Cardiomyopathy: how far have we come in 25 years, how far yet to go?

Twenty-five years ago clinical investigators began to appreciate that cardiomyopathy is an important and reasonably common form of heart disease. Since then, several functional classifications have been proposed, the specific myocardial diseases have been classified and chronic ischemic ventricular failure has been described. The boundary separating myocarditis from dilated cardiomyopathy remains hazy and, despite intensive research, the causes of dilated cardiomyopathy remain obscure. In particular, we still do not understand the role that may be played by viral infection and alcohol. Myocardial biopsy has proved useful in patients with specific myocardial disorders, heart transplant recipients and patients receiving Adriamycin, but is disappointing in patients with dilated cardiomyopathy. It has become increasingly evident that exercise capacity does not correlate with ventricular function, being highly dependent on peripheral factors. Measurements of oxygen consumption during exercise promise to be useful in assessing treatment of dilated cardiomyopathy. True restrictive cardiomyopathy is uncommon, and the term should be reserved for cardiomyopathies that meet strict criteria. A restrictive component to filling is common to many cardiac disorders, including some cases of cardiac amyloidosis. The concept of hypertrophic cardiomyopathy has evolved rapidly over the past 25 years, and continues to evolve. The importance of arrhythmia as a cause of sudden death is becoming increasingly clear. The place of calcium channel blocking agents in the treatment of hypertrophic cardiomyopathy will probably emerge soon. Amiodarone is finding an increasing role in the treatment of dilated and hypertrophic cardiomyopathy. Surgical treatment is still required for some patients despite unanswered questions on how it works.

Paradoxical pulmonary vasoconstriction induced by nitroglycerin in idiopathic pulmonary hypertension.

Administration of intravenous nitroglycerin in a patient with idiopathic pulmonary hypertension resulted in an increase in pulmonary artery pressure associated with a decrease in blood flow that is best explained by an increase in pulmonary vascular resistance. This observation highlights the need for hemodynamic monitoring when potent vasodilators are used in this disorder.

Doppler-detected paradoxus of mitral and tricuspid valve flows in chronic lung disease.

An echocardiographic Doppler study in a patient with pulsus paradoxus of respiratory origin demonstrated a large inspiratory increase of tricuspid flow velocity and a corresponding decrease of mitral flow velocity. This "flow paradoxus" is therefore not specific for cardiac tamponade, and provides evidence that decreased left ventricular filling is an important mechanism of pulsus paradoxus observed in severe chronic lung disease.

Oral amrinone for the treatment of chronic congestive heart failure: results of a multicenter randomized double-blind and placebo-controlled withdrawal study.

A placebo-controlled study was employed to evaluate the effects of oral amrinone in patients with congestive heart failure. After a baseline period of at least 4 weeks of standard treatment for refractory congestive heart failure, oral amrinone was added to the treatment regimen of 173 patients. Patients were predominantly male (89%), aged 24 to 76 years (mean 54), with ischemic (52%) or idiopathic (37%) dilated cardiomyopathy, in New York Heart Association functional class II (40%), III (59%) and IV (1%) and having a mean (+/- standard deviation) left ventricular ejection fraction of 25 +/- 15%. Phase 1: After the addition of amrinone (113 +/- 33 mg three times daily), 52 patients (30%) showed a maximal increase in treadmill exercise time exceeding 2 minutes (Naughton protocol), 72 (42%) had a lesser increase, 24 (14%) developed limiting adverse reactions, 20 (12%) died and 5 dropped out of the study. Fifty-two "responders" (30%) who were free of limiting side effects and had a greater than 2 minute increase in exercise time were randomized in double-blind fashion to continued amrinone or switched to placebo (each plus standard treatment) for an additional 12 weeks. Phase 2: Comparison of 31 of these 52 responders who continued to receive amrinone with the remaining 21 randomized to placebo revealed no significant differences in vital signs, indexes of left ventricular size and function, systolic time intervals or maximal exercise time. Continued follow-up study of patients receiving either amrinone or placebo revealed decreases in exercise times of 7 and 10%, respectively (both p less than 0.05 compared with before randomization). Episodes of worsened congestive heart failure severe enough to mandate termination of double-blind treatment were as frequent in patients taking placebo (4[18%] of 21) as in those taking amrinone (4[13%] of 31; p = NS). The average symptom score and functional class of each treatment group remained comparable. Adverse effects such as gastrointestinal and central nervous system complaints were more common with amrinone treatment as were elevations of serum liver enzymes and reduced platelet counts. This large multicenter, randomized double-blind withdrawal study revealed no change in estimates of cardiac performance after the discontinuation of amrinone. These findings suggest that amrinone, in the dosages tested, does not importantly improve cardiac function beyond that provided by standard treatment with digoxin, diuretic drugs and vasodilators.

Prognostic importance of digitalis after acute myocardial infarction.

Because previous reports have suggested that digitalis administration may lead to increased mortality after hospital discharge for acute myocardial infarction, the independent importance of digitalis therapy in long-term prognosis after acute myocardial infarction was investigated by analyzing 1,599 patients after definite myocardial infarction. After hospital discharge, mortality rate for the entire group at 4 months was 7.7% and after 1 year 14.2%. At discharge, 36.6% of the patients were taking digitalis. Compared with those not taking digitalis, those taking digitalis had more historical risk factors and a higher incidence of important clinical prognostic variables during the hospitalization. Their cardiac mortality rate after 4 months and 1 year (12.5 and 22.4%, respectively) was significantly higher than that of patients not taking digitalis (5.0 and 9.6%, respectively). Mortality was higher for patients taking digitalis whether or not they had congestive heart failure during hospitalization. However, in a multivariate Cox analysis for 1 year outcome, neither digitalis nor any other medication variable displaced the important clinical variables of age, congestive heart failure during the hospitalization, previous myocardial infarction, maximal heart rate during the hospitalization and previous angina. Quinidine and digitalis at discharge were selected sixth and seventh (not significant) by the analysis. It is concluded that digitalis therapy at discharge after myocardial infarction was not an independent predictor of late mortality in these patients.

M-mode echocardiography in constrictive pericarditis.

M-mode echocardiograms from 40 patients with proven constrictive pericarditis and 40 subjects without evidence of cardiac disease were reviewed for features previously described in constrictive pericarditis. In this large series, no single feature of the M-mode echocardiogram could be considered diagnostic, although a pattern of normal left ventricular size and systolic function, mild left atrial dilation, flattened diastolic left ventricular posterior wall motion and abnormal septal motion was found in most patients. It is concluded that the M-mode echocardiogram can provide findings suggestive of constrictive pericarditis but must be used in conjunction with hemodynamic and other studies to establish the diagnosis.

Heterogeneity of vasomotor response to acetylcholine along the human coronary artery.

OBJECTIVES: In view of the segmental occurrence of coronary atherosclerosis, we postulated that acetylcholine may cause heterogeneous vasomotion, depending on the extent of vessel analyzed, criteria for change in vessel caliber and dose of drug administered. BACKGROUND: Previous studies have reported that acetylcholine causes constriction of atherosclerotic arteries. This dysfunction of endothelium-dependent dilation may be seen without angiographically detectable disease. METHODS: We developed algorithms to quantitate the dimensions of a single coronary artery over virtually its entire length during a control state and during graded doses of intracoronary acetylcholine. On the basis of triplicate control angiograms, the limit of detection of a change from control diameter was 0.31 mm (> or = 2 SD). RESULTS: Analysis of multiple segments (each 5.6 +/- 1.1 [mean +/- SD] mm) along a single coronary artery revealed a heterogeneous response to acetylcholine in 27 of 31 patients at the 10(-4) mol/liter dose and in 29 of 31 patients when responses at 10(-6), 10(-5) and 10(-4) mol/liter doses were combined; in this latter analysis, constriction and dilation in the same vessel occurred in 45% of the patients. With acetylcholine, most of 349 segments demonstrated no change, but the greatest frequency of vasoconstriction (24.6%) and vasodilation (6.9%) was seen at the 10(-4) mol/liter dose. Inducible vasomotion was observed as far distally as 7.3 cm from the site of acetylcholine infusion. CONCLUSIONS: Response to intracoronary acetylcholine with mild coronary disease is heterogeneous; disparate dimensional responses may occur in different segments of the same vessel. Inclusion of all analyzable regions of a coronary artery and the use of a reproducibility limit for quantitative angiography are optimal for assessment of segmental coronary vasomotion.

Effects of equiblocking doses of nadolol and propranolol on left ventricular performance.

Nadolol, a recently developed noncardioselective beta-adrenergic blocker, has the potential advantages of a longer oral half-life (t 1/2) than propranolol and, in animal studies, markedly fewer direct myocardial depressant effects. Neither the relative intravenous potency of nadolol and propranolol nor the comparative effects of the 2 drugs on left ventricular performance has been studied in man. We compared equiblocking intravenous doses of nadolol and propranolol in 10 subjects with ischemic wall-motion disorders. Nadolol was on the average 6.2 times as potent on a milligram-for-milligram basis. Both drugs decreased resting heart rate (p less than 0.02) and produced small rises in both mean pulmonary artery (p less than 0.03) and mean pulmonary artery wedge (p less than 0.03) pressures without significantly reducing the cardiac output. Both drugs also produced depression of the radionuclide ejection fraction (p less than 0.002). There were no significant differences between the effects of the 2 drugs on any of the aforementioned variables. Thus, the effects of nadolol on left ventricular performances are similar to those of propranolol. Because of its long oral t 1/2, nadolol may prove to be a clinically useful drug.

Pravastatin alone and in combination with low-dose cholestyramine in patients with primary hypercholesterolemia and coronary artery disease.

This randomized, open-label study compared the cost efficiency of low-dose pravastatin combined with low-dose cholestyramine with high-dose pravastatin monotherapy in 59 patients with moderate hypercholesterolemia and coronary disease. Both regimes were effective in improving lipid profiles in these patients; however, low-dose combination therapy enhanced achievement in therapeutic goals and cost efficiency.

Regional left ventricular wall motion abnormalities in idiopathic dilated cardiomyopathy.

An evaluation and a comparison of left ventricular regional wall motion were performed in 32 patients with idiopathic dilated cardiomyopathy, none of whom had coronary artery diameter stenosis exceeding 20% in any major artery, and 17 control subjects, using frame by frame video intensity analysis of digitized ventriculograms. This technique evaluates the whole cardiac cycle in short overlapping intervals and yields information for systolic and diastolic events, without assumptions regarding the position and orientation of the ventricle. Diastolic regional wall motion abnormalities were found in 31 of 32 patients and systolic abnormalities were present in 16 patients. Asynchronous regions most commonly detected during diastole were anteroapical and apical; they were found in 19 of 32 patients. Regional contraction abnormality was observed in the apical and the anteroapical regions in 6 of 16 patients. Dilatation-induced changes in left ventricular shape exaggerate the phenomenon of higher wall stress at the apex of the normal ventricle. Basal wall motion is thus relatively preserved in dilated cardiomyopathy.

Clinical assessment and follow-up of functional capacity in patients with chronic congestive cardiomyopathy.

The presumption that the results of left ventricular systolic function tests performed at rest are related to the symptoms of chronic congestive heart failure or to exercise capacity is unproved. Thirty-three patients with chronic congestive cardiomyopathy underwent serial exercise tests, determinations of ejection fraction and systolic time intervals, echocardiograms, assessment of symptom score, chest roentgenogram, and physical examination over a mean ( +/- standard deviation) of 24.8 +/- 14.1 months. Maximal exercise performance achieved correlation with symptoms (r = 0.66) but not with indexes of left ventricular function. Edema, elevated jugular venous pressure, rales and radiologic evidence of pulmonary venous hypertension were more common in patients with severe limitation of exercise capacity. in 17 patients whose functional capacity changed during the follow-up period, congruent changes in left ventricular function measured at rest were not consistently observed. Thus the findings on history, physical examination and radiologic examination correlate with exercise capacity, but indexes of left ventricular performance at rest do not and therefore are of limited use in assessing treatment. The clinical course of patients with chronic congestive cardiomyopathy can be followed up safely, effectively and economically by simple clinical observations. Serial laboratory testing of left ventricular function can be reserved for specific indications, research and patients with valvular heart disease.

Loss of adrenergic control of the force-frequency relation in heart failure secondary to idiopathic or ischemic cardiomyopathy.

This study was designed to determine whether the force-frequency effect on myocardial contractility, known to be importantly regulated by the adrenergic nervous system in experimental animals, can be enhanced by beta-adrenergic receptor stimulation in patients with heart failure. Animal experiments have demonstrated that the positive force-frequency relation in most mammals is subject to enhancement by beta-adrenergic receptor stimulation during exercise or infusion of a beta-receptor agonist. In animal models of heart failure, this regulatory mechanism generally is lost. The response to progressive increases in heart rate to 150 to 160 beats/min by right atrial pacing before and during dobutamine infusion was studied in 3 relatively normal subjects and in 5 patients with severe dilated cardiomyopathy. Left ventricular (LV) pressure and its first derivative (LV dP/dt(max)) were measured with a micromanometer, and the time constant of LV relaxation was assessed. The slopes of the relations between heart rate and LV dP/dt(max) in control subjects were positive at baseline and the mean slope increased substantially and significantly during dobutamine infusion. In patients with heart failure, the heart rate versus LV dP/dt(max) relations were depressed and flattened without a descending limb. Dobutamine infusion shifted this relation upward slightly, without increase in mean slope, indicating lack of amplification. The rate of isovolumic relaxation significantly decreased as heart rate increased at baseline and was further shortened by dobutamine. In patients with heart failure, a depressed and flattened relation between heart rate and LV dP/dt(max) (force-frequency effect) did not show the amplification of myocardial contractility by beta-adrenergic stimulation observed in the normal heart. This abnormality in control of the force-frequency relation undoubtedly plays an important role in the impairment of cardiac function during exercise in heart failure.

Hemodynamic and electrocardiographic effects in man of a new nonionic contrast agent (iohexol): advantages over standard ionic agents.

Iohexol is a new, nonionic contrast material that has been shown in animal studies to hold great promise as an agent for coronary arteriography and ventriculography with fewer adverse hemodynamic effects than standard ionic media. At present, it has not been studied systematically in man. Fifty patients referred for elective cardiac catheterization were randomized to receive either iohexol or meglumine sodium diatrizoate (Renografin-76). Both operator and patient were blinded as to which agent was being used. Hemodynamic variables measured were pulmonary artery wedge pressure and systemic blood pressure. In addition, the following electrocardiographic indexes were evaluated: S-T segment shifts, changes in Q-T interval, changes in T-wave amplitude, and changes in heart rate. These variables were measured after left ventriculography and after both left and right coronary arteriography. Both iohexol and sodium meglumine diatrizoate produced small transient elevations in pulmonary artery wedge pressure. Systemic hypotension occurred with both agents but was more profound and longer-lasting with sodium meglumine diatrizoate. Iohexol injection resulted in no electrocardiographic changes, whereas sodium meglumine diatrizoate produced marked Q-T prolongation, as well as changes in T-wave amplitude and heart rate. Iohexol was well tolerated by the patients, and radiographic opacification was good to excellent in all cases. Thus, iohexol produces fewer deleterious hemodynamic and electrocardiographic changes than sodium meglumine diatrizoate when studied in a typical adult population requiring diagnostic cardiac catheterization. This favorable preliminary experience in man has potential widespread importance because of the large number of patients undergoing angiographic procedures.

Cardiac amyloidosis, contrictive pericarditis and restrictive cardiomyopathy.

Cardiac amyloidosis is not characterized by a single hemodynamic pattern. Some of the cases present the clinical findings of restrictive cardiomyopathy and in these differentiation from constrictive pericarditis remains difficult in spite of the introduction of techniques designed to assess myocardial contractility and ventricular diastolic compliance. The clinical features and the demonstration of left ventricular diastolic pressure greater than right remain the most useful means of distinguishing restrictive cardiomyopathy from constrictive pericarditis. In other cases of cardiac amyloidosis the diastolic pressure is elevated throughout diastole and ventricular ejectile ability is lost. These cases do not simulate constrictive pericarditis and should not be classified as restrictive cardiomyopathy.

The role of the pericardium in conditioning the effects of physical training.

More work needs to be done on the extent to which the pericardium can modulate the cardiovascular response to exercise and the mechanisms whereby this modulation is brought about. Studies are needed to differentiate the effects of the pericardium on the cardiovascular exercise response, comparing trained with untrained subjects. Evidence is accumulating that exercise training in patients with heart failure improves not only the performance of exercising muscles, but also has some beneficial effects on central hemodynamics. The extent to which these beneficial effects can be attributed to conditioning the pericardium remains speculative.

Automatic analysis of left ventricular ejection fraction using stroke volume images.

The purpose of this study was to analyze, validate, and report on an automatic computer algorithm for analyzing left ventricular ejection fraction and to indicate future applications of the technique to other chambers and more advanced measurements. Thirty-eight patients were studied in the cardiac catheterization laboratory by equilibrium radionuclide ventriculography and concurrent contrast ventriculography. The temporal and spatial behavior of each picture element in a filtered stroke volume image series was monitored throughout the cardiac cycle. Pixels that met specific phase, amplitude, and derivative criteria were assigned to the appropriate chamber. Volume curves were generated from regions of interest for each chamber to enable calculation of the left ventricular ejection fraction. Left ventricular ejection fractions showed a good correlation (r = 0.89) between the two techniques. Ejection fractions ranged between 0.12 and 0.88, showing a wide range of application. It is concluded that automatic analysis of left ventricular ejection fraction is possible using the present algorithm and will be useful in improving the reproducibility and providing more accurate information during exercise protocols, pharmaceutical interventions, and routine clinical studies.

Influence of the pericardium on right and left ventricular filling in the dog.

We compared the influence of the pericardium on left and right ventricular (LV, RV) filling by measuring LV and RV pressures and segment lengths (SL, LV free wall, and RV inflow and outflow tracts) in six open-chest, pentobarbital sodium-anesthetized dogs before and after pericardiectomy. End-diastolic pressure (EDP) was varied by partial caval occlusion and dextran infusion. At each site the ln EDP-SL relation was fitted by linear regression and characterized by its slope and 1-Torr EDP intercept. The slope and 1-Torr intercept of the LV ln EDP-SL relation changed variably after pericardiectomy, but in each dog a change occurred that shifted this relation downward. In contrast, the RV inflow tract slope invariably decreased significantly after pericardiectomy, whereas its intercept was unchanged in all but one dog. The RV outflow tract results were similar to the inflow tract but less consistent. By the use of the raw EDP-SL data points, we calculated that the absolute contribution of the pericardium to EDP (i.e., the effective pericardial surface pressure) was similar at the three sites. However, as EDP values increased the proportional contribution of the pericardium to right ventricular end-diastolic pressure (RVEDP) increased, whereas that to left ventricular end-diastolic pressure (LVEDP) remained relatively constant. As a result, at the higher EDP values tested, the pericardium was responsible for a larger proportion of RVEDP than LVEDP.(ABSTRACT TRUNCATED AT 250 WORDS)

Characterization and surgical resection of an organized pericardial hematoma assisted by transesophageal echocardiography.

We describe the echocardiographic features of a rare pericardial hematoma causing elevated venous pressure in a patient who had suffered blunt chest trauma in the past. Transesophageal echocardiography demonstrated a large, partially calcified mass in the right cardiophrenic angle impinging on the tricuspid annulus and facilitated intraoperative assessment of surgical resection.

Acute pericarditis.

Acute pericarditis may be of viral or idiopathic origin, may be induced by certain drugs, may occur as a consequence of thoracic surgery, may result from infection by bacteria or other organisms, or may be associated with noninfectious systemic disease. In some instances, pericarditis may be detected quickly, and in other cases it may not be recognized until late. This article discusses clinical findings, clinical course, and treatment of acute pericarditis. In addition, diagnosis and treatment of pericardial effusion are presented.

Effect of pravastatin-to-simvastatin conversion on low-density-lipoprotein cholesterol.

The effects of a pravastatin-to-simvastatin conversion program on low-density-lipoprotein (LDL) cholesterol levels were studied. Patients receiving pravastatin at a Veterans Affairs medical center were switched to simvastatin beginning in 1997. The dosage of simvastatin was based on the additional percent reduction in LDL cholesterol needed to achieve the goal specified by the National Cholesterol Education Program. The primary endpoint was the change in the percentage of patients meeting their LDL cholesterol goal at baseline and follow-up. Changes in lipid indices, the relative risk (RR) of coronary heart disease (CHD), and program costs were also evaluated. A total of 1032 patients completed the program. The mean +/- S.D. daily doses of pravastatin and simvastatin were 25.2 +/- 11.3 and 22.7 +/- 13.3 mg, respectively. Median baseline and follow-up LDL cholesterol concentrations were 116 and 99 mg/dL, respectively (p < 0.001). Overall, 44% of the patients met their LDL cholesterol goal while taking pravastatin, compared with 69% after conversion to simvastatin (p < 0.001). The predicted mean RR of a future CHD event (based on changes in serum lipids) was 0.87 (95% confidence interval, 0.83-0.91) four years after conversion. The total cost of the program was $40,644 in the first year, and there was a net saving thereafter. Therapeutic interchange between pravastatin and simvastatin increased the number of patients meeting their LDL cholesterol goal.