ATLANTA--New insights about the management of acidemia were presented at the American Heart Association's 72nd Scientific Sessions, which were attended by more than 35,000 cardiologists and other health professionals. Other highlights of the meeting included recent findings about the pathogenesis of heart failure, the role of inhaled nitric oxide therapy in patients with pulmonary hypertension, and strategies for diagnosing chest pain in the emergency department.

MECHANISMS OF CONGESTIVE HEART FAILURE

A variety of plenary sessions and symposia, as well as poster and platform presentations, focused on the pathophysiology of congestive heart failure (CHF)--the fastest-growing problem in the field of cardiology. Successful treatment of acute ischemic events means more and more patients are surviving with infarcted myocardium, only to develop subsequent chronic CHF, which is responsible for substantial morbidity and mortality in this country.

In a session entitled "Heart Failure in the New Millennium," speakers examined emerging concepts of the pathophysiology of CHF, which may ultimately lead to new approaches in treatment of this devastating disease. In his presentation, Marvin Konstam, MD, of the New England Medical Center, Boston, discussed the underlying pathophysiology leading from injury, through the development of left ventricular hypertrophy, and ultimately to heart failure and death. "In this country, the initial injury is most often ischemic infarct secondary to atherosclerotic disease, but CHF can also arise from primary myocardial disease or a direct increase in myocardial load," he explained.

These injuries lead to a variety of recently identified systemic responses, including neurohormonal activation, involvement of cytokines, and alteration in oxidative stress. Such responses result in changes in the myocardium, including alteration in molecular expression, ultrastructural changes, myocyte hypertrophy and contractile dysfunction, apoptosis, fibroblast proliferation, collagen deposition, and ventricular remodeling, said Dr. Konstam.

"Then, this aggregate of responses, including the responses in the myocardium, lead to hemodynamic derangement, clinical heart failure, and demise associated with arrhythmia," he said. "Each of these points represents an important potential therapeutic target." For example, cytokines, such as tumor necrosis factor alpha (TNF-alpha), have been shown to play a pathophysiologic role in the progression of heart failure. Furthermore, it is now possible to block the action of TNF-alpha, Dr. Konstam explained.

More recently, cellular calcium homeostasis has been implicated in influencing transcriptional factors that may lead to the hypertrophic response within myocytes. These and other insights into the array of responses that occur during the progression of heart failure represent "exciting potential therapeutic targets for the next several years," Dr. Konstam concluded.

ACID-BASE THERAPY DURING CPR

During another presentation on emergency cardiac care, Max Harry Weil, MD, of West Palm Springs, Calif, who is a pioneer in the field of cardiopulmonary resuscitation (CPR), discussed the role of acid-base therapy during CPR. He proposed limited indications that justify the use of buffer agents, such as sodium bicarbonate, sodium lactate, "carbicarb" (an equimolar combination of sodium carbonate and sodium bicarbonate), or tromethamine. One of the few indications for the use of these agents is the reversal of drug intoxication in the setting of hyperuricemia.

However, Dr. Weil stressed, "I think we now have to put to rest the argument that acidosis--or, more specifically, acidemia--always deserves reversal." While acidemia may "offend us as clinicians" since it carries a poor prognosis, it is worth remembering that acidemia is an epiphenomenon, he said. In other words, acidemia carries a poor prognosis because it results from conditions that have a poor prognosis. Lactic acidosis and metabolic acidosis associated with low-flow states, for example, should draw attention to the low-flow state, whether it be cardiogenic shock, obstructive shock due to pulmonary embolization, or septic shock. "You look at the cause and you treat the cause … not the epiphenomenon," he said.

In fact, "mild acidemia, which may occur during cardiogenic shock, is actually a favorable condition," suggested Dr. Weil. "It preserves red blood cells and is characteristic of animal hibernation. Identifying the underlying cause of severe acidemia is critical, however, in order to reverse it," he concluded.

NEWS IN PULMONARY HYPERTENSION MANAGEMENT

Inhaled nitric oxide (NO) therapy appears to offer some short-term benefits in selected patients with severe pulmonary hypertension (PH), according to a study at Children's Hospital and Brigham and Women's Hospital in Boston. Investigators conducted a nonrandomized pilot study to assess the effects of NO inhaled at home in patients with primary and secondary PH. Study subjects included eight patients with primary PH, as well as 10 with secondary PH who were noncompliant with other therapies or in whom such therapies had failed. All patients used a system of pulsed, inspiration-triggered NO in combination with oxygen.

At three months' follow-up, six-minute walking capacity increased by a mean 156 yards for the whole cohort, which represented a statistically significant difference over baseline. The amount of improvement did not differ between the primary or secondary PH patients. All patients survived three months, although the expected three-month survival rate in these patients is only 79%, noted lead author Jacques Benisty, MD.

Adverse events included syncope or near-syncope, which was usually associated with transient NO discontinuation, either accidentally or during transition from portable to stationary administration units. "We conclude that home nitric oxide may offer short-term and intermediate-term benefit in selected patients with severe pulmonary hypertension," Dr. Benisty said. A randomized trial of this approach should be considered in these patients, he added.

In a separate study, researchers at Massachusetts General Hospital investigated whether a pulmonary vasodilator, sildenafil, could augment and prolong the effects of inhaled NO therapy in patients with PH. In this study, the researchers enrolled 22 patients with chronic PH of at least one year's duration. Hemodynamic measurements were obtained after the patients received each of the following: oxygen alone, oxygen followed by NO therapy, sildenafil, or a combination of NO and sildenafil. The investigators discovered that the combination of NO and sildenafil functioned as a selective pulmonary vasodilator, which decreased pulmonary vascular resistance and increased cardiac index to a greater extent than did either agent alone. Furthermore, it did so without producing systemic hypotension.

The authors concluded "that in patients with pulmonary hypertension from pulmonary vascular disease or from congestive heart failure, sildenafil augments and prolongs the selective pulmonary vasodilator effects of inhaled NO without altering myocardial function."

IMAGING TECHNIQUES HELP DIAGNOSE ACUTE CHEST PAIN

A session entitled "Diagnosing Chest Pain in the ER" explored new options to aid the rapid diagnosis of chest pain. Among the new technologies available are bedside evaluation of cardiac biomarkers and imaging techniques, including echocardiography and perfusion imaging.

Allan Jaffe, MD, of the Mayo Clinic, Rochester, Minnesota, investigated the utility of biomarkers in the rapid assessment of chest pain patients presenting to the emergency department. There is a growing feeling that biomarkers should "do everything and be everything, and I think we have to be careful," he cautioned. "In urgent patients, waiting for marker assays is not recommended, but in many cases, biomarkers may help in the risk stratification of chest pain or facilitate the discharge of patients with noncardiac problems," he suggested.

Many biomarkers have been evaluated as potential diagnostic aids in identifying chest pain. They include the MB fraction of creatine kinase, myosin, and fatty acid binding proteins, according to Dr. Jaffe. Although biomarkers can be very sensitive, they are not specific to cardiac injury. Recent work with bedside assays of troponin I and troponin T, however, has shown that these markers have substantially increased specificity in this setting.

"Right now, there is controversy over which of these strategies should be implemented; some of that is related to difficulties with the assays that are involved, and some has to do with the specific needs of emergency departments," Dr. Jaffe said. "Nonetheless, I think it's clear that strategies based on these sensitive troponin markers are likely to be the ones that will move the field most rapidly."

In his presentation, Sanjiv Kaul, MD, of the University of Virginia, Charlottesville, discussed the role of newer imaging techniques in the assessment of chest pain in the emergency department. Among the imaging techniques covered was the use of echocardiography, which has now been shown to identify not only patients having acute events, but also those at risk of future events. According to Dr. Kaul, echocardiography directly evaluates the left ventricle and can therefore identify acute events as they occur; it can also identify regional dysfunction of both the right and left ventricles. "Echocardiography gives more incremental information than indirect methods such as the electrocardiogram (ECG). It can also identify structural problems, including left ventricular aneurysms and pseudoaneurysms," he added.

Nuclear perfusion imaging using markers such as sestamibi has also been employed successfully in the acute care setting to identify perfusion abnormalities in patients with chest pain. A recent development is myocardial contrast echocardiography, which can identify not only blockages in the large coronary arteries but perfusion abnormalities as well. The addition of these technologies "will make a very big difference in the care of these patients," Dr. Kaul concluded.

The use of nuclear perfusion imaging can reduce unnecessary hospitalization and therefore cut costs, according to results from the ERASE Chest Pain (Emergency Room Assessment of Sestamibi for Evaluating Chest Pain) trial. The findings were presented by James Udelson, MD, of the New England Medical Center, Boston. The study enrolled 2,456 patients with chest pain who had a nondiagnostic ECG. Patients were randomized to receive either the standard chest pain evaluation protocol or the standard protocol with the addition of resting sestamibi nuclear perfusion imaging.

Among patients whose final diagnosis was acute myocardial infarction (MI), the hospital admission rate was 97% in each group, a "high and appropriate" rate, Dr. Udelson said. However, a large difference was seen among the patients whose final diagnosis was not an acute cardiac problem. In this group, 52% of those who had received the standard evaluation were admitted to the hospital, "in what could be classified, in retrospect, as an unnecessary admission." Among the patients who received perfusion imaging, only 42% were admitted, representing a 10% absolute reduction and a 20% relative reduction in the rate of unnecessary admissions. "The use of imaging was associated with improved overall emergency department triage effectiveness and lower overall hospital costs," he concluded. "When projected nationally, these data suggest the possibility of safely avoiding at least 240,000 unnecessary hospital admissions per year."

CLINICAL TRIALS UPDATE

The angiotensin-converting enzyme inhibitor ramipril reduced morbidity and mortality rates in patients who participated in the HOPE (Heart Outcomes and Prevention Evaluation) trial. The double-blind study compared ramipril, vitamin E, and placebo in over 9,000 patients from 19 countries. Patients were included if they were over the age of 55 years and were at high risk of cardiovascular events either because they had had a previous stroke or transient ischemic attack or because they showed evidence of vascular or coronary heart disease. Diabetic patients who were age 55 years or older and had at least one other coronary risk factor, such as hypertension or smoking, were also included in the study.

The study was stopped after four years of follow-up because the researchers found a statistically significant benefit in the patients who received ramipril. Those patients experienced fewer cardiac events (ie, MI, stroke, or cardiovascular death) compared with patients in the placebo group (14.1% vs 17.7%, respectively). This represented a 22% reduction in the relative risk.

Treatment also reduced new cases of congestive heart failure as well as the need for revascularization; these results were consistent across all subgroups. Interestingly, treatment also reduced the onset of complications among diabetic patients and the development of new diabetes among nondiabetic patients. There were no differences between outcomes in the vitamin E and the placebo groups.

In a separate study, the oral glycoprotein IIb/IIIa inhibitor sibrafiban was associated with increased morbidity and mortality rate (when compared with aspirin) in patients with postacute coronary syndromes. The finding is based on the SYMPHONY (Sibrafiban Versus Aspirin to Yield Maximum Protection from Ischemic Heart Events Post Acute Coronary Syndromes) trial, which was discussed by Robert Califf, MD, of Duke University, Durham, NC. The data showed that neither low-dose nor high-dose sibrafiban provided an incremental benefit over aspirin. Furthermore, there was a trend toward increased mortality and increased bleeding risk in the groups treated with sibrafiban.

"This is on top of two other trials of oral IIb/IIIa inhibitors, all of which have shown a trend toward an excess mortality, raising considerable concern about this class of agents," Dr. Califf concluded. "In light of other studies that have shown similar results, an in-depth biological examination of this class of drugs is needed."

A second SYMPHONY trial, in which aspirin was added to low-dose sibrafiban, was halted when the results of the first trial were found to be negative. The data from the second trial will be presented at the upcoming American College of Cardiology meeting in March 2000.

--Susan Jeffrey

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