Hearts and Minds
The voice of Sigmund Freud (1856–1939) was heard at the 2003 Congress of the European Society of Cardiology (ESC), held in his native city of Vienna, Austria. The great biologist and psychologist, had he been alive to attend, would doubtless have paid special attention to presentations on mental disturbance and the heart. An example is depression, an important risk factor for poor outcome after myocardial infarction (MI). At the Congress, a meta-analysis of the published work was reported by Dr J. Van Melle (University Hospital Groningen, Groningen, the Netherlands). His group identified 17 prospective studies of the impact of depression (assessed by established psychiatric methods) on mortality rate and cardiac events in the first 2 years after MI. The 17 studies described results in 3804 patients (12 cohorts), and the combined data pointed to an excess mortality risk of at least twice that of the nondepressed. Odds ratios (with 95% confidence intervals) were 2.58 (1.71 to 3.89) for all-cause mortality, 2.50 (1.71 to 3.68) for cardiac mortality, and 2.75 (1.41 to 5.34) for cardiac events. These results should dispel any residual doubts about the clinical importance of post-MI depression, and other work indicates that physicians can identify the condition with reasonable accuracy simply by asking, “Are you feeling blue or sad? Have you lost interest in your activities?” However, the kind of univariate analyses examined by Dr Van Melle tell us nothing about other relevant factors or even the direction of causation. For example, depression might act indirectly by lessening adherence to drug regimens or by undermining resolve to stop smoking, and an adverse prognostic feature such as left ventricular failure might itself predispose to depression. The matter of cause and effect and the question of whether treatment for depression improves cardiac outcome should both be answerable by prospective trials of antidepressant treatment after MI. One such trial, the Myocardial Infarction and Depression-Intervention Trial (MIND-IT), is underway, and the first results are expected next year.
Depression is not the only mental state worthy of study in relation to the cardiovascular system, and Freud might well have taken an interest in the effects of sympathetic activation. Excess cardiac mortality has been recorded, for example, in populations under stress from earthquakes or missile attacks. Spectator sport is another reported hazard, and this was the subject of an investigation by Dr E. Katz and colleagues (Centre Hospitalier Universitaire Vaudois, Lausanne, Switzerland). They hypothesized that the 2002 World Cup (soccer), which was watched by a sizeable proportion of Swiss citizens, would have caused an excess of cardiac arrests by generating excitement and anger. They retrospectively examined mobile intensive care unit registers for nontraumatic out-of-hospital cardiac arrests in 7 cities during the Cup season and the same period in the previous year. The number of arrests during the World Cup period was 59, compared with 37 in 2001 (P<0.005). The subgroups were too small for useful analysis, and a weakness of the study is the lack of information on the relation of arrests to television viewing. Also, sympathetic activation is not the only risky aspect of football watching, which tends to be accompanied by alcohol consumption and tobacco smoking. One suggestion at the meeting would certainly have appealed to Freud the dream expert: Might the excess incidence of MI between midnight and 5 am be explained by nightmares and resultant sympathetic activation?
Community Diagnosis of Heart Failure
For best results, heart failure must be diagnosed and treated early in its course, and this demands efficient diagnosis in primary care. Yet the rate of incorrect diagnosis by general practitioners is very high. The prime need in this context is a good method for ruling out the diagnosis, to reduce the numbers referred unnecessarily for specialist investigation. At the ESC Congress, the main contenders under discussion were ultrasonic indices and measurement of brain natriuretic peptide (BNP). On the ultrasound front, Dr J. Roelandt (Erasmus MC, Thoraxcenter, Rotterdam, the Netherlands) spoke enthusiastically of echo devices small enough to be carried in the coat pocket—“the stethoscope of the third millennium.” Their performance, he declared, can be almost as good as that of full-size machines, and students need only a few hours to learn the essential techniques for ruling out heart failure; a bonus is the ability to move slightly downward and diagnose abdominal aortic aneurysms. The method, in his opinion, is ripe for inclusion in medical school curricula. Other speakers were less convinced that the time for this revolution has arrived. A more widely held view was that, for excluding heart failure, practitioners should use a BNP test. Two important studies were described.
First, Dr R. Doughty (University of Auckland Department of Medicine, Auckland, New Zealand) reported a study in which echo measurements of systolic and diastolic dysfunction were compared with N-BNP in 305 patients who had presented to their general practitioners with symptoms of heart failure. The “gold standard” was diagnosis by an expert panel applying ESC criteria, and just 70 (23%) of the referred patients met these criteria. Receiver-operator-characteristic curves were used to assess the N-BNP assay and echo variables as diagnostic tests for heart failure, first in the whole group and then in the group with abnormal N-BNP (>50 pmol/L). In the whole cohort, no single echo measurement reached the diagnostic accuracy of N-BNP, but the Auckland group did note a “gray zone” of values between 50 and 150 pmol/L, where ultrasonic measures of systolic function (eg, fractional shortening) were slightly superior. Their conclusion was that BNP should be the initial diagnostic test for symptomatic patients.
The second study, reported by Dr A. Zaphiriou (National Heart and Lung Institute, Imperial College London, UK), was conducted in 5 centers that offered specialist rapid-assessment clinics for suspected heart failure. Three hundred and six patients were recruited, all with new symptoms believed by their general practitioners to be caused by heart failure. They were examined clinically and had chest radiographs, electrocardiograms, and transthoracic echocardiograms. Blood was drawn for measurement of urea, electrolytes, and both BNP (near-patient test) and NT-proBNP (laboratory test). The examining doctors, blind to the result of the BNP test and applying ESC criteria, confirmed the existence of heart failure in 34% of the patients. As in the New Zealand study, receiver-operator-characteristic curves were used to assess the diagnostic value of the tests. At a cutoff of 166 pg/mL, the negative predictive value for NT-proBNP was 96%; at a cutoff of 65 pg/mL, the negative predictive value for BNP was 90%.
The findings of these 2 studies make a strong case for BNP testing in primary care as a way to rule out cardiac failure with reasonable certainty. That the method is also useful in hospital emergency departments was confirmed by further presentations at the Congress. Yet to be assessed is the value of BNP tests in screening for incipient heart failure in selected patients without symptoms, such as those with poorly controlled diabetes or hypertension.
Stem Cell Developments
At the ESC Congress, it seemed at times as if the “SC” stood for “stem cells,” but the scattering of presentations under many different headings reflected a prevailing uncertainty about how these cells act in the heart and how they might be used therapeutically. In humans, immediate hopes are pinned on adult stem cells; clinical application of embryonic stem cells, with their potential for replacing damaged tissues of all kinds, is thought be to a decade away. Already, several studies indicate that adult stem cells, when introduced into failing or infarcted heart muscle, can improve both perfusion and function. A published example is the phase 1 US/Brazil study conducted by E.C. Perin and others (Circulation. 2003;107:2294–2302; 13 May 2003), in which 14 patients with severe heart failure received intramyocardial injections of autologous bone marrow cells; 4 months later, compared with a control group, the treated patients had a better ejection fraction and lower end-systolic volume than the untreated controls. New data from this study, reported at the Congress by Dr Perin’s coinvestigator Dr H.F.R. Dohmann (Pró-Cardíaco Hospital, Rio de Janeiro, Brazil), concerned a subgroup of 5 patients who had been listed for heart transplantation: Six months after treatment, 4 of them had improved to the extent that they were no longer eligible for the operation. In another presentation, Dr V. Schächtinger (J.W. Goethe University, Frankfurt, Germany) reported the effects of progenitor cells, derived from blood or bone marrow, injected via coronary catheters into infarct arteries after stent implantation. Looking at coronary flow reserve at 4 months in patients without restenosis, they found near normalization in the treated vessels but negligible change in untreated reference vessels. A less optimistic note was sounded by Dr H.R. Figulla (Friedrich-Schiller University, Jena, Germany). He used a technique similar to that of the Frankfurt workers in patients with large infarcts, and 1 year after treatment there was no improvement in either regional blood flow or contractility.
These are all phase 1 studies. Proof of efficacy demands randomized, controlled trials. Moreover, despite the remarkable rate of progress in this research, there is scant information on how the cells act in the heart—is it by promoting angiogenesis, by replacing cardiomyocytes, by preventing remodeling, or some other way?