John P. Wexler

Dobutamine echocardiography and resting-redistribution thallium-201 scintigraphy predicts recovery of hibernating myocardium after coronary revascularization

The value of dobutamine echocardiography and resting thallium-201 scintigraphy to predict reversal of regional left ventricular wall motion dysfunction after revascularization in patients with chronic coronary artery disease was assessed. Improvement in wall motion during dobutamine echocardiography and normal or mildly decreased uptake on thallium-201 scanning are strong predictors of reversible left ventricular dysfunction. Dobutamine echocardiography and resting thallium-201 scanning are simple and safe methods of assessing hibernating myocardium.

Sustained beneficial effects of oral amrinone on cardiac and renal function in patients with severe congestive heart failure

Although effectiveness of oral amrinone has been demonstrated in animals, amrinone has been shown in human subjects to improve cardiac performance in the failing heart only after acute intravenous administration. Therefore, we studied the hemodynamic and renal effects of orally administered amrinone (50 to 300 mg) in 10 patients with advanced congestive heart failure. Cardiac index increased from 1.56 ± 0.41 (mean ± standard deviation) to 2.20 ± 0.43 liters/min per m2 (p < 0.001); pulmonary wedge pressure decreased from 26.1 ± 5.7 to 17.0 ± 5.7 mm Hg (p < 0.001). Mean arterial pressure decreased from 86.0 ± 8.4 to 81.3 ± 7.7 mm Hg (p < 0.001) and systemic vascular resistance from 2,406 ± 603 to 1,693 ± 261 dynes sec cm−5 (p < 0.001). Heart rate was unchanged. The onset of action ranged from 30 to 120 minutes and the duration of action from 4 to 7 hours after a single oral administration. After 24 hours of continuous therapy, no tachyphylaxis to amrinone was observed. A correlation (r = 0.62, p < 0.001) was found between the oral dose of amrinone and the percent increase in cardiac index. Left ventricular ejection fraction, determined in five patients, increased from 14 ± 8 to 21 ± 8 percent (p < 0.01). Effective renal plasma flow, measured in six patients, increased from 186.0 ± 72.0 to 231.1 ± 88.8 ml/min (p < 0.05) and the glomerular filtration rate from 82.2 ± 14.9 to 110.0 ± 20.6 ml/min (p < 0.05). Thus, this study demonstrates the cardiotonic efficacy of orally administered amrinone in human subjects and recommends its further investigation as a therapeutic agent for the continued treatment of congestive heart failure.

Dependence of enhanced maximal exercise performance on increased peak skeletal muscle perfusion during long-term captopril therapy in heart failure.

Maximal oxygen uptake (VO2), skeletal muscle blood flow by xenon-133 washout technique and femoral vein arteriovenous oxygen difference and lactate were measured at rest and during maximal bicycle exercise in eight patients with severe congestive heart failure before and after 8 weeks of therapy with captopril. During therapy, skeletal muscle blood flow at rest increased significantly from 1.5 +/- 0.6 to 2.6 +/- 1.0 ml/100 g per min (p less than 0.05), with a concomitant decrease in the femoral arteriovenous oxygen difference from 10.0 +/- 1.7 to 8.3 +/- 1.9 ml/100 ml (p less than 0.05). Maximal VO2 increased significantly from 13.4 +/- 3.0 to 15.5 +/- 4.1 ml/kg per min (p less than 0.05). In four patients, the increase in maximal VO2 averaged 3.7 ml/kg per min (range 2.7 to 4.9), whereas in the remaining four patients, it was less than 1 ml/kg per min. Overall, peak skeletal muscle blood flow attained during exercise did not change significantly during long-term therapy with captopril (19.6 +/- 6.2 versus 27.6 +/- 14.3 ml/100 g per min, p = NS). However, the four patients with a significant increase in maximal VO2 experienced substantial increases in peak skeletal muscle blood flow and the latter changes were linearly correlated with changes in maximal VO2 (r = 0.95, p less than 0.001). Femoral arteriovenous oxygen difference at peak exercise was unchanged (12.6 +/- 2.6 versus 12.6 +/- 2.4 ml/100 ml). Thus, improvement in maximal VO2 produced by long-term therapy with captopril is associated with an increased peripheral vasodilatory response to exercise, and this improvement only occurs when the peak blood flow is augmented.(ABSTRACT TRUNCATED AT 250 WORDS)

Radionuclide ventriculographic responses to graded supine and upright exercise: critical role of the Frank-Starling mechanism at submaximal exercise

To assess the influence of work load and posture on the response to exercise, 25 patients with coronary artery disease (CAD) and 17 normal subjects underwent graded supine and upright exercise radionuclide ventriculography. In both groups, end-diastolic counts increased with supine exercise (p less than 0.001). The ejection fraction and peak systolic pressure-end-systolic volume relation increased in normal subjects (p less than 0.02), but not in patients with CAD. At upright rest, end-diastolic counts decreased in both groups (p less than 0.001) and then increased with exercise (p less than 0.001). The increase in end-diastolic counts was most pronounced on the transition from upright rest to the 150-kpm work load and resulted in a significant increase in stroke counts (p less than 0.05) for both patients with CAD and normal subjects, without a measurable change in the ejection fraction or the peak systolic pressure-end-systolic volume relation. Later in exercise, end-diastolic counts plateaued, and the ejection fraction and the peak systolic pressure, end-systolic volume relation increased only among normal subjects. Thus, low-level upright exercise is highly dependent on the Starling mechanism in both normal subjects and patients with CAD, with enhanced contractility apparent only during more vigorous exercise in normal subjects.

Pharmacological stress testing.

Pharmacological stress in conjunction with radionuclide myocardial perfusion imaging has become a widely used noninvasive method of assessing patients with known or suspected coronary artery disease. In the United States, over one third of perfusion imaging studies are performed with pharmacological stress. Pharmacological stress agents fall into two categories: coronary vasodilating agents such as dipyridamole and adenosine, and cardiac positive inotropic agents such as dobutamine and arbutamine. For both, in the presence of coronary artery disease (CAD), perfusion image abnormalities result from heterogeneity of coronary blood flow reserve. Vasodilating agents work directly on the coronary vessels to increase blood flow, whereas inotropic agents work indirectly by increasing myocardial work load, which then leads to an increase in coronary blood flow. Both classes of agents have high accuracies for diagnosing coronary artery disease, and they have excellent safety records with acceptably low occurrences of side effects. For dipyridamole planar thallium imaging, pooled analysis yields a sensitivity of 85% and a specificity of 87% for diagnosis of coronary disease, but there is a large variation in reported values depending on various factors, such as the extent of postcatheterization referral bias, the type of imaging (planar versus single photon emission computed tomography [SPECT]), the types of patients being studied (single versus multivessel disease, men versus women), and the imaging agent used (thallium versus one of the technetium-based agents). Diagnostic accuracies for adenosine are similar to those of dipyridamole, with reported overall sensitivities ranging from 83% to 97%, and specificities ranging from 38% to 94%. For dobutamine, pooled analyses yield a sensitivity of 82% and a specificity of 75%. There is some concern that dobutamine may interfere with uptake of technetium-99m sestamibi, lowering the sensitivity for detection of disease, and thus the vasdodilating agents are generally preferred. Pharmacological stress testing has high clinical use for risk stratifying patients with known or suspected CAD, in patients after myocardial infarction, and in patients needing noncardiac surgery. Vasodilating agents are particularly advantageous in assessing post-myocardial infarction patients, allowing testing as soon as 2 days after the event. Like patients undergoing exercise stress testing, patients with normal perfusion images by pharmacological stress have a <1% annual incidence of cardiac events. The likelihood of an event increases with the extent and severity of perfusion abnormalities. However, it is important to consider clinical variables when using perfusion imaging for risk stratification, particularly in the presurgery patients. As with exercise testing, adjunct markers such as ST segment depression during testing, lung uptake of radiotracer (if thallium is used), and ventricular cavity dilatation add additional prognostic information to that available from the perfusion images alone. The aim of current research is to find better agents that are easier to use and that have fewer side effects. MRE-0470 is an experimental vasodilating agent that is more receptor selective than adenosine and promises a lower incidence of hypotension. Arbutamine more closely simulates exercise than dobutamine, and it can be administered by a closed-loop computerized delivery device. Work is also underway to look at novel uses of pharmacological stress agents, such as acquiring gated SPECT images during dobutamine infusion to enhance detection of myocardial viability. With increasing use of noninvasive testing in elderly patients and in patients with comorbidities that preclude adequate exercise, pharmacological stress testing has become an indispensable tool for radionuclide myocardial perfusion imaging studies. A good understanding of pharmacological stress testing is essential for performing high-quality nuclear cardiology

Cardiovascular disease in patients on chronic hemodialytic therapy

D URING the early 1970s it became apparent that patients maintained on chronic hemodialysis programs died of cardiovascular disease with an incidence greatly in excess of the age-adjusted expected rate. As a larger number of patients with diabetes, severe hypertension, and preexisting heart disease have become candidates for chronic hemodialysis, elucidation of the exact causes of and factors contributing to the development and progression of cardiovascular disease in end-stage renal failure has become an issue of practical significance. Several earlier reviews of mortality in highly selected, “better risk” dialysis patients reveal an extremely high incidence of cardiovascular complications.‘*2 Lindner et a1.2 reported a sharp increase in the cause-specific mortality from cardiac problems beginning 4 yr after the institution of hemodialysis. Included in this report were three patients with intractable congestive heart failure, as well as eight with myocardial infarction and three patients with stroke. When considered as a single risk factor, the death rate from myocardial infarction rose steeply after 6 yr. A comparison of these data with the incidence of coronary artery disease in the Framingham study3 demonstrates that young dialysis patients have a mortality 2.5 times that reported for older men with severe levels of hypertension.4 Data collected from European centers indicate a similar pattern.’ Among 12,000 deaths occurring in patients on chronic dialysis programs through 1976, 58% were due to cardiovascular disease. Of these, almost half were attributed to “hypertensive cardiac failure,” cardiac arrest, and “other causes of cardiac failure.” Lazarus et a1.,4 after reviewing these data, data from the U.S. National Registry, and data from their own series, concluded that “hemodialysis patients are dying from complications of vascular disease. ” “Accelerated atherosclerosis” was the term used by Lindner et al.* to characterize this unexpected increase in cardiovascular deaths. Although several physical and metabolic abnormalities associated with cardiovascular disease can be shown to be prevalent in the hemodialysis population, there is no direct evidence that these abnormalities can either cause or accelerate atherosclerosis in this patient group. Indeed, a more recent study by Burke et al.’ indicates that patients who do not have diabetes, underlying heart disease, or malignant hypertension before entering dialysis programs have a very low incidence of subsequent atherosclerotic complications. None of the 24 deaths in this group was due to cardiac disease, although 7 deaths occurred after more than 5 yr on dialysis. Almost half of the deaths Burke et al. reported were due to infection, while small numbers were due to dialysis dementia, hyperkalemia, voluntary discontinuance, and miscellaneous other causes. In contrast, 8 of 10 deaths occurring after more than 5 yr of dialysis in Lindner’s group were due directly to cardiac disease, and 7 of these were “coronary deaths.“* Burke et al.* suggested that the discordant experiences may be due to a fundamental change in the physical composition of the dialysis population. They point out that case selection greatly influences the conclusions drawn from these retrospective studies, since the incidence of myocardial infarction and stroke was 34% in a group of patients excluded from their analysis (Table 1). In order to estimate the contribution of chronic hemodialysis to cardiovascular disease, it is necessary to evaluate the cardiac status of patients before entry into dialysis programs. Studies of cardiac function have the disadvantage that day-to-day alterations in diet, fluid balance, or compliance with medical therapy may be responsible for large fluctuations in a

Determination of plasma lactic acid concentration and specific activity using high-performance liquid chromatography

Assessment of lactate metabolism is of particular interest during exercise and in disease states such as diabetes, shock, and absorptive abnormalities of short-chain fatty acids by the colon. We describe an analytical method that introduces radio-active tracers and high-performance liquid chromatography (HPLC) to simultaneously analyze concentrations and specific activities (SAs) of plasma lactate. The HPLC conditions included separation on a reversed-phase column (octadecylsilane) and an isocratic buffer (30% acetonitrile in water). [3H]Acetate served as an internal standard. Lactate and acetate were extracted from plasma samples with diethyl ether following a pH adjustment to less than 1.0 and back-extracted into a hydrophilic phase with sodium carbonate (2 mM, pH greater than 10.0). Lactate is detected in the ultraviolet range (242 and 320 nm) by derivatization with alpha-bromoacetophenone. Control plasma samples were studied after an overnight fast for precision and analytical recovery. Calibration curves were linear in the range 0.18-6.0 mM (r = 0.92). The precision was 3% and the analytical recovery was 87%. The detection limit of the method was 36 pmol. Determination of lactate metabolism was performed in a patient with chronic congestive heart failure who was administered primed-continuous L-[U-14C]lactate (10 microCi bolus and 0.3 microCi/min continuously) during a 60-min rest period. Mean arterial lactate concentration and SA were 1.69 +/- 0.2 mM and 253.8 +/- 22 dpm/mumol, respectively. Systemic lactate turnover was 25.65 mumol/kg per min. Lactic acid systemic turnover, organ uptake and release rates can be accurately determined by isocratic HPLC.

Improvement in exercise capacity despite cardiac deterioration: Noninvasive assessment of long-term therapy with amrinone in severe heart failure

Seven patients with severe congestive heart failure (CHF) were treated with oral amrinone for a mean duration of 39 weeks (range 16 to 72). During the first week of therapy, exercise capacity as assessed on a treadmill using the Naughton protocol, increased substantially from 7.6 +/- 4.2 to 12.1 +/- 4.4 minutes (p less than 0.01). At an early period of follow-up (8 to 12 weeks), a further significant increase in exercise capacity to 14.7 +/- 5.0 minutes (p less than 0.05) was demonstrated, while at a later follow-up exercise capacity had decreased to 11.4 +/- 6.8 minutes (p less than 0.05). This was still significantly greater than prior to amrinone therapy (p less than 0.01). Left ventricular ejection fraction was increased from 14 +/- 4 to 19 +/- 4% (p less than 0.05) during the first week of therapy, but was not significantly different from control at the early and late periods of follow-up. Left ventricular end-diastolic dimension index increased from control value of 43 +/- 5 to 47 +/- 7 mm/m2 (p less than 0.01) at the late period of follow-up. Thus long-term amrinone therapy resulted in a substantial improvement in exercise capacity despite a slow, but progressive decline in cardiac performance.

Cardiovascular consequences of primary antihypertensive therapy with prazosin hydrochloride

Ten patients with essential hypertension who had no end-organ damage were treated with prazosin, starting with a dose of 1 mg/day. The dose was titrated to a maximal tolerated dose not exceeding 20 mg/day in divided doses or until diastolic blood pressure decreased to 90 mm Hg or lower. Among this study population a statistically significant decrease in blood pressures was achieved in the supine, sitting and standing positions. Baseline studies were repeated after 8 weeks of continuous therapy. There was no significant change in peripheral plasma renin activity, serum aldosterone or urinary sodium excretion. Plasma volume increased significantly and the patient weight increased proportionately. Cardiac ejection fraction at rest did not change significantly after prazosin therapy. Exercise ejection fraction also was not changed significantly from baseline during therapy, and the exercise-induced increase in blood pressure was significantly blunted. No adverse effects of prazosin on cardiac function were detected in this short-term study.

Beneficial Effects of Sublingual Nifedipine in Patients with Ischemic Heart Disease and Depressed Left Ventricular Function

The effects of sublingual nifedipine, a calcium channel beta-blocking drug, were assessed in eleven patients with coronary artery disease and depressed left ventricular function. All patients had a previous documented myocardial infarction. Specifically examined were the effects of a 20 mg dose on left ventricular ejection fraction as assessed through gated pool nuclear imaging. All patients had their anti-anginal drugs stopped forty-eight hours prior to inclusion in the study. Baseline resting determinations included a mean heart rate of 80 beats/minute, mean arterial pressure of 97 mmHg and an ejection fraction of 36 percent. Thirty minutes following a 20 mg sublingual dose, these parameters were reassessed. Mean heart rate increased to 89 beats/minute, p<0.02; mean arterial pressure decreased to 78 mmHg, p<.002; while ejection fraction increased to 48± 17 percent, p<.001. No adverse reactions were reported. These results demonstrate that nifedipine will acutely improve de creased left ventricular function in patients with coronary artery disease. While calcium blockers can significantly depress myocardial contractility, nifedipines ability to decrease mean arterial pressure and peripheral vascular resistance reduces afterload, improves myocardial performance which offsets any negative effects on contractility that may exist. This drug promises to be especially useful in patients with coronary artery disease and severely de pressed left ventricular function where agents such as beta-blockers are con traindicated.