 patients. The a wave was the most prominent wave in the right and left atrial pressure pulses in almost every patient. The resting cardiac index varied widely. The mean left atrial pressure was abnormally elevated in 18 of the 42 patients in whom it was measured, while the left ventricular enddiastolic pressure exceeded the upper limit of normal in 47 of the 64 patients. The peak systolic left ventricular outflow pressure gradient, measured in the basal state, exceeded 100 mm. Hg in 14 patients, ranged between 50 and 100 mm. Hg in 21 patients and between 10 and 50 mm. Hg in 15 patients. The other 14 patients did not exhibit significant obstruction to left ventricular outflow in the basal state. No correlation was found between the most common symptoms in IHSS and the severity of obstruction. A distinct notch on the ascending limb of the left ventricular pressure pulse was usually recorded and its level was approximately equal to the peak pressure distal to the obstruction. In addition to obstruction to ventricular outflow, IHSS is characterized by an abnormally low ventricular compliance, an important consequence of which is impedance of ventricular filling. Atrial hypertrophy results and atrial systole assumes a particularly important role in ventricular filling.One of the most important features of IHSSis the variability of the hemodynamic findings. In 28 patients in whom measurements of the systolic pressure gradient were carried out at intervals

ACC/AHA Clinical Performance Measures for Adults With ST-Elevation and Non-ST-Elevation Myocardial Infarction. A Report of the American College of Cardiology/American Heart Association Task Force on Performance Measures (Writing Committee to Develop Performance Measures on ST-Elevation and Non-ST-Elevation Myocardial Infarction)

ACC/AHA TASK FORCE ON PERFORMANCE MEASURES Frederick A. Masoudi, MD, MSPH, FACC, Chair; Robert O. Bonow, MD, MACC, FAHA#; Elizabeth DeLong, PhD; N.A. Mark Estes III, MD, FACC, FAHA; David C. Goff, Jr, MD, PhD, FAHA, FACP; Kathleen Grady, PhD, RN, FAHA, FAAN; Lee A. Green, MD, MPH; Ann Loth, RN, MS, CNS; Eric D. Peterson, MD, MPH, FACC, FAHA; Martha J. Radford, MD, FACC, FAHA; John S. Rumsfeld, MD, PhD, FACC, FAHA; David M. Shahian, MD, FACC

Immediate versus deferred beta-blockade following thrombolytic therapy in patients with acute myocardial infarction. Results of the Thrombolysis in Myocardial Infarction (TIMI) II-B Study.

In the Thrombolysis in Myocardial Infarction (TIMI) Phase II trial, patients received intravenous recombinant tissue-type plasminogen activator (rt-PA) and were randomized to either a conservative or an invasive strategy. Within this study, the effects of immediate versus deferred beta-blocker therapy were also assessed in patients eligible for beta-blocker therapy, a group of 1,434 patients of which 720 were randomized to the immediate intravenous group and 714 to the deferred group. In the immediate intravenous group, within 2 hours of initiating rt-PA metoprolol was given (5 mg intravenously at 2-minute intervals over 6 minutes, for a total intravenous dose of 15 mg, followed by 50 mg orally every 12 hours in the first 24 hours and 100 mg orally every 12 hours thereafter). The patients assigned to the deferred group received metoprolol, 50 mg orally twice on day 6, followed by 100 mg orally twice a day thereafter. The therapy was tolerated well in both groups and the primary end point, resting global ejection fraction at hospital discharge, averaged 50.5% and was virtually identical in the two groups. The regional ventricular function was also similar in the two groups. Overall, there was no difference in mortality between the immediate intravenous and deferred groups, but in the subgroup defined as low risk there were no deaths at 6 weeks among those receiving immediate beta-blocker therapy in contrast to seven deaths among those in whom beta-blocker therapy was deferred. These findings for a secondary end point in a subgroup were not considered sufficient to warrant a recommendation regarding clinical use. There was a lower incidence of reinfarction (2.7% versus 5.1%, p = 0.02) and recurrent chest pain (18.8% versus 24.1%, p less than 0.02) at 6 days in the immediate intravenous group. Thus, in appropriate postinfarction patients, beta-blockers are safe when given early after thrombolytic therapy and are associated with decreased myocardial ischemia and reinfarction in the first week but offer no benefit over late administration in improving ventricular function or reducing mortality.

Hemorrhagic events during therapy with recombinant tissue-type plasminogen activator, heparin, and aspirin for acute myocardial infarction : results of the thrombolysis in myocardial infarction -TIMI), phase II trial

OBJECTIVES To assess the effects of invasive procedures, hemostatic and clinical variables, the timing of beta-blocker therapy, and the doses of recombinant plasminogen activator (rt-PA) on hemorrhagic events. DESIGN A multicenter, randomized, controlled trial. SETTING Hospitals participating in the Thrombolysis in Myocardial Infarction, Phase II trial (TIMI II). INTERVENTIONS Patients received rt-PA, heparin, and aspirin. The total dose of rt-PA was 150 mg for the first 520 patients and 100 mg for the remaining 2819 patients. Patients were randomly assigned to an invasive strategy (coronary arteriography with percutaneous angioplasty [if feasible] done routinely 18 to 48 hours after the start of thrombolytic therapy) or to a conservative strategy (coronary arteriography done for recurrent spontaneous or exercise-induced ischemia). Eligible patients were also randomly assigned to either immediate intravenous or deferred beta-blocker therapy. MEASUREMENTS Patients were monitored for hemorrhagic events during hospitalization. MAIN RESULTS In patients on the 100-mg rt-PA regimen, major and minor hemorrhagic events were more common among those assigned to the invasive than among those assigned to the conservative strategy (18.5% versus 12.8%, P less than 0.001). Major or minor hemorrhagic events were associated with the extent of fibrinogen breakdown, peak rt-PA levels, thrombocytopenia, prolongation of the activated partial thromboplastin time (APTT) to more than 90 seconds, weight of 70 kg or less, female gender, and physical signs of cardiac decompensation. Immediate intravenous beta-blocker therapy had no important effect on hemorrhagic events when compared with delayed beta-blocker therapy. Intracranial hemorrhages were more frequent among patients treated with the 150-mg rt-PA dose than with the 100-mg rt-PA dose (2.1% versus 0.5%, P less than 0.001). The extent of the plasmin-mediated hemostatic defect was also greater in patients receiving the 150-mg dose. CONCLUSIONS Increased morbidity due to hemorrhagic complications is associated with an invasive management strategy in patients with acute myocardial infarction. Our findings show the complex interaction of several factors in the occurrence of hemorrhagic events during thrombolytic therapy.

A composite view of cardiac rupture in the United States National Registry of Myocardial Infarction.

OBJECTIVES This study was done to determine the incidence, timing and prevalence as a cause of death from cardiac rupture in patients with acute myocardial infarction. BACKGROUND Several clinical trials and overview analyses have suggested that the survival benefit conferred by thrombolytic therapy may be offset by a paradoxic increase in early deaths from cardiac rupture. METHODS Demographic, procedural and outcome data from patients with acute myocardial infarction were collected at 1,073 United States hospitals collaborating in the United States National Registry of Myocardial Infarction. RESULTS Among the 350,755 patients enrolled, 122,243 received thrombolytic therapy. In-hospital mortality for the overall patient population, those not treated with thrombolytics (n = 228,512) and those given thrombolytics were 10.4%, 12.9% and 5.9%, respectively (p<0.001). Cardiogenic shock was the most common cause of death in each patient group. Although the incidence of cardiac rupture was low (<1.0%), it was responsible for 7.3%, 6.1% and 12.1%, respectively, of in-hospital deaths (p<0.001). Death from rupture occurred earlier in patients given thrombolytic therapy, with a clustering of events within 24 h of drug administration. Despite the early risk, death rates were comparatively low in thrombolytic-treated patients on each of the first 30 days. By multivariable analysis, thrombolytics, prior myocardial infarction, advancing age, female gender and intravenous beta-blocker use were independently associated with cardiac rupture. CONCLUSIONS This large registry experience, including over 350,000 patients with myocardial infarction, suggests that thrombolytic therapy accelerates cardiac rupture, typically to within 24 to 48 h of treatment. The possibility that rupture represents an early hemorrhagic complication of thrombolytic therapy should be investigated.

ACC/AHA Clinical Performance Measures for Adults With Chronic Heart Failure

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Factors influencing the time to administration of thrombolytic therapy with recombinant tissue plasminogen activator (data from the national registry of myocardial infarction)

Very early administration of thrombolytic therapy for acute myocardial infarction (AMI) has significantly reduced mortality in eligible patients. The purpose of this study was to evaluate factors which influenced the time from symptom onset to hospital presentation and the time from hospital presentation to the onset of thrombolytic treatment in a large population of patients with AMI. This study included 212,990 patients from 904 hospitals that participated in the National Registry of Myocardial Infarction. The median time from symptom onset to hospital presentation for those treated was 1.5 hours versus 2.7 hours for those not receiving thrombolytic treatment. Older patients and women had increased delay times, as did those who arrived at the hospital during daytime hours. Of the 59,802 (28%) patients who received thrombolytic treatment, 23% were treated < 30 minutes from admission; 63%, < 60 minutes; and 83%, < 90 minutes. Time to treatment increased with age and was longer for women and for patients arriving between midnight and early morning. The most important factor associated with shorter time to treatment was the initiation of thrombolytic treatment in the emergency department rather than in the coronary care unit (47 vs 73 minutes, p < 0.0001). Hospital treatment times are much too long, given that quick identification and treatment of eligible patients are of primary importance in reducing mortality from AMI. To shorten these times, thrombolytic treatment should be initiated in the emergency department, and the effectiveness of hospital programs aimed at reducing time to treatment should be subject to continuing quality improvement surveillance.

Thrombin Generation, Inhibition and Clinical Outcomes in Patients With Acute Myocardial Infarction Treated With Thrombolytic Therapy and Heparin: Results From the GUSTO-I Trial

OBJECTIVES We sought to assess the effects of antithrombotic therapy after thrombolysis for acute myocardial infarction on markers of thrombin generation and activity and to determine the relation of these markers with clinical outcomes. BACKGROUND Thrombin activation and generation often occur with thrombolysis for acute myocardial infarction. Antithrombotic regimens have been developed to reduce the resulting thrombotic complications. METHODS We sampled plasma markers of thrombin generation and activity after thrombolysis in 292 patients. We assessed the relations of these markers with clinical outcomes at 30 days. RESULTS Fibrinopeptide A (FPA), a marker of thrombin activity toward fibrinogen, was elevated at baseline (12.3 ng/ml) and increased to 18.4 ng/ml by 90 min after streptokinase and subcutaneous heparin treatment. With intravenous heparin, this increase was attenuated, but intravenous heparin did not prevent thrombin generation, as measured by prothrombin fragment 1.2 (F1.2). Heparin level, measured by anti-Xa activity, correlated with activated partial thromboplastin time (aPTT, r = 0.62 to 0.67). Thrombin activity, measured by FPA, was as closely related to aPTT as to the heparin level. Baseline levels of F1.2 were significantly related to the risk of death or reinfarction at 30 days (p = 0.008); values 12 h after enrollment also were related to 30-day mortality (p = 0.05). CONCLUSIONS Although intravenous heparin partly suppresses the increased thrombin activity associated with thrombolysis, it does not inhibit thrombin generation. The aPTT was as good a measure of suppression of thrombin activity as the heparin level itself. Hematologic markers of thrombin generation were found to be related to the subsequent risk of thrombotic events.

Idiopathic Hypertrophic Subaortic Stenosis: II. Operative Treatment and the Results of Pre- and Postoperative Hemodynamic Evaluations

In 10 of 64 patients with IHSS, operations designed to relieve obstruction were performed. The pertinent preoperative clinical and hemodynamic findings in these patients, the operative methods employed, and the results of operation are presented in the present report.Eight of the patients were males, 2 were females, and at the time of operation their ages ranged from 10 to 54 years. All of the patients were symptomatic and all but 2 were in functional classes III and IV. In each patient left heart catheterization proved the presence of left ventricular outflow obstruction and the peak systolic gradients between the left ventricle and a systemic artery ranged from 68 to 175 mm. Hg (average 110 mm. Hg). The effective orifice areas ranged from 0.44 to 0.99 cm.2 (average 0.61 cm.2). Pulmonary hypertension was present in 2 patients.In 5 patients simple left ventriculomyotomy was performed, and in the other 5 ventriculomyotomy was combined with resection of a portion of the hypertrophied interventricular septum. One patient, in whom operative pressure measurements indicated satisfactory relief of obstruction, died suddenly on the eighth postoperative day, apparently from arrhythmia. Complete heart block was prod2 patients, and these patients have implanted pacemakers. Seven of the 9 surviving patients have been followed for periods of 7 to 51 months, and each has had striking symptomatic improvement. Left heart catheterizations have been carried out postoperatively on one or more occasions in all 7 patients. In 6 no intraventricular pressure gradient was present at rest or during exercise, while in the remaining patient a peak gradient of 24 mm. Hg was evident.The pertinent clinical findings in these 10 patients, the operative methods utilized, and the results of their pre- and postoperative hemodynamic assessments are presented in detail. Consideration is also given to present concepts in the selection of patients for operation, and in the choice of operative techniques.

Recommended guidelines for training in adult clinical cardiac electrophysiology

Abstract Training in clinical cardiac electrophysiology should take place in an Accreditation Council for Graduate Medical Education accredited cardiology program, and the electrophysiology training program itself should be accredited by the Council. Each trainee must be eligible for board certification in Internal Medicine and either eligible for certification in Cardiovascular Diseases or in a program leading to eligibility. Training faculty should be certified in clinical cardiac electrophysiology or demonstrate equivalent credentials. At least two training faculty members are preferred. The faculty must be dedicated to teaching, active in performing or promoting research and must spend a substantial portion of their time in research, teaching and practice of clinical electrophysiology. A curriculum of training should be established. Faculty experts in the related basic sciences should be available and involved in teaching. The institution should have a fully equipped clinical electrophysiology laboratory and complete noninvasive capabilities. A close working relation with a cardiac surgery faculty member skilled in surgical treatment of arrhythmias is required. Training in application of pharmacologic and all current nonpharmacologic therapies, in the outpatient and inpatient setting, is necessary. The clinical exposure must include all facets of arrhythmia diagnosis and treatment and must be quantitatively sufficient to allow the trainee to develop proficiency. The period of training should not be less than one year in addition to the period of cardiology fellowship required by the ABIM for board eligibility. A continuous period of training is preferred.